Document Z4JnMnmO6z2wDBVgVzeQyRbYY

DownloadViewSend us a messageRandom document
t\^r&-05Vt, FINAL REPORT PROTOCOL 418-015 ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS SPONSOR'S STUDY NUMBER: T-6295.14 FINAL REPORT DATE: 23 JULY 1999 001001 PROTOCOL 418-015 ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS SPONSOR'S STUDY NUMBER: T-6295.14 TABLE OF CONTENTS SUBJECT PAGE I. SUMMARY AND CONCLUSION 1-1 A. Methods 1-1 B. Results I-3 C. Conclusion I-4 II. DESCRIPTION OF TEST PROCEDURES 11-1 A. Conduct of Study 11-1 A.1. Sponsor 11-1 A.2. Testing Facility 11-1 A.3. Study Number 11-1 A.4. Sponsor's Study Number 11-1 A.5. Purpose of the Study 11-1 A.6. Study Design 11-1 001002 SUBJECT A.7. Regulatory Compliance A.8. Ownership of the Study A.9. Study Monitor A. 10. Alternate Study Monitor A.11. Study Director A. 12. Technical Performance A.13. Report Preparation A. 14. Report Review A.15. Date Protocol Signed A.16. Dates of Technical Performance A. 17. Records Maintained B. Test Article Information B.1. Description B.2. Lot/Batch Number B.3. Date Received and Storage Conditions B.4. Special Handling Instructions B.5. Analysis of Activity C. Vehicle Information C.1. Description C.2. Lot Numbers C.3. Dates Received, Source and Storage Conditions C.4. Special Handling Instructions PAGE 11-1 II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-3 II-3 II-3 II-3 II-3 II-4 II-4 II-4 II-4 II-4 II-4 II-4 11-4 C01003 SUBJECT C.5. Analysis of Purity D. Test Article Preparation and Storage Conditions D.1. Sample Information D.2. Analytical Results E. Test System E.1. Species E.2. Strain E.3. Supplier (Source) E.4. Sex E.5. Rationale for Test System E.6. Test System Data E.7. Breeder Male Rat Data E.8. Method of Randomization E.9. System of Identification F. Husbandry F.1. Research Facility Registration F.2. Study Rooms F.3. Housing F.4. Lighting F.5. Sanitization F.6. Feed F.7. Feed Analysis iii PAGE II-5 II-5 II-5 II-5 II-5 II-5 II-6 II-6 II-6 II-6 II-6 11-6 II-6 II-7 II-7 II-7 II-7 II-7 II-8 II-8 11-8 11-8 001004 SUBJECT F.8. Water F.9. Water Analysis F.10. Bedding F . 11. Bedding Analysis G. Methods G.1. Dosage Administration G.2. Rationale for Dosage Selection G.3. Route of Administration G.4. Rationale for Route of Administration G.5. Frequency of Administration G.6. Length of Study G.7. Method of Study Performance G.8. Pharmacokinetic Sample Collection G.9. Gross Necropsy G.10. Statistical Analyses III. RESULTS A. Mortality, Clinical and Necropsy Observations A.1. Mortality A.2. Clinical Observations A. 3. Necropsy Observations B. Body Weights and Body Weight Changes B.1. Precohabitation IV PAGE 11-8 11-8 II-9 II-9 II-9 II-9 II-9 11-10 11-10 11-10 11-10 11-11 11-12 11-13 11-14 111-1 111-1 111-1 111-1 111-1 111-1 111-1 001005 SUBJECT B.2. Gestation PAGE 111-2 B. 3. Lactation 111-2 C. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 111-2 C.1. Precohabitation III-2 C.2. Gestation III-2 C. 3. Lactation III-3 D. Natural Delivery and Litter Observations III-3 E. Clinical Observations from Birth to Day 21 Postpartum and Necropsy Observations III-3 REFERENCES IM-4 APPENDIX A - REPORT FIGURE Figure 1. Body Weights - Fo Generation Female Rats A-1 APPENDIX B - REPORT TABLES Table 1. Clinical Observations - Summary - Fo Generation Female Rats B-1 Table 2. Necropsy Observations - Summary - Fo Generation Female Rats B-4 Table 3. Body Weights - Precohabitation - Summary - Fo Generation Female Rats B-5 Table 4. Body Weight Changes - Precohabitation - Summary Fo Generation Female Rats B-6 Table 5. Maternal Body Weights - Gestation - Summary Fo Generation Female Rats B-7 Table 6. Maternal Body Weight Changes - Gestation - Summary Fo Generation Female Rats B-9 v 001006 SUBJECT Table 7. Maternal Body Weights - Lactation - Summary Fo Generation Female Rats PAGE B-10 Table 8. Maternal Body Weight Changes - Lactation - Summary Fo Generation Female Rats B-12 Table 9. Absolute Feed Consumption Values (g/day) Precohabitation - Summary - Fo Generation Female Rats B-13 Table 10. Relative Feed Consumption Values (g/kg/day) Precohabitation - Summary - Fo Generation Female Rats B-14 Table 11. Maternal Absolute Feed Consumption Values (g/day) Gestation - Summary - Fo Generation Female Rats B-15 Table 12. Maternal Relative Feed Consumption Values (g/kg/day) Gestation - Summary - Fo Generation Female Rats B-16 Table 13. Maternal Absolute Feed Consumption Values (g/day) Lactation - Summary - Fo Generation Female Rats B-17 Table 14. Maternal Relative Feed Consumption Values (g/kg/day) Lactation - Summary - Fo Generation Female Rats B-18 Table 15. Natural Delivery Observations - Summary - Fo Generation Female Rats B-19 Table 16. Litter Observations (Naturally Delivered Pups) - Summary F1 Generation Litters B-20 Table 17. Clinical Observations from Birth to Day 21 Postpartum Summary - F1 Generation Pups B-23 Table 18. Necropsy Observations - Summary - F1 Generation Pups B-24 Table 19. Clinical Observations - Individual Data - Fo Generation Female Rats B-25 Table 20. Necropsy Observations - Individual Data - Fo Generation Female Rats B-28 01007 VI SUBJECT Table 21. Body Weights - Precohabitation - Individual Data Fo Generation Female Rats PAGE B-30 Table 22. Maternal Body Weights - Presumed Gestation - Individual Data - Fo Generation Female Rats B-36 Table 23. Maternal Body Weights - Lactation - Individual Data Fo Generation Female Rats B-39 Table 24. Feed Consumption Values - Precohabitation - Individual Data - Fo Generation Female Rats B-42 Table 25. Maternal Feed Consumption Values - Presumed Gestation - Individual Data - Fo Generation Female Rats B-44 Table 26. Maternal Feed Consumption Values - Lactation - Individual Data - Fo Generation Female Rats B-47 Table 27. Natural Delivery, Implantation Sites, and Pup Viability and Sex - Individual Data - Fo Generation Female Rats/ F1 Generation Litters B-49 Table 28. Pup Body Weight Litter Averages from Birth to Day 21 Postpartum - Individual Data - F1 Generation Litters B-51 Table 29. Pup Body Weights from Birth to Day 21 Postpartum Individual Data - F1 Generation Pups B-53 Table 30. Pup Vital Status and Sex from Birth to Day 21 Postpartum - Individual Data - F1 Generation Pups B-65 Table 31. Clinical Observations from Birth to Day 21 Postpartum Individual Data - F1 Generation Pups B-67 Table 32. Necropsy Observations - Individual Data - F1 Generation Pups B-68 APPENDIX C - PROTOCOL AND AMENDMENT C-1 to 0 3 4 APPENDIX D - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY D-1 001008 vii SUBJECT APPENDIX E - TEMPERATURE AND RELATIVE HUMIDITY REPORTS APPENDIX F - STATEMENT OF THE STUDY DIRECTOR APPENDIX G - QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT PAGE E-1 to E-9 F-1 G-1 to G-6 viii 0 0 1 0 09 418-015:PAGE 1-1 TITLE: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-015 SPONSOR'S STUDY NUMBER: T-6295.14 I. SUMMARY AND CONCLUSION A. Methods3 Twenty-four presumed pregnant Crl:CDBR VAF/Plus (Sprague-Dawley) rats were assigned to three dosage groups (Groups I through III), eight rats per dosage group. The rats were administered the test article, PFOS (FC-95), or the vehicle, 0.5% Tween 80 in reverse osmosis membrane processed deionized water (R.O. deionized water), orally (via gavage), once daily beginning 43 days prior to cohabitation until confirmed evidenced of mating. Dosages of 0 (Vehicle), 0.1 and 1.6 mg/kg/day were administered at a dosage volume of 5 mL/kg. A.1. Fo Generation Rats: The female rats were observed for viability at least twice each day of the study. The rats were examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before and approximately one hour after dosage. Rats were observed for clinical observations and general appearance once daily during all other periods of study. Body weights were recorded daily during the dosage and postdosage periods and at sacrifice. Feed consumption values were recorded weekly prior to cohabitation, daily during gestation and on days 1 ,4 , 7, 10 and 14 of lactation (DLs 1 ,4 , 7, 10 and 14). The female rats were evaluated for duration of gestation, litter sizes and pup viability at birth. Pups that either appeared stillborn or that died before initial examination of the litters for viability were examined for vital status at birth. Maternal behavior of the dams was evaluated daily when the pups were examined during the 21-day postpartum period. Observed maternal behavior was recorded on DLs 1 ,4 , 7, 10, 14 and 21. a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections of this report and in APPENDIX C (PROTOCOL AND AMENDMENT). COIOIO 418-015:PAGE I-2 Urine and fecal sample were collected from female rats for the following intervals: one day prior to initiation of cohabitation to the following morning, days 6 to 7, 14 to 15 and 20 to 21 of presumed gestation (DGs 6 to 7, 14 to 15 and 20 to 21), and DLs 21 to 22. Following each 24-hour collection interval, samples were shipped to the Sponsor for analysis. Blood samples were collected from each of the maternal rats on the day cohabitation was initiated (prior to cohabitation), DGs 7, 15 and 21, and DLs 14 and 22. Serum samples were shipped to the Sponsor for analysis. All surviving rats assigned to the study were sacrificed on DL 22 following the final collection interval for urine and fecal samples and blood sample collection and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Tissues with gross lesions were retained. The number and distribution of implantation sites was recorded. A liver section from each dam was collected and shipped to the Sponsor for analysis. A.2. Fi Generation Litters: Day 1 of lactation (postpartum) was defined as the day of birth and was also the first day on which all pups in a litter were individually weighed. The litters were observed for viability at least twice each day during the postpartum period. Litters were observed for clinical observations and general appearance once daily during the postpartum period. The pups in each litter were counted once daily. Body weights were recorded on DLs 1 (birth), 4, 7, 14 and 21. Pups found dead were examined for gross lesions and for the cause of death. For all pups found dead on DLs 2 to 4, all lungs were preserved. On DL 4, litters were culled to five male pups and five female pups per litter, where possible. The lungs and the livers were collected from the first ten pups culled determined to be at DL 4 from each dosage group (irrespective of litter). The lungs and the livers were individually retained. Remaining culled pups were sacrificed and discarded without evaluation. All remaining pups on study were sacrificed and examined for gross lesions on DL 21. Gross lesions were retained. The liver from each pup was collected, pooled (per litter) and shipped to the Sponsor for analysis. Blood samples were collected and pooled (per litter). Serum samples were shipped to the Sponsor for analysis. c o lo n B. Results 418-015:PAGE I-3 No deaths or premature deliveries were attributed to PFOS treatment. One vehicle control group rat was injured and died after orbital sinus bleeding on DG 15. All other rats survived to scheduled sacrifice. All adverse clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test article. A red substance was found in the thoracic cavity of the rat that died. All other rats appeared normal at necropsy. Rats administered the 1.6 mg/kg/day dosage of the test article had reduced body weight gains or body weight losses in each week of the precohabitation period. Dams in the 1.6 mg/kg/day dosage group had reduced body weight gains during the first week of the gestation period (DGs 0 to 7). Body weight gains were then increased as compared to the control group value on DGs 7 to 10, 13 to 15 and 15 to 18. Reflecting this rebound effect, body weight gains were increased for the entire gestation period (DGs 0 to 20) in the 1.6 mg/kg/day dosage group, as compared to the control group value. Body weight gains for dams administered the 1.6 mg/kg/day dosage of the test article during the precohabitation period generally continued to be increased during the lactation period. Absolute (g/day) and relative (g/kg/day) feed consumption values were reduced in the 1.6 mg/kg/day dosage group in each week of the precohabitation period. Dams in the 1.6 mg/kg/day dosage group had reduced absolute and relative feed consumption values during the first week of the gestation period (DGs 0 to 7). Feed consumption values were then generally comparable to control group values for the remainder of the gestation period. Absolute and relative feed consumption values in this dosage group were slightly reduced, as compared to control group values, for the entire gestation period (DGs 0 to 20). Absolute and relative feed consumption values during the lactation period were reduced in the groups administered 0.1 or 1.6 mg/kg/day of the test article during the precohabitation period, however the reductions were not strictly dosagedependent. Administration of the test article at dosages as high as 1.6 mg/kg/day did not adversely affect any parameter evaluated at natural delivery or during the 22-day lactation period. No clinical or necropsy observations in the F1 generation pups were attributable to dosages of the test article as high as 1.6 mg/kg/day. 001012 C. Conclusion 418-015.PAGE I-4 The purpose of the study, as stated in the protocol, was to evaluate the pharmacokinetics of PFOS in Fo generation pregnant female rats following PFOS treatment during the pre-cohabitation period. This report includes study data from the in-life portion which was conducted at Argus Research laboratories, Inc. The pharmacokinetic samples that were collected during the in-life portion of the study were sent to the Sponsor for analysis and will be reported separately. It is the responsibility of the Sponsor, 3M Corporate Toxicology, to combine the in-life results with the analytical results into a final pharmacokinetic report. Mildred S. Christian, Ph.D., Fellow, ATS Executive Director of Research Date Alan M. Hoberman, Ph.D., DABT Director of Research Date Raymond G. York/Ph.D., DABT Associate Director ofResearch and Study Director Date 001013 418-015.PAGE 11-1 II. DESCRIPTION OF TEST PROCEDURES A. Conduct of Study: A.1. Sponsor: 3M Corporate Toxicololgy, 3M Center, Building 220-2E-02, St. Paul, Minnesota 55144-1000 A.2. Testing Facility: Argus Research Laboratories, Inc., 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 A.3. Study Number: 418-015 A.4. Sponsor's Study Number: T-6295.14 A.5. Purpose of the Study: The purpose of this study was to evaluate the pharmacokinetics of PFOS in Fo generation and F1 generation rats during gestation and lactation following cessation of PFOS treatment of Crl:CDBR VAF/Plus female rats at confirmed mating. A.6. Study Design: The requirements of the U.S. Food and Drug Administration (FDA)<1) were used as the basis of study design. A.7, Regulatory Compliance: The study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the U.S. Food and Drug Administration (FDA)(2), the Japanese Ministry of Health and Welfare (MHW)<3) and the European Economic Community (EEC)(4). There were no deviations from the GLP regulations that affected the quality or integrity of the study. Quality Assurance Unit findings derived from the inspections during the conduct of this study are documented and have been provided to the Study Director and the Testing Facility Management. 001014 418-015:PAGE II-2 A.8. Ownership of the Study: The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the property of the Sponsor. A.9. Study Monitor: Marvin T. Case, D.V.M., Ph.D. A.10. Alternate Study Monitor: Andrew M. Seacat, Ph.D. A.11. Study Director: Raymond G. York, Ph.D., DABT (Associate Director of Research) A.12. Technical Performance: John F. Barnett, B.S. (Director of Laboratory Operations) Paul E. Ciotti (Team Leader) Todd J. Killino, B.S. (Laboratory Technician) A.13. Report Preparation: Raymond G. York, Ph.D., DABT Jo Ann Frazee, M.S. (Study Coordinator) Denise P. Gasiorowski (Data Management Specialist) Karen G. Parker, A.A. (Report Administrator) A.14. Report Review: Mildred S. Christian, Ph.D., Fellow, ATS (Executive Director of Research) Alan M. Hoberman, Ph.D, DABT (Director of Research) A.15. Date Protocol Signed: 16 November 1998 001015 A.16. Dates of Technical Performance: 418-015:PAGE II-3 Rat Arrival Date Dosage Period [43 days prior to the first day of cohabitation3 until confirmed mating (DG 0)] Cohabitation Period DGb0 Delivery Period (DLC1) Sacrifice of Fo generation rats not selected for continued evaluation DL 4 Culling (pups not selected for continued observation) DG 25 Sacrifice (dam with no confirmed date of mating) DL 21 Scheduled Sacrifice (F1 generation pups) DL 22 Scheduled Sacrifice (Fo generation dams) 17 NOV 98 23 NOV 98 - 08 JAN 99 04 JAN 99 PM - 09 JAN 99 AM 05 JAN 99 - 08 JAN 99 26 JAN 99 - 30 JAN 99 15 JAN 99 29 JAN 99 - 02 FEB 99 02 FEB 99 15 FEB 9 9 - 1 9 FEB 99 16 FEB 9 9 - 2 0 FEB 99 A.17. Records Maintained: The original report, raw data and reserve samples of the test article and vehicle components are retained in the archives of Argus Research Laboratories, Inc. Any preserved tissues are retained in the archives of the Testing Facility for one year after the mailing of the final report, after which time the Sponsor will decide their final disposition. All unused prepared formulations were discarded at the Testing Facility. All remaining bulk test article was returned to the Study Monitor upon completion of all work with the test article. B. Test Article Information: B.1. Description: PFOS (FC-95) - off-white powder B.2. Lot/Batch Number: 217 (Expiration date: May 2000) a. See APPENDIX D (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. b. DG is used as an abbreviation for day of (presumed) gestation. c. DL is used as an abbreviation for day of lactation or day postpartum. C0101G B.3. Date Received and Storage Conditions: 418-015:PAGE II-4 The test article was received on 21 October 1998, and stored at room temperature. B.4. Special Handling Instructions: Standard safety precautions (use of protective clothing, gloves, dust-mist respirator, safety goggles or safety glasses and a face-shield) were taken when handling the bulk test article and prepared suspensions. B. 5. Analysis of Activity: Information regarding the identity, composition, strength and purity of the test article is on file with the Sponsor. C. Vehicle information: C.1. Description: 0.5% Tween 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Tween 80 - a clear or yellow viscous liquid C.2. Lot Numbers: Tween 80 - M29477 and M03H05 C.3. Dates Received. Source and Storage Conditions: Tween 80 was received from J.T. Baker, Phillipsburg, New Jersey, on 17 September 1998 (lot M29477) and 3 December 1998 (lot M03H05), and stored at room temperature. The R.O. deionized water is available from a continuous source at the Testing Facility and is maintained at room temperature. C.4. Special Handling Instructions: Standard safety precautions (use of protective clothing, gloves, dust-mist respirator, safety goggles or safety glasses and a face-shield) were taken when handling the vehicle. C01017 418-015:PAGE II-5 C. 5. Analysis of Puritv: Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study. D. Test Article Preparation and Storage Conditions: Suspensions of PFOS (PC-95) were prepared daily at concentrations of 0, 0.02, and 0.32 mg/ml_. Prepared formulations were stored at room temperature. D.1. Sample Information: Sample Type Concentration (all levels) Bulk Test Article Reserve Vehicle Components Reserve Tween 80 Lot M29477 Lot M03H05 R.O. Water Size 2mL* 1g 5 mL 5 mL 5 mL Date Retained 22 NOV 98 07 JAN 99 Storage Conditions Frozen 19 NOV 98 Room temperature 19 NOV 98 10 DEC 98 19 NOV 98 Room temperature Shipped To Sponsor Testing Facility Archives Date Shipped 23 NOV 98 12 JAN 99 27 JAN 99 Testing Facility Archives 27 JAN 99 27 JAN 99 27 JAN 99 a. Duplicate samples were taken from the first and last preparation. One sample of each set was shipped for analysis; the remaining samples were retained as backups. Backup samples were stored frozen (-70C or below) and will be discarded at the Testing Facility upon the request of the Sponsor. D. 2. Analytical Results: Information on the stability and homogeneity of the prepared formulations and of the stability of the bulk test article are on file with the Sponsor. Data verifying the stability of the test article in the vehicle for 48 hours under the conditions of administration are on file with the Sponsor. Records were maintained to document how the test article formulations were prepared. Results of the concentration analyses were not available at the time of the writing of this report. E. Test System: E.1. Species: Rat C01018 E.2. Strain: 418-015:PAGE II-6 Crl:CDBR VAF/Plus (Sprague-Dawley) E.3. Supplier (Source): Charles River Laboratories, Inc., Raleigh, North Carolina E.4. Sex: Female (Note: Male rats were used only for the purposes of breeding and are not considered part of the Test System.) E.5. Rationale for Test System : The Crl:CDBR VAF/Plus (Sprague-Dawley) rat was selected as the Test System because: 1) this strain of rat was used in the reproductive and developmental toxicity studies; 2) historical data and experience exist at the Testing Facility^7'; and 3) the test article is pharmacologically active in the species and strain. E.6. Test System Data: Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) on the Day After Arrival Weight (g) at Study Assignment 37 14 SEP 98 65 days 181 - 2 2 2 192-231 E.7. Breeder Male Rat Data: Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) on the Day After Arrival Weight (g) at Cohabitation 112 13 JAN 98 78 days 300 - 356 515-893 E.8. Method of Randomization: Upon arrival, rats were assigned to individual housing on the basis of computer generated random units. After acclimation, 36 virgin female rats were placed into groups on the basis of physical appearance and body weights recorded during acclimation. Female rats were assigned to three dosage groups (Groups I through III), 12 rats per dosage group, using a computer-generated (weight-ordered) randomization procedure. After these 36 rats were cohabitated, 001013 418-015:PAGE II-7 eight mated female rats (those with confirmed evidence of mating) were selected for the study from each dosage group. On DL 4, a table of random units was used to cull the litters to five male pups and five female pups per litter, where possible. E.9. System of Identification: E.9.a. Fo Generation Rats: Male rats were given unique permanent identification numbers upon assignment to the Testing Facility's breeder male rat population. Female rats were assigned temporary numbers at receipt and given unique permanent identification numbers before cohabitation. Each rat was individually identified with a Monel self-piercing ear tag (Gey Band and Tag Co., Inc., No. MSPT 20101). E. 9.b. Fi Generation Pups: Pups were not individually identified during lactation; all parameters were evaluated in terms of the litter. F. Husbandry: F.1. Research Facility Registration: USDA Registration No. 23-R-099 under the Animal Welfare Act, 7 U.S.C. 2131 et seq. F.2. Study Rooms: The study rooms were maintained under conditions of positive airflow relative to a hallway and independently supplied with a minimum of ten changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters. Room temperature and humidity were monitored constantly throughout the study. Room temperature was targeted at 64F to 79F (18C to 26C); relative humidity was targeted at 30% to 70%. See APPENDIX E (TEMPERATURE AND RELATIVE HUMIDITY REPORTS). F.3. Housing: All cage sizes and housing conditions were in compliance with the Guide for the Care and Use o f Laboratory AnimalsTM. Fo generation rats were individually housed in stainless steel, wire-bottomed cages, except during the cohabitation and postpartum periods. During cohabitation, each pair of rats was housed in the male rat's cage. Beginning no later than DG 20, Fo generation female rats 418-015:PAGE II-8 were individually housed in nesting boxes, except during collection intervals for urine and fecal samples. During these collection intervals, the female rats were housed individually in metabolism cages. Each dam and delivered litter were housed in a common nesting box during the postpartum period. F.4. Lighting: An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. F.5. Sanitization: Cage pan liners were changed approximately three times each week. Cages were changed approximately every other week. F.6. Feed: Rats were given ad libitum access to Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in individual feeders. F.7. Feed Analysis: Analyses were routinely performed by the feed supplier. No contaminants at levels exceeding the maximum concentration or deviations from expected nutritional requirements were detected by these analyses. Copies of the results of the feed analyses are available in the raw data. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the feed that would have interfered with the results of this study. F.8. Water: Local water that had been processed by passage through a reverse osmosis membrane (R.O. water) was available to the rats ad libitum from an automatic watering access system and/or individual water bottles. Chlorine was added to the processed water as a bacteriostat. F.9. Water Analysis: The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copies of the results of the water analyses are available in the raw data. 418-015:PAGE II-9 Neither the Sponsor nor the Study Director nor the Sponsor was aware of any potential contaminants likely to have been present in the water that would have interfered with the results of this study. F.10. Bedding: Bed-o'cobs was used as the nesting material (The Andersons' Industrial Products Groups, Maumee, Ohio). F. 11. Bedding Analysis: Bedding was changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination were conducted annually and documented in the raw data. Neither the Study Director nor the Sponsor was aware of any agent present in the bedding that was known to interfere with the results of this study. G. Methods: G.1. Dosage Administration: Dosage Group I Dosage Concentration (mg/kg/day)1 (mg/mL) 0 (Vehicle) 0 Dosage Volume (mL/kg) 5 Number of Female Rats 8 II 0.1 0.02 5 8 III 1.6 0.32 5 8 Assigned Rat Numbers 13726-13728, 13731, 13734 - 13737 13739 -13741, 13744 - 13746, 13748-13749 13751 - 13756, 13758 - 13859 a. The test article was considered 100% pure for the purpose of dosage calculations. G.2. Rationale for Dosage Selection: Dosages were selected on the basis of a previous study conducted with the test article (Argus Research Laboratories, Inc., Protocol 418-008). In this study the Fo generation maternal and paternal no-observable-effect-level (NOEL) of PFOS was 0.1 mg/kg/day (0.4 mg/kg/day and higher dosages caused reductions in body weight gain and reduced feed consumption values). The Fo generation reproductive NOEL was greater than 3.2 mg/kg/day; no effects on mating, fertility or estrous cycling occurred. The NOEL for viability and growth in the F1 generation offspring was 0.4 mg/kg/day (1.6 mg/kg/day and higher dosages caused preimplantation loss and reductions in litter size, pup viability, growth and survival). CG1022 418-015:PAGE 11-10 The F1 generation maternal and paternal NOEL of PFOS was 0.1 mg/kg/day (0.4 mg/kg/day dosage caused reductions in body weight gain and reduced feed consumption values). The F1 generation reproductive NOEL was greater than a dosage of 0.4 mg/kg/day; no effects on mating or fertility occurred. The NOEL for viability and growth in the F2 generation offspring was 0.1 mg/kg/day (0.4 mg/kg/day dosage caused stillbirths and reductions in litter size, pup viability, growth and survival). G.3. Route of Administration: Oral (gavage) G.4. Rationale for Route of Administration: The oral (gavage) route was selected for use because: 1) this was the route of administration in the developmental and reproductive toxicology studies; and 2) it is one of the possible routes of human exposure. G.5. Frequency of Administration: G.5.a. Fo Generation Female Rats: Appropriate dosages3 of the test article or vehicle were administered orally (via gavage) once daily to female rats beginning 43bdays prior to cohabitation until DG 0 (confirmed evidenced of mating, such as observation of spermatozoa in a smear of the vaginal contents or a copulatory plug in situ). Female rats were not given the test article or vehicle on DG 0. Dosages were adjusted daily on the basis of the individual body weights recorded before intubation. The rats were intubated once daily at approximately the same time each day. G.5.b. F1 Generation Pups: F1 generation pups were not directly given the test article, but may have been possibly exposed to the test article during maternal gestation (in utero exposure) or via maternal milk during the lactation period. G.6. Length of Study: Approximately 14 weeks a. See APPENDIX D, item 2. b. See APPENDIX D, item 1. C01023 418-015:PAGE 11-11 G.7. Method of Study Performance: G.7.a. Fo Generation Rats: After acclimation and 43 days of dosage administration, 36 healthy virgin female rats were placed into cohabitation with 36 breeder male rats (one male rat per female rat in the male rat's cage). The cohabitation period consisted of a maximum of five days. Mating was evaluated daily during the cohabitation period. Female rats with spermatozoa observed in a smear of the vaginal contents or a copulatory plug in situ were considered to be at DG 0 and returned to individual housing. Twenty-four mated female rats, eight per dosage group, were selected for the study, as previously discussed. The female rats were observed for viability at least twice each day of the study and for general appearance at least once during acclimation. The rats were also examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before and approximately one hour after dosage. Rats were observed for clinical observations and general appearance once daily during all other periods of study. Body weights were recorded once during acclimation. Body weights were recorded daily during the dosage and postdosage periods and at sacrifice. Feed consumption values were recorded once during acclimation, weekly prior to cohabitation, daily during gestation and on DLs 1,4, 7, 10 and 14. Feed consumption was not tabulated after DL 14, when it was expected that pups would begin to consume maternal feed. The female rats were evaluated for duration of gestation (DG 0 to the day the first pup was observed), litter sizes (defined as all pups delivered), live litter size (live bom pups only) and pup viability at birth. Pups that either appeared stillborn or that died before initial examination of the litters for viability were examined for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sank were considered stillborn; pups with lungs that floated were considered livebom and to have died shortly after birth. Maternal behavior of the dams was evaluated daily when the pups were examined during the 21-day postpartum period. Observed maternal behavior was recorded on DLs 1, 4, 7, 10, 14 and 21. Deviations from expected maternal behavior were recorded, if and when present, on all other days during the postpartum period. G.7.b. F1 Generation Rats: Day 1 of lactation (postpartum) was defined as the day of birth and was also the first day on which all pups in a litter were individually weighed (pup body weights were recorded after all pups in a litter were delivered and groomed by the dam). 001024 418-015:PAGE 11-12 The litters were observed for viability at least twice each day during the postpartum period. Dead pups observed at these times were removed from the nesting box. Litters were observed for clinical observations and general appearance once daily during the postpartum period. The pups in each litter were counted once daily. Body weights were recorded on DLs 1 (birth), 4, 7, 14 and 21. G.8. Pharmacokinetic Sample Collection: G.8.a. Fo Generation Rats: Urine and fecal sample were collected from female rats for the following intervals: one day prior to initiation of cohabitation to the following morning, DGs 6 to 7, 14 to 15 and 20 to 21, and DLs 21 to 22. Following each 24-hour collection interval, samples were collected into centrifuge tubes, placed on dry ice and stored frozen (-70C or below) and shipped, frozen on dry ice, to the Sponsor for analysis. Blood samples were collected from each of the maternal rats following removal from metabolism caging (prior to test article or vehicle administration) on each of the following days: on the day cohabitation is initiated (prior to cohabitation), DGs 7, 15 and 21, and DLs 14 and 22. On all days of collection except DL 22, blood samples (approximately 1 mL each) were collected from the orbital sinus. On DL 22, blood samples (approximately 4 mL each) were collected via the inferior vena cava. Blood was collected and transferred into serum separator tubes. The samples were spun in a refrigerated centrifuge. The serum was transferred into polypropylene tubes labeled with the study number, rat identification, date of collection, study day and collection timepoint. All samples were immediately frozen on dry ice and maintained frozen (-70C or below), and shipped, frozen on dry ice, to the Sponsor for analysis. G.8.b. F1 Generation Litters: On DL 21, blood samples were collected from all remaining pups on study. Blood samples were collected via the inferior vena cava from each pup, pooled (per litter) and transferred into serum separator tubes. The samples were spun in a refrigerated centrifuge. The serum was transferred into polypropylene tubes labeled with the study number, rat identification, date of collection, study day and collection timepoint. All samples were immediately frozen on dry ice and maintained frozen (-70C or below) and shipped to the Sponsor for analysis. 001025 G.9. Gross Necropsy: 418-015:PAGE 11-13 G.9.a. Fo Generation Rats: Female rats, with or without confirmed evidence of mating, that were cohabited but not assigned to the study, were sacrificed by carbon dioxide asphyxiation and discarded without further evaluation. All surviving rats assigned to the study were sacrificed by carbon dioxide asphyxiation on DL 22 following the final collection interval for urine and fecal samples and blood sample collection. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Tissues with gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs of maternal lesions are available in the raw data. The number and distribution of implantation sites was recorded. A liver section (right lateral lobe) from each dam was collected, frozen and stored (-70C or below) until shipment to the Sponsor for analysis. All other maternal tissues were discarded. The rat that did not deliver a litter was sacrificed on DG 25 and examined for gross lesions. Uteri were stained with 10% ammonium sulfide to confirm the absence of implantation sites(9). The rat that was found dead was examined for the cause of death on the day of the death. The rat was examined for gross lesions. A liver section (right lateral lobe) was collected and stored, as described above. Pregnancy status was recorded; fetuses were examined to the extent possible. G.9.b. F1 Generation Pups: All pups culled on DL 4 were sacrificed via decapitation. The lungs and the livers were collected from the first ten pups culled determined to be at DL 4 from each dosage group (irrespective of litter) and preserved for possible future histopathological evaluation. The lungs were individually retained in Bouin's solution, and the livers were individually retained in neutral buffered 10% formalin for possible future evaluation. Remaining culled pups were sacrificed and discarded without evaluation. Pups found dead were examined for gross lesions and for the cause of death. For all pups found dead on DLs 2 to 4, all lungs were preserved in Bouin's solution for possible future evaluation. All remaining pups on study were sacrificed on DL 21 by carbon dioxide asphyxiation and examined for gross lesions. Gross lesions were preserved in neutral buffered 10% formalin. The liver from each pup was collected, pooled C01026 418-015:PAGE 11-14 (per litter), frozen and stored (-70C or below) and shipped to the Sponsor for analysis. G.10. Statistical Analyses: Averages and percentages were calculated. Litter values were used where appropriate. 001027 III. RESULTS 418-015.PAGE 111-1 A. Mortality, Clinical and Necropsy Observations (Summaries - Tables 1 and 2: Individual Data - Tables 19 and 201 A.1. Mortality No deaths or premature deliveries were attributed to PFOS treatment. One vehicle control group rat was injured and died after orbital sinus bleeding on DG '15. All other rats survived to scheduled sacrifice. A.2. Clinical Observations All adverse clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test article because the incidences were not dosage-dependent and/or the observation occurred in only one rat in a group. These observations included dental problems (missing, broken and/or misaligned incisors), chromodacryoiThea, abrasion on the forepaw, localized alopecia on the head or limbs, chromorhinorrhea, exophthalmos, hemorrhagic area on the eye, urine-stained abdominal fur, missing eye, comeal opacity, swollen area on chest or around eye, red, dried perioral substance, tom ear and soft or liquid feces. A red perinasal substance, blue paws and gasping were agonal signs for the rat that died. A. 3. Necropsy Observations A red substance was found in the thoracic cavity of the rat that died. All other rats appeared normal at necropsy. B. Body Weights and Body Weight Changes (Figure 1: Summaries Tables 3 through 8: Individual Data - Tables 21 through 23) B.1. Precohabitation Rats administered 1.6 mg/kg/day dosage of the test article had reduced body weight gains or body weight losses in each week of the precohabitation period. Reflecting these effects of the test article, body weight gains were 46.1 % of the control group value for the entire precohabitation period (DSs 1 to 43) in the 1.6 mg/kg/day dosage group. Precohabitation body weights and body weight gains were unaffected by the 0.1 mg/kg/day dosage of the test article. 001028 B.2. Gestation 418-015:PAGE III-2 Dams administered 1.6 mg/kg/day dosage of the test article during the precohabitation period (treatment ended on DG 0) had reduced body weight gains during the first week of the gestation period (DGs 0 to 7). Body weight gains were then increased as compared to the control group value on DGs 7 to 10, 13 to 15 and 15 to 18. Reflecting this rebound effect, body weight gains were increased for the entire gestation period (DGs 0 to 20) in the 1.6 mg/kg/day dosage group, as compared to the control group value. Gestation body weights and body weight gains were unaffected by the 0.1 mg/kg/day dosage of the test article. B.3. Lactation Body weight gains for dams administered the 1.6 mg/kg/day dosage of the test article during the precohabitation period generally continued to be increased during the lactation period. Lactation body weights and body weight gains were unaffected by the 0.1 mg/kg/day dosage of the test article. C. Absolute fa/dav) and Relative (q/kq/dav) Feed Consumption Values /Summaries - Tables 9 through 14: Individual Data - Tables 24 through 261 C.1. Precohabitation Absolute (g/day) and relative (g/kg/day) feed consumption values were reduced in the 1.6 mg/kg/day dosage group in each week of the precohabitation period. Reflecting these effects of the test article, feed consumption values were reduced for the entire precohabitation period (DSs 1 to 43) in the 1.6 mg/kg/day dosage group. Precohabitation feed consumption values were unaffected by the 0.1 mg/kg/day dosage of the test article. C.2. Gestation Dams administered 1.6 mg/kg/day dosage of the test article during the precohabitation period (treatment ended on DG 0) had reduced absolute and relative feed consumption values during the first week of the gestation period (DGs 0 to 7). Feed consumption values were then generally comparable to control group values for the remainder of the gestation period. Absolute and 01029 418-015:PAGE III-3 relative feed consumption values in this dosage group were slightly reduced, as compared to control group values, for the entire gestation period (DGs 0 to 20). Gestation feed consumption values were unaffected by the 0.1 mg/kg/day dosage of the test article. C. 3. Lactation Absolute and relative feed consumption values during the lactation period were reduced in the groups administered 0.1 or 1.6 mg/kg/day of the test article during the precohabitation period, however the reductions were not strictly dosagedependent. D. Natural Delivery and Litter Observations (Summaries - Tables 15 and 16: Individual Data - Tables 27 through 30) Natural delivery observations were based on 7, 8 and 7 pregnant rats in each of the three respective dosage groups. Administration of the test article at dosages as high as 1.6 mg/kg/day did not adversely affect any parameter evaluated at natural delivery or during the 22-day lactation period (duration of gestation, averages for implantations and live litter sizes, numbers of dams with no livebom pups or all pups dying during lactation, gestation, viability and lactation indices, surviving pups per litter, litter size at weighing, pup weight per litter and pup sex ratios). E. Clinical Observations from Birth to Day 21 Postpartum and Necropsy Observations (Summaries - Tables 17 and 18; Individual Data - Tables 31 and 32) No clinical or necropsy observations in the F1 generation pups were attributable to maternal dosages of the test article as high as 1.6 mg/kg/day because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one or two pups. The only adverse clinical observation was a black tip of tail in one 0.1 mg/kg/day dosage group pup. No milk in stomach occurred in 0, 1 and 2 pups that were found dead in the three respective dosage groups. All pups appeared normal at necropsy on DL 4 or 21. 001030 REFERENCES 418-015:PAGE III-4 1. U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detection of toxicity to reproduction for medicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. 2. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 3. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. 4. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community o f an OECD decision/recommendation on compliance with principles o f good laboratory practice. Official Journal of the European Communities: Legislation. 32 (No. L 315; 28 October): 1-17. 5. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 7. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 8. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use o f Laboratory Animals. National Academy Press, Washington, D.C. 9. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. C01031 APPENDIX A REPORT FIGURE 001032 BODY WEIGHTS Fo GENERATION FEMALE RATS Figure 1 418-015: PAGE A-1 001033 DAY OF STUDY a. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. b. Last value recorded before cohabitation. DAY OF GESTATION 0 (VEHICLE) MG/KG/DAY DAY OF LACTATION 01 MG/KG/DAY a 16 MG/KG/DAY a APPENDIX B REPORT TABLES C01034 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 1 (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II 0 (VEHICLE) 0.1b HI 1.6b PRECOHABITATION (DAY 1 OF STUDY TO THE DAY OF COHABITATION) : MAXIMUM POSSIBLE INCIDENCE 516/ 12 516/ 12 516/ 12 MORTALITY 00 0 INCISORS: TOTAL MISALIGNED MISSING/BROKEN 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 16/ 1 16/ 1 5/ 1 CHROMODACRYORRHEA 0/ 0 0/ 0 10/ 1 RIGHT FOREPAW: ABRASION 0/ 0 0/ 0 5/ 1 LOCALIZED ALOPECIA: HEAD 0/ 0 2/ 1 0/ 0 MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS) /NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015: PAGE B-1 CO 103 01 PROTOCOL 4X8-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 1 (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II 0 (VEHICLE) 0.1b III 1.6b PRESUMED GESTATION: C MAXIMUM POSSIBLE INCIDENCE 190/ 12 192/ 11 201/ 12 ACCIDENTAL DEATH Id 0 0 LOCALIZED ALOPECIA: LIMBS 0/ 0 5/ 2 11/ 2 CHROMODACRYORRHEA 5/ 1 12/ 3 5/ 1 CHROMORHINORRH EA 1/ 1 9/ 2 3/ 1 INCISORS: MISALIGNED 0/ 0 0/ 0 5/ 1 EXOPHTHALMOS 5/ I 4/ 1 0/ 0 EYES: HEMORRHAGIC AREA 5/ 1 4/ 1 0/ 0 URINE-STAINED ABDOMINAL FUR 0/ 0 2/ 1 0/ 0 RIGHT EYE: REMOVED 0/ 0 1/ 1 0/ 0 GASPING 1/ id 0/ 0 0/ 0 PAWS : BLUE 1/ id 0/ 0 0/ 0 RED PERINASAL SUBSTANCE 1/ Id 0/ 0 0/ 0 MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N n TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Restricted to rats with a confirmed mating date. d. Dam 13731 had an accidental death on day 15 of gestation. 418-015: PAGE B-2 CO10 3 Ci PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 1 (PAGE 3) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II 0 (VEHICLE) 0.1b III 1.6b LACTATION : MAXIMUM POSSIBLE INCIDENCE 154/ 7 176/ 8 154/ 7 MORTALITY 000 CHROMODACRYORRHEA 0/ 0 10/ 2 1/ 1 CORNEAL OPACITY 0/ 0 0/ 0 7/ 1 CHROMORHINORRHEA 0/ 0 20/ 4 0/ 0 RIGHT EYE: MISSING 0/ 0 22/ 1 0/ 0 CHEST OR AROUND RIGHT EYE: SWOLLEN 1/ 1 7/ 1 0/ 0 RED DRIED PERIORAL SUBSTANCE RIGHT EAR : TORN 0/ 0 3/ 1 1/ 1 0/ 0 0/ 0 0/ 0 SOFT OR LIQUID FECES 3/ 1 0/ 0 0/ 0 MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N * TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION. a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015:PAGE B-3 00103 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II 0 (VEHICLE) 0 .lb III 1.6b RATS EXAMINED C N 8d Bd 8d ACCIDENTAL DEATH N le 0 0 APPEARED NORMAL N 788 THORACIC CAVITY: RED SUBSTANCE N le 0 0 a. Dosage occurred on day 1 of study until day 0 of presumed gestation, b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rata were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study, c. Refer to the individual clinical observations table (Table 19) for external observations confirmed at necropsy. d. Excludes values for rats Chat were not selected for continuation on study. e. Dam 13731 had an accidental death on day 15 of gestation. 418-015: PAGE B-4 O o O U 00 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 3 (PAGE 1): BODY WEIGHTS - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 BODY WEIGHT (G) DAY 1 MEAN+ S .D 225.0 + 10.2 227.2 + 8.9 226.3 + 12.3 DAY 8 MEAN+ S .D 235.4 + 10.B 236.6 + 10.5 233.9 + 13.0 DAY 15 MEAN*S.D 246.2 + 10.9 253.1 + 12.0 242.3 + 14.4 DAY 22 MEAN*S .D 252.2 + 13.4 257.5 + 14.4 245.2 + 15.7 DAY 29 MEAN*S .D 259.6 + 12.7 262.0 + 15.5 246.9 + 14.5 DAY 36 MEAN+S.D 267.6 + 15.8 269.6 + 15.8 250.3 + 18.6 DAY 43C MEAN+S.D 274.5 + 17.9 276.4 + 18.6 249.2 + 21.5 DAY = DAY OF STUDY a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Last value recorded before cohabitation. 418-015: PAGE B-5 o o *> PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 4 (PAGE 1): BODY WEIGHT CHANGES - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a 1 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 BODY WEIGHT CHANGE (G) DAYS 1 - 8 MEAN+S.D . +10.4 4.9 +9.4 f 3.3 +7.6 6.7 DAYS 8 - 15 MEAN+S.D . +10.8 5.6 +16.5 6.8 +8.4 + 4.4 DAYS 15 - 22 MEAN+S.D . +6.1 6.6 +4.4 + 6.5 +2.9 jf 3.8 DAYS 22 - 29 MEAN+S.D . +7.3 6.9 +4.5 + 6.8 +1.7 + 3.0 DAYS 29 - 36 MEAN+S.D . +8.0 6.3 +7.6 6.8 +3.4 + 5.8 DAYS 36 - 43c MEAN+S.D . +6.9 6.6 +6.8 6.9 -1.2 5.3 DAYS 1 - 43C MEAN+S.D. +49.5 + 14.5 +49.2 14.0 +22.8 f 16.3 DAYS = DAYS OF STUDY a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Last value recorded before cohabitation. 418-015: PAGE B-6 '01040 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 5 (PAGE 1): MATERNAL BODY WEIGHTS - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8C 8c PREGNANT N8 8 7 MATERNAL BODY WEIGHT (G) DAY 0 MEAN+S.D . 279.6 + 20.2 281.1 + 20.9 261.0 19.7 DAY 1 MEAN+S.D . 284.1 + 18.0 290.8 + 18.6 268.7 19.9 DAY 2 MEAN+S.D . 289.5 + 16.7 297.2 + 17.5 272.7 21.0 DAY 3 MEAN+S.D. 296.5 + 19.4 300.2 19.0 273.6 + 20.2 DAY 4 MEAN+S.D. 299.9 + 19.7 301.1 19.2 275.1 + 19.4 DAY 5 MEAN+S.D . 302.6 + 18.9 303.5 + 17.6 277.0 + 16.7 DAY 6 MEAN+S.D . 307.2 21.3 307.6 + 16.6 279.7 f 15.0 DAY 7 MEAN+S.D . 305.9 + 18.0 309.5 + 15.5 277.1 + 15.0 DAY 8 MEAN+S.D. 305.1 + 21.1 306.9 + 17.7 279.4 f 16.2 DAY 9 MEAN+S.D . 310.2 20.3 311.5 + 17.3 287.0 + 16.1 DAY 10 MEAN+S.D . 314.1 + 19.2 318.1 19.3 291.6 + 17.5 DAY 11 MEAN+S.D . 322.0 + 24.2 323.8 + 18.9 298.8 f 21.1 DAY 12 MEAN+S.D . 328.1 + 20.8 330.6 + 16.3 301.7 + 15.9 r> DAY 13 MEAN+S.D. 330.8 + 22.9 331.5 f 18.6 307.6 + 21.7 0X0 DAY = DAY OF GESTATION a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. 418-015:PAGE B-7 PROTOCOL 418-015 : ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 5 (PAGE 2): MATERNAL BODY HEIGHTS - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N8 8 7 MATERNAL BODY WEIGHT (G) DAY 14 MEAN+S.D . 334.5 + 22.6 338.5 + 17.9 311.7 + 19.2 DAY 15 DAY 16 DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 MEAN+S.D . MEAN+S.D . MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 342.2 + 24.1 ( 7]d 341.1 + 23.5 ( 7]d 355.6 + 25.8 ( 7]d 367.1 + 27.2 ( 7)d 383.7 + 29.5 [ 71 d 398.0 + 31.0 I 7] d 412.4 + 34.5 ( 71 d 347.1 + 20.9 348.5 + 18.6 361.2 + 17.2 376.9 + 21.2 390.1 + 20.5 399.4 + 21.7 413.4 + 31.2 321.8 + 22.0 328.6 + 20.8 341.6 19.3 359.3 19.6 369.4 + 18.0 390.0 + 25.1 402.3 + 20.6 DAY DAY OF GESTATION ( ) = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for dam 13731, which had an accidental death on day 15 of gestation. 418-015: PAGE B-8 001042 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 6 (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0 lb III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N8 8 7 MATERNAL BODY WEIGHT CHANGE (G) DAYS 0 - 7 MEAN+S.D . +26.2 + 7.0 +28.4 + 9.4 +16.1 + 7.0 DAYS 7 - 10 MEAN+S.D . +8.2 + 8.1 +8.6 + 9.0 +i4.4 + 7.8 DAYS 10 - 13 MEAN+S.D . +16.6 + 6.5 +13.4 + 8.8 +16.0 + 7.9 DAYS 13 - 15 MEAN+S.D. 11.5 6.9 +15.6 + 12.1 +3.4.3 + 8.6 DAYS 15 - 18 DAYS 18 - 20 DAYS 0 - 20 MEAN+S.D . MEAN+S.D . MEAN+S.D. +28.7 + 7.4 [ 71d +30.8 + 6.1 l 7) d 119.6 + 16.3 l 7)d +29.8 + 14.1 22.5 + 8.7 +118.2 + 18.4 +37.4 + 5.3 +30.7 + 6.9 +129.0 + 16.8 DAYS DAYS OF GESTATION ( ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for dam 13731, which had an accidental death on day 15 of gestation. 418-015: PAGE B-9 C01043 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 7 (PAGE 1): MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N 8 8 7 DELIVERED LITTERS N 7d 8 7 MATERNAL BODY WEIGHT (G) DAY 1 DAY 2 MEAN+S.D . MEAN+S.D . 299.6 + 20.6 302.6 + 25.8 311.1 . 19.7 302.4 + 23.3 293.6 + 23.8 289.0 20.8 DAY 3 MEAN+S.D . 307.7 23.5 308.1 + 28.4 292.0 + 15.9 DAY 4 MEAN+S.D . 305.3 22.9 307.8 f 31.7 291.4 + 19.6 DAY 5 MEAN+S.D . 308.7 23.5 312.8 + 18.6 297.1 16.7 DAY 6 MEAN+S.D . 310.4 + 23.1 314.1 16.5 299.7 f 15.4 DAY 7 MEAN+S.D . 314.4 + 17.9 319.2 + 12.5 304.4 + 17.6 DAY 8 MEAN+S.D . 321.0 + 21.2 328.1 + 14.4 309.8 f 14.3 DAY 9 MEAN+S.D. 324.3 20.3 333.8 12.7 316.0 13.3 DAY 10 MEAN+S.D . 328.8 + 19.6 341.4 13.1 321.1 14.6 DAY 11 MEAN+S.D . 333.4 21.4 343.6 + 13.1 329.1 + 11.8 DAY 12 MEAN+S.D . 341.8 f 21.2 346.4 + 11.5 333.6 + 1 2 .6 DAY = DAY OF LACTATION a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for dam 13731, which had an accidental death on day 15 of gestation. 418-015: PAGE B-10 COIO'14 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 7 (PAGE 2) : MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N 8 8 7 DELIVERED LITTERS N 7d 8 7 MATERNAL BODY WEIGHT (G) DAY 13 MEAN+S.D. 342.4 + 23.5 342.2 + 17.0 339.8 + 23.5 DAY 14 DAY 15 DAY 16 MEAN+S.D. MEAN+S.D . MEAN+S.D. 331.4 + 16.9 342.6 + 19.2 341.8 + 19.4 344.1 + 20.7 348.9 + 19.1 353.0 + 15.5 337.8 4- 16.2 335.8 + 17.8 341.4 + 19.9 DAY 17 MEAN+S.D. 338.8 + 21.2 356.8 + 14.0 334.7 + 23.1 DAY 16 DAY 19 DAY 20 DAY 21 MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D. 348.8 + 19.2 346.0 + 11.1 344.8 + 14.5 339.1 + 14.0 357.1 + 16.8 355.5 + 13.7 351.8 + 19.4 348.8 + 20.5 343.4 + 21.7 337.7 + 19.6 346.0 + 17.4 339.1 20.9 DAY 22 MEAN+S.D. 331.7 + 16.7 338.5 + 22.5 337.8 + 23.3 DAY = DAY OF LACTATION a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for dam 13731, which had an accidental death on day 15 of gestation. 418-015: PAGE B-11 COlO-1 01 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 8 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) a I 0 (VEHICLE) II 0.1b HI 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c Be 8c PREGNANT N 8 8 7 DELIVERED LITTERS N 7d 8 7 MATERNAL BODY WEIGHT CHANGE (G) DAYS 1 - 4 MEAN+S.D . +5.7 + 6.7 -3.4 + 30.1 -2.1 + 11.4 DAYS 4 - 7 MEAN+S.D . +9.1 + 6.3 +11.5 + 25.5 +13.0+ 8.8 DAYS 7 - 10 MEAN+S.D . +14.4 + 4.2 +22.1 + 4.7 +16.7 + 5.4 DAYS 10 - 14 MEAN+S.D . +2.6 + 12.7 +2.8 + 13.0 +16.7 + 5.5 DAYS 14 - 22 MEAN+S.D . +0.3 + 14.5 -5.6 + 24.3 +0.0 + 11.5 DAYS 1 - 22 MEAN+S.D . +32.1 + 10.0 +27.4 + 22.2 +44.3 +21.7 DAYS DAYS OF LACTATION a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for dam 13731, which had an accidental death on day 15 of gestation. 418-015:PAGE B-12 001046 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 9 (PAGE 1): ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 FEED CONSUMPTION (G) DAYS 1 - 8 DAYS 8 - 15 DAYS 15 - 22 DAYS 22 - 29 DAYS 29 - 36 DAYS 36 - 43d DAYS 1 - 43d MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 19.6 + 1.2 ( 11]C 18.8 + 1.5 [ 10)C 19.6 + 1.8 [ 10)C 18.4 + 2.2 ( 101c 19.1 + 2.0 ( lOJc 20.4 + 1.9 [ ll)c 19.4 + 1.5 1 11]C 18.9 + 1.2 ( 10]c 20.2 + 1.9 19.2 + 1.4 ( 10]c 18.1 + 2.1 ( 101c 19.2 + 1.6 l 91c 20.3 + 2.1 l 111c 19.6 + 1.8 ( 111c 18.3 + 1.7 17.8 + 1.4 17.5 + 1.3 I 111c 15.8 + 1.5 16.6 + 1.6 [ lllc 17.5 + 2.8 17.4 + 1.6 DAYS = DAYS OF STUDY ( ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values that were associated with spillage. d. Last value recorded before cohabitation. 418-015: PAGE B-13 COlO-17 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 10 (PAGE 1): RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a RATS TESTED N I 0 (VEHICLE) 12 II 0 .lb 12 III 1.6b 12 FEED CONSUMPTION (G/KG/DAY) DAYS 1 - 8 DAYS 8 - 15 DAYS 15 - 22 DAYS 22 - 29 DAYS 29 - 36 DAYS 36 - 4 3 d DAYS 1 - 4 3 d MEAN+S.D. MEAN+S.D . MEAN+S.D. MEAN+S.D . MEAN+S.D. MEAN+S.D. MEAN+S.D. 85.0 + 5.2 [ ll)c 77.4 + 5.4 ( 10]c 78.8 + 6.7 [ 10]C 71.7+ 7.8 I 10) C 72.2 + 5.9 ( 10] C 74.5+ 4.5 ( HI C 76.7 + 4.9 ( lllc 82.3 + 3.8 ( 101 C 82.2 + 5.6 76.1 + 4.2 ( 10]c 69.1 + 5.3 ( 10}C 72.4 + 4.5 [ 9] C 73.6 + 5.8 ( lllc 76.6+ 4.7 [ lllc 79.3+ 4.9 74.8 + 4.5 71.7 + 3.3 l lllc 64.4 + 5.2 66.8 + 4.6 I lllc 70.0 + 9.2 71.7 + 4.7 DAYS = DAYS OF STUDY ( ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values that were associated with spillage. d. Last value recorded before cohabitation. 418-015: PAGE B-14 C01043 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR1S STUDY NUMBER: T-629S.14) TABLE 11 (PAGE 1); MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N8 8 7 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 0 - 7 DAYS 7 - 10 MEAN+S.D. MEAN+S.D . 25.2 + 1.2 [ 71d 23.8 + 2.4 24.2 + 2.0 24.1 + 2.3 21.1 + 2.4 22.1 + 3.0 DAYS 10 - 13 MEAN+S.D. 26.5 + 2.6 26.4 + 1.4 22.5 + 2.8 DAYS 13 - 15 MEAN+S.D . 24.9 + 3.0 25.5 + 2.3 26.1 + 2.7 DAYS 15 - 18 DAYS 18 - 20 DAYS 0 - 20 MEAN+S.D. MEAN+S.D. MEAN+S.D. 26.0 + 1.9 ( 7) e 25.4 + 3.3 [ 7] e 25.2 + 1.3 ( 7] e 27.5 + 2.8 27.1 + 2.4 25.4 + 0.8 26.2 + 1.6 23.8 + 3.7 23.0 + 2.0 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values that were associated with spillage. e. Excludes values for rat 13731, which had an accidental death on day 15 of gestation. 418-015: PAGE B-15 CQ104 & PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 12 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - GESTATION - SUMMARY - FO GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N8 8 7 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 0 - 7 DAYS 7 - 10 MEAN+S.D. MEAN+S.D . 84.5 + 6.6 1 7]d 76.9 + 5.3 81.1 + 7.6 77.3 + 6.2 77.9 + 11.9 78.1 + 12.3 DAYS 10 - 13 MEAN +S .D . 81.9 + 5.5 81.0 + 6.5 75.0 + 9.0 DAYS 13 - 15 MEAN+S.D . 74.6 + 10.5 75.2 + 6.1 83.4 + 8.8 DAYS 15 - 18 DAYS 18 - 20 DAYS 0 - 20 MEAN+S.D . MEAN+S.D . MEAN+S.D. 74.1 + 4.5 ( 7je 66.3 + 5.9 [ 7]e 78.6 + 4.3 1 7]e 77.0 + 10.3 70.1 + 8.9 77.8 + 5.0 77.8 + 5.9 63.7 + 7.1 76.1 + 7.8 DAYS > DAYS OF GESTATION ( ] * NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rata were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values that were associated with spillage. e. Excludes values for rat 13731, which had an accidental death on day 15 of gestation. 418-015: PAGE B-16 OTOO o</? PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 13 (PAGE 1): MATERNAL ABSOLUTE PEED CONSUMPTION VALUES (G/DAY) LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0. lb III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8C PREGNANT N 8 8 7 DELIVERED LITTERS N 7d 8 7 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 1 - 4 MEAN+S.D. 31.3 1 s.l 30.1 + 18.9 23.2 + 3.5 DAYS 4 - 7 DAYS 7 - 10 MEAN+S.D. MEAN+S.D. 47.7 + 10.7 ( 61 e 54.4 + 3.1 42.1 + 12.4 ( 7)e 54.8 + 8.6 40.1 + 5.6 51.0 + 6.3 DAYS 10 - 14 f DAYS 1 - 14 f MEAN+S.D. MEAN+S.D. 68.1 2.9 61 e 52.9 + 2.8 ( 6) e 6 1 .4+ 5.2 l 7) e 41.7 + 8.3 [ 7) e 59.5 + 3.4 44.7 + 3.9 DAYS = DAYS OF LACTATION I 1 = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rata were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for rat 13731, which had an accidental death on day 15 of gestation. e. Excludes values that were associated with spillage. f. Because it is presumed that the pups begin to consume maternal feed after day 14 of lactation, maternal feed consumption values were not tabulated on days 14 to 22 of lactation. 418-015: PAGE B-17 O O CT PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 14 (PAGE 1): MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS TESTED N 12 12 12 INCLUDED IN ANALYSES N 8c 8c 8c PREGNANT N 8 8 7 DELIVERED LITTERS N 7d a 7 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 1 - 4 MEAN+S.D . 103.6 + 20.3 98.7 + 65.9 80.1 + 14.9 DAYS 4 - 7 DAYS 7 - 10 MEAN+S.D. MEAN+S.D . 152.0 + 33.1 ( 6)e 169.3 + 12.9 134.8 +44.5 ( 7) e 166.2 + 28.4 135.2 + 23.8 163.2 +21.1 DAYS 10 - 14f DAYS 1 - 14f MEAN+S.D. MEAN+S.D. 202.0 + 17.6 ( 6] e 165.3 + 16.6 ( 6) e 178.4 + 16.5 I 7) e 144.5 + 28.9 I 7) e 179.3 + 13.1 144.1 + 16.6 DAYS = DAYS OF LACTATION ( 1 = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for rats that were not selected for continuation on study. d. Excludes values for rat 13731, which had an accidental death on day 15 of gestation. e. Excludes values that were associated with spillage. f. Because it is presumed that the pups begin to consume maternal feed after day 14 of lactation, maternal feed consumption values were not tabulated on days 14 to 22 of lactation. 418-015. PAGE B-18 r> o M O PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 15 (PAGE 1) : NATURAL DELIVERY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b RATS ASSIGNED TO NATURAL DELIVERY N 8 8 8 PREGNANT N8 8 7 DELIVERED LITTERS N 7c 8 7 DURATION OF GESTATION d MEAN+S.D. IMPLANTATION SITES N PER DELIVERED LITTER MEAN+S.D . 22.6 4 0.5 ( 5) e 106 15.1 + 0.9 23.0+ 0.0 ( 6) e 119 14.9 + 2.0 22.2 + 0. ( 6le 108 15.4 + 2 DAMS WITH STILLBORN PUPS N (%) 1( 14.3) 1< 12.5) 0( 0.0) DAMS WITH NO LIVEBORN PUPS N 0 0 0 GESTATION INDEX f % N/N 100.0 7/ 7 100.0 8/ 8 100.0 7/ 7 DAMS WITH ALL PUPS DYING DAYS 1-4 POSTPARTUM N 0 0 0 DAMS WITH ALL PUPS DYING DAYS 5-21 POSTPARTUM N 0 0 0 ( ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Excludes values for dam 13131, which had an accidental death on day 15 of gestation. d. Calculated as the time (in days) elapsed between confirmed mating (arbitrarily defined as day 0) and the time (in days) the first pup was delivered. e. Excludes values for rats that did not have delivery observations recorded. f. Number of rats with live offspring/number of pregnant rats. 418-015: PAGE B-19 C0105 CO PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 16 (PAGE 1): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0 .lb III 1.6b DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 7 a 7 PUPS DELIVERED (TOTAL) N MEANtS.D . 97 13.8 + 1.6 103 12.9 + 3.0 97 13.8 + 1.7 LIVEBORN STILLBORN CULLED MEAN+S.D. N (%) MEAN+S.D. N (%) N 13.7 + 1.4 96( 99. 0) 0.1 + 0.4 1( 1. 0) 23 12.8 + 3.0 102 ( 99.0) 0.1 + 0.4 K 1.0) 26 13.8 + 1.7 97(100. 0) 0.0 + 0.0 0( 0. 0) 24 PUPS FOUND DEAD OR PRESUMED CANNIBALIZED DAY 1 DAYS 2- 4 DAYS 5- 7 DAYS 8-14 DAYS 15-21 N / N (%) N / N (%) N / N (%) N / N (%) N / N (%) 0/ 96 ( 3/ 96 ( 0/ 70 ( 0/ 70 ( 0/ 70 ( 0.0) 3.1) 0.0) 0.0) 0.0) 0/102( 1/1021 0/ 75( 0/ 75( 0/ 75( 0.0) 1.0) 0.0) 0.0) 0.0) 1/ 97 ( 2/ 96 ( 0/ 70 ( 0/ 70 ( 0/ 70 ( 1.0) 2.1) 0.0) 0.0) 0.0) VIABILITY INDEX C 1 N/N 96 .9 93/ 96 99.0 101/102 96 .9 94/ 97 LACTATION INDEX d % N/N 100 .0 70/ 70 100.0 75/ 75 100 .0 70/ 70 DAY(S) = DAY(S) POSTPARTUM a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Number of live pups on day 4 (preculling) postpartum/number of liveborn pups on day 1 postpartum. d. Number of live pups on day 21 (weaning) postpartum/number of live pups on day 4 (postculling) postpartum. o o in 418-015:PAGE B-20 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER; T-629S.14) TABLE 16 (PAGE 2): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 7 8 7 SURVIVING PUPS/LITTER c DAY 1 d MEAN+S.D . DAY 4 PRECULLING MEAN+S.D . DAY 4 POSTCULLING MEAN+S.D . DAY 7 MEAN+S.D. DAY 14 MEAN+S.D . DAY 21 MEAN+S.D . PERCENT MALE PUPS PER NUMBER OF PUPS SEXED 13.7 + 1.4 13.3 + 1.0 10.0 + 0.0 10.0 + o.o 10.0 + 0.0 10-0 t 0.0 12.8 + 3.0 12.6 + 3.0 9.4 + 0.9 9.4 + 0.9 9.4 + 0.9 9.4 + 0.9 13.8 + 1.7 13.4 + 1.8 10.0 + 0.0 10.0 + 0.0 10.0 +_ 0.0 10.0 0.0 DAY 1 d MEAN+S.D . 44.9 + 17.9 46.6 + 11.2 50.9 9.7 DAY 4 PRECULLING DAY 4 POSTCULLING DAY 7 DAY 14 DAY 21 MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D. MEAN+S.D . 46.2 + 17.9 48.6 + 12.1 48.6 + 12.1 48.6 + 12.1 48.6 12-1 47.3 + 12.1 46.5 + 5.2 46.5 + 5.2 46.5 + 5.2 46.5 5.2 50.4 + 10.9 48.6 + 3.8 48.6 + 3.8 48.6 + 3.8 48.6 + 3.8 DAY = DAY POSTPARTUM a. Dosage occurred on day 1 of study until day 0 of gestation. n b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed 0 with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. !* c. Average number of live pups per litter, including litters with no surviving pups. d. Includes pups born alive, found dead day 1 postpartum. 01 418-015: PAGE B-21 PROTOCOL 410-015: ORAL IGAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 16 (PAGE 3): LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1b III 1.6b DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS N 7 8 7 LIVE LITTER SIZE AT WEIGHING DAY 1 MEAN+S.D . 13.7 +_ 1.4 12.8 + 3.0 13.6 + 1.7 DAY 4 PRECULLING MEAN+S.D . 13.3 + 1.0 12.6 + 3.0 13.4 + 1.8 DAY 4 POSTCULLING MEAN+S.D . 10.0 0.0 9.4 + 0.9 10.0 0.0 DAY 7 MEAN+S.D . 10.0 + 0.0 9.4 0.9 10.0 0.0 DAY 14 MEAN+S.D. 10.0 + 0.0 9.4 + 0.9 10.0 0.0 DAY 21 MEAN+S.D . 10.0 0.0 9.4 _+ 0.9 10.0 0.0 PUP WEIGHT/LITTER (GRAMS) DAY 1 MEAN+S.D . 6.4 0.4 6.5 0.5 6.2 + 0.6 DAY 4 PRECULLING MEAN+S.D . 8.9 + 0.9 8.5 + 1.4 8.2 + 0.8 DAY 4 POSTCULLING MEAN+S.D . 9.0 0.9 8.5 1.4 8.3 + 0.8 DAY 7 MEAN+S.D . 14.1 1.3 13.2 + 1.8 12.8 + 1.3 DAY 14 MEAN+S.D . 29.8 f 1.6 29.4 f 2.4 26.6 + 2.6 DAY 21 MEAN+S.D . 47.1 + 3.6 47.5 + 2.9 42.4 3.9 DAY = DAY POSTPARTUM a. Dosage occurred on day 1 of study until day 0 of presumed gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rats were dosed o with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 6 po c/i 0) 418-015:PAGE B-22 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 17 (PAGE 1) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 21 POSTPARTUM - SUMMARY - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)a LITTERS EXAMINED (N) I II 0 (VEHICLE) 0.1b 78 III 1.6b 7 PERSISTENT CLINICAL OBSERVATIONS: C TIP OF TAIL, BLACK N/N 0/ 0 15/ 1 0/ 0 N/N TOTAL FREQUENCY (DAYS X PUPS)/LITTERS WITH OBSERVATIONS a. Dosage occurred on day l of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Tabulation restricted to adverse observations; all other pups appeared normal. 418-015: PAGE B-23 001057 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 18 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)a LITTERS EXAMINED (N) I 0 (VEHICLE) 7 II 0.1b 8 III 1.6b 7 TOTAL PUPS STILLBORN OR FOUND DEAD c N2 2 2 STILLBORN N1 1 0 FOUND DEAD N1 1 2 o o o NO MILK IN STOMACH e N (%) 1(100.0) 2(100.0) PUPS SACRIFICED AND NECROPSIED ON DAY 4 AND/OR 21 POSTPARTUM d LITTERS EXAMINED N7 8 7 PUPS EVALUATED N 80 85 80 APPEARED NORMAL LITTER INCIDENCE PUP INCIDENCE Nit) N(t) 7(100.0) 80(100.0) 8(100.0) 85(100.0) 7(100.0) 80(100.0) a. Dosage occurred on day 1 of study until day 0 of gestation. b. As a result of an error in calculation, which resulted in an error in test article preparation, Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days 1 through 4 of study. c. Restricted to pups in which complete necropsies were performed. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. d. Refer to the individual pup clinical observations table (Table 31) for external clinical observations confirmed at necropsy. e. Analysis restricted to pups found dead and necropsied. PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 19 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY RAT It DESCRIPTION 13126 13727 13728 13729 13730 13731 13732 13733 13734 13735 13736 13737 DL( 22 ) DS( 44- 45) DS( 44- 45) DS( 44- 45) DG( 0- 4) DG ( 0- 4) DG ( 0- 4) DG ( 4 ) DG ( 4 ) DG ( 15 ) DG ( 15 ) DG ( 15 ) DG ( 15 ) DG ( 4 ) DG ( 4 ) DG ( 14 ) DL( 16- 18) DL( 20- 22) NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHEST: SWOLLEN (RIGHT SIDE, 2.0 CM X 1.5 CM; LEFT SIDE, 2.0 CM X 1.0 CM)a CHROMODACRYORRHEA EXOPHTHALMOS RIGHT EYE: HEMORRHAGIC AREA CHROMODACRYORRHEA EXOPHTHALMOS RIGHT EYE: HEMORRHAGIC AREA EXCLUDED FROM STUDY EXCLUDED FROM STUDY RED PERINASAL SUBSTANCE a FORE AND HINDPAWS: BLUE GASPING ACCIDENTAL DEATH EXCLUDED FROM STUDY EXCLUDED FROM STUDY NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA SOFT OR LIQUID FECES RIGHT EAR: TORN a NO ADVERSE FINDINGS DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION DL = DAY OF LACTATION a. Observation confirmed at necropsy. 418-015: PAGE B-25 CO 105 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 19 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a RAT 8 DESCRIPTION 13738 13739 13740 13741 13742 13743 13744 13745 13746 13747 13748 13749 DS ( 45 ) DG( 0- 1) DG( 4 > DG ( 11- 12) DL ( 2- 11) DGl 4- 6) DG ( 6 ) DS ( 1- 2) DS ( 3 ) DS ( 50 ) DL ( 16 ) DL ( 16 ) DG ( 16- 19) DG ( 16- 19) DG ( 16- 20) DG ( 20 > DL ( 1- 22) DL ( 1- 7) DL ( 1- 7) DL ( 8 ) DL ( 18- 20) DL ( 18- 22) DG( 3- 4) DG ( 4 ) DG ( 9- 13) DG( 10- 16) DL( 4- 7) DG ( 4- 5) URINE-STAINED ABDOMINAL FUR URINE-STAINED ABDOMINAL FUR EXCLUDED FROM STUDY NO ADVERSE FINDINGS CHROMORHINORRHEA CHROMORHINORRHEA NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS EXCLUDED FROM STUDY LOCALIZED ALOPECIA: HEAD ALOPECIA NO LONGER APPARENT EXCLUDED FROM STUDY CHROMORHINORRHEA RED DRIED PERIORAL SUBSTANCE EXOPHTHALMOS RIGHT EYE: HEMORRHAGIC AREA CHROMODACRYORRHEA RIGHT EYE : REMOVED RIGHT EYE: MISSING b CHROMODACRYORRHEA AROUND RIGHT EYE: SWOLLEN SWELLING RESOLVED CHROMODACRYORRHEA CHROMORHINORRHEA b LOCALIZED ALOPECIA: LIMBS EXCLUDED FROM STUDY CHROMODACRYORRHEA CHROMORHINORRHEA CHROMORHINORRHEA CHROMODACRYORRHEA DS * DAY OF STUDY DG = DAY OF PRESUMED GESTATION DL = DAY OF LACTATION a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. C5 b. Observation confirmed at necropsy. Coi 418-015: PAGE B-26 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 19 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a RAT DESCRIPTION 13750 13751 13752 13753 13754 13755 13756 13757 13758 13759 13760 13761 DS ( 28- 32) DS ( 33 ) DS ( 28- 45) DS ( 34- 45) DG ( 0- 4) DG ( 0- 4) DG ( 4 ) DL ( 16- 22) DG ( 9- 16) DG ( 17 ) DL( 17 ) DS ( 36- 40) DS ( 41 ) DG ( 4- 6) DG ( 6 ) DG ( 6 ) DG ( 1- 3) DG ( 3 ) INCISORS: MISSING/BROKEN INCISORS: GROWN IN INCISORS: MISALIGNED CHROMODACRYORRHEA CHROMODACRYORRHEA INCISORS: MISALIGNED EXCLUDED FROM STUDY NO ADVERSE FINDINGS RIGHT EYE: CORNEAL OPACITY b NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS ALOPECIA NO LONGER APPARENT CHROMODACRYORRHEA FOREPAW: RIGHT. ABRASION (0.2 CM X 0.3 CM) ABRASION HEALED LOCALIZED ALOPECIA: LIMBS EXCLUDED FROM STUDY NO ADVERSE FINDINGS NO ADVERSE FINDINGS EXCLUDED FROM STUDY CHROMORHINORRHEA EXCLUDED FROM STUDY DS = DAY OF STUDY DG = DAY OF PRESUMED GESTATION DL = DAY OF LACTATION a. As a result of an error in calculation, which resulted in an error in test article preparation, 2 mg/kg/day on days 1 through 4 of study. b. Observation confirmed at necropsy. rats were dosed with 418-015: PAGE B-27 n O o o PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 20 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a I 0 (VEHICLE) 13726 DL 22 P 45 ALL TISSUES APPEARED NORMAL. 13727 DL 22 P 43 ALL TISSUES APPEARED NORMAL. 13728 DL 22 P 43 CERVICAL MAMMARY GLAND: LARGE. ALL OTHER TISSUES APPEARED NORMAL. 13731 DG 15 P 44 ACCIDENTAL DEATH ON DAY 15 OF GESTATION. THORACIC CAVITY: RED SUBSTANCE. ALL OTHER TISSUES APPEARED NORMAL. UTERINE CONTENTS: 17 IMPLANTATION SITES (16 DEAD FETUSES AND ONE EARLY RESORPTION).b 13734 DL 22 P 45 ALL TISSUES APPEARED NORMAL. 13735 DL 22 P 43 ALL TISSUES APPEARED NORMAL. 13736 DL 22 P 46 ALL TISSUES APPEARED NORMAL. 13737 DL 22 P 46 ALL TISSUES APPEARED NORMAL. II 0.1C 13739 DL 22 P 44 ALL TISSUES APPEARED NORMAL. 13740 DL 22 P 43 ALL TISSUES APPEARED NORMAL. 13741 DL 22 P 45 ALL TISSUES APPEARED NORMAL. 13744 DL 22 P 46 ALL TISSUES APPEARED NORMAL. 13745 DL 22 P 43 ALL TISSUES APPEARED NORMAL. 13746 DL 22 P 46 ALL TISSUES APPEARED NORMAL. 13748 DL 22 P 43 ALL TISSUES APPEARED NORMAL. 13749 DL 22 P 43 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG DAY OF GESTATION DL * DAY OF LACTATION a. Refer to the individual clinical observations table (Table 19) for external observations confirmed at necropsy. b. Viability of fetuses unable to be determined because of maternal death. c. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. O o 418-015: PAGE B-28 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 20 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a III 1.6b 13751 DL 22 P 44 ALL TISSUES APPEARED NORMAL. 13752 DL 22 P 45 ALL TISSUES APPEARED NORMAL. 13753 DL 22 P 44 ALL TISSUES APPEARED NORMAL. 13754 DL 22 P 46 ALL TISSUES APPEARED NORMAL. 13755 DG 25 NP 46 ALL TISSUES APPEARED NORMAL. 13756 DL 22 P 45 ALL TISSUES APPEARED NORMAL. 13758 DL 22 P 46 ALL TISSUES APPEARED NORMAL. 13759 DL 22 P 43 ALL TISSUES APPEARED NORMAL. P PREGNANT NP NOT PREGNANT DG = DAY OF GESTATION DL = DAY OF LACTATION a. Refer to the individual clinical observations table (Table 19) for external observations confirmed at necropsy. b. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 90X00 418-015: PAGE B-29 CJ PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 21 (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY RAT II 12 3 DOSAGE GROUP I 4 13726 13727 13728 13729 13730 13731 13732 13733 13734 13735 13736 13737 203. 242. 229. 225. 219. 229. 218. 228. 222. 227. 219. 239. 198. 248. 231. 219. 214. 237. 216. 237. 218. 229. 220. 248. 206. 249. 226. 225. 219. 239. 222. 236 . 218. 227. 216. 250. 210 251 235 227 224 239 225 236 227 220 224 253 DAY 13726 13727 13728 13729 13730 13731 13732 13733 13734 13735 13736 13737 11 229. 258. 252. 258. 241. 270. 236. 258. 244 . 239. 236. 256. 18 226. 258. 254 . 256. 233. 268. 244 . 256. 247. 241. 234. 256 . 19 232 . 254 . 266. 253. 239. 262. 243 . 265. 251. 241. 226 . 256 . 20 235 260 268 254 245 262 246 269 255 234 232 260 DAY DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). 56 7 VEHICLE CONTROL 213. 246. 238. 229. 221. 236. 228. 233. 232 . 228. 222. 258. 210. 244 . 242. 228. 220. 241. 226. 242. 233. 230. 218. 247. 215. 251. 238. 235. 226. 243 . 221. 246. 234 . 232. 221. 247. 21 22 23 235. 262. 266 . 259. 242. 269. 241 . 263 . 255. 240. 236 . 268 . 234 . 257. 261. 259. 241 . 273 . 241. 267. 251. 243. 234 . 266 . 239. 253. 271. 262. 242. 270. 247. 263. 252 . 240 . 225 . 261. 8 216. 252. 244 . 238. 228. 244 . 232. 240. 230. 224 . 228. 249. 24 241. 249. 270. 262. 248. 265. 248. 263 . 252. 233. 232 . 270 . 9 10 11 12 0 (VEHICLE) MG/KG/DAY 214. 245. 243. 237. 226. 238. 228. 244 . 235. 226. 222. 247. 212 247 250 237 225 241 230 247 239 232 223 242 218. 252 . 244. 243. 230. 245. 228. 250. 236. 234 . 224. 239. 221. 255. 244 . 245. 232. 251. 228. 246. 233. 229. 231. 245. 25 26 27 28 237. 253. 273 . 263. 250. 258. 250. 263 . 258 . 242. 239. 268 . 237 258 272 265 246 266 246 262 259 244 237 269 243 . 259. 266. 267. 255. 272. 248 . 263 . 266. 244 . 234 . 269. 246. 260. 268. 269. 256. 273. 258. 273. 268. 238. 236. 277 . 13 224 . 252. 252. 246. 233. 257. 236. 247. 235. 234 . 232. 252. 29 244. 253. 271. 268. 258. 268. 255. 273. 260. 244 . 241 . 280 . 14 223. 253. 260. 247. 230 . 257. 237. 257. 244 . 239. 236. 252. 30 244 . 256. 272 . 269. 256. 267. 256. 272. 261. 247. 238. 280 . 15 229. 262. 259. 247. 238. 258. 236. 257. 245. 241. 234. 248. 31 249. 263 . 273 . 276. 258. 272. 254 . 270. 258. 248. 232. 273 . 16 227 260 259 253 242 263 236 260 248 233 235 256 32 251 267 275 274 263 280 248 271 265 243 240 283 418-015: PAGE B-30 o a PROTOCOL 418-015: ORAL 1GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 21 (PAGE 2) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 33 34 35 36 37 38 39 40 RAT tf DOSAGE GROUP I VEHICLE CONTROL 13726 13727 13728 13729 13730 13731 13732 13733 13734 13735 13736 13737 248. 260. 276. 277. 261. 280. 255. 271. 269. 251. 242 . 285. 244 . 259. 280. 273. 258. 276. 257. 275. 268. 254 . 241. 284 . 248. 268. 278. 279. 267. 276. 260. 271. 268. 250. 234 . 285. 256. 269. 284 . 282. 268. 282. 255. 273 . 266. 247. 239. 290. 25S. 267. 290. 284 . 263. 291. 255. 280. 272. 250. 243 . 292. 252. 266. 288. 281. 260. 293. 261. 282. 277. 253. 243. 295. 257. 262. 289. 284 . 267. 284. 262. 276. 274. 255. 238. 292. 260. 271. 287. 287. 271. 285. 260. 277. 269. 248. 242. 298. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. 41 42 43a 0 (VEHICLE) MG/KG/DAY 258. 280. 288. 290. 272. 289. 261. 284 . 271. 256. 248. 298. 251. 278. 290. 284. 270. 290. 259. 278. 275. 258. 245. 296. 251. 274. 289. 287. 272. 288. 270. 294 . 278. 254. 241. 296. SOTO 3 418-015: PAGE B-31 01 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 21 (PAGE 3): BODY HEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 RAT tt DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a 13738 13739 13740 13741 13742 13743 13744 13745 13746 13747 13748 13749 208. 242. 233. 232. 218. 233 . 225. 228 . 221. 235. 224. 227. 209. 240. 241. 228. 219. 235. 228. 233. 221. 231. 223. 219. 208. 235. 235. 231. 219. 242. 226. 227. 219. 235. 220. 228. 205. 239. 234. 240. 222. 235. 228. 226. 226. 242. 226. 237 . 214. 249. 236. 239. 229. 241 . 234 . 235. 229. 239. 228. 234 . 216. 253 . 242. 239. 230. 249. 237. 241. 234 . 236. 232. 229. 216. 252. 240. 240. 224 . 253. 241. 242. 232. 240. 227. 226. 215. 251. 238. 247. 227. 248. 237. 237. 226 . 245. 232. 236 . 213 . 249. 238. 243 . 236. 254 239. 242. 234 247 234 244 216. 256. 241. 240. 242. 258. 245. 244 . 239. 242. 240. 242. 219. 260. 244 . 246. 242. 259. 247. 246. 242. 247. 241. 242. 218. 259. 243. 252. 241. 255. 246. 244 . 238. 251. 238. 237. 221. 255. 248. 249. 246. 266. 248. 249. 236 . 251. 239. 247. 220. 266. 254. 245. 250. 274 . 258. 254 . 244 . 248. 246. 250. 225. 270. 254. 252. 254. 274 . 256. 250. 247. 254. 253. 248. 228. 266. 248. 257. 250. 268. 256. 249. 248 . 255. 249. 247. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 13738 13739 13740 13741 13742 13743 13744 13745 13746 13747 13748 13749 229. 259. 254 . 259. 247. 284 . 261. 254 . 246. 254. 255. 245. 228. 268. 255. 256. 250. 275. 259. 255. 242. 250. 255. 254 . 225. 268. 257. 259. 252. 280 . 263 . 256. 247. 251. 252. 256. 228. 266. 253. 265. 256 . 278 . 261 . 251 . 252. 257. 248. 257. 236. 262 . 255. 259. 253. 286 . 263. 257 . 252 . 258 . 250 . 250 . 234 . 272 . 261. 258 . 250. 290. 265. 263 . 244. 253. 252. 248. 233. 269. 260. 260. 255. 285. 264. 256. 243. 256. 246. 254 . 228. 268. 255. 266 . 259. 280. 261. 255. 248. 258. 241. 259. 233 263 258 265 258 286 267 260 251 259, 244 256 237. 271. 265. 261. 255. 290. 270. 264 . 249. 256. 248. 256 . 237. 268. 263. 272. 255. 291. 273. 263 . 243 . 259. 244 . 258. 235. 272 . 264. 272. 259. 283. 268. 261. 240. 264. 242 . 260. 232 . 267. 264 . 271. 264 . 292. 276. 266. 245. 260. 247. 260. 238. 273 . 269. 269. 261. 295. 277. 270. 253. 256. 245. 261. 243. 280. 271. 271. 262. 296. 280. 264 . 253. 259. 247. 265. 243 . 275. 270. 278. 260. 288. 276 . 264. 244 . 263. 240. 270. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. 418-015: PAGE B-32 SOTO & PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 21 (PAGE 4) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 33 34 35 36 37 38 39 40 41 42 43a RAT # DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAYb 13738 13739 13740 13741 13742 13743 13744 13745 13746 13747 13748 13749 241. 274. 271. 278. 264. 299. 274. 266. 246. 264. 244. 270. 240. 286. 279. 276. 268. 302. 283 . 270. 252. 260. 247. 266. 249. 290. 277. 284. 268. 301. 286. 275. 251. 265. 246. 267. 252. 283. 273. 281. 265. 296. 284. 269. 249. 272. 242. 269. 247. 284. 276. 281. 266. 302. 279. 272, 254 266 248 274 251. 291. 281. 281. 267. 308. 280. 275. 251. 268. 252. 272. 246. 294 . 276. 287. 267. 311. 285. 273. 252. 268. 247. 268. 251. 288. 276. 291. 265. 306. 293. 266. 259. 272. 242. 273. 252. 289. 280. 292. 274 , 312. 297 275 263 273 251 279 251. 302. 282. 287. 274. 316. 290. 271. 255. 269. 252. 276. 254. 298. 269. 295. 269. 314. 286 . 271. 257. 278. 256. 270. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. b. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. rats were dosed with 418-015: PAGE B-33 C10G o PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 21 (PAGE 5): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 RAT tt DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAYa 13750 13751 13752 13753 13754 13755 13756 13757 13758 13759 13760 13761 213. 256. 225. 227. 219. 236. 218. 233. 219. 235. 212. 223. 206. 260. 223 . 233. 224 . 235. 227. 241. 219. 238. 213. 227. 214 . 266. 227. 225. 217. 231. 228. 235. 218. 232. 214. 220. 217. 263. 237. 239. 224 . 238. 232. 235. 221. 232. 211. 226. 215. 256 . 231. 240. 227. 240. 230. 239. 226. 239. 220. 228. 212. 259. 233. 237. 224. 239. 230. 248. 229. 240 . 215. 228. 218. 260. 239. 233. 222 . 235. 236. 246 . 223 . 240. 215. 230. 216. 261. 238. 237. 226. 240. 240. 247. 226. 231. 214 . 231. 214 . 257. 237. 233. 227. 236. 238. 243. 223 . 223 . 215. 231. 212. 259. 236. 238. 227. 241. 242. 246. 228. 233. 216 . 231. 217. 262. 244. 235. 228. 235. 239. 250. 227. 233. 215. 232. 223 . 268. 245. 247. 229. 238. 246. 254 . 233 . 236. 220. 236 . 218. 262. 245. 250. 232. 244. 248. 255 . 239. 236. 224 . 238. 215. 274 . 24S. 244 . 231. 240 . 2S0. 252 . 235. 236. 223 . 241 . 221. 274. 252 . 245. 230. 239. 250. 256. 238. 241. 226 . 236 . 222. 271. 252. 250. 233. 225. 249. 260. 237. 240. 225 . 241. DAY 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 13750 13751 13752 13753 13754 13755 13756 13757 13758 13759 13760 13761 221. 268. 250. 250. 237. 248. 254. 257. 239. 243. 229. 240. 214 . 277. 247. 246. 234. 244 . 250. 260. 236. 239. 222 . 238. 222. 277. 252. 245. 228. 240. 252. 259. 238. 244 . 225. 237. 226. 278. 256. 248. 231. 242. 253. 260. 238. 241. 225 . 242. 223 . 271. 253. 252 . 235. 244 . 247. 266. 241. 242 . 232. 246. 218. 274. 250. 254. 232. 244 . 253. 265. 243 . 245. 226. 239. 223. 277. 252. 248. 232. 240. 254. 257. 232. 238. 226. 234. 220. 274. 253. 251. 236. 240. 254. 256. 232. 239. 232. 240. 216. 261. 252. 253. 235. 239. 251. 263. 234 . 238. 231. 241. 214 . 267. 249. 254. 232. 241. 252. 267. 234. 237. 229. 241. 221. 275. 255. 254 . 233. 239. 257. 269. 228. 237. 230. 237. 215. 277. 255. 257. 237. 240. 253 . 265 . 234 . 241. 232. 243 . 221. 271. 256. 259. 234 . 245. 253. 265. 241. 244 . 231. 243 . 214 . 276 . 257. 262 . 236. 240 . 255. 273 . 236 . 239. 233 . 242 . 220. 279. 262. 258. 232. 238. 251. 273. 233 . 241. 234 . 237 . 223 . 283 . 261. 255. 236. 239. 254. 274 . 233. 244 . 236. 243. DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. D o O a 00 418-015: PAGE B-34 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 21 (PAGE 6): BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAY 33 34 35 36 37 38 39 40 41 42 43a RAT DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAYb 13750 13751 13752 13753 13754 13755 13756 13757 13758 13759 13760 13761 217. 269. 259. 262 . 236. 240. 254 . 269. 238. 245. 239. 243. 219. 279. 257. 264. 235. 239. 255. 266. 235. 243. 239. 243. 226. 282. 262. 264 . 229. 241. 253. 275. 238. 245. 239. 242. 223. 286. 265. 259. 232. 246. 253. 277. 238. 244 . 237. 244. 222. 278 . 267. 256. 238. 244 . 259. 276 . 240. 246. 240. 246. 219. 288. 265. 261. 233. 246. 260. 272. 238. 246. 236. 243 . 218. 291. 267. 264. 229. 242. 255. 269. 237. 239. 234. 239. 224 . 289. 267. 265. 233 . 244 . 254. 280. 239. 244. 236. 246. 223 . 285. 266. 260. 236. 243 . 256. 286. 243. 238. 242. 247. 223. 284. 262. 263. 234. 242. 262. 282. 240. 242. 242. 247. 212. 287. 269. 263 . 231. 239. 256. 276. 232. 240. 244. 241. DAY DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recored before cohabitation. b. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015:PAGE B-35 n O O a ca PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 22 (PAGE 1): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 13726 P 13727 P 13728 P 13729 a 13730 a 13731 P 13732 a 13733 a 13734 P 13735 P 13736 P 13737 P 259. 281. 295. 281. 281. 288. 278. 298. 279. 259. 260. 316. 265. 270. 292. 297. 289. 293. 297. 302. 281. 285. 291. 302. 282. 282. 309. 311. 283. 292. 262. 270. 273. 275. 31B 317. 275. 296. 308. 302. 288. 306. 288. 310. 300. 272. 284 . 331. 282. 303. 309. 303. 296. 309. 294. 311. 302. 274. 284 . 336. 283. 304 . 314. 323. 303. 277. 288. 329. 282. 320. 325 322. 305 281 288 335 281. 305. 323. 310. 316. 285. 295. 332. 278. 316. 320. 322. 313. 284. 279. 329. 283 . 316. 320. 328. 312. 289. 293 . 341. DAY 13 14 15 16 17 18 19 20 21 22 13726 P 13727 P 13728 P 13729 a 13730 a 13731 P 13732 a 13733 a 13734 P 13735 P 13736 P 13737 P 306 . 335. 342. 308. 348. 353. 358. 357. 334 . 298. 314 . 359. 332. 309. 310. 359. 312. 354. 364 . 315. 348. 368. 326. 366. 384 . 337. 379. 399. 352 397 427 360. 413. 441. 370. 421. 464. 372 . 369. ACCIDENTAL DEATH ON DAY 15 OF GESTATION 344 . 314. 318. 363. 347. 313. 327. 370. 363 . 324 . 340. 386 . 367. 333. 355. 400,. 385 346 371 408 399. 362. 385. 426 . 406 . 373. 409. 444 . 360. P PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Rat was not selected for continuation on study; values excluded from group averages. 10 293. 325. 329. 330. 320. 286. 296. 334. 23 11 291. 333. 335. 12 301. 340. 352. 347. 342. 317. 294 . 304 . 355. 24 328. 303. 310. 349. 25 418-015: PAGE B-36 Q /..O TG O PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 22 (PAGE 2): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 13738 b 13739 P 13740 P 13741 P 13742 b 13743 b 13744 P 13745 P 13746 P 13747 b 13748 P 13749 P 261. 294. 282. 310. 282. 302. 280. 252. 293. 254. 275. 265. 308. 288. 314 . 284 . 311. 281. 268. 295. 267. 289. 269. 315. 297. 319. 291. 311. 288. 275. 296. 273. 300. 272. 313. 298. 325. 296. 318. 294 . 279. 295. 270, 305, 282. 309. 298. 333. 295. 318. 292 . 278. 305. 277. 304. 316. 300. 331. 291. 320. 294 . 282 . 283. 302. 314. 313. 323. 300. 321. 307. 276. 289. 318. 305. 317. 331. 326. 308. 292. 286. 311, 319. 310. 326. 322. 310. 327. 330 . 316. 341. 335. 320. 339. 326 . 297. 281. 284 . 312. 332. 304 . 287. 288. 322. 334 . 316. 290 . 290. 328. 351 . 315. 301. 297. 332. DAY 13 14 15 16 17 18 19 20 21 22 23 24 13738 b 13739 P 13740 P 13741 P 13742 b 13743 b 13744 P 13745 P 13746 P 13747 b 13748 P 13749 P 347. 322. 349. 358. 322. 318. 303. 333. 348. 334. 352. 364 . 341 . 364. 367, 337 364 363. 339. 314 . 312. 346. 366 . 350. 308. 326. 358. 374 336 332 324 354 379. 347. 377 . 401. 356. 397. 415. 368. 415. 436 374 407 385. 347. 346. 344 . 365. 402 . 358 . 362. 355 . 384. 410. 369. 379. 374 . 391. 425 384 385 387 397 455 . 385. 437 . 448. 392. 405. 369. 416 . 387. P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. b. Rat was not selected for continuation on study; values excluded from group averages. rats were dosed with 12 335. 325. 343 . 357. 328. 311. 308. 338. 25 418-015: PAGE B-37 00107 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 22 (PAGE 3): MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a PREGNANCY STATUS DAY 0 1 2 3 4 5 6 7 8 9 10 11 12 13750 b 13751 P 13752 P 13753 P 13754 P 13755 NP 13756 P 13757 b 13758 P 13759 P 13760 b 13761 b 232. 295. 277. 263. 246. 252 . 261. 284 . 243. 242. 236. 252. 221. 302. 287. 274 . 254. 255. 262. 296. 254. 248. 243. 257. 229. 315. 278. 276. 256. 258. 271. 302. 254. 259. 250. 255. 237. 314 . 279. 278. 259. 263 . 271. 302. 256. 258. 250. 266. 241. 312. 282. 280. 259. 264 . 276. 305. 256. 261. 252. 309. 278. 287. 263. 263. 274 . 305. 263. 265. 258. 310. 284 . 284. 267. 266. 274 . 321. 269. 270. 261. 305. 289. 270. 264. 269. 278. 265. 269. 312 . 281. 281. 264 . 265. 282 . 267. 269. 321. 289. 289. 275. 273. 282. 275. 278. 326. 290. 292. 271. 266. 298. 281. 283. 342. 296 . 308. 281. 280. 295. 283. 287. 333. 298. 304 . 288. 282. 306. 284. 299. DAY 13 14 15 16 17 18 19 20 21 22 23 24 25 13750 b 13751 P 13752 P 13753 P 13754 P 13755 NP 13756 P 13757 b 13758 P 13759 P 13760 b 13761 b 352. 297. 318. 290. 279. 306 . 294 . 296. 349. 304 . 321. 288. 275. 308. 302. 310. 361. 324. 334 . 294 . 276. 319. 301. 320 . 370. 326. 335. 302. 274 . 322 . 321. 324. 380 . 348. 345. 321. 276 . 336. 330. 331. 398. 359. 367. 336. 282 . 351. 348. 356. 395. 371. 382. 337. 278. 364. 364. 373. 436 384 405 355 284 380 381 389 432. 411. 413. 366. 287. 394. 394 . 406 . 437. 278. 289. 290 . 298 . P PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a As a result of an error in calculation, which resulted in an error in test article preparation rats were dosed with o 2 mg/kg/day on days 1 through 4 of study. o b Rat was not selected for continuation on study; values excluded from group averages. q 3 418-015:PAGE B-38 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 23 (PAGE 1): MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT 8 DOSAGE GROUP I VEHICLE CONTROL DAY 1 2 3 4 5 13726 13727 13728 13731 13734 13735 13736 13737 270 , 270. 278. 280. 282. 309. 325. 332. 325. 331. 324. 318. 329. 327. 333 . ACCIDENTAL DEATH ON DAY 15 OF GESTATION 310. 313. 317. 320. 326 . 276, 265. 279. 275. 280. 292 299. 294. 289. 291. 316 328. 325. 321. 318. DAY 14 15 16 17 18 13726 13727 13728 13731 13734 13735 13736 13737 323 321. 325. 336. 332. 352 360. 360. 358. 359. 344 367. 362. 356. 375. ACCIDENTAL DEATH ON DAY 15 OF GESTATION 325 337. 338. 343 . 353 . 312 328. 327. 319. 329. 314 325. 318. 303. 328. 350 360. 363. 357. 366. DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 6 284 . 338. 333. 323 . 286. 290. 319. 19 332. 357. 358. 350. 341. 332. 352. 0 (VEHICLE) MG/KG/DAY 789 293. 327. 337. 299. 335. 348. 298. 339. 348. 324. 295. 300. 325. 332. 293 . 306. 334. 331. 298. 317. 339. 20 21 22 337 328. 312. 356 342. 327. 352 354. 353. 337 327. 330. 339 328 . 313. 325 333. 334. 368 362. 353. 10 303. 336. 352. 341. 308. 316. 346. 11 310. 346. 358. 326. 312. 321. 361. 12 325. 351. 358. 360. 309. 327. 363. 13 322. 351. 36B. 343. 316. 322. 375. 418-015: PAGE B-39 o o CO PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 23 (PAGE 2) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT H DOSAGE GROUP II LOW DOSAGE 0. 1 MG/KG/DAY a DAY 1 2 3 4 5 6 7 8 9 10 11 12 13739 13740 13741 13744 13745 13746 13748 13749 316. 310. 320. 327. 313. 284. 281. 338. 302. 297. 315. 339. 279. 272. 288. 327. 317. 303. 333. 340. 253 . 293 . 296. 330 . 324. 296. 333. 342. 242. 302. 297. 326 325. 307. 323. 336. 282. 298. 301. 330. 329. 307. 324 . 322. 299. 295. 298. 339. 323. 313. 317. 343. 312. 307. 308. 331. 335. 317. 336. 350. 312. 319. 314 . 342. 337. 324. 342. 358. 325. 325. 320. 339. 345. 338. 346. 367. 330. 333. 325. 347. 350. 337. 343 . 364. 338. 348. 319. 350. 345. 340. 358. 366 . 343 . 337. 331. 351. DAY 14 15 16 17 18 19 20 21 22 13739 13740 13741 13744 13745 13746 13748 13749 352. 340. 366. 367. 309. 324 . 336 . 359. 356. 334 . 359. 375. 357. 316. 334 . 360. 352. 341. 359. 379. 368. 331. 342. 352 . 347 343 366 378 363 340 348 369 342. 343. 382 371 360, 339 346 374 355. 338. 364. 378. 365. 340. 346. 358. 350 333 352 389 357 327 342 364 362. 335. 340. 386. 362. 320. 338. 347. 362. 306. 338. 374. 348 .b 316. 331. 333 . DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. A3 a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. b. Dead body weight. rats were dosed with 13 351. 348. 356. 351. 354. 344. 306. 328. 418-015:PAGE B-40 oxoo A PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 23 (PAGE 3): MATERNAL BODY HEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT 8 DOSAGE GROUP III HIGH DOSAGE 1. 6 MG/KG/DAY a DAY 1 2 3 4 5 6 7 8 9 10 11 12 13751 13752 13753 13754 13755 13756 13758 13759 333. 321. 278. 289. 299. 300. 264. 253 . NOT PREGNANT 311. 296. 296. 284. 274. 280. 323. 298. 290. 272. 292 . 283. 286. 331. 293. 293 . 271. 290. 288. 274 . 333. 292. 300. 281. 292. 291. 291. 331. 298. 305. 285. 299. 292. 288. 341. 312. 300. 297. 298. 289. 294 . 341. 307. 309. 303. 309. 302. 298. 342. 315. 320. 319. 305. 309. 302. 353. 319. 321. 314. 316. 309. 316. 355. 331. 325. 325. 321. 322. 325. 361. 329. 336. 330. 328. 326. 325. DAY 14 15 16 17 18 19 20 21 22 13751 13752 13753 13754 13755 13756 13758 13759 370 371. 333 333. 340 333. 322 324 . NOT PREGNANT 340 328. 322 317. 338 345. 380. 342. 321. 340. 344 . 320. 343. 372. 340. 333 . 338. 295. 323 . 342. 389. 343. 339 334. 323 329 347 370. 334. 343 . 304 . 341. 330. 342. 376 325 344 333 342 340 362 367. 319. 342. 332. 356. 308. 350. 386. 330. 326. 336. 337. 311. 339. DAY = DAY OF LACTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). a. As a result of an error In calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 13 389. 338. 336. 315. 342. 325. 334 . 418-015: PAGE B-41 Q01075 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 24 (PAGE 1) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1- 8 8- IS 15- 22 22- 29 29- 36 36- 43a RAT tt DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY 13726 13727 13728 13729 13730 13731 13732 13733 13734 13735 13736 13737 140. 141. 135. 131. 140 . 144 . 127. 144 . 134 . b 122 . 151. b 129. 149. 143. 135. 138. 114. 138. 129. b 119. 126. 138. 128. 139. 141. 146. 144 . 120. b 147. b 114. 155. 131. 106. 143. 136. 147. 120. 117. b 136. b 107. 143 . 137. 130. 141. 142. 154. 130. 118. b 129. b 108. 150. 137. 137. 159. 142. 155. 146. 124. 141. 144 . b 120. 163. RAT DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY c 13738 13739 13740 13741 13742 13743 13744 13745 13746 13747 13748 13749 116. b 138. 137. 131. b 139. 139. 128. 142. 135. 119. 114. 147. 135. 130. 150. 164. 143. 144 . 133. 153. 150. 131. 124. 140. 138. 139. 137. b 146. 133. 121. b 148. 121. 114 . 122 . 126. 132 . 137. 155. 130. 126. 99. b b 124 . 128. 144. 146 . 142. 142. b 143 . 126. 116. b b 122. 128. 144 . 141. 153. 146. 163. 139. 135. 120. 168. b 126. DAYS DAYS OF STUDY ALL HEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. b. Spilled feed precluded the calculation of this value. c. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. rats were dosed with 418-015: PAGE B ^2 o to o C5 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 24 (PAGE 2) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1- 8 8- 15 15- 22 22- 29 29I- 36 36 - 43a RAT # DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY b 13750 13751 13752 13753 13754 13755 13756 13757 13758 13759 13760 13761 114 . 148. 134. 131. 123. 121. 129. 131. 124 . 149. 109. 122. 110. 134. 126. 128. 119. 113. 128. 133. 130. 141. 113. 122. 111. 135. 124. 123. 121. 115. 121. 133 . 133. c 108. 123. 98. 111. 114. 122. 108. 105. 105. 124. 105. 134 . 99. 107. 100. 124. 117. 131. 12S. 113. 107. 135. 108. c 111. 111. 89. 133. 123. 171. 116. 114 . 115. 134. 117. 137. 112. 110. DAYS DAYS OF STUDY ALL HEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation. b. As a result of an error in calculation, which resulted in an error in test article preparation, 2 mg/kg/day on days 1 through 4 of study. c. Spilled feed precluded the calculation of this value. rats were doBed with 418-015:PAGE B ^3 001077 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 25 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT ft DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY PREGNANCY STATUS DAYS 0 - 1 1 - 2 2 - 3 3 - 4 4 - 5 5 - 6 6 - 7 7-8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13726 P 13727 P 13728 P 13729 a 13730 a 13731 p 13732 a 13733 a 13734 p 13735 p 13736 p 13737 p 25. 24 . 28. 22. 23 . 22. 41. 19. 22 . 23 . 27. 19. 26. 24 . 21. 27. 25. 25. 24 . 21. 24 . 25. 29. 20. 18. 41. 14 . 28 . 28. 27. 23 . 24 . 25. 28. 30. 29. b 24 . 25. 18. 24 . 25 . 28. 25. 16. 28. 26. 27. 25. 27. 13. 29. 26. 27. 30. 29. 25. 22 . 24 . 20. 28. 27. 25. 21. 23. 27. 27. 22. 27. 28. 30. 27. 28. 24 . 35. 22. 24. 25. 28. 23 . 29. 24 . b 24 . 22 . 20. 23 . 22. 28. 23. 23. 23 . 25. 24 . 24. 16. 20. 27. 19. 25. 24 . 25. 26 . 29. 24 . 27. 28. 21. 25. 24. 24. 26. 26. 31. 31. 25. 32. 28. 26. 29. DAYS 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 13726 P 13727 P 13728 P 13729 a 13730 a 13731 p 13732 a 13733 a 13734 p 13735 p 13736 p 13737 p 22. 18. 20. 27. 27. 20. 24. 24 . 33. 22. 25. 29. 27. 32. 20. 29. 22. 23. 23 . 24. 20. 19. 29. 27. 30. 26. 26. 29. 29. 34. 29. ACCIDENTAL DEATH ON DAY 15 OF GESTATION 25. 27. 25. 29. 25. 26. 24 . 32. 31. 31. 21. 25. 24 . 24 . 23 . 26 . 20 . 26. 22. 25. b 23. 24 . 26. 29. 25. 25 . 14. 10. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Rat was not selected for continuation on study; values excluded from group averages. b. Spilled feed precluded the calculation of this value. 418-015:PAGE B-44 001078 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 25 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT It DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a PREGNANCY STATUS DAYS 0 - 1 1 - 2 2 - 3 3 - 4 4 - 5 5 - 6 6 - 7 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13738 b 13739 P 13740 P 13741 P 13742 b 13743 b 13744 P 13745 P 13746 P 13747 b 13748 P 13749 P 24 . 21. 22. 21. 22. 28. 26. 23. 20. 25. 19. 25. 24. 27. 22. 32. 20. 24 . 24. 27. 25. 26. 26. 23. 25. 25. 25. 24. 28. 26. 27. 30. 26. 24. 24. 27. 20. 21. 23. 30. 18. 26. 24. 24. 28. 27. 27. 24 . 25. 23. 22. 22. 26. 24 . 27. 26. 21. 32. 23. 28. 29. 19. 23. 27. 23. 25. 23. 24. 21. 27. 26. 25. 26. 30. 24 . 22. 15. 16 . 20. 22. 23. 20. 19. 25. 19. 30. 31. 29. 24 . 28. 23. 25. 23. 28. 39. 29. 23. 22. 21. 24 . 20. 24. 25. 30. 27. 22. 29. 26. 26. 24 . 14. 22. 31 . 28. 29. 25. 33. DAYS 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 13738 b 13739 P 13740 P 13741 P 13742 b 13743 b 13744 P 13745 P 13746 P 13747 b 13748 P 13749 P 24. 34. 23. 27. 28. 27. 27. 39. 23. 25. 24 . 26. 28. 26. 27. 20. 23. 26. 26 . 27. 28. 28. 18. 28. 27. 22. 25. 29. 27. 22. 29. 27. 25. 30. 19. 24, 26. 27. 34. 25. 27. 17. 28. 34. 35. 30. 25. 28. 16 . 34 . 26. 32. 31. 30 . 30. 10. 14 . 22. 33. 21. 33. 33. 24. 30. 29. P * PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS WERE RECORDED IN GRAMS (G). a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. b. Rat was not selected for continuation on study; values excluded from group averages. rats were dosed with 418-015: PAGE B-45 001079 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 25 (PAGE 3): MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS RAT DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a PREGNANCY STATUS DAYS 0 - 1 1-2 2-3 3-4 4-5 5- 6 6-7 7-8 8 - 9 9 - 1 0 1 0 - 1 1 11 - 12 12 - 13 13750 b 13751 P 13752 P 13753 P 13754 P 13755 NP 13756 p 13757 b 13758 P 13759 P 13760 b 13761 b 8. 18. 21. 12. 20. 29. 22. 23. 16. 21. 18. 20. 26. 23. 23. 28. 23. 28. 15. 16. 16. 16. 17. 23. 17. 20. 15. 25. 15. 21. 23. 21. 23 . 23. 18. 18. 16. 19. 23. 23. 22. 27. 19. 22. 22. 18. 20. 20. 20. 24 . 20. 20. 24 . 19. 25. 22. 22. 21. 18. 22. 22. 20. 29. 25. 23. 26. 22. 25. 19. 17. 20. 18. 16. 16. 16. 26. 18. 20. 23. 25. 18. 20. 26. 22. 25. 26. 26. 26. 23. 22. 18. 21. 22. 22. 45. 28. 22. 30. 17. 16. 25. 20. 25. 22. 24. 25. 23 . 28. 23. 23 . 27. 24 . 28. 30. 15. 18. 19. 20. 19. 17. 20. 19. 20. DAYS 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 13750 b 13751 P 13752 P 13753 P 13754 P 13755 NP 13756 P 13757 b 13758 P 13759 P 13760 b 13761 b 25. 29. 33 . 25. 25. 23 . 35. 24 . 23 . 19. 32. 25. 25. 26. 22. 22. 30. 24. 32. 23. 29. 24. 27. 26. 22. 23 . 24 . 27. 29. 14. 23. 27. 21. 21. 22. 25. 25. IS. 38. 27. 17. 20. 20. 22. 20. 25. 24 . 24. 24. 21. 21. 28. 27. 24 . 30. 34. 28. 26. 28 . 28. 24 . 23 . 23. 30. 28. 26. 33. 32. P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. As a result of an error in calculation,, which resulted in an error in test article preparation. 2 mg/kg/day on days 1 through 4 of study. b. Rat was not selected for continuation on study; values excluded from group averages. rats were dosed with 418-015: PAGE B-46 001080 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 26 (PAGE 1): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1 - 4 4 - 7 7 - 10 10 - 14a RAT DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY 13726 13727 13728 13731 13734 13735 13736 13737 85. 144. 171. 281. 106. 128. 152. 252. 91. 136. 173. 282. ACCIDENTAL DEATH ON DAY 15 OF GESTATION 93. 136. 170. 268. 119. c 161. 280. 71. 110. 150. c 92. 204 . 165. 271. RAT tf DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY b 13739 13740 13741 13744 13745 13746 13748 13749 49. 74 . 99. 97. 20. 121. 206. 57. 108. 130. 127. 109. 111. 206 . c 93 . 146. 149. 169. 175. 166. 219. 159. 133. 223. 233 . 268. 265. 250. c 262. 218. DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. It is presumed that the pupa begin to consume the maternal feed after day 14 of lactation. b. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. c. Spilled feed precluded the calculation of this value. rats were dosed with 418-015:PAGE B-47 001081 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 26 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS DAYS 1 - 4 4 - 7 7 - 10 10 - 14a RAT 8 DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY b 13751 13752 13753 13754 13755 13756 13758 13759 65. 110. 72. 119. 69. 115. 70. 151. NOT PREGNANT 52. 99. 72. 115 . 87. 133 . 157. 140. 161. 181. 121. 150. 161. 234. 232. 244. 240 . 228. 223 . 264. DAYS DAYS OF LACTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). a. It is presumed that the pups begin to consume the maternal feed after day 14 of lactation. b. As a result of an error in calculation, which resulted in an error in test article preparation, 2 mg/kg/day on days 1 through 4 of study. rats were dosed with 418-015: PAGE B ^8 001082 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 27 (PAGE 1): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA Fo GENERATION FEMALE RATS/F1 GENERATION LITTERS RAT/ LITTER NUMBER DURATION OF GESTATION (DAYS) N LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN NNN 1 MF NUMBER OF LIVE PUPS AT COMPLETION OF' DAY POSTPARTUM 4a 4b 7 MF MF MF 14 MF 21 MF TOTAL IMPLANTATIONS N MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY 13726 13727 13728 13731 13734 13735 13736 13737 23 13 0 13 4 23 14 0 14 7 23 15 1 16 7 ACCIDENTAL DEATH ON DAY 15 OF GESTATION 23 13 0 13 7 23 12 0 12 3 c 13 0 13 10 c 16 0 16 5 9 7 8 6 9 3 11 49 77 76 76 39 10 3 5 10 46 55 55 55 37 73 55 46 55 55 55 37 73 55 46 55 55 55 37 73 55 46 55 55 55 37 73 55 14 16 16 15 14 15 16 MATERNAL DOSAGE GROUP II LOW DOSAGE 0 .1 MG/KG/DAY d 13739 13740 13741 13744 13745 13746 13748 13749 23 23 23 c c 23 23 23 16 0 16 909 16 0 16 14 0 14 12 0 12 13 1 14 14 0 14 808 97 45 79 4 10 75 85 68 35 97 45 79 4 10 74 85 68 35 55 45 55 46 44 55 55 35 55 45 55 46 44 55 55 35 55 45 55 46 44 55 55 35 55 45 55 46 44 55 55 35 16 16 16 15 13 17 15 11 M - MALE F = FEMALE a. Number of live pups preculling. b. Number of live pups postculling. c. Delivery observations were not recorded, values excluded from group averages. d. As a result of an error in calculation, which resulted in an error in test article preparation, 2 mg/kg/day on days 1 through 4 of study. rats were dosed with 418-015: PAGE B-49 001083 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 27 (PAGE 2): NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA FO GENERATION FEMALE RATS/F1 GENERATION LITTERS MATERNAL DOSAGE GROUP III HIGH DOSAGE 1. 6 MG/KG/DAY a RAT/ LITTER NUMBER DURATION OP GESTATION (DAYS) N LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN NNN 1 MF NUMBER OF LIVE PUPS AT COMPLETION OF DAY POSTPARTUM 4b 4C 7 MF MF MF 14 MF 21 MF TOTAL IMPLANTATIONS N 13751 13752 13753 13754 13755 13756 13758 13759 23 22 22 d N0T PREGNANT 22 22 22 13 (1) 15 14 11 13 15 16 0 0 0 0 0 0 0 13 15 14 11 13 15 16 75 69 77 47 76 96 10 6 7S 59 77 47 66 96 10 6 55 55 55 46 55 55 55 55 55 55 46 55 55 55 55 55 55 46 55 55 55 55 55 55 46 55 55 55 17 17 16 11 14 17 16 M = MALE F = FEMALE ( ) NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. b. Number of live pups preculling. c. Number of live pups postculling. d. Delivery observations were not recorded, values excluded from group averages. rats were dosed with 418-015: PAGE B-50 001084 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 28 (PAGE 1): PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M FT DAY 4 M PT DAY 7 M FT DAY 14 M FT DAY 21 M FT MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY 13726 13727 13728 13731 13734 13735 13736 13737 7.0 6.3 6.5 9.8 9.2 9.4 15.4 6.2 6.0 6.1 9.4 9.0 9.2 15.2 7.0 6.3 6.6 10.2 9.6 9.9 15.8 ACCIDENTAL DEATH ON DAY 15 OF GESTATION 6.3 5.7 6.0 9.0 8.3 8.7 15.3 6.4 5.8 6.0 9.0 8.4 8.5 14.0 7.3 6.8 7.2 9.6 9.1 9.4 14.9 6.5 6.1 6.2 7.4 6.9 7.0 11.9 14.7 14.1 14.9 13.9 12.2 14.3 11.5 15.0 14.7 15.3 14.6 12.8 14.7 11.7 31.2 30.4 30.8 30.3 28.7 29.5 33.3 31.7 32.5 29.6 29.7 30.8 28.7 28.2 27.2 29.0 27.9 28.9 28.0 30.3 28.3 50.7 48.3 49.3 48.6 48.0 48.3 55.0 51.8 53.4 44.3 46.5 46.4 45.6 41.1 43.2 45.6 45.1 42.7 44.2 46.2 45.4 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a 13739 13740 13741 13744 13745 13746 13748 13749 6.4 6.2 6.3 7.8 7.5 7.7 11.6 11.6 11.6 25.9 26.2 26.0 42.8 42.2 42.5 7.3 6.6 6.9 10.6 9.6 10.0 15.6 13.8 14.6 32.4 29.9 31.0 51.8 47.2 49.3 6.4 6.0 6.2 9.4 9.2 9.3 16.0 15.3 15.7 32.6 31.6 32.1 49.9 47.7 48.8 6.8 6.4 6.5 7.2 6.9 7.0 11.5 11.1 11.3 31.6 31.0 31.2 46.0 44.0 44.8 5.7 5.1 5.4 6.5 6.3 6.4 11.3 10.8 11.0 28.8 27.8 28.3 50.2 48.6 49.4 6.9 6.5 6.7 9.0 8.3 8.8 14.2 13.5 13.8 26.9 25.3 26.1 47.3 46.6 47.0 7.0 6.5 6.7 8.7 8.4 8.5 13.1 13.0 13.0 30.0 28.5 29.2 48.2 45.2 46.7 7.3 6.9 7.1 11.0 10.4 10.6 15.7 14.7 15.0 32.6 30.9 31.5 54.1 49.9 51.5 M MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY = DAY POSTPARTUM ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. 418-015:PAGE B-51 001085 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 28 (PAGE 2) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS RAT/ LITTER NUMBER DAY 1 M FT DAY 4 M FT DAY 7 M FT DAY 14 M FT DAY 21 M FT MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a 13751 13752 13753 13754 13755 13756 13758 13759 7.3 6.6 7.0 10.0 8.9 9.5 15.0 13.4 14.2 30.9 28.0 29.4 45.3 48.5 46.9 6.1 S .9 6.0 8.7 8.0 8.3 13.5 12.3 12.9 26.7 25.8 26.2 42.4 40.0 41.2 6.5 6.4 6.5 8.6 8.7 8.7 13.1 13.6 13.3 28.6 28.7 28.6 45.4 45.2 45.3 7.1 6.8 6.9 8.6 8.6 8.6 14.2 13.9 14.0 29.3 28.9 29.1 47.9 46.0 46.8 NOT PREGNANT 6.1 5.7 5.9 7.9 7.3 7.6 10.8 10.3 10.5 23.7 20.8 22.3 38.5 35.3 36.9 5.5 5.6 5.6 7.1 7.2 7.1 11.6 11.8 11.7 24.3 24.9 24.6 38.9 39.0 39.0 6.0 5.6 5.8 8.0 7.5 7.8 12.9 12.4 12.7 26.4 25.3 25.8 42.0 40.2 41.1 M MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY - DAY POSTPARTUM ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015: PAGE B-52 001086 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 29 (PAGE 1): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS pup 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER # MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 1 13726 13727 13728 13731 13734 13735 13736 13737 7.6 6.9 6.6 7.0 6.2 6.1 6.4 6.3 6.0 5.8 6.4 7.2 6.1 6.3 6.4 6.1 6.1 6.4 6.3 6.2 5.8 6.1 5.9 6.1 5.7 6.2 6.0 7.1 6.9 6.9 7.2 7.4 6.4 7.2 6.3 4.5 7.1 6.4 6.1 6.8 6.4 7.0 FS ACCIDENTAL DEATH ON DAY 15 OF GESTATION 6.4 6.3 5.5 6.8 6.2 6.4 6.8 6.0 5.7 5.6 6.0 5.3 5.5 6.3 7.0 5.9 6.3 6.2 6.0 5.6 6.0 5.6 5.7 5.0 5.9 7.7 7.6 6.6 7.6 7.6 6.9 7.7 7.4 7.2 7.1 7.0 6.9 6.4 6.8 6.3 6.2 6.8 6.3 6.4 5.7 6.0 6.1 6.1 6.7 6.1 6.0 5.9 5.8 5.9 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a POSTPARTUM DAY 1 13739 13740 13741 13744 13745 13746 13748 13749 6.3 6.8 5.7 5.9 6.7 6.2 6.8 6.3 6.5 6.1 6.2 6.4 6.3 6.4 6.1 6.0 7.2 7.8 6.8 7.5 6.8 6.6 6.6 6.9 6.2 6.1 6.1 6.7 6.7 6.3 6.5 6.2 5.6 6.2 6.2 5.7 6.3 6.0 5.7 6.4 6.3 7.0 7.1 6.8 6.5 6.0 6.2 6.8 6.4 6.3 6.0 6.2 6.8 6.5 6.6 5.8 5.8 5.8 5.7 5.8 5.7 5.1 4.0 5.3 5.4 5.4 5.5 6.6 6.8 7.2 7.4 6.9 6.8 7.5 5.9 MS 6.6 6.0 6.2 6.7 6.9 7.3 7.2 7.6 6.6 6.8 6.6 6.6 7.0 6.9 6.6 6.2 5.8 6.0 6.6 7.3 7.5 7.1 6.6 6.9 6.8 7.0 7.3 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. 20 418-015: PAGE B-53 001087 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 2): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP ft 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER ft MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a POSTPARTUM DAY 1 13751 13752 13753 13754 13755 13756 13758 13759 7.0 7.9 7.2 7.0 7.6 7.4 7.2 6.3 6.6 6.4 6.6 7.0 FD 1 4.1 6.5 6.2 6.8 6.4 6.6 6.0 6.0 5.2 5.9 6.0 6.1 6.4 5.5 5.8 6.9 6.8 7.0 6.2 6.8 5.5 6.5 6.8 6.6 6.3 6.2 6.2 7.1 6.0 7.0 7.4 7.0 7.1 6.8 6.6 7.0 7.1 6.7 6.6 7.1 NOT PREGNANT 6.1 6.4 5.8 5.9 6.0 6.2 6.2 5.7 6.3 5.7 5.4 5.5 5.7 5.4 5.7 5.4 5.6 5.5 5.6 5.5 5.3 MA 5.5 5.4 5.3 6.0 5.7 6.0 5.7 6.1 6.2 6.2 6.2 4.9 6.5 5.9 6.1 6.1 5.2 5.9 4.6 5.8 5.9 6.0 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, 2 mg/kg/day on days 1 through 4 of study. rats were dosed with 20 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 3): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP ft 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER 0 MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 4 (PRECULLING) 13726 13727 13728 13731 13734 13735 13736 13737 9.7 9.2 10.5 9.8 8.9 9.9 9.2 9.2 9.0 9.5 9.2 9.4 9.0 9.5 9.4 9.1 9.4 9.2 9.7 9.4 8.5 9.4 8.8 9.2 9.1 9.2 8.9 10.3 10.6 9.9 10.0 10.4 9.9 10.4 10.3 9.8 9.3 9.0 9.0 10.0 FD 3 FM 2 FS ACCIDENTAL DEATH ON DAY 15 OF GESTATION 9.0 9.2 9.5 8.8 9.6 9.3 7.8 8.9 7.8 8.8 8.6 7.1 8.4 9.4 9.0 8.5 8.7 8.8 7.9 8.3 8.7 8.7 8.5 7.2 8.4 9.1 8.8 9.6 9.8 10.1 8.8 10.0 9.1 10.2 10.1 9.6 8.4 9.3 7.6 7.6 7.2 6.9 7.7 7.1 6.9 6.9 7.5 7.1 6.8 7.0 5.7 6.7 7.0 FM 4 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a POSTPARTUM DAY 4 (PRECULLING) 13739 13740 13741 13744 13745 13746 13748 13749 8.1 8.4 8.5 7.9 7.7 7.2 7.8 7.5 7.4 7.9 7.7 7.3 7.9 7.0 7.4 7.3 10.7 10.8 10.2 10.9 9.5 9.4 9.7 9.5 9.8 9.7 9.1 9.9 8.8 9.0 9.2 10.2 8.6 9.3 9.8 9.8 8.3 9.8 9.5 8.2 9.4 6.1 7.5 7.5 7.5 7.7 7.5 6.0 7.0 6.7 6.8 7.4 6.7 5.9 7.0 6.6 5.8 6.5 6.8 6.6 6.8 6.6 6.3 6.2 6.4 6.3 FD 2 9.3 9.0 8.6 9.2 9.6 8.8 9.7 8.2 MS 8.4 9.0 9.1 7.4 7.6 9.3 9.7 8.8 7.8 8.5 7.9 8.3 8.1 7.9 9.0 8.9 9.3 7.1 8.6 10.9 11.2 10.8 10.6 10.8 10.2 10.2 10.4 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. rats were dosed with 418-015: PAGE B-55 680TOO PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 4): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP If 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER If MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY POSTPARTUM DAY 4 (PRECULLING) 13151 13752 13753 13754 13755 13756 13758 13759 10.1 10.1 10.0 9.6 10.0 10.5 9.8 9.0 9.2 8.1 9.8 8.2 FD 1 9.2 7.6 8.5 8.9 9.1 MD 4 7.1 8.1 8.1 8.6 8.1 7.0 8.3 8.8 8.3 7.7 8.8 9.2 9.4 8.8 . 8.4 8.3 8.2 9.2 8.9 8.3 8.4 8.4 9.6 8.4 8.9 8.5 8.8 9.6 8.1 9.2 8.7 8.8 7.7 8.0 NOT PREGNANT 8.2 7.7 7.8 8.0 8.0 7.8 MM 3 6.6 6.9 7.3 7.0 7.4 8.5 7.1 6.6 7.1 7.7 7.1 7.4 7.3 6.9 6.5 7.5 6.9 7.2 6.7 7.7 6.9 8.0 8.9 8.3 6.6 8.3 7.4 8.2 8.8 8.0 8.0 5.9 8.0 8.2 7.3 7.6 8.1 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015: PAGE B-56 001090 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 5) : PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP tt 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER ft MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 4 (POSTCULLING) 13726 13727 13728 13731 13734 13735 13736 13737 9.7 9.2 10.5 9.8 FC 4 9.9 9.2 9.5 MC 4 9.1 9.4 9.2 9.7 MC 4 10.3 10.6 9.9 MC 4 MC 4 9.9 10.4 ACCIDENTAL DEATH ON DAY 15 OF GESTATION 9.0 9.2 MC 4 8.8 9.6 9.3 MC 4 9.4 9.0 8.5 8.7 FC 4 7.9 8.3 MC 4 MC 4 9.6 MC 4 10.1 8.8 10.0 7.6 7.6 7.2 6.9 7.7 7.1 6.9 9.2 FC 4 10.3 8.9 8.7 9.1 FC 4 FC 4 9.4 FC 4 FC 4 8.7 10.2 7.5 9.5 8.8 9.3 8.8 8.5 10.1 7.1 9.2 9.2 9.0 8.6 7.2 9.6 FC 4 FC 4 9.1 9.0 7.1 FC 4 8.4 7.0 9.0 FC 4 10.0 8.4 9.3 FC 4 8.9 FD 3 FC 4 FM 2 FC 4 FS FM 4 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a POSTPARTUM DAY 4 (POSTCULLING) 13739 13740 13741 13744 13745 13746 13748 13749 MC 4 10.7 MC 4 6.1 MC 4 MC 4 9.3 10.9 MC 4 10.8 9.1 7.5 MC 4 MC 4 9.7 11.2 MC 4 10.2 9.9 7.5 6.5 8.6 8.8 10.8 7.9 10.9 8.8 7.5 MC 4 9.2 7.8 10.6 MC 4 9.5 MC 4 7.7 6.6 9.6 8.5 10.8 7.2 9.4 9.2 7.5 6.8 8.8 MC 4 10.2 7.8 9.7 10.2 6.0 6.6 MC 4 FC 4 10.2 7.5 9.5 8.6 7.0 6.3 8.2 8.1 10.4 7.4 9.8 9.3 FC 4 6.2 MS FC 4 7.9 FC 4 6.8 6.4 8.4 9.0 7.7 FC 4 7.4 6.3 9.0 FC 4 7.3 8.3 FC 4 FD 2 9.1 9.3 FC 4 9.8 FC 4 7.4 7.1 7.0 PC 4 FC 4 7.6 8.6 7.4 FC 4 FC 4 9.4 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE. U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), X-OTHER NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015:PAGE B-57 001091 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 29 (PAGE 6): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS pup n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 RAT/ LITTER * MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY POSTPARTUM DAY 4 (POSTCULLING) 13751 13752 13753 13754 13755 13756 13758 13759 MC 4 10.1 MC 4 9.6 10.0 10.5 9.8 9.0 9.2 8.1 9.8 8.2 FD 1 9.2 7.6 8.5 8.9 9.1 MD 4 FC 4 FC 4 8.1 FC 4 FC 4 7.0 8.3 8.8 8.3 7.7 8.8 MC 4 9.4 MC 4 8.4 8.3 FC 4 9.2 8.9 8.3 FC 4 8.4 9.6 8.4 8.9 8.5 8.8 9.6 8.1 9.2 8.7 8.8 7.7 FC 4 NOT PREGNANT 8.2 MC 4 7.8 8.0 8.0 7.8 MM 3 6.6 6.9 7.3 7.0 7.4 FC 4 MC 4 MC 4 7.1 MC 4 7.1 7.4 7.3 MC 4 6.5 7.5 6.9 7.2 FC 4 7.7 6.9 MC 4 8.9 8.3 MC 4 MC 4 MC 4 8.2 8.8 8.0 MC 4 FC 4 8.0 8.2 7.3 7.6 8.1 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), X-OTHER NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015: PAGE B-58 001092 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 29 (PAGE T): <BUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER # MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 7 13726 13727 13728 13731 13734 13735 13736 13737 15.3 15.1 16.6 14.4 FC 4 14.7 15.1 15.6 MC 4 14.7 15.4 14.9 15.5 MC 4 15.1 15.6 15.9 MC 4 MC 4 16.0 16.2 ACCIDENTAL DEATH ON DAY 15 OF GESTATION 15.6 15.6 MC 4 14.5 15.1 15.6 MC 4 14.2 13.2 14.5 11.7 FC 4 10.7 13.9 MC 4 MC 4 15.6 MC 4 15.9 14.6 13.3 12.9 13.0 11.1 10.6 12.0 12.6 11.7 14.3 FC 4 15.6 12.6 11.2 15.1 FC 4 FC 4 14.6 FC 4 FC 4 12.0 15.9 11.3 14.5 14.7 14.8 14.4 13.3 13.8 10.5 15.0 13.7 15.6 14.3 12.8 14.8 FC 4 FC 4 13.4 14.2 13.6 FC 4 14.5 11.4 14.6 FC 4 14.4 14.7 13.5 FC 4 14.3 FD 3 FC 4 FM 2 FC 4 FS FM 4 MATERNAL DOSAGE GROUP II 0.1 MG/KG/DAY a POSTPARTUM DAY 7 13739 13740 13741 13744 13745 13746 13748 13749 MC 4 16.1 MC 4 12.0 MC 4 MC 4 12.7 15.5 MC 4 14.7 15.4 11.9 MC 4 MC 4 14.0 15.4 MC 4 15.2 15.9 10.3 11.2 14.1 12.8 16.1 11.4 16.2 16.9 11.7 MC 4 14.3 10.9 14.2 MC 4 14.4 MC 4 11.1 11.8 14.2 15.1 14.4 12.3 13.6 16.4 11.6 11.0 15.3 MC 4 15.0 12.2 13.1 15.5 12.2 11.2 MC 4 FC 4 14.4 11.4 13.8 14.8 11.2 10.8 13.2 13.1 15.3 10.8 13.9 15.9 FC 4 11.1 MS FC 4 10.9 FC 4 10.6 10.6 11.9 13.6 12.4 FC 4 10.0 10.7 12.4 FC 4 10.8 14.4 FC 4 FD 2 14.4 10.2 FC 4 14.8 FC 4 14.9 14.5 12.5 FC 4 FC 4 13.8 13.5 11.3 FC 4 FC 4 16.6 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED). X-OTHER NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. 20 418-015: PAGE B-59 001093 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 8): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP tt 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER * MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a POSTPARTUM DAY 7 13751 13752 13753 13754 13755 13756 13758 13759 MC 4 15.7 MC 4 14.0 14.0 12.1 13.1 13.2 MC 4 13.5 14.4 14.7 NOT PREGNANT 13.0 MC 4 12.3 MC 4 MC 4 11.5 MC 4 12.5 12.4 15.2 14.2 14.1 14.0 8.8 MC 4 MC 4 15.2 13.3 MC 4 14.4 11.6 11.5 MC 4 14.2 MD 4 13.2 14.1 8.4 11.8 MC 4 14.8 FC 4 11.8 13.7 MM 3 11.4 12.6 13.4 FC 4 FC 4 12.3 10.8 MC 4 13.2 13.3 10.4 14.4 15.0 8.7 12.0 14.0 13.7 FC 4 12.5 13.8 12.2 FC 4 13.9 FC 4 11.0 11.0 12.6 11.6 MC 4 FC 4 14.4 12.9 FC 4 9.8 12.1 12.9 FD 1 13.1 12.8 12.9 14.2 FC 4 FC 4 11.3 11.5 12.7 12.4 11.2 12.2 12.7 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 20 418-015: PAGE B-60 001094 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 9) : PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP It 1 2 3 4 5 6 7 B 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 14 13726 13727 13728 13731 13734 13735 13736 13737 31.2 29.8 31.1 32.9 FC 4 30.4 30.4 29.8 MC 4 30.5 29.0 31.7 30.5 MC 4 32.8 33.6 33.0 MC 4 MC 4 33.9 33.0 ACCIDENTAL DEATH ON DAY 15 OF GESTATION 30.7 30.3 MC 4 29.8 28.1 29.2 MC 4 30.8 30.0 28.4 28.3 FC 4 27.7 24.5 MC 4 MC 4 32.2 MC 4 32.1 29.1 29.8 30.1 29.7 26.3 28.2 29.0 27.9 27.5 29.5 FC 4 32.8 28.6 30.1 30.2 FC 4 FC 4 28.9 FC 4 FC 4 27.7 31.6 27.7 30.6 27.5 30.8 31.3 26.3 31.0 30.0 31.1 29.3 30.0 28.3 26.1 29.1 FC 4 FC 4 28.6 32.9 24.1 FC 4 28.4 26.4 30.6 FC 4 31.8 28.9 29.6 FC 4 29.0 FD 3 FC 4 FM 2 FC 4 FS FM 4 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a POSTPARTUM DAY 14 13739 13740 13741 13744 13745 13746 13748 13749 MC 4 31.7 MC 4 31.9 MC 4 MC 4 30.7 33.1 MC 4 31.3 32.9 31.3 MC 4 MC 4 26.9 32.5 MC 4 33.5 33.4 28.7 28.7 27.4 32.4 32.2 25.0 33.3 33.8 34.5 MC 4 26.5 29.6 29.8 MC 4 29.8 MC 4 32.3 29.2 26.6 30.3 30.0 26.9 30.8 31.2 27.5 28.4 27.5 MC 4 31.9 25.4 30.2 31.6 31.5 28.7 MC 4 FC 4 32.8 26.9 28.8 31.4 33.2 28.5 26.6 30.3 29.9 25.5 29.7 33.9 FC 4 28.1 MS FC 4 25.9 FC 4 28.9 26.5 24.6 29.4 27.0 FC 4 32.6 28.2 26.9 FC 4 27.0 30.3 FC 4 FD 2 24.6 29.9 FC 4 33.0 FC 4 26.5 28.1 24.9 FC 4 FC 4 24.1 24.7 26. 0 FC 4 FC 4 29.6 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 tng/kg/day on days 1 through 4 of study. rats were dosed with 20 418-015.PAGE B-61 001095 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 10): PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP It 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER It MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a POSTPARTUM DAY 14 13751 13752 13753 13754 13755 13756 13758 13759 MC 4 32.0 MC 4 28.6 26.4 27.4 29.8 29.7 MC 4 29.9 30.2 28.2 NOT PREGNANT 18.5 MC 4 24.7 MC 4 MC 4 26.0 MC 4 26.5 27.9 30.9 25.7 29.0 28.8 27.3 MC 4 MC 4 31.2 25.3 MC 4 29.9 28.5 25.6 MC 4 30.6 MD 4 27.8 30.2 19.6 23.8 MC 4 29.6 FC 4 26.7 29.0 MM 3 22.3 26.5 28.4 FC 4 FC 4 28.7 19.5 MC 4 25.7 27.6 26.2 29.4 27.2 26.2 24.0 25.4 30.0 FC 4 27.8 28.6 21.4 26.2 MC 4 26.3 FC 4 29.0 FC 4 17.7 23.7 FC 4 27.8 27.0 FC 4 19.3 26.6 23.4 FD 1 26.2 29.6 FC 4 FC 4 25.1 23.0 27.6 24.9 25.2 26.5 23.3 26.9 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER* INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, 2 mg/kg/day on days 1 through 4 of study. rats were dosed with 20 418-015: PAGE B-62 001096 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 29 (PAGE 11) : PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP ft 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER ft MATERNAL DOSAGE GROUP i VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY POSTPARTUM DAY 21 13726 13727 13728 13731 13734 13735 13736 13737 49.7 49.6 52.8 50.6 FC 4 48.7 48.0 48.2 MC 4 48.4 48.9 52.3 45.1 MC 4 54.4 55.6 54.1 MC 4 MC 4 55.0 55.9 ACCIDENTAL DEATH ON DAY 15 OF GESTATION 45.8 46.3 MC 4 41.8 42.4 45.4 MC 4 48.2 45.3 46.1 44.3 FC 4 42.9 38.3 MC 4 MC 4 47.8 MC 4 48.3 45.9 45.6 46.7 48.5 44.4 41.2 47.4 44.9 42.4 48.1 FC 4 52.2 42.1 41.1 48.7 FC 4 FC 4 47.7 FC 4 FC 4 43.9 45.2 45.5 47.5 48.2 52.4 41.0 48.7 43.4 49.0 48.4 47.9 53.4 43.3 43.6 45.7 FC 4 FC 4 47.6 50.5 40.4 FC 4 45.1 43.6 49.3 FC 4 50.4 38.6 46.0 FC 4 48.4 FD 3 FC 4 FM 2 FC 4 FS FM 4 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a POSTPARTUM DAY 21 13739 13740 13741 13744 13745 13746 13748 13749 MC 4 48.6 MC 4 45.0 MC 4 MC 4 48.5 53.8 MC 4 53.7 51.4 46.6 MC 4 MC 4 47.6 55.4 MC 4 54.2 49.0 45.9 49.7 50.9 44 .B 53.2 43.6 50.9 49.2 46.4 MC 4 47.7 49.7 47.3 MC 4 47.5 MC 4 41.9 52.2 43.3 50.4 51.0 46.1 44.6 51.0 42.6 49.9 47.6 MC 4 52.5 40.5 49.7 49.0 44.2 49.0 MC 4 FC 4 50.9 42.2 47.6 46.7 47.1 48.3 47.1 40.8 47.7 41.5 46.4 49.5 FC 4 47.9 MS FC 4 39.2 FC 4 46.1 49.2 42.4 45.1 41.8 FC 4 41.8 48.8 46.4 FC 4 44.1 51.9 FC 4 FD 2 50.4 47.2 FC 4 45.1 FC 4 50.4 46.7 44.0 FC 4 FC 4 43.3 46.2 41.8 FC 4 FC 4 45.5 ALL WEIGHTS WERE RECORDED IN GRAMS (G). MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. rats were dosed with 20 418-015: PAGE B-63 001097 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 29 (PAGE 12) : PUP BODY WEIGHTS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP || 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RAT/ LITTER K MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a POSTPARTUM DAY 21 13751 13752 13753 13754 13755 13756 13758 13759 MC 4 46.7 MC 4 41.3 46.4 42.5 46.5 45.3 MC 4 46.8 50.4 46.4 NOT PREGNANT 39.7 MC 4 42.4 MC 4 MC 4 39.6 MC 4 41.9 44.1 48.4 40.5 45.6 48.1 33.8 MC 4 MC 4 43.4 41.5 MC 4 46.8 33.4 38.7 MC 4 44.0 MD 4 47.8 44.2 43.0 39.0 MC 4 44.1 FC 4 41.9 44.9 MM 3 38.4 39.8 51.6 FC 4 FC 4 47.5 33.9 MC 4 40.8 48.3 40.4 47.5 46.1 41.6 39.0 43.2 46.3 FC 4 46.5 46.7 30.7 36.9 MC 4 50.9 FC 4 43.4 FC 4 34.1 39.0 FC 4 45.4 35.4 FC 4 36.4 40.7 41.8 FD 1 40.4 43.4 FC 4 FC 4 39.3 40.8 45.2 41.3 36.7 42.9 37.3 41.2 ALL WEIGHTS WERE RECORDED IN GRAMS (G) . MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS. FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 20 418-015: PAGE B-64 oo o 00 PROTOCOL 418-0X5: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 30 (PAGE 1): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS pup 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 RAT/ LITTER tt MATERNAL DOSAGE GROUP I VEHICLE CONTROL 0 (VEHICLE) MG/KG/DAY 13726 13727 13728 13731 13734 13735 13736 13737 M A M A M A M A FC 4 F A F A F A FC 4 M A MC 4 M A M A M A M A MC 4 FC 4 F A M A M A M A MC 4 MC 4 M A M A F A FC 4 ACCIDENTAL DEATH ON DAY 15 OF GESTATION M A M A MC 4 M A M A M A MC 4 F A FC 4 M A M A M A F A FC 4 F A F A F A F A MC 4 MC 4 M A MC 4 M A M A M A M A M A M A M A M A M A M A F A F A FC 4 F A F A F A FC 4 F A F A F A F A FC 4 F A F A F A F A F A FD 3 FM 2 F S FA FA FA FA F A F A FC 4 MA FA FA FA F A FC 4 F A FC 4 FC 4 FC 4 FM 4 MATERNAL DOSAGE GROUP II LOW DOSAGE 0.1 MG/KG/DAY a 13739 13740 13741 13744 13745 13746 13748 13749 MC 4 MC 4 MC 4 M A MC 4 M A M A MA MA M A MA FA FA FA MC 4 M A M A M A MC 4 M A M A MA MA MA MA FA FA FA MC 4 MC 4 M A MC 4 M A M A M A MC 4 MC 4 M A M A M A M A MC 4 M A M A M A M A M A MC 4 FC 4 MA MA MA FA FA FA FA M A M A F A F A F A FC 4 F A F A FC 4 FA FA F A F A FC 4 FC 4 F A F A FC 4 FC 4 F A F A FC 4 F A F A FC 4 FC 4 FC 4 F A F A F A F A FD 2 M A M S FA FA FA FA FA F A FC 4 F A FC 4 F A F A F A FA FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, 0.125 mg/kg/day on days 1 through 4 of study. rats were dosed with 418-015:PAGE B-65 001099 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 30 (PAGE 2): PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS PUP k 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 RAT/ LITTER # MATERNAL DOSAGE GROUP III HIGH DOSAGE 1.6 MG/KG/DAY a 13751 MC 4 M A MC 4 M A M A M A M A F A F A F A F A F A FD 1 13752 M A M A M A M A M A MO 4 FC 4 FC 4 F A FC 4 FC 4 F A F A F A F A 13753 M A M A MC 4 M A MC 4 M A M A FC 4 F A F A F A FC 4 F A F A 13754 M A M A M A M A F A F A F A F A F A F A FC 4 13755 NOT PREGNANT 13756 M A MC 4 M A M A M A M A MM 3 F A F A F A F A F A FC 4 13758 MC 4 MC 4 M A MC 4 M A M A M A MC 4 M A F A F A F A FC 4 F A F A 13759 MC 4 M A M A MC 4 MC 4 MC 4 M A M A M A MC 4 FC 4 F A F A F A F A F A FIRST LETTER -- M-MALE, F-FEMALE SECOND LETTER -- A-ALIVE, S-STILLBORN, D-DIED, C-CULLED, M-MISSING (PRESUMED CANNIBALIZED), NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED. a. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015:PAGE B-66 001100 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OP PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 31 (PAGE 1): CLINICAL OBSERVATIONS FROM BIRTH TO DAY 21 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY(S) POSTPARTUM OBSERVATION a I 0 (VEHICLE) - - - II 0 .lb 13746 7-21 1/10 PUPS: TIP OF TAIL, BLACK. C III 1.6b - ' " a. Tabulation restricted to adverse observations; all other pups appeared normal. b. As a result of an error in calculation, which resulted in an error in test article preparation. Group II rats were dosed with 0.125 mg/kg/day and Group III rats were dosed with 2 mg/kg/day on days I through 4 of study. c. Observation confirmed at necropsy. 418-015:PAGE B-67 001101 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR1S STUDY NUMBER: T-629S.14) TABLE 32 (PAGE 1): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY(S) POSTPARTUM OBSERVATIONS a I 0 (VEHICLE) 13726 13727 4, 21 4. 21 ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. 13728 1 3 4, 21 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL. ALL PUPS APPEARED NORMAL. 13734 13735 13736 13737 4, 21 4 , 21 4, 21 4 , 21 ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table 31) for external observations confirmed at necropsy. 418-015: PAGE B-68 001102 PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-629S.14) TABLE 32 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY(S) POSTPARTUM OBSERVATIONS a II 0.1b 13739 13740 13741 13744 4, 21 21 4, 21 4, 21 ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. 13745 2 4, 21 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. ALL PUPS APPEARED NORMAL. 13746 1 4, 21 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. ALL PUPS APPEARED NORMAL. 13748 13749 4, 21 21 ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table 31) for external observations confirmed at necropsy. b. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 0.125 mg/kg/day on days 1 through 4 of study. 418-015: PAGE B-69 o CO PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS (SPONSOR'S STUDY NUMBER: T-6295.14) TABLE 32 (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL. DATA - FI GENERATION PUPS MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTER NUMBER DAY (S) POSTPARTUM OBSERVATIONS a III 1.6b 13751 1 4, 21 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL. ALL PUPS APPEARED NORMAL. 13752 4 21 1 PUP: FOUND DEAD. NO MILK IN STOMACH. TISSUES APPEARED NORMAL. ALL OTHER PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL OTHER 13753 13754 13756 13758 13759 4, 21 4, 21 4, 21 4, 21 4, 21 ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. ALL PUPS APPEARED NORMAL. a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table 31) for external observations confirmed at necropsy. b. As a result of an error in calculation, which resulted in an error in test article preparation, rats were dosed with 2 mg/kg/day on days 1 through 4 of study. 418-015:PAGE B-70 oo I-* h* O A P P E N D IX C PROTOCOL AND AMENDMENT 001105 418-015:PAGE C-1 OPrimedica Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, PA 19044 Telephone: (215) 443-8710 Telefax: (215) 443-8587 PROTOCOL 418-015 S P O N S O R 'S S TU D Y NUM BER: T-6295 .14 STUDY TITLE: Oral (G avage) Pharmacokinetic Recovery Study of P F O S in Rats PURPOSE: The purpose of this study is to evaluate the pharmacokinetics o f P F O S in Fo generation and F1 generation rats during gestation and lactation following cessation of PFO S treatment of Crl:CDBR VA F/Plus fem ale rats at confirmed mating. TESTING FA CILITY: Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215) 443-8710 Telefax: (215)443-8587 STUDY DIRECTO R: Raymond G. York, Ph.D., DABT Associate Director of Research SPONSOR: 3M Corporate Toxicology 3M Center, Building 2 2 0 -2 E -0 2 St. Paul, Minnesota 55144-1000 STUDY M ONITOR: Marvin T. Case, D.V.M ., Ph.D. Telephone: (65 1 )7 3 3 -5 1 8 0 Telefax: (651)733-1773 ALTERNATE STUDY MONITOR: Andrew M. Seacat, Ph.D. Telephone: (651) 575-3161 Telefax: (651)733-1773 001106 418-015:PAGE C-2 Protocol 418-015 Page 2 REGULATORY CITATIO NS: U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detection of toxicity to reproduction for medicinal products. Federal Register, Septem ber 22, 1994, Vol. 59, No. 183. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministry of Health and W elfare (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, M H W Ordinance Number 21, March 26, 1997. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice. Official Journal of the European Communities: Legislation. 32 (No. L 315; 28 October): 1-17. REGULATORY CO M PLIANCE: This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. All changes or revisions of this protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. T h e Quality Assurance Unit (Q A U) will audit the protocol, the raw data and the report, and will inspect critical phases of the study in accordance with the Standard Operating Procedures of Argus Research Laboratories, Inc. T h e final report will include a statem ent signed by the Study Director that the report accurately reflects the raw data obtained during the performance of the study and that all applicable G LP regulations w ere followed in the conduct of the study. Should significant deviations from G LP regulations occur, each will be described in detail, together with how the deviation might affect the quality or integrity of the study. SCHEM ATIC OF STUDY DESIGN AND STUDY SCHEDULE: See A T T A C H M E N T 1 to the protocol. 001107 418-015:PAGE C-3 Protocol 418-015 Page 3 TE ST AR TICLE AND VEHICLE: Identification: Test Article: Name: Physical Description: Lot/Batch Number: Specific Gravity: Purity: Expiration Date: PFOS (Synonym: FC-95). Light-colored powder. 217. - 0.6. 98.9% . May 2000. Information on the identity, composition, strength and purity of the test article is on file with the Sponsor. Vehicle: 0.5% T w e e n 80 in Reverse Osmosis M em brane Processed Deionized W a te r (R.O . Deionized W ater). Supplier and lot identification of T w e e n 80 to be docum ented in the raw data. Neither the Sponsor nor the Study Director is aw are of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study. Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gloves, mask, appropriate eye protection and a uniform/lab coat are to be worn during formulation preparation and administration. T he M aterial Safety D ata S heet (M S D S ) is attached to the protocol (ATTA C H M EN T 2). Storage: Bulk Test Article: Vehicle Components: Prepared Vehicle: Prepared Formulations: Room temperature. Room temperature. Room temperature. Room temperature. All test article shipments to the Testing Facility should be addressed to the attention of Julian Gulbinski, M anager of Formulations, at the previously cited address and telephone number. Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. T he recipient should be notified in advance of shipment. ^,, 001108 418-015:PAGE C-4 Protocol 418-015 Page 4 FO RM ULATIO N: Frequency of Preparation: Formulations (suspensions) will be prepared daily at the Testing Facility. Data verifying the stability of the test article in the vehicle for 4 8 hours under the conditions of administration are on file with the Sponsor. Detailed preparation procedures are attached to this protocol (A T T A C H M E N T 3). Adjustm ent for Purity: The test article will be considered 100% pure for the purpose of dosage calculations. Testing Facility Reserve Sam ples: The Sponsor will reserve a sam ple (1 g) of each lot of the bulk test article used during the course of this study. T h e Testing Facility will reserve a sam ple (5 mL) of each lot of the vehicle components used during the course of this study. Sam ples will be stored under the previously cited conditions. ANALYSES: Samples additional to those described below m ay be taken if deem ed necessary during the course of the study. Bulk Test Article S am pling: No analyses of the bulk test article will be conducted during the course of this study. Information on the stability of the bulk test article is on file with the Sponsor. Analyses o f Prepared Form ulations: Hom ogeneity and stability of prepared formulations is on file with the Sponsor. However, records will be maintained to docum ent how the test article formulations w ere prepared. Concentration of Test Article Formulations: Concentration of the prepared formulations will be verified during the course of this study. Duplicate sam ples (2 mL each) will be taken from the first and last preparation on the day prepared. O ne sam ple of each set will be shipped for analysis; the remaining sam ples will be retained at the Testing Facility as backup sam ples. Backup sam ples will be stored frozen (-7 0 C or below) and discarded at the Testing Facility upon request of the Sponsor. 001109 418-015: PAGE C-5 Protocol 418-015 Page 5 Shipping Instructions: Sam ples to be analyzed will be shipped (frozen on dry ice) to: Kris J. Hansen, Ph.D. 3M Environmental Technology and Safety Services 935 Bush Avenue Building 2 -3 E -0 9 St. Paul, Minnesota 55133-3331 Telephone: (612)778 -60 18 Telefax: (612) 778-6176 T h e recipient will be notified in advance o f sam ple shipment. DISPOSITION: Prepared formulations will be discarded at the Testing Facility. All remaining bulk test article will be returned to the Study Monitor at the previously cited address upon completion of ail work with the test article. TEST SYSTEM: Species/Strain and Reason for Selection: The Cri:CDBR VAF/Plus (Sprague-Dawley) rat was selected as the Test System because: 1) this strain o f rat was used in the reproductive and developm ental toxicity studies: 2) historical data and experience exist at the Testing Facility'1'3'; and 3) the test article is pharmacologically active in the species and strain. N um ber: Initial population acclimated: Population selected for study: Body Weight and Aae: 36 virgin fem ale rats. 24 mated fem ale rats (8 per dosage group). Fem ale rats will be ordered to have body weights of 2 0 0 g to 2 2 5 g each at receipt, at which time they will be expected to be at least 6 0 days of age. Actual body weights will be recorded the day after receipt and will be docum ented in the raw data. T h e weight range will be included in the final report. Sex: Fem ale rats will be given the test article. M ale rats of the sam e source and strain will be used only as breeders and are not considered part of the Test System. O O lllO 418-015:PAGE C-6 Protocol 418-015 Page 6 Source: Charles River Laboratories, Inc. T h e rats will be shipped in filtered cartons by air freight and/or truck from Charles River Laboratories, Inc., to the Testing Facility. Identification: Fo Generation: Rats are permanently identified using M onel self-piercing e a r tags (G ey Band and Tag Co., Inc., No. M S P T 20101). M ale rats are given unique perm anent identification numbers upon assignment to the Testing Facility's breeder m ale rat population. Fem ale rats are assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study. F1 G eneration: Pups will not be individually identified during lactation; ail param eters will be evaluated in terms of the litter. ANIMAL HUSBANDRY: All cage sizes and housing conditions are in compliance with the Guide for the Care and Use o f Laboratory A n im a l. Housing: Fo Generation Rats/F1 Generation Litters: Fo generation rats will be individually housed in stainless steel, wire-bottomed cages, except during the cohabitation and postpartum periods. During cohabitation, each pair of rats will be housed in the male rat's cage. Beginning no later than day 2 0 of presumed gestation, Fo generation fem ale rats will be individually housed in nesting boxes, except during collection intervals for urine and fecal samples. During these collection intervals, the fem ale rats will be housed individually in m etabolism cages. Each dam and delivered litter will be housed in a common nesting box during the postpartum period. O O llll 418-015: PAGE C-7 Protocol 418-015 Page 7 Nesting Material: Nesting material (bed-o'cobs) will be provided. Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination are conducted annually and docum ented in the raw data. Room Air. Temperature and Humidity: The animal room is independently supplied with at least ten changes per hour of 100% fresh air that has been passed through 9 9 .9 7 % H E P A filters (Airo C le a n room). Room temperature will be maintained at 6 4 F (1 8 C ) to 7 9 F (2 6 C ) and monitored constantly. Room humidity will also be monitored constantly and m aintained a t 3 0 % to 70%. Light An automatically controlled 12-hour light: 12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours ES T. Diet: Rats will be given Certified Rodent D iet # 5 0 0 2 (PM I Nutrition International) available ad libitum from individual feeders. Water: W ater will be available ad libitum from individual bottles attached to the cages or from an automatic watering access system. All w ater will be from a local source and passed through a reverse osmosis m em brane before use. Chlorine will be added to the processed w ater as a bacteriostat; processed w ater is expected to contain no m ore than 1.2 ppm chlorine at the time of analysis. W ater is analyzed monthly for possible bacterial contamination and twice annually for possible chemical contamination. Contaminants: Neither the Sponsor nor the Study Director is aw are of any potential contam inants likely to be present in the certified diet, the drinking w ater or the nesting m aterial at levels that would interfere with the results of this study. Therefore, no analyses other than those routinely performed by the feed supplier or those mentioned in this protocol will be conducted. 001112 418-015: PAGE C-8 Protocol 418-015 Page 8 RANDOMIZATION AND COHABITATION. Upon arrival, male and fem ale rats will be assigned to individual housing on the basis of com puter-generated random units. After acclimation, 36 virgin fem ale rats will be selected for study on the basis of physical appearance and body weights recorded during acclimation. T he fem ale rats will be assigned to dosage groups (12 fem ale rats per dosage group) based on computer-generated (weight-ordered) randomization procedures and treated with either the vehicle or the test article for 4 2 days prior to cohabitation. W ithin each dosage group, consecutive order will be used to assign fem ale rats to cohabitation with breeder male rats, one m ale rat per fem ale rat. The cohabitation period will consist of a maximum of five days. Fem ale rats with sperm atozoa observed in a sm ear of the vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 of presumed gestation and assigned to individual housing. Eight m ated fem ale rats (those with confirmed evidence of mating) will be assigned to each dosage group. Any remaining fem ale rats with or without confirmed evidence of mating that were assigned to either of the treated groups or the control group prior to cohabitation will be sacrificed and discarded without further evaluation at the discretion of the Study Director and the Study Monitor. Day 1 of lactation (postpartum) is defined as the day of birth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after all pups in a litter are delivered and groomed by the dam ). On day 4 postpartum, litters will be culled to five male pups and five fem ale pups per litter, w here possible. Pups not selected for continued evaluation will be sacrificed via decapitation; the lungs (saved in Bouin's solution) and the liver (saved in neutral buffered 10% formalin) will be collected from the first ten culled pups from each dosage group (irrespective o f litter) determined to be at day 4 postpartum and preserved for possible future histopathological evaluation. Remaining culled pups will be sacrificed via decapitation and discarded without necropsy evaluation. ADMINISTRATION: Route and Reason for Choice: The oral (gavage) route was selected for use because: 1) this was the route of administration in the developm ental and reproductive toxicology studies; and 2) it is one of the possible routes of human exposure. 01113 418-015: PAGE C-9 Protocol 418-015 Page 9 Method and Frequency: Fo Generation Fem ale Rats: Fem ale rats will be given the test article once daily beginning 4 2 days prior to cohabitation until day 0 of presumed gestation (confirmed evidence of mating, such as observation of sperm atozoa in a sm ear of the vaginal contents or a copulatory plug in situ). Fem ale rats will not be given the test article or the vehicle on day 0 of presumed gestation. Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. F1 Generation P u d s : F1 generation pups will not be directly given the test article, but m ay be possibly exposed to the test article during maternal gestation (in utero exposure) or via maternal milk during the lactation period. Rationale for Dosage Selection: Dosages w ere selected on the basis of a previous study conducted with the test Article (Argus Research Laboratories, Inc., Protocol 418-008). Dosage Levels. Concentrations and Volumes: Dosage Group Number of Female Rats Dosage (mg/kg/day) 1 8 0 (Vehicle) II 8 0.1 III 8 1.6 Concentration (mg/mL) 0 0.02 0.32 Dosage Volume (mUkg) 5 5 5 Argus Batch Number B-418-015-A(Day.Month.Year) B-418-015-B(Day.Month Year) B-418-015-C(Day.Month.Year) The test article will be considered 100% pure for the purpose of dosage calculations. TESTS. ANALYSES AND MEASUREMENTS - Fo GENERATION: Viability: All Periods: At least twice daily. Clinical Observations and/or General Appearance: Acclimation Period: At least once. 001114 418-015:PAGE C-10 Protocol 418-015 Page 10 Dosage Period: Twice daily. Prior to administration and once approximately one hour postdosage. All O ther Periods: Once daily. Maternal Behavior Days 1, 4, 7, 10, 14 and 21 postpartum. Observed abnorm al behavior will be recorded daily. Clinical observations may be recorded more frequently than cited above, if deem ed appropriate by the Study Director and/or Study Monitor. Body Weights: Acclimation Period: At least once. Dosage Period: Daily. All O ther Periods: Daily. Sacrifice: Terminal weight. Feed C onsum ption V alues (recorded and tabulated): Acclimation Period: At least once. Dosage Period: W eekly to cohabitation. All Other Periods: Daily during presumed gestation and days 1, 4, 7, 10 and 14 postpartum. Feed consumption will not be tabulated after day 14 postpartum, when it is expected that pups will begin to consum e maternal feed. Feed consumption values m ay be recorded more frequently if it is necessary to replenish the feed. These intervals will not be tabulated. M ating Perform ance: Mating will be evaluated daily during the cohabitation period and confirmed by observation of sperm atozoa in a sm ear of the vaginal contents and/or a copulatory plug observed in situ. 001115 418-015: PAGE C-11 Protocol 418-015 Page 11 Natural Delivery: Fem ale rats will be evaluated fo r Duration of Gestation (day 0 of presumed gestation to the day the first pup is observed). Litter Size (defined as all pups delivered). Live Litter Size (live bom pups only). Pup Viability at Birth. Pharmacokinetic Sample Collection: Urine and Fecal Sam ples: Fem ale rats will be housed individually in metabolism cages for collection of urine and fecal samples for the following intervals: one day prior to initiation of cohabitation to the following morning and days 6 to 7, 14 to 15 and 20 to 21 of presumed gestation, as well as days 21 to 22 postpartum. Following each 24-hour collection interval, sam ples will be collected into centrifuge tubes, placed on dry ice and stored frozen (-7 0 C or below) until shipment for analysis. In the event that a dam begins to defiver before completion o f urine and fecal sam ple collection on day 2 0 to day 21 of presumed gestation, the dam will be removed from the metabolism cage and placed in a nesting box with sufficient bedding. Blood Sam ples: Blood samples will be collected from each of the maternal rats following removal from metabolism caging (prior to administration) on each of the following days: on the day cohabitation is initiated (prior to cohabitation), and on days 7, 15 and 21 of presumed gestation, as well as on days 14 and 2 2 postpartum. T h e tim e of blood collection will be recorded in the raw data. 001116 418-015:PAGE C-12 Protocol 418-015 Page 12 On all days of collection except day 22 postpartum, blood sam ples (approximately 1 mL each) will be collected from the orbital sinus. If necessary, w hole blood m ay be collected from an alternate site; if so, the alternate site will be docum ented in the raw data. O n day 22 postpartum, blood samples (approximately 4 mL each) will be collected via the inferior vena cava. Blood will be collected and transferred into serum separator tubes. T h e sam ples will be spun in a refrigerated centrifuge. T h e serum will be transferred into polypropylene tubes labeled with the study number, animal identification, date of collection, study day and collection timepoint. All sam ples will be immediately frozen on dry ice and maintained frozen (-7 0 C or below) until shipment to the Sponsor for analysis. Shipping Instructions: All sam ples will be maintained frozen (-7 0 C or below) until shipment for analysis. Sam ples will be shipped on frozen on dry ice via overnight mail. A packing list will be included with the sam ples and sent to Kris J. Hansen, Ph.D ., at the previously cited address. Both the recipient and the Study Monitor will be notified in advance of sam ple shipment. METHOD OF SACRIFICE - Fo GENERATION RATS: Rats will be sacrificed by carbon dioxide asphyxiation. NECROPSY - Fo GENERATION RATS: Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation (a table of random units will be used to select one control group rat from which all tissues exam ined at necropsy will be retained, in order to provide control tissues for any possible histopathological evaluations of gross lesions). Unless specifically cited below, all other tissues will be discarded. Rats Not Selected for Continued Evaluation: Any remaining fem ale rats with or without confirmed evidence of mating that w ere assigned to either of the treated groups or the control group prior to cohabitation will be sacrificed and discarded without further evaluation at the discretion of the Study Director and the Study Monitor. Rats Not Delivering a Litter: Rats that do not deliver a litter will b e sacrificed on day 2 5 of presum ed gestation and exam ined for gross lesions. Uteri will be stained with 10% am m onium sulfide to confirm the absence of implantation sites<5). 001H 7 418-015:PAGE C-13 Protocol 418-015 Page 13 Scheduled Sacrifice: On day 22 postpartum, following the final collection interval for urine and fecal samples and blood sam ple collection, fem ale rats will be sacrificed, and a gross necropsy of the thoracic, abdominal and pelvic viscera will be performed. T he num ber and distribution of implantation sites will be recorded. A liver section (right lateral lobe) from each dam will be collected, frozen and stored (-7 0 C or below) until shipment to the Sponsor for analysis. Dams with No Surviving Pups: Dams with no surviving pups will be sacrificed after the last pup is found dead, missing or presumed cannibalized. Prior to sacrifice, a blood sam ple (approximately 4 mL) will be collected from the maternal rat via the inferior vena cava and transferred into serum separator tubes. The sample will be spun in a refrigerated centrifuge. The serum will be transferred into a polypropylene tube labeled with the study number, animal identification, date of collection, study day and collection timepoint. The sam ple will be im m ediately frozen on dry ice and maintained frozen (-7 0 C or below) until shipment to the Sponsor for analysis. A gross necropsy of the thoracic, abdominal and pelvic viscera will be performed. A liver section (right lateral lobe) from each dam will be collected, frozen and stored (-7 0 C or below) until shipment to the Sponsor for analysis. Postpartum data for these dams will be excluded from summary tables. Rats Found Dead or Moribund: Rats that die or are sacrificed because of moribund condition, abortion or premature delivery will be exam ined for the cause of death or moribund condition on the day the observation is m ade. T he rats will be exam ined for gross lesions. A liver section (right lateral lobe) from each dam will be collected, frozen and stored (-7 0 C or below) until shipment to the Sponsor for analysis. Pregnancy status and uterine contents of female rats will be recorded. Aborted fetuses and/or delivered pups will be exam ined to the extent possible. Uteri of apparently nonpregnant rats will be stained with 10% am m onium sulfide to confirm the absence of implantation sites'5'. Shipping Instructions: All sam ples will be maintained frozen (-7 0 C or below) until shipm ent for analysis. Sam ples will be shipped frozen on dry ice via overnight mail. A packing list will be included with the sam ples and sent to Kris J. Hansen, Ph.D ., at the previously cited address. Both the recipient and the Study Monitor will be notified in advance of sample shipment. 001118 418-015: PAGE C-14 Protocol 418-015 Page 14 TESTS. ANALYSES AND MEASUREMENTS - F1 GENERATION: Viability: Postpartum Period: Litters will be observed for dead pups at least twice daily. The pups in each litter will be counted once daily. Clinical Observations and/or Generai Appearance: Postpartum Period: Once daily. Clinical observations m ay be recorded more frequently than cited above, if deem ed appropriate by the Study Director and/or the Study Monitor. Body Weights: Postpartum Period: Days 1 (birth), 4, 7, 14 and 21 postpartum. Sacrifice: Terminal weight. METHOD OF SACRIFICE - F1 GENERATION RATS: As previously cited for Fo generation rats. NECROPSY - F1 GENERATION RATS: Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation (a table of random units will be used to select one control group rat of each sex from which ail tissues exam ined at necropsy will be retained, in order to provide control tissues for any possible histopathological evaluations of gross lesions). Unless specifically cited below, all other tissues will be discarded. Caps and labeled tubes will be w eighed (combined weight, to the nearest .001 gram) before and after retention of pooled pup samples. T h e se weights will be docum ented in the raw data, and copies of these weights will be included with the packing list prior to shipment. 001119 418-015:PAGE C-15 Protocol 418-015 Page 15 Puds Found Dead on Day 1 Postpartum: Pups that die before examination of the litter for pup viability will be evaluated for vital status at birth. T he lungs will be removed and immersed in w ater. Pups with lungs that sink will be identified as stillborn; pups with lungs that float will be identified as iivebom, and to have died shortly after birth. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation. All lungs will be preserved in Bouin's solution for possible future evaluation. Puds Found Dead or Moribund on Davs 2 to 21 Postpartum: Pups found dead or sacrificed because of moribundity will be exam ined for gross lesions and for the cause of death or the moribund condition. Pups with gross lesions found on days 2 to 4 postpartum will be preserved in Bouin's solution for possible future evaluation; gross lesions of pups found on days 5 to 21 postpartum will be preserved in neutral buffered 10% formalin. For all pups found dead on days 2 to 4 postpartum, all lungs will be preserved in Bouin's solution for possible future evaluation. For all pups found dead on days 5 to 21 postpartum, all lungs will be preserved in neutral buffered 10% formalin for possible future evaluation. Pups Not Selected for Continued Observation - Dav 4 Postpartum: All pups culled on day 4 postpartum will be sacrificed via decapitation. All lungs and livers will be collected from the first ten pups culled (irrespective of litter) from each dosage group; the lungs will be individually retained in Bouin's solution, and the livers will be individually retained in neutral buffered 10% formalin for possible future evaluation. Remaining culled pups will be sacrificed and discarded without evaluation. Scheduled Sacrifice: On day 21 postpartum, blood samples will be collected from all remaining pups on study. Blood sam ples will be collected via the inferior ven a cava from each pup, pooled (per litter) and transferred into serum separator tubes. T h e sam ples will be spun in a refrigerated centrifuge. T h e serum will be transferred into polypropylene tubes labeled with the study number, animal identification, date of collection, study day and collection timepoint. All sam ples will be immediately frozen on dry ice and m aintained frozen (-7 0 C or below) until shipment to the Sponsor for analysis. The pups will be exam ined for gross lesions. T h e liver from each pup will be collected, pooled (per litter), frozen and stored (-7 0 C or below) until shipm ent to the Sponsor for analysis. 001120 418-015: PAGE C-16 Protocol 418-015 Page 16 Shipping Instructions: All samples will be maintained frozen (-7 0 C or below) until shipment for analysis. Sam ples will be shipped frozen on dry ice via overnight mail. A packing list will be included with the samples and sent to Kris J. Hansen, Ph.D., at the previously cited address. Both the recipient and the Study Monitor will be notified in advance of sam ple shipment. STATISTICAL EVALUATION: Averages and percentages will be calculated. Litter values will be used w here appropriate. Additional procedures and/or analyses m ay be performed, if deem ed appropriate. DATA ACQUISITION. VERIFICATION AND STORAGE: Data will be hand- and/or computer-recorded. Records will be reviewed by the Study Director and/or appropriate m anagem ent personnel within 21 days after generation. All original records will be stored in the archives of the Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing of the draft final report, after which time the Sponsor will be contacted to determine the disposition of these materials. 001121 418-015: PAGE C-17 Protocol 418-015 Page 17 RECO RDS TO BE M AINTAINED: Protocol and Amendments. Test Article, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatm ent (if prescribed by Staff Veterinarian). General Comments. Clinical Observations and/or General Appearance. Tissue and Sample Collection, Processing and Shipment. Cap and Labeled Tube Weights. Body Weights. Feed Consumption Values. Natural Delivery Observations. Litter Observations. Gross Necropsy Observations. Organ Weights (if required). Photographs (if required). Study M aintenance (room and environmental records). Feed, W ater and Bedding Analyses. Packing and/or Shipment Lists. KEY PERSONNEL: Executive Director of Research: Mildred S. Christian, Ph.D., Fellow, A TS Director of Research: Alan M. Hoberman, Ph.D., DABT Associate Director of Research and Study Director. Raymond G. York, Ph.D., DABT Director of Laboratory Operations: John F. Barnett, B.S. Director of Study Management: Valerie A. Sharper, M.S. M anager of Animal Operations and Chairperson, Institutional Anim al C are and Use Committee: Dena C. Lebo, V.M .D. Director of Operations and Compliance: Barbara J. Patterson, B.A. Consultant, Veterinary Pathology: W . Ray Brown, D .V.M ., Ph.D., A C VP CC1122 418-015: PAGE C-18 Protocol 418-015 Page 18 FINAL REPORT: A com prehensive draft final report will be prepared on completion of the study and will be finalized following consultation with the Sponsor. T h e report will include the following: Summary and Conclusion. Experimental Design and Method. Evaluation of Test Results. Appendices: Figures, Summ ary and Individual Tables Summ arizing the Above Data, Protocol and Associated Amendments and Deviations, Study Director's G LP Compliance Statement, Reports of Supporting Data (if appropriate) and QAU Statement. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: The procedures described in this protocol have been reviewed by the Testing Facility's Institutional Animal C are and Use Committee. All procedures described in this protocol that involve study animals will be conducted in a m anner to avoid or m inim ize discomfort, distress or pain to the animals. The Sponsor's signature below documents the fact that information concerning the necessity for conducting this study and the fact that this is not an unnecessarily duplicative study m ay be obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the stated purposes of the study. 001123 418-015:PAGE C-19 Protocol 418-015 Page 19 REFERENCES: 1. Christian, M .S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, W ashington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, V A 22161. 2. Christian, M .S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academ y of Sciences, Novem ber 7, 1983), J. Clin. Psychiat. 45(9):7-10. 3. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Cr1:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academ y Press, W ashington, D.C. 5. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 001124 PROTOCOL APPROVAL: FOR THE TESTING FACILITY Alan M. Hoberman, Ph.D., DABT Director of Research 418-015: PAGE C-20 Protocol 418-015 Page 20 / 6 - suo v~ r & Date Study Director Date Dena C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee FOR THE SPONSOR Date Marvin T. Case, D.V.M., Ph.D. Study Monitor Date 001125 418-015:PAGE C-21 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 001126 ATTACHMENT 1 418-015: PAGE C-22 Protocol 418-015 Page 1 of 2 STUDY SCHEMATIC PHARMACOKINETIC RECOVERY STUDY* Start of Dosage Female Rats Premating Period (42 Days) End of Dosage* Scheduled Sacrifice Cohabitation Period (5 days) Presumed Gestation Period Postpartum/ lactation Period Dosage Period. a. For additional details see Tests, Analyses and Measurements" section of the protocol. b. Fo generation female rats will receive test article or vehicle until mating is confirmed (day 0 of presumed gestation). 001127 attachment 1 418-015:PAGE C-23 Protocol 418-015 Page 2 of 2 SCHEDULE* 17 NOV 98 23 NOV 98 04 JAN 99 PM - 09 JAN 99 AM 05 JAN 99 09 JAN 99 26 JAN 99 03 FEB 99 29 JAN 99 06 FEB 99 30 JAN 99 03 FEB 99 15 FEB 9 9 -2 3 FEB 99 16 FEB 99 - 24 FEB 99 29 JUN 99 Animals Arrive - Acclimation Begins. Dosage Period - Female Rats [42 days prior to cohabitation until confirmed mating (day 0 of presumed gestation)]. Cohabitation Period. First Possible Day 0 of Presumed Gestation. Last Possible Day 0 of Presumed Gestation. First Possible Delivery (Day 21 of presumed gestation). Last Possible Delivery (Day 25 of presumed gestation). First Possible Day 4 Postpartum Culling. Last Possible Day 4 Postpartum Culling. First Possible Day 25 of Presumed Gestation Female Sacrifice. Last Possible Day 25 of Presumed Gestation Female Sacrifice. Scheduled Sacrifice - F1 Generation Pups (Day 21 postpartum). Scheduled Sacrifice - Fo Generation Dams (Day 22 postpartum). Draft Final Report. a. The study initiation date is the day the Study Director signs the protocol. 001128 418-015: PAGE C-24 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 001129 418-015:PAGE C-25 MATERIAL SAFETY d a t a SHEET 3M 3M Center St. Paul, Minnesota 55144-1000 1-500-364-3577 or (612) 737-6501 (24 hours) Copyright, 1998, Minnesota Mining and Manufacturing Coapany. All rights reserved. Copying and/or downloading of this Inforaatlon for the purpose of properly utilizing 3M products is allowed provided that: 1) the inforaatlon Is copied in full with no changes unless prior agreeaent Is obtained from 3M, and 2) neither the copy nor the original Is resold or otherwise distributed with the Intention of earning a profit thereon. DIVISION: 3M CHEMICALS TRADE NAME: FC-95 FLUORAD Brand Fluorocheaical Surfactant ID NUMBER/U.P.C.: 98-0207-0103-7 00-51135-09054-1 98-0207-0104-5 98-0211-0888-5 00-51135-09362-7 98-0211-3916-1 ZF-0002-1044-1 ISSUED: January 29, 1998 SUPERSEDES: Noveaber 05, 1997 DOCUMENT: 10-3796-9 00-51135-09055-8 00-51135-02311-2 1. INGREDIENT C.A.S. NO. PERCENT POTASSIUM PEHFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE.... POTASSIUM PEHFLUOROALKYL SULFONATE.... POTASSIUM PEHFLUOROALKYL SULFONATE____ POTASSIUM PERFLUOROALKYL SULFONATE.... 2795-39-3 3871-99-6 29420-49-3 60270-55-5 3872-25-1 82 3 3 2 1 - 86 -8 -7 -6 -3 2. PHYSICAL DATA BOILING POINT:..... VAPOR PRESSURE:.... VAPOR DENSITY:..... EVAPORATION RATE:... SOLUBILITY IN WATER: SPECIFIC GRAVITY:... PERCENT VOLATILE:... P H : ................ VISCOSITY:......... MELTING POINT:..... N/A N/A N/A N/A slight ca. 0.6 Waterl (Bulk) 0% 7 -8 (0.1% Aqueous) N/D N/D APPEARANCE AND ODOR: Light colored, free flowing powder. Abbreviations: N/D - Not Deterained N/A - Not Applicable CA - Approximately 001130 MSOS: FC-95 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 3 . FIRE ANO EXPLOSION HAZARD DATA 418-015: PAGE C-26 PAGE 2 FLASH POINT:.................. Nona FLAMMABLE LIMITS - LEL:.. N/A FLAMMABLE LIMITS - UEL:.. N/A AUTOIGNITION TEMPERATURE:..... N/A EXTINGUISHING MEDIA: Mater, Carbon dioxide, Dry chemical, Foaa SPECIAL FIRE FIGHTING PROCEDURES: Hear full protective clothing, including helaet, aelf-contained, positive pressure or pressure deaand breathing apparatus, bunker coat and pants, bands around aras, waist and legs, face aask, and protective covering for exposed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decoaposition section for products of coabustion. 4. REACTIVITY DATA STABILITY: Stable INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: Not applicable. HAZARDOUS POLYMERIZATION: Hazardous polyaerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions froa other sections. Vacuua, use wet sweeping coapound or water to avoid dusting. CAUTION! A vacuum cleaner could be an ignition source. Clean up residue with water. Place in an approved aetal container. Seal the container. RECOMMENDED DISPOSAL: Do not release to waterways or sewer. Do not use in products or processes that could result in aquatic concentrations greater than 1/10 of the lowest EC50 or LCSO concentration. Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permitted to 001X31 Abbreviations: N/D - Not Determined N/A - Not Applicable c ___CA - Approximate USDS: FC-95 FLUORAD Brand Fluorochemieal Surfactant January 29, 1998 5. ENVIRONMENTAL INFORMATION (continued) 418-015: PAGE 0 -2 1 PAGE 3 accept chemical waste. ENVIRONMENTAL DATA: 96-Hr. Aquatic Fish LCSO, Fathead Minnow(Piaephales promelas)*38 eg/1, Bluegill Sunfish(Lepoaia aacrochirua)-68 ag/1, Rainbow Trout(Salao gairdneri)-11 eg/1; 48-Hr. ECSO, Daphnia Magna 50 ag/1; COO*.004 g/g; 80020 - Nil. REGULATORY INFORMATION: Volatile Organic Coapounds: N/A. VOC Less H20 & Except Solvents: N/A. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Haste Nuaber " None (Not U.S. EPA Hazardous). This product complies with the cheaical registration requireaents of TSCA, EINECS, COSL, AICS, MITI and Korea. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID EYE CONTACT: Immediately flush eyes with large amounts of water for at least 15 minutes. Get immediate medical attention. SKIN CONTACT: Immediately flush skin with large amounts of water. Remove contaminated clothing. If irritation persists, call a physician. Wash contaminated clothing before reuse. INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SWALLOWED: Drink two glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid eye contact. Hear vented goggles. 001132 Abbreviations: N/D - Mot Determined N/A - Not Applicable CA - Approximately MSDS: FC-95 FLUORAO Brand Fluorochemical 8urfactant January 2, 1998 7 . PRECAUTIONARY INFORMATION (continued) 418-015: PAGE C-28 PAGE 4 SKIN PROTECTION: Avoid skin contact. Hoar appropriate gloves when handling this aterial. A pair of gloves aade froa the following notarial(s) are recoeeended: butyl rubber. Use one or more of the following personal protection iteas as necessary to prevent skin contact: head covering, coveralls. Protective garaents (other than gloves) should be aade of either of the following aaterials: polyethylene/polyvinylidene chloride (Saranex). RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Use in a wellventilated area. Provide sufficient ventilation to aaintain eaissions below recoaaended exposure liaits. If exhaust ventilation is not adequate, use appropriate respiratory protection. RESPIRATORY PROTECTION: Avoid breathing of dust. Select one of the following NIOSH approved respirators based on airborne concentration of contaainants and in accordance with OSHA regulations: half-aask dust and aist respirator, half-eask supplied air respirator, full-face dust and aist respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or saoke when using this product. Hash exposed areas thoroughly with soap and water. Hash hands after handling and before eating. RECOMMENDED STORAGE: Keep container dry. Keep container closed when not in use. FIRE AND EXPLOSION AVOIDANCE: Nonflammable. OTHER PRECAUTIONARY INFORMATION: No smoking: Smoking while using this product can result in contamination of the tobacco and/or saoke and lead to the formation of the hazardous decomposition products mentioned in section 4 of this MSDS. HMIS HAZARD RATINGS: HEALTH: 2 FLAMMABILITY: 0 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 TWA 3M TWA 3M TWA 3M THA 3M Y Y Y Y Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 001133 418-015: PAGE C-29 MSOS: FC-95 FLUORAD Brand Fluoroehamical 8urfactant January 29, 1998 EXPOSURE LIMITS (continuad) PAGE S INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUORQALKYL SULFONATE... 0.1 MG/M3 TWA 3M Y * SKIN NOTATION: Listed substances indicated with *Y' under SKIN refer to the potential contribution to the overall exposure by the cutaneous route including aucous aeabrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recoaaended Exposure Guidelines 8. HEALTH HAZARD DATA EYE CONTACT: Mild Eye Irritation: signs/syaptoas can include redness, swelling, pain, and tearing. SKIN CONTACT: Mild Skin Irritation (after prolonged or repeated contact): signs/syaptoas can include redness, swelling, and itching. May be absorbed through the skin and persist in the body for an extended time. INHALATION: May be harmful if inhaled. May be absorbed by inhalation and persist in the body for an extended tine. Single overexposure, above recoaaended guidelines, aay cause: Irritation (upper respiratory): signs/syaptoas can include soreness of the nose and throat, coughing and sneezing. IF SWALLOWED: Ingestion is not a likely route of exposure to this product. Illness aay result fron a single swallowing of a noderate quantity of this material. May be harmful if swallowed. MUTAGENICITY: Mutagenicity assays indicate the product is not autagenic. Abbreviations: N/D - Not Determined N/A * Not Applicable CA - Approximately 001134 418-015:PAGE C-30 USDS: FC-95 FLUORAD Brand Fluorocheaical Surfactant January 29, 1998 PAGE 6 8 . HEALTH HAZARD DATA (continued) REPRODUCTIVE/DEVELOPHENTAL TOXINS: Not teratogenic in the rat at oral doses below aaternally toxic levels. OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under California Proposition 65. A Product Toxicity Summary Sheet is available. SECTION CHANGE DATES HEADING SECTION CHANGED SINCE Noveaber 05, 1997 ISSUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately The information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3H product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's aethod of use or application. 3M provides information in electronic fora as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the information in the MSDS available directly froa 3M. 1135 418-015:PAGE C-31 ATTACHMENT 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 001136 418-015: PAGE C-32 ATTACHMENT 3 Protocol 418-015 Version: 418-015(06 NOV 981 Page 1 of 2 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE Test Article: Vehicle: PFOS 0.5% Tween 80 in R.O. Deionized Water A. Purpose: The purpose of this procedure is to provide a method for the preparation of dosage suspensions of PFOS and the vehicle for oral administration to rats on Argus Study 418-015. B. General Information: 1. All suspension containers will be labeled and color coded. Each label will specify the protocol number, test article identification, Argus batch number, concentration, dosage level, preparation date, expiration date and storage conditions. 2a. Suspensions will be prepared: X Daily __ Weekly For days of use Vehicle will be prepared: __ Daily X Weekly For days of use 3. Suspensions will be prepared at a final dosage volume of 5 mL/kg. 4. Safety: X Gloves, lab coat, goggles or safety glasses and faceshield X Dust-Mist Respirator __ Half-Face Respirator __ Full-Face Respirator/Positive Pressure Hood __ Tyvek Suit/Apron 5. Dosage suspensions adjusted for Free base and % Purity. __ Yes X No (Calculations based on 100%) ___ Free Base ___ Purity 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol. i01137 418-015:PAGE C-33 ATTACHMENT 3 Protocol 418-015 Version: 418-015 (06 NOV 98) Page 2 of 2 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE NOTE: Test article will be prepared as a serial dilution from the high dosage to the low dosage. Once the final volumes are achieved, stir bars are to be added to the containers; mixing should occur during sampling and/or administration. C. Preparation of Vehicle 1. Add the required amount of R.O. deionized water to an appropriately labeled container. Heat the water to 50C 5C, add the required amount of Tween 80 and mix until uniform (See TEST ARTICLE CALCULATIONS). D. Test Article Suspension Preparation: 1. To prepare the 0.32 mg/mL, Group III suspension, add the required amount of test article (See TEST ARTICLE CALCULATIONS) into an appropriately sized, labeled container. QS ad to the required amount with vehicle and heat the mixture to 80C 5C for approximately 30 minutes or until the TA/S dissolves. 2. Once the test article has dissolved; spin while the suspension cools. (Be sure there is a visible vortex, this will achieve the desired emulsion. This may be prepared the day before use.) 3. To prepare the 0.02 mg/mL, Group II suspension, remove the required amount of stock suspension (Group III) (See TEST ARTICLE CALCULATIONS), QS ad with the vehicle and mix. 4. To prepare the 0 mg/mL, Group I suspension, add required amount of vehicle to an appropriately sized, labeled container (See TEST ARTICLE CALCULATIONS) and mix. Written by: Approved bv:j^--^ Date: Clarification: No es (See attached clarification form.) Initials/Date : 001138 418-015: PAGE C-34 OPrimedica Aig9u0s5TReSelTheseepeealhehroHcfyanhoxeDrL::sra((hi22vba11eom.55ra.))Bt4P4ou4A4ri3il3ed--1si88n9.570gI81n4A07c4. PROTOCOL 418-015 Oral (Gavage) Pharmacokinetc Recovery Study of PFOS in Rats SPONSOR'S STUDY NUMBER: T-6295.14 Amendment 1 - 0 7 January 1999 1. Analyses of Preoared Formulations. Concentration of Test Article Formulations (Page 4 of the protocol): [Effective date: 06 January 1999] Duplicate samples (2 mL each) will be taken from the first and last preparation rather than, the first and last preparation on the day prepared. Reason for Change: The preparation occurs the day before it is used for dosage administration and, according the to protocol, day 0 of gestation is the last day of dosage administration. Since day 0 of gestation is the day that the rats are confirmed pregnant, the sample cannot be taken of the last day of preparation. O zJ& ZJ? 07-dfUJ -99 Alan M. Hoberman, Ph.D., DABT Date fond G. YorkJ^hJD., DABT Date Director of Research Associate Director bf-Research and Study Director dUu 6IfUn f) Dena C. Lebo, V.M.D. Date Chairperson, Institutional Animal Care and Use Committee T X jz. Marvin T. Case, D.V.M., Ph.D. Date Study Monitor 001139 APPENDIX D DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 001140 418-015:PAGE D-1 DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 1 . All rats were administered the test article or vehicle on premating day 43, 4 January 1999. The rats should have been placed into cohabitation on premating day 42 after dosage administration. This deviation did not adversely affect the outcome or interpretation of the study because no data were lost. 2. From 23 November 1998 to 26 November 1998 (days 1 to 4 of the premating period), the following Fo generation female rats received the incorrectly calculated amount of test article in vehicle, resulting in the rats receiving 25% more of the test article than required. Dosage Group II III Dosage (ma/ko/davl 0.1 1.6 Rat Numbers 13738-13749 13750-13761 These deviations did not adversely affect the outcome or interpretation of the study because the dosages were only for the first four days out of a total of 43 days of test article administration prior to mating. All deviation K&ymbnd G. York, f^ rD ), DABT Associate DirectorofResearch and Study Director Date 001141 APPENDIX E TEMPERATURE AND RELATIVE HUMIDITY REPORTS 001142 ARGUS 418-015: PAGE E-1 Temperature and Relative Humidity Report Location: Room 15 Protocol Number: 418-015 Range of Dates: 17-Nov-1998 14:00 to 27-Nov-1998 08:55 Target Range: Species: rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64*F to 79"F 11 234.72 235 Relative Humidity 30% to 70% 11 234.72 235 Mean (1 SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 67.0 ( 0.9) 44.6 (4.8) 68.9 53.4 67.2 45.6 63.4 30.3 232 (98.7) 235 (100.0) 0 (0.0) 0 (0.0) 3 (1.3) 0 (0.0) Report Generated: 28-Apr-1999 at 12:33 COMMENTS: REVIEWED BY: DATE: C um ulative by Location (v 0 4 .0 1 .97) 001143 ARGUS 418-015:PAGE E-2 Temperature and Relative Humidity Report Location: Room 04 Protocol Number 418-015 Range of Dates: 27-Nov-1998 08:55 to 30-Nov-1998 09:15 Target Range: Species: rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64*F to 79*F 4 71.99 75 Relative Humidity 30% to 70% 4 71.99 75 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 72.4 ( 0.9) 45.1 (4.8) 74.3 68.7 72.3 44.1 69.6 40.0 75 (100.0) 75 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Report Generated: 28-Apr-1999 at 12:35 COMMENTS: REVIEWED BY: J L & l DATE: Cum ulative by Location (v 0 4 .0 1 .9 7 ) 001144 ARGUS 418-015:PAGE E-3 Temperature and Relative Humidity Report Location: Room 27 Protocol Number 418-015 Range of Dates: 30-Nov-1998 09:15 to 09-Dec-1998 14:30 Target Range: Species: rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64*F to 79*F 10 221.0 222 Relative Humidity 30% to 70% 10 221.0 222 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 71.3 (0.5) 59.3 ( 6.7) 72.4 68.8 71.3 61.2 70.0 37.0 222 (100.0) 222 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Report Generated: 28-Apr-1999 at 12:37 COMMENTS: REVIEWED BY: ^LH DATE: C um ulative by Location (v 0 4 .0 1 .9 7 ) 001145 ARGUS 418-015:PAGE E-4 Temperature and Relative Humidity Report Location: Room 28-29 Protocol Number 418-015 Range of Dates: 09-Dec-1998 14:30 to 15-Dec-1998 15:44 Target Range: Species: rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64*F to 79*F 7 145.01 146 Relative Humidity 30% to 70% 7 145.01 146 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 70.7 (1.1) 49.0 ( 3.5) 76.5 59.4 70.4 48.8 69.1 39.6 146 (100.0) 146 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Report Generated: 28-Apr-1999 at 12:39 COMMENTS: REVIEWED BY: DATE: r/ Cum ulative by Location (v 0 4 .0 1 .9 7 ) 001146 ARGUS 418-015: PAGE E-5 Temperature and Relative Humidity Report Location: Room 27 Protocol Number: 418-015 Range of Dates: 15-Dec-1998 15:44 to 21-Dec-1998 13:45 Target Range: Species: rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64*F to 79*F 7 141.77 143 Relative Humidity 30% to 70% 7 141.77 143 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 70.6 ( 0.8) 59.9 ( 2.6) 72.5 64.8 70.5 60.1 69.0 49.1 143 (100.0) 143 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Report Generated: 28-Apr-1999 at 12:41 COMMENTS: REVIEWED BY: DATE: S7 Cum ulative by Location (v 0 4 .0 1 .9 7 ) 001147 ARGUS 418-015: PAGE E-6 Temperature and Relative Humidity Report Location: Room 28-29 Protocol Number: 418-015 Range of Dates: 21-Dec-1998 13:45 to 20-Feb-1999 15:00 Target Range: Species: rat Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 64*F to 79*F 62 1464.99 1466 Relative Humidity 30% to 70% 62 1464.99 1466 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 69.0 71.9 69.0 66.9 1466 0 0 (1.1) (100.0) (0.0) (0.0) 49.0 81.6 48.7 10.0 1407 49 10 (10.6) (96.0) (3.3) (0.7) Report Generated: 28-Apr-1999 at 12:46 COMMENTS: REVIEWED BY: DATE: 5/vr> a. Cum ulative by Location (v 0 4 .0 1 .97) 001148 ARGUS 418-015:PAGE E-7 Temperature Deviations Report Location: Room 15 Protocol Number: 418-015 Range of Dates: 17-Nov-1998 14:00 to 27-Nov-1998 08:55 Temperature Target Range: Species: rat Date 25-NOV-1998 25-NOV-1998 25-Nov-i 998 Time 03:00 06:00 07:00 Temp. 63.8 L 63.7 L 63.4 L 64F to 79F Date Time Temp. H * Value out of range - High L = Value out of range - Low Temp. * Temperature *F Report Generated: 28-Apr-1999 at 12:34 These deviations did not adversely affect the outcome or interpretation of the study. The following deviation(s) impacted on the outcome of the study as described: Deviations by Location (v 0 4 .0 1 .97) 001149 ARGUS 418-015: PAGE E-8 Relative Humidity Deviations Report Location: Room 28-29 Protocol Number: 418-015 Range of Dates: 21-Dec-1998 13:45 to 20-Feb-1999 15:00 Humidity Target Range: Species: rat 30% to 70% Date 21-Dec-1998 29-Dec-1998 04-Jan-1999 OS-Jan-1999 05-Jart-1999 06-Jan-1999 06-Jan-1999 06-Jan-1999 06-Jan-1999 06-Jan-1999 06-Jan-1999 06-Jan-1999 18-Jan-1999 18-Jan-1999 18-Jan-1999 18-Jan-1999 18-Jan-1999 Time 18:00 12:00 13:00 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00 06:00 11:00 15:00 18:00 20:00 21:00 R.H.i 77.2 H 70.3 H 29.4 L 26.3 L 26.8 L 19.3 L 20.7 L 17.0 L 14.7 L 15.7 L 10.0 L 10.2 L 75.4 H 72.4 H 72.0 H 73.4 H 75.4 H Date 21-Jan-1999 22-Jan-1999 22-Jan-1999 22-Jan-1999 22-Jan-1999 22-Jan-1999 23-Jan-1999 23-Jan-1999 23-Jan-1999 23-Jan-1999 23-Jan-1999 23-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 Time 18:00 03:00 05:00 07:00 09:00 21:00 06:00 09:00 13:00 18:00 19:00 23:00 00:00 03:00 04:00 05:00 06:00 R.H. 76.4 H 70.9 H 71.7 H 70.4 H 70.4 H 70.5 H 71.4 H 72.3 H 73.9 H 78.2 H 75.1 H 77.9 H 73.1 H 80.7 H 72.4 H 72.2 H 73.4 H H Value out of range - High L = Value out of range - Low R.H. = Relative Humidity (%) Report Generated: 28-Apr-1999 at 12:53 These deviations did not adversely affect the outcome or interpretation of the study. __ The following deviation(s) impacted on the outcome of the study as described: Study Directo Deviations by Location (v 0 4 .0 1 .97) 001150 ARGUS 418-015:PAGE E-9 Relative Humidity Deviations Report Location: Room 28-29 Protocol Number 418-015 Range of Dates: 21-Dec-1998 13:45 to 20-Feb-1999 15:00 Humidity Target Range: Species: rat 30% to 70% Date 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 24-Jan-1999 26-Jan-1999 26-Jan-1999 26-Jan-1999 26-Jan-1999 26-Jan-1999 26-Jan-1999 Time 07:00 09:00 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18:00 11:00 15:00 16:00 17:00 18:00 20:00 R.H. 70.1 H 70.3 H 75.5 H 75.6 H 75.8 H 78.2 H 81.6 H 75.5 H 80.3 H 78.7 H 75.9 H 70.9 H 74.5 H 75.7 H 76.1 H 73.6 H 70.6 H Date 02-Feb-1999 02-Feb-1999 02-Feb-1999 02-Feb-1999 03-Feb-1999 03-Feb-1999 03-Feb-1999 06-Feb-1999 Time 19:00 20:00 21:00 23:00 01:00 03:00 07:00 12:00 R.H. 77.7 H 77.7 H 70.7 H 77.7 H 76.7 H 75.4 H 75.2 H 72.9 H H * Value out of range - High L * Value out of range - Low R.H. * Relative Humidity (%) Report Generated: 28-Apr-1999 at 12:54 ^ These deviations did not adversely affect the outcome or interpretation of the study. ___ The following deviations) impacted on the outcome of the study as described: Deviations by Location (v 0 4 .0 1 .9 7 ) 001151 APPENDIX F STATEMENT OF THE STUDY DIRECTOR 001152 C/Pmmedica 418-015:PAGE F-1 Arg9u0s5TReSelThseeepeaelherhoHcfyanhoxeDLr::sra((hi2b2va1o1em,5r5a,)B)t4Po4u4A4rii3l3ed--1si88n,957g0I1n84Ac074. PROTOCOL 418-015: ORAL (GAVAGE) PHARMACOKINETIC RECOVERY STUDY OF PFOS IN RATS SPONSOR'S STUDY NUMBER: T-6295.14 STATEMENT OF THE STUDY DIRECTOR This final report accurately reflects the raw data obtained during the performance of the study. No deviations from the U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations; Final Rule3, the Japanese Ministry of Health and Welfare (MHW) Good Laboratory Practice Standard fo r Safety Studies on DrugsP and the European Economic Community (EEC) Council decision on 28 July 1989 on the acceptance by the European Economic Community o f an OECD decision/recommendation on compliance with principles o f good laboratory practice0occurred that affected the quality or integrity of the study. Associate Directorof-Research and Study Director a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1988). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. c. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community o f an OECD decision/recommendation on compliance with principles o f good laboratory practice. Official Journal of the European Communities: Legislation. 32(No. L 315; 28 October): 1-17. 001153 APPENDIX G QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT 001154 OPrimedo. 418-015:PAGE G-1 Aig9u0s5TReSelThseeepeaelherhocHfyanhoxeDLr::sra(h(i22bva11oem.55ra.))BtP4o4uA4r4iil33ed--1si88n.975g0In184Ac074. QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT Study Director: Raymond G. York, Ph.D., DABT Executive Director of Research: Mildred S. Christian, Ph.D., Fellow, ATS Protocol 418-015: Oral (Gavage) Pharmacokinetic Recovery Study of PFOS in Rats Sponsor's Study Number T-6295.14 The draft protocol for this study was audited for adherence to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and European Economic Community (1989) council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice on 18 OCT 98. Critical phases of this study were inspected 10 times; study information and raw data were audited twice (see tables 1 and 2 for dates and phases/data). The draft final report and the raw data for this study were compared and audited for accuracy, for adherence to protocol requirements, and for adherence to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and European Economic Community (1989) council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice between 10 MAY 99 and 15 JUN 99, and for revisions requested by the Sponsor on 20 JUL 99, 22 JUL 99, and for finalization on 23 JUL 99. 001155 418-015.-PAGE G-2 This study was conducted according to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs. And European Economic Community (1989) council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice. Nancy J. Gongliewski Date Quality Assurance Manager 2' h m i Dl/Lisa A. zaborowski, B.S. ' Date Senior Quality Assurance Associate and Principal Auditor 001156 TABLE 1 CRITICAL PHASES INSPECTED 418-015:PAGE G-3 Test Article Administration - Gavaae Date of inspection: 23 NOV 98 Date results reported to the Study Director and Management: 25 NOV 98 Test Article Preparation Date of inspection: 01 DEC 98 Date results reported to the Study Director and Management: 02 DEC 98 Urine/Fecal Collection Date of inspection: 04 JAN 99 Date results reported to the Study Director and Management: 04 JAN 99 Blood Collection Dates of inspection: 04 JAN 99, 17 FEB 99 Dates results reported to the Study Director and Management: 04 JAN 99, 17 FEB 99 Cohabitation Date of inspection: 05 JAN 99 Date results reported to the Study Director and Management: 07 JAN 99 Natural Deliverv/Litter Watch Date of inspection: 27 JAN 99 Date results reported to the Study Director and Management: 02 FEB 99 001157 418-015:PAGE G-4 Culling. Pud Scrifice: Day 4 Date of inspection: 01 FEB 99 Date results reported to the Study Director and Management: 03 FEB 99 Necropsy. Fo Dams. Fi P uds Dates of inspection: 17 FEB 99, 17 FEB 99 Dates results reported to the Study Director and Management: 22 FEB 99, 22 FEB 99 001158 418-015:PAGE G-5 TABLE 2 RAW DATA AUDIT(S) The following study information and raw data were audited from 07 APR 99 to 13 APR 99: Protocol. Protocol amendment. List of personnel and computer operator codes. Error codes and codes for clinical sign observations. Animal receipt, randomization, physical examination and acclimation. In-life transaction record. Feed consumption. Cohabitation. Natural delivery observations. Litter observations. Pup body weights and status. Pup Randomization. Necropsy. Organ weights. Tissue packing lists. Male breeder colony records. General comments. Study maintenance records. Temperature and relative humidity reports. Feed, water and bedding analyses. Edit requests. Deviations. Data review page. Blood collection data and packing lists. Key for testing facility computer backup record abbreviations. Urine/Fecal collection data and packing lists. The results of this audit were reported to the Study Director and Management on 15 APR 99. 001159 418-015.PAGE G-6 The following study information and raw data were audited on 20 APR 99: Vehicle receipt, preparation and use. Test article receipt, preparation and use. Test article packing lists. Deviations. The results of this audit were reported to the Study Director and Management on 23 APR 99. 001160
Contact UsLoginSign Up
CUNY - The Graduate CenterColumbia University Mailman School of Public Health - Sociomedical Sciences