Document 99bYjEpNe3vb9V73OGQkmmJL6

ARJ26-0/W / >~r-Y COV/MtfCE> THE DEVELOPMENT SERVICES COMPANY UNAUDITED DRAFT August 20, 1998 Sponsor: 3M St. Paul, Minnesota FINAL REPORT Study Title: 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys Author: Peter J. Thomford, PhD Study Completion Date: To be determined Performing Laboratory: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Project Identification: Covance 6329-222 Sponsor Project Identification: 3M Study No. T-6295.6 Page 1 of 212 002408 Covance 6329-222 3M T-6295.6 COMPLIANCE STATEMENT 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys All aspects of this study were in accordance with the Environmental Protection Agency Good Laboratory Practice Standards, 40 CFR 792. Peter J. Thomford, PhD Study Director Covance Laboratories Inc. Andrew M. Seacat, PhD Study Monitor 3M Date Date 2 002409 Covance 6329-222 3M T-6295.6 QUALITY ASSURANCE STATEMENT This report, with the exception of Appendices 6, 7, 8, and 9, has been reviewed by the Quality Assurance Unit of Covance Laboratories Inc., in accordance with the Environmental Protection Agency (EPA) Good Laboratory Practice Standards, 40 CFR 792. The data in Appendices 6, 7, 8, and 9 were generated by and are the responsibility of the Sponsor and the Sponsor's designees. The following inspections were conducted and findings reported to the study director and study director management. Written status reports of inspections and findings are issued to Covance management according to standard operating procedures. Inspection Dates From To 04/21/98 04/21/98 05/20/98 05/20/98 05/20/98 05/20/98 05/21/98 05/21/98 06/01/98 06/01/98 07/08/98 07/13/98 08/14/98 08/14/98 08/10/98 08/18/98 Phase Protocol Review Protocol Amendment Review Protocol Amendment Review Clinical Laboratory Inspection Postlife Data Review Protocol Amendment Review Report Review Date Reported to Study Director and Study Director Management 04/21/98 05/20/98 05/20/98 05/21/98 06/01/98 07/13/98 08/14/98 08/18/98 Representative Quality Assurance Unit Date 002410 3 Covance 6329-222 3M T-6295.6 STUDY IDENTIFICATION 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys Test Material Sponsor Study Monitor Alternate Study Monitor Study Location Study Director Study Timetable Study Initiation Date In-Life (Experimental) Start Date In-Life Termination Date Experimental Termination Date Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 Andrew M. Seacat, PhD 3M 612.575.3161 Marvin T. Case, DVM, PhD 3M 612.733.5180 Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Peter J. Thomford, PhD Covance Laboratories Inc. P.O. Box 7545 Madison, Wisconsin 53707-7545 608.241.7207 April 17,1998 April 23,1998 May 22, 1998 To be determined 4 002411 KEY PERSONNEL Covance 6329-222 3M T-6295.6 Study Director Study Toxicologist Study Coordinator Supervisor, Large Animal Toxicology Supervisor, Dose Formulation Supervisor, Laboratory Animal Medicine Clinical Pathologist Supervisor, Clinical Pathology Anatomical Pathologist Supervisor, Anatomical Pathology Peter J. Thomford, PhD Dale Aldridge, BS Patricia K. McKee Pesik, BS, LAT Meechelle Bordeaux, LAT Dixie Bushee, BS, LATG Donna J. Clemons, DVM, MS Diplomate, ACLAM Robert L. Hall, DVM, PhD Diplomate, ACVP (Clinical Pathology) Ronald Markevitch, BS, MT (ASCP) Thomas E. Palmer, PhD Kimberly W. Durland, BS, HT 002412 5 Covance 6329-222 3M T-6295.6 CONTENTS Page ABSTRACT......................................................................................................................... 9 PURPOSE...........................................................................................................................11 REGULATORY COMPLIANCE...................................................................................... 11 TEST MATERIAL AND VEHICLE................................................................................. 11 Test Material...................................................................................................................11 Vehicle............................................................................................................................11 Reserve (Archive) Samples........................................................................................... 12 Disposition......................................................................................................................12 TEST SYSTEM..................................................................................................................12 Test Animal....................................................................................................................12 Identification...................................................................................................................12 Acclimation....................................................................................................................12 Housing and Maintenance..............................................................................................13 Justification....................................................................................................................13 PROCEDURES...................................................................................................................14 Group Designations and Dose Levels........................................................................... 14 Dose Preparation........................................................................................................... 14 Dose Analyses................................................................................................................16 Method of Administration............................................................................................. 16 Clinical Observations.................................................................................................... 16 Body Weights..................................................................... Rectal Body Temperatures...................................................... Blood Hormone Determination..................................................................................... 17 Serum PFOS Level Determination................................................................................ 17 Clinical Pathology..........................................................................................................18 Additional Blood Collection......................................................................................... 18 Necropsy.........................................................................................................................19 Palmitoyl CoA Oxidase Determinations....................................................................... 19 Cell Proliferation Evaluation......................................................................................... 19 Liver PFOS Determination............................................................................................ 19 Tissue Preservation........................................................................................................ 19 Histopathology............................................................................................................... 20 Statistical Analyses........................................................................................................ 20 RECORD RETENTION.................................................................................................... 21 RESULTS........................................................................................................................... 22 Dose Analyses............................................................................................................... 22 Clinical Observations.................................................................................................... 22 Body Weights................................................................................................................ 22 6 cor4ia Covance 6329-222 3M T-6295.6 CONTENTS (Continued) Page RESULTS (Continued) Food Consumption........................................................................................................ 22 Rectal Body Temperatures........................................................ 22 Blood Hormone Analyses.............................................................................................. 23 Serum PFOS Level Determination................................................................................ 23 Clinical Pathology......................................................................................................... 23 Cell Proliferation Evaluation......................................................................................... 23 Liver PFOS Determination............................................................................................ 24 Anatomical Pathology................................................................................................... 24 CONCLUSIONS................................................................................................................ 24 SIGNATURES................................................................................................................... 25 REFERENCES................................................................................................................... 26 PATHOLOGY REPORT................................................................................................... 27 COMMENTS ON THE DATA.......................................................................................... 30 CODES, ABBREVIATIONS, AND UNITS.....................................................................31 General Codes and Abbreviations................................................................................. 32 Codes for Clinical Pathology......................................................................................... 33 Abbreviations and Units for Clinical Hematology........................................................35 Abbreviations and Units for Clinical Chemistry...........................................................37 Codes for Anatomical Pathology................................................................................... 39 TABLE 1 Summary of Clinical Observations - AM./Weekly............................................... 40 2 Summary of Clinical Observations - 30 Minutes Postdose................................... 41 3 Summary of Clinical Observations - 60 Minutes Postdose................................... 42 4 Summary of Clinical Observations - 90 Minutes Postdose................................... 43 5 Summary of Clinical Observations - Unscheduled............................................... 44 6 Summary of Body Weight Data (kg).......................................................................45 7 Summary of Rectal Body Temperature Data (C)...................................................47 8 Summary of Clinical Hematology Data - Day -7 ...................................................49 9 Summary of Clinical Hematology Data - Day 29....................................................53 10 Summary of Clinical Chemistry Data - Day -7 ......................................................57 11 Summary of Clinical Chemistry Data - Day 2.........................................................63 12 Summary of Clinical Chemistry Data - Day 7 ........................................................69 13 Summary of Clinical Chemistry Data - Day 14......................................................75 14 Summary of Clinical Chemistry Data - Day 29....................................................... 81 15 Summary of Clinical Chemistry Data - Day 30.......................................................87 16 Incidence of Macroscopic Observations.................................................................. 89 17 Incidence of Microscopic Observations.................................................................. 90 7 002414 Covance 6329-222 3M T-6295.6 CONTENTS (Continued) Page APPENDIX 1 ............................................................................... 92 Protocol Deviations....................................................................................................... 93 Protocol......................................................................................................................... 95 Protocol Amendment No. 1......................................................................................... 113 Protocol Amendment No. 2 ......................................................................................... 115 Protocol Amendment No. 3 ......................................................................................... 117 Material Safety Data Sheet.......................................................................................... 120 APPENDIX 2 ....................................................................................................................126 Individual Animal Fate D ata....................................................................................... 127 Individual Clinical Observations................................................................................. 128 Individual Rectal Body Temperature Data (C)........................................................... 135 APPENDIX 3 ....................................................................................................................137 Individual Body Weight Data (kg).............................................................................. 138 APPENDIX 4 ....................................................................................................................140 Individual Clinical Hematology Data.......................................................................... 141 Individual Clinical Chemistry Data............................................................................. 153 APPENDIX 5 ....................................................................................................................185 Individual Animal Pathology Data.............................................................................. 186 APPENDIX 6 ....................................................................................................................198 Summary and Individual Hormone Analyses D ata..................................................... 199 Figure 1 - Mean Estradiol Data - Males...................................................................... 203 Figure 2 - Mean Estradiol Data - Females...................................................................204 Figure 3 - Mean Triiodothyronine Data - M ales.........................................................205 Figure 4 - Mean Triiodothyronine Data - Females......................................................206 APPENDIX 7 ................................................................................................................... 207 Dose Analysis.............................................................................................................. 208 APPENDIX 8 ................................... 209 Serum and Liver PFOS Level Determinations............................................................210 APPENDIX 9 ................................................................................................................... 211 Cell Proliferation Evaluation....................................................................................... 212 002415 8 ABSTRACT Covance 6329-222 3M T-6295.6 The purpose of this study was to provide data for determining an estimated maximum-tolerated dose and lower dose levels to be used in a chronic toxicity study and to assess the effect of the test material, Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295), on critical enzyme levels, hormones, and other selected biochemical parameters. Male and female cynomolgus monkeys were assigned to three groups (two animals/sex in Group 1, three animals/sex in Group 2, and one animal/sex in Group 3). Animals in Groups 2 and 3 received gelatin capsules containing 0.02 and 2.0 PFOS/kg of body weight/day (mg/kg/day), respectively, triturated with lactose (1:999 and 1:9, w:w, respectively). Animals in Group 1 received gelatin capsules containing lactose only. The total material dose level for each group was 20.0 mg/kg/day. Food was provided once or twice daily. Water was provided ad libitum. The animals were observed twice daily (a.m. and p.m.) for mortality and moribundity. At least once daily, animals were examined for abnormalities and signs of toxicity, and food consumption was assessed qualitatively. In addition, animals were observed approximately 30, 60, and 90 minutes postdose for signs of poor health or abnormal behavior. Body weight data were collected twice weekly beginning 2 weeks before initiation of treatment, on Day -1, on the first day of treatment, and twice weekly thereafter. Rectal body temperatures were recorded twice weekly beginning 2 weeks before initiation of treatment. Blood samples for hormone analyses [estradiol, estrone, estriol, thyroid stimulating hormone, triiodothyronine (T3), and thyroxin (T4)] were collected before initiation of treatment and predose on Day 29. Serum was harvested, and the samples were sent to Ani Lytics Inc., for analyses. Blood samples for serum PFOS concentration analyses were collected before initiation of treatment and predose on Days 2, 3 (approximately 24 hours after the first and second dose, respectively), 7, 14, and 29. Serum was harvested, and samples were sent to the Sponsor for analyses. Blood samples were collected for hematology and clinical chemistry tests before initiation of treatment and on Day 29. In addition, blood for clinical chemistry tests was collected predose on Days 2, 7, and 14. Additional blood was collected at the time of exsanguination, and samples were shipped to the Sponsor for possible future analysis. On Day 30, the animals were anesthetized, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, and selected tissues were collected 9 CC2416 Covance 6329-222 3M T-6295.6 and preserved. In addition, a sample of liver was collected from each animal for palmitoyl CoA oxidase activity analyses. Representative samples of liver, testes, and pancreas were collected from each animal and sent to Pathology Associates International for proliferation cell nuclear antigen evaluation. A sample of liver was collected from each animal and sent to the Sponsor for PFOS concentration analyses. Microscopic examinations were done on the adrenals, eye, femoral bone marrow, lung, liver, kidney, pancreas, spleen, testes, and thymus from each animal. All animals survived to the scheduled sacrifice. There were no test material-related effects on clinical observations, body weights, food consumption, rectal body temperatures, clinical pathology, or macroscopic or microscopic findings. There were no apparent test material-related effects on estrone, estriol, thyroid stimulating hormone, or thyroxin. There were no apparent test material-related effects on estradiol or triiodothyronine at 0.02 mg/kg/day. Given the low number of animals in this study, it is not possible to determine conclusively whether there was a test material-related effect on estradiol or triiodothyronine. Estradiol levels for the male and female given 2.0 mg/kg/day were numerically lower than those of the control animals on Day 29 and their respective prestudy values. Triiodothyronine levels for the male and female given 2.0 mg/kg/day were numerically lower than those of the control animals on Day 29; however, their prestudy values were also considerably lower than the control values. Triiodothyronine levels for animals given 0 or 0.02 mg/kg/day were numerically higher on Day 29 compared with their prestudy levels while triiodothyronine levels for animals given 2.0 mg/kg/day were numerically lower compared with their prestudy levels. In cynomolgus monkeys treated with 0, 0.02, or 2.0 mg PFOS/kg/day orally for at least 4 weeks, there were no apparent test material-related effects on clinical observations, body weights, food consumption, rectal body temperatures, or clinical or anatomical pathology findings. The one male and one female treated with 2.0 mg PFOS/kg/day appeared to have lower levels of estradiol on Day 29. Data from liver and serum PFOS analyses and cell proliferation evaluations will be provided by the Sponsor and Pathology Associates International, respectively. 10 002417 PURPOSE Covance 6329-222 3M T-6295.6 The purpose of this study was to provide data for determining an estimated maximum-tolerated dose and lower dose levels to be used in a chronic toxicity study and to assess the effect of the test material, Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295), on critical enzyme levels, hormones, and other selected biochemical parameters. REGULATORY COMPLIANCE All aspects of this study were done in accordance with the Environmental Protection Agency Good Laboratory Practice Standards, 40 CFR 792. TEST MATERIAL AND VEHICLE Test Material The test material, Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295), Lot No. 217, is a white to off-white powder. It was received at Covance on September 4,1997. The test material was stored at room temperature. Information on synthesis methods, stability, purity, composition, or other characteristics that define the test material is on file with the Sponsor. Vehicle The vehicle was lactose (Spectrum, New Brunswick, New Jersey), Lot No. NN0192 (expiration date February 13,1999). It was received at Covance on March 30,1998. The vehicle was stored at room temperature. Information on synthesis methods, purity, composition, or other characteristics that define the vehicle is on file with the manufacturer. 11 002418 Covance 6329-222 3M T-6295.6 Reserve (Archive) Samples A reserve sample (10 g each) of each lot of the test material, vehicle, and each test material/lactose trituration was taken before initiation of treatment and stored at room temperature. These samples will be transferred to the Sponsor after completion of the in-life phase. Disposition Remaining test material will be retained at Covance for use in possible future studies. TEST SYSTEM Test Animal Young adult to adult cynomolgus monkeys were obtained from Covance Research Products Inc. (Alice, Texas), on March 10,1998. The animals weighed 2.0 to 2.5 kg at initiation of treatment. Identification Each animal was assigned a permanent number upon arrival and identified with collar tag before initiation of treatment. All data for an animal are recorded under this number. Acclimation Seven males and seven females were received on March 10,1998, transferred from the Covance in-house stock colony on March 16,1998, and acclimated in Animal Room 2015 for 38 days before initiation of treatment. In general, animals in this shipment appeared healthy. During acclimation, the animals were examined for abnormalities indicative of health problems. In addition, three tuberculosis tests, a physical examination, and a fecal flotation for parasites were done on each animal. The physical examination done after the animals were received revealed no major abnormalities. Results of the tuberculosis tests were negative for all animals; the results are recorded in the data. The results of the fecal flotation tests indicated the animals were negative for parasite ova. One male and one female were eliminated from study consideration based on clinical pathology findings or abnormal fecal observations during 12 002419 Covance 6329-222 3M T-6295.6 acclimation. There were six males and six females in the randomization for assignment to groups (two animals/sex in Group 1, three animals/sex in Group 2, and one animal/sex in Group 3). Animals not selected for the study were transferred to the Covance stock colony. Housing and Maintenance Animal Room 2015 was used for this study. Environmental controls for the animal room were set to maintain 18 to 29EC, a relative humidity of 30 to 70%, and a 12-hour light/12-hour dark cycle. Variations from these conditions are documented in the data and are considered to have had no effect on the outcome of the study. The animals were housed individually in stainless steel cages. Certified primate diet (#8726C, Harlan Teklad) was provided once or twice daily. The lot numbers are recorded in the data. The diet is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Results of specified nutrient and contaminant analyses are on file with Covance-Madison. Fruits or additional supplements were provided, but did not require analysis. Water was provided ad libitum. Samples of the water are analyzed for specified microorganisms and environmental contaminants. The results are on file with Covance-Madison. There were no known contaminants in the diet or water at levels that would have interfered with this study. Justification PFOS is a known hepatic peroxisome proliferator (PP) in the rat. When exposed to PP, nonhuman primates (such as the cynomolgus monkey) respond similarly to humans (i.e., low to no hepatic response) and therefore are an appropriate human surrogate species. 002420 13 PROCEDURES Covance 6329-222 3M T-6295.6 This study was conducted in accordance with the Protocol dated April 17, 1998, and Protocol Amendment Nos. 1 through 3. The protocol, protocol amendments, and protocol deviations are in Appendix 1. Group Designations and Dose Levels Selection of animals for the study was based on clinical observations, clinical pathology, and other data as appropriate. Animals were assigned to treatment groups using a computerized blocking procedure designed to achieve body weight balance with respect to treatment group. Dose Level Total Material Dose Number of Animals Group (mg/kg/day) Level (mg/kg/day) Males Females 1 (control) 0a 20.0a 2 2 2 (low dose) 0.02 20.0b 3 3 3 (high dose) 2.0 20.0C 1 1 a The control group (Group 1) received an equivalent amount of lactose in gelatin capsules as the total material administered to Group 3. b The low-dose group received the test material triturated with lactose (1:999, w:w). c The high-dose group received the test material triturated with lactose (1:9, w:w). Dose Preparation Gelatin capsules (Torpac, Inc., Fairfield, New Jersey), Size No. 2, Lot No. 122630 (expiration date June 26, 2002), were used for dose administration. The test material triturated with lactose and lactose only (control group) were dispensed into capsules twice weekly and stored at room temperature. Vehicle. Lactose was used as the vehicle in the dose preparations. Dose levels were based on the vehicle as supplied for Group 1. 14 002421 Covance 6329-222 3M T-6295.6 For Group 1 dose preparations, the specified amount of lactose was weighed and transferred into the gelatin capsule. The top and bottom halves of each capsule were joined, and the capsule was placed into the appropriate container labeled with study number, group number, animal number, and dose level. Test Material. For Group 2 and 3 dose preparations, the test material was dissolved in acetone and triturated with lactose (1:999 and 1:9, w:w, respectively) once before initiation of treatment. Acetone (Spectrum, Gardena, California), Lot No. LH0253 (expiration date June 2000) was used to dilute the test material with lactose. Trituration with lactose was necessary to facilitate capsule preparation. For Group 3 dose preparations, the specified amount of test material was weighed, placed into a labeled mixing container, and the appropriate volume of acetone was added to the container. The preparation was stirred manually until the test material was dissolved. The specified amount of lactose was weighed, placed into the mixing container, and thoroughly mixed using a spatula. This preparation was exposed to air until the acetone was evaporated and stirred periodically. Samples of the finished preparation for dose analyses were taken directly from the container. The triturated test material was transferred to a container and stored at room temperature and protected from light and moisture. For Group 2 preparations, the required amount of the Group 3 preparation was measured and placed into a labeled mixing container. The specified amount of lactose was weighed, placed into the mixing container, and thoroughly mixed using a spatula for approximately 5 minutes. Samples of the finished preparation for dose analyses were taken directly from the container. The triturated test material was transferred to a container and stored at room temperature and protected from light and moisture. The specified amount of triturated test material was weighed and transferred into the gelatin capsule. The top and bottom halves of each capsule were joined, and the capsule was placed into the appropriate container labeled with study number, group number, animal number, and dose level. 15 C02422 Covance 6329-222 3M T-6295.6 Dose Analyses Samples (1 g each) were collected from the top, middle, and bottom of the test material/lactose preparations for the low- and high-dose groups and stored at room temperature. The samples were shipped under ambient conditions to the Sponsor for analysis. Homogeneity samples collected from the middle of the preparations were used for the prestudy stability analysis. One set of samples (1 g each) were taken from the low- and high-dose test material/lactose preparations at the end of the in-life phase and shipped to the Sponsor for analysis. Results of the homogeneity, stability, and dose confirmation analyses provided by the Sponsor are in Appendix 7. Method of Administration Gelatin capsules were used for test material preparation administration to compare with data from previous toxicology studies using the oral route, which is the most likely route of exposure. The dose preparations were administered orally in gelatin capsules once daily (7 days/week) for 29 days (see Protocol Deviations for exceptions). The dosing tubes were flushed with 5 mL of reverse osmosis water. Individual doses were calculated based on the most recently recorded body weights, with the exception of body weight collection days when the previous body weight was used. Animals were dosed at approximately the same time each day. Clinical Observations The animals were observed twice daily (a.m. and p.m.) for mortality and moribundity. Each animal was observed daily, and food consumption was assessed qualitatively; abnormal findings were recorded. Animals were observed approximately 30, 60, and 90 minutes postdose for signs of poor health or abnormal behavior. Effects were recorded as they were observed. Animals were observed once weekly; abnormal findings or an indication of normal was recorded. 16 002423 Covance 6329-222 3M T-6295.6 Body Weights Individual body weight data were recorded twice weekly beginning 2 weeks before initiation of treatment (Monday and Thursday), on the first day of treatment, and twice weekly thereafter. An additional body weight was recorded on Day -1 for the Day 1 dose calculations. Rectal Body Temperatures Rectal body temperatures were taken at approximately 11:00 twice weekly beginning 2 weeks before initiation of treatment [Monday and Thursday (see Protocol Deviations for exceptions)]. Animals were not anesthetized for the procedure. Blood Hormone Determination Approximately 5 mL of whole blood were collected from a femoral vein of each animal before initiation of treatment (Day -7) and predose on Day 29. Blood was collected between 07:00 and 09:00. Animals were fasted overnight before collections. All samples were collected without anticoagulant, maintained at room temperature, and allowed to clot. Samples were centrifuged within 1 hour after collection, and serum samples were harvested. Serum was divided into two approximately equal aliquots (blood collected on Day 29 only) and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped to Ani Lytics Inc., for analyses. The samples were analyzed for estradiol, estrone, estriol, thyroid stimulating hormone, triiodothyronine (T3), and thyroxin (T4). Results of these analyses were provided by Ani Lytics Inc., and are in Appendix 6. Serum PFOS Level Determination Approximately 5 (Day -7 only) or 2 mL of whole blood were collected from a femoral vein of each animal before initiation of treatment (Day -7) and predose on Days 2,3 (approximately 24 hours after the first and second dose, respectively), 7,14, and 29. Animals were fasted overnight before collections. All samples were collected without anticoagulant, maintained at room temperature, and allowed to clot. Samples were centrifuged within 1 hour after collection, and serum was harvested and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped to the Sponsor for analyses. The samples were analyzed for PFOS. Results of analyses provided by the Sponsor are in Appendix 8. 17 002424 Covance 6329-222 3M T-6295.6 Clinical Pathology Blood samples were collected from each animal on Days -7 and 29 for hematology and clinical chemistry tests. In addition, blood for clinical chemistry tests was collected from each animal predose on Days 2, 7, and 14. Animals were fasted overnight; water was provided ad libitum. Blood was collected from the femoral vein. The following were evaluated: Hematology red blood cell (erythrocyte) count hemoglobin hematocrit mean corpuscular volume mean corpuscular hemoglobin mean corpuscular hemoglobin concentration platelet count white blood cell (leukocyte) count differential blood cell count segmented neutrophil count lymphocyte count monocyte count eosinophil count basophil count blood cell morphology reticulocyte count Clinical Chemistry glucose urea nitrogen creatinine total protein albumin globulin total bilirubin cholesterol triglycerides aspartate aminotransferase alanine aminotransferase alkaline phosphatase gamma glutamyl transferase sorbitol dehydrogenase creatine kinase calcium inorganic phosphorus sodium potassium chloride serum bile acids amylase lipase pancreatic-specific amylase Additional Blood Collection Whole blood (approximately 20 mL) was collected from the vena cava of each animal at the time of exsanguination (See Protocol Deviations for exceptions). The anticoagulant was potassium EDTA. Samples were transferred into containers (approximately 5 mL each) and stored in a freezer set to maintain -60 to -80 C until packed on dry ice and shipped to the Sponsor possible future analysis. 002425 18 Covance 6329-222 3M T-6295.6 Necropsy On Day 30, animals that were fasted overnight were anesthetized with ketamine and xylazine, weighed, bled for required tests, exsanguinated, and necropsied. Animals were necropsied in random order. The necropsy included a macroscopic examination of the external surface of the body; all orifices; the cranial cavity; the brain and spinal cord; the nasal cavity and paranasal sinuses; cervical tissues and organs; and the thoracic, abdominal, and pelvic cavities and viscera. Palmitoyl CoA Oxidase Determinations A sample of the right lateral lobe of liver was collected from each animal at scheduled sacrifice. The sample was flash-frozen in liquid nitrogen and stored in a freezer set to maintain -60 to -80C until analyzed for palmitoyl CoA oxidase activity. Cell Proliferation Evaluation Representative samples of the liver, testes, and pancreas were collected and preserved in zinc formalin. After fixation, samples for proliferation cell nuclear antigen (PCNA) evaluation were embedded in paraffin and shipped to Pathology Associates International for PCNA evaluation. Results of the evaluation provided by Pathology Associates International are in Appendix 9. Liver PFOS Determination A sample of liver was collected from each animal at sacrifice, weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped with plasma samples to the Sponsor for PFOS analysis. Results of these analyses provided by the Sponsor are in Appendix 8. Tissue Preservation The following tissues (when present) or representative samples were collected and preserved in 10% neutral-buffered formalin, unless otherwise specified, for possible future microscopic examination: 19 002426 adrenal (2) aorta brain cecum cervix colon duodenum epididymis (2) esophagus eyes [preserved in Davidson=s fixative (2)] femur with bone marrow (articular surface of the distal end) gallbladder heart ileum jejunum kidney (2) liver lung lymph node (mesenteric) mammary gland Covance 6329-222 3M T-6295.6 muscle (thigh) ovary (2) pancreas pituitary prostate rectum salivary gland [mandibular (2)] sciatic nerve seminal vesicle (2) skin spinal cord (cervical, thoracic, and lumbar) spleen sternum with bone marrow stomach testis (2) thymus thyroid (2) with parathyroid trachea urinary bladder uterus vagina Histopathology The adrenals, eye, femoral bone marrow, lung, liver, kidney, pancreas, spleen, testes, and thymus were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically from each animal (see Protocol Deviations for exceptions). Bone marrow smears from the sternum of each animal at the scheduled sacrifice were prepared, stained with Wright's stain, and retained for possible examination. Statistical Analyses Only data collected on or after the first day of treatment were analyzed statistically. Statistical analyses were not done on data collected for Group 3 due to the small number of animals. 20 002427 Covance 6329-222 3M T-6295.6 One-way analysis of variance [ANOVA (Winer, 1971a)] was used to analyze initial body weights, rectal body temperature, palmitoyl CoA oxidase activities, and continuous clinical pathology values. Levene's test (Levene, 1960) was done to test for variance homogeneity. In the case of heterogeneity of variance at p < 0.05, transformations were used to stabilize the variance. ANOVA was done on the homogeneous or transformed data. If the ANOVA was significant, Dunnett's t-test (Dunnett, 1964) was used for control versus treated group comparisons. One-way analysis of covariance [ANCOVA (Winer, 1971b)] was used to analyze body weights, with initial body weights as the covariate. Although Levene's test for variance homogeneity was done (see above), no transformations were used because covariance adjustment removed extraneous heterogeneity. If the ANCOVA was significant, least squares means t-test was used for control versus treated group comparisons. For each sex, Group 2 was compared with Group 1 (Control). Group comparisons were evaluated at the 5.0% two-tailed probability level. RECORD RETENTION All raw data, documentation, records, protocol, and specimens generated as a result of this study will be archived in the storage facilities of Covance-Madison for a period of 1 year. One year after the submission of the final report, the Sponsor will determine the final disposition of the materials. All raw data stored on magnetic media and an original copy of the final report will be retained by Covance-Madison. Within 1 year after submission of the final report, all of the aforementioned materials (as appropriate) from the Sponsor's designees (3M E.T. & S, Ani Lyrics Inc., and Pathology Associates International) will be sent to the Sponsor (Andrew Seacat, PhD, 3M). 002428 21 RESULTS Dose Analyses Results of analyses provided by the Sponsor are in Appendix 7. Results of the dose analyses will be provided by the Sponsor. Covance 6329-222 3M T-6295.6 Clinical Observations Clinical observations are summarized in Tables 1 through 5; individual data are in Appendix 2. All animals survived to the scheduled sacrifice. There were no test material-related clinical observations. Body Weights Body weight data are summarized in Table 6; individual data are in Appendix 3. There were no apparent test material-related effects on body weights. Food Consumption Food consumption data are summarized in Table 1 (Summary of Clinical Observations - A.M.AVeekly); individual data are included in the individual clinical observations in Appendix 2. There were no test material-related effects on food consumption. Rectal Body Temperatures Rectal body temperature data are summarized in Tables 7; individual data are in Appendix 2. There were no test material-related effects on rectal body temperatures. 002429 22 Covance 6329-222 3M T-6295.6 Blood Hormone Analyses Summary and individual hormone analyses data are in Appendix 6. Estradiol and triiodothyronine analyses data are illustrated in Figures 1 through 4 (Appendix 6). There were no apparent test material-related effects on estrone, estriol, thyroid stimulating hormone, or thyroxin. There were no apparent test material-related effects on estradiol or triiodothyronine at 0.02 mg/kg/day. Given the low number of animals in this study, it is not possible to determine conclusively whether there was a test material-related effect on estradiol or triiodothyronine. Estradiol levels for the male and female given 2.0 mg/kg/day were numerically lower than those of the control animals on Day 29 and their respective prestudy values. Triiodothyronine levels for the male and female given 2.0 mg/kg/day were numerically lower than those of the control animals on Day 29; however, their prestudy values were also considerably lower than the control values. Triiodothyronine levels for animals given 0 or 0.02 mg/kg/day were numerically higher on Day 29 compared with their prestudy levels while triiodothyronine levels for animals given 2.0 mg/kg/day were numerically lower compared with their prestudy levels. Serum PFOS Level Determination Results of serum PFOS level determination provided by the Sponsor are in Appendix 8. Results of the serum PFOS level determination will be provided by the Sponsor. Clinical Pathology Hematology and clinical chemistry data are summarized in Tables 8 through 15; individual data are in Appendix 4. The Pathology Report contains a discussion of the data. Administration of PFOS had no effects on clinical pathology test results. Cell Proliferation Evaluation Results of cell proliferation evaluation provided by Pathology Associates International are in Appendix 9. 23 002430 Covance 6329-222 3M T-6295.6 Results of the cell proliferation evaluation will be provided by Pathology Associates International. Liver PFOS Determination Results of liver PFOS level determination provided by the Sponsor are in Appendix 8. Results of the liver PFOS level determination will be provided by the Sponsor. Anatomical Pathology Incidences of macroscopic and microscopic observations are summarized in Tables 16 and 17. Individual data are in Appendix 5. The Pathology Report contains a discussion of the data. There were no test material-related macroscopic or microscopic changes in the organs and tissues examined. CONCLUSIONS In cynomolgus monkeys treated with 0,0.02, or 2.0 mg PFOS/kg/day orally for at least 4 weeks, there were no apparent test material-related effects on clinical observations, body weights, food consumption, rectal body temperatures, or clinical or anatomical pathology findings. The one male and one female treated with 2.0 mg PFOS/kg/day appeared to have lower levels of estradiol on Day 29. Data from liver and serum PFOS analyses and cell proliferation evaluations will be provided by the Sponsor and Pathology Associates International, respectively. 002431 24 SIGNATURES Covance 6329-222 3M T-6295.6 Patricia K. McKee Pesik, BS, LAT Study Coordinator Covance Laboratories Inc. Peter J. Thomford, PhD Study Director Covance Laboratories Inc. Date Date 002432 25 Covance 6329-222 3M T-6295.6 REFERENCES Dunnett, C. W., "New Tables for Multiple Comparisons with a Control," Biometrics, 20:482-491 (1964). Levene, H., "Robust Tests for Equality of Variances," Contributions to Probability and Statistics, (eds.) I. Olkin et al., Ch. 25, pp. 278-292, Stanford University Press: Stanford, California (1960). Winer, B. J., "Design and Analysis of Single-Factor Experiments," Statistical Principles in Experimental Design. Second Ed., Ch. 3, pp. 149-260, McGraw-Hill: New York, New York (1971a). Winer, B. J., "Analysis of Covariance," Statistical Principles in Experimental Design, Second Ed., Ch. 10, pp. 752-812, McGraw-Hill: New York, New York (1971b). 002433 26 PATHOLOGY REPORT Covance 6329-222 3M T-6295.6 SUMMARY The purpose of this study was to provide data for determining an estimated maximum-tolerated dose and lower dose levels to be used in a chronic toxicity study and to assess the effect of the test material, Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295), on critical enzyme levels, hormones, and other selected biochemical parameters. Administration of PFOS had no effects on clinical pathology test results and caused no test material-related macroscopic or microscopic changes in the organs and tissues examined. METHODS Three groups of male and female cynomolgus monkeys were administered the test material orally via capsule at a dose level of 0 (control group; received the vehicle, lactose), 0.02, or 2.0 mg/kg of body weight/day (mg/kg/day) for 29 days. The control group had two animals/sex, the low-dose group had three animals/sex, and the high-dose group had one animal/sex. Blood was collected for hematology and clinical chemistry tests before initiation of treatment (Day -7) and on Day 29. In addition, blood for clinical chemistry tests was collected on Days 2, 7, and 14. The animals were sacrificed and necropsied on Day 30; macroscopic observations were recorded, and tissues were preserved in fixative as specified by the protocol. Samples of liver were collected and frozen for determination of hepatic palmitoyl CoA oxidase activity and for determination of PFOS content (by the Sponsor). Samples of liver, testes, and pancreas were collected and preserved in zinc formalin for evaluation of proliferation cell nuclear antigen (PCNA; by Pathology Associates International). Microscopic examinations were done on adrenals, eye, femoral bone marrow, lung, liver, kidney, pancreas, spleen, testes, and thymus from all animals. Results of clinical pathology tests for the control and low-dose groups were compared statistically. 02434 27 RESULTS AND DISCUSSION Mortality All animals survived to the scheduled sacrifice. Covance 6329-222 3M T-6295.6 Clinical Pathology Individual values for hematology and clinical chemistry tests are in Appendix 4. Mean values and the results of statistical comparisons are in Tables 8 through 15. Day -7. Clinical pathology test results indicated no obvious group or individual health abnormalities. Days 2,7, and 14. Administration of the test material had no effects on clinical chemistry test results at these collection intervals. Statistically significant differences for clinical chemistry results between the control and low-dose groups were inconsistent over time and between the sexes. Several of the differences were similar to differences present at Day -7, and none of the differences exhibited a strong dose relationship (i.e., the high-dose animals did not exhibit notable differences for the same parameters). Day 29. Administration of the test material had no effects on hematology or clinical chemistry test results at Day 29. Statistically significant differences for red blood cell count, neutrophil count, monocyte count, and hepatic palmitoyl CoA oxidase were inconsistent between the sexes and exhibited no dose relationship. Statistically significant differences for triglycerides and alkaline phosphatase were similar to differences observed at Day -7. Anatomical Pathology Anatomical pathology findings for each animal are in Appendix 5. Incidence summaries of the macroscopic and microscopic observations are in Tables 16 and 17. 002435 28 Covance 6329-222 3M T-6295.6 Week 5. There were no macroscopic and few microscopic findings in the organs and tissues examined, and there were no major differences between control and treated animals in the incidence of any finding. All microscopic observations were considered incidental and unrelated to the test material. Robert L. Hall, DVM, PhD Diplomate, ACVP Clinical Pathology Thomas E. Palmer, PhD Pathologist Date Date 002436 29 COMMENTS ON THE DATA Covance 6329-222 3M T-6295.6 Various models of calculators, computers, and computer programs were used to analyze data in this study. Because different models round off or truncate numbers differently, values in some tables (e.g., means, standard deviations, or individual values) may differ slightly from those in other tables, from individually calculated data, or from statistical analysis data. Neither the integrity nor the interpretation of the data was affected by these differences. Some tabular data were compiled using Excel7Version 7.0 software. The summary tables for clinical observations indicate the number of animals for which a condition was observed without regard to the specific nature, severity, reversibility, number of incidences/animal, or the length of time the condition persisted. Only observations other than normal are indicated on the summary clinical observations tables. The day of initiation of treatment is "Day 1." 002437 30 CODES, ABBREVIATIONS, AND UNITS Covance 6329-222 3M T-6295.6 General Codes and Abbreviations Codes for Clinical Pathology Abbreviations and Units for Clinical Hematology Abbreviations and Units for Clinical Chemistry Codes for Anatomical Pathology Note: The following lists of codes, abbreviations, and units are used by Covance. Some, but not necessarily all, of this information may be needed for this report. 002438 31 Covance 6329-222 3M T-6295.6 General Codes and Abbreviations WK N Mean; MEAN CAM SD; S.D.; STAND DEV; STANDARD DEV; sd -; NA P UNSCHED DISPATCH MIN OBS Week. Number of measurements in a group. Arithmetic mean. Covariate-adjusted mean. Standard deviation. Group 2 mean is significantly different from the mean of the control group (Group 1) at p # 0.05. No value; not applicable; not present. Present. Unscheduled. Observations transferred from the in-life module of the data collection system to the necropsy module for reference during necropsy. Observations are duplicates of the last in-life observations. Minute. Observation. Animal Death Codes: T Terminal sacrifice. 002439 32 NS QS/QNS NR FS SC SH H SL L SI I NF U DT/DOT DB TJ TE RE EE SE PC PD PI PL PA CO HB PLASMO NO AGG FR UTD NO COAG Covance 6329-222 3M T-6295.6 Codes for Clinical Pathology GENERAL CODES No sample Quantity not sufficient No repeat (sample volume not sufficient for repeat analysis) Fibrin strands Sample clotted Slightly hemolyzed Hemolyzed Slightly lipemic Lipemic Slightly icteric Icteric Animal not fasted Unscheduled/moribund bleed Animal died on test Died during bleeding Technician judgment to repeat test Technical error (instrument or technician error that results in unacceptable data, e.g., unacceptable instrument output, sample spilled, entry of invalid data) Recording error (recorded incorrect data, e.g., wrong number, spelling error, incorrect date) Entry error (incorrect keyboard entry) Sampling error Platelets clumped Platelets decreased Platelets increased Platelets large Platelets appear adequate Color interferes with test Heinz bodies observed Plasmodium No aggregation Fractious Unable to determine No coagulation 002440 33 Covance 6329-222 3M T-6295.6 Codes for Clinical Pathology (Continued) RESULTS NOT INCLUDED IN STATISTICAL ANALYSES Hemolyzed clinical chemistry or coagulation samples Samples from animals at unscheduled intervals Prothrombin times (PT) greater than 50 seconds Activated partial thromboplastin times (PTT) greater than 110 seconds Bleed times (BLETIME) greater than 30 minutes CODES FOR BLOOD CELL MORPHOLOGY The following scale was used to measure the degree of anisocytosis (ANISO), poikilocytosis (POIK), polychromasia (POLY), hypochromasia (HYPO), and toxic neutrophils (TOXNEUT): Scale - 1 2 3 4 Degree Normal for the species Slight Moderate Marked Not applicable Presence Not present Rare Few Moderate Many 002441 34 Covance 6329-222 3M T-6295.6 Abbreviations and Units for Clinical Hematology Test Red blood cell count Hemoglobin Hematocrit Mean corpuscular volume Mean corpuscular hemoglobin Mean corpuscular hemoglobin concentration Platelet count Mean platelet volume Reticulocyte count Absolute reticulocyte count Heinz body count Erythrocyte sedimentation rate Prothrombin time Activated partial thromboplastin time Thrombin time Activated coagulation time Fibrinogen Fibrin/fibrinogen degradation products Platelet aggregation Collagen Adenosine diphosphate Alpha 2-antiplasmin Bleeding time Methemoglobin Plasma hemoglobin Myeloid/erythroid ratio Estimated myeloid/erythroid ratio White blood cell count Differential blood cell count Nucleated red blood cell count Corrected white blood cell count Segmented neutrophil count Band neutrophil count Lymphocyte count Monocyte count Eosinophil count Basophil count Anisocytosis Polychromasia 35 Abbreviation (Units) RBC (E6/UL or X106/<i>L) HGB (G/DL) HCT (%) MCV (FL) MCH (PG) MCHC (%) PLT (E3/UL or X103/OL) MPV(FL) RETIC (%) RETIC (E3/UL or X103/<DL) HEINZ (%) ESR (MM/HR) PT (SEC) PTT (SEC) TT (SEC) ACT (SEC) FBR (MG/DL) FDP (UG/ML) PAGG/COL (%) PAGG/ADP (%) ANTIPLAS (%) BLE TIME (SEC) METHGB (%) PLA HGB (MG/DL) M/E RATIO EST M/E RATIO WBC (E3/UL or X103/<DL) NRBC (/100 WBC) COR WBC (E3/UL or X103M>L) N-SEG (E3/UL or X103/0>L) and % N-BAND (E3/UL or XIOVOL) and % LYMPH (E3/UL or X103M>L) and % MONO (E3/UL or X103M>L) and % EOSIN (E3/UL or X103/<L) and % BASO (E3/UL or X103/d>L) and % ANISO (-,1,2,3) POLY (-,1,2,3) 002442 Covance 6329-222 3M T-6295.6 Abbreviations and Units for Clinical Hematology (Continued) Test Poikilocytosis Hypochromasia Howell-Jolly bodies Basophilic stippling Toxic neutrophils Atypical lymphocytes Aqueous white blood cell count (right eye) Aqueous white blood cell count (left eye) Abbreviation (Units) POIK (-,1,2,3) HYPO (-,1,2,3) HJBODY (-,1,2,3,4) BASTIP (-,1,2,3) TOXNEUT (-,1,2,3,4) ATYPLYM (-,1,2,3,4) R EYE (WBC/UL) L EYE (WBC/UL) 002443 36 Covance 6329-222 3M T-6295.6 Abbreviations and Units for Clinical Chemistry Test Glucose Urea nitrogen Urea Creatinine Total protein Albumin Globulin Albumin/globulin ratio Total bilirubin Direct bilirubin Indirect bilirubin Cholesterol Triglyceride Urea nitrogen/creatinine ratio Total lipids Phospholipids High-density lipoprotein cholesterol Low-density lipoprotein cholesterol Uric acid Aspartate aminotransferase Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transferase Sorbitol dehydrogenase Lactate dehydrogenase Creatine kinase Amylase Lipase Palmitoyl CoA oxidase Calcium Ionized calcium Inorganic phosphorus Sodium Potassium Chloride Magnesium Zinc Strontium Iron Abbreviation (Units) GLU (MG/DL) UN (MG/DL) UREA (MG/DL) CREAT (MG/DL) T PRO (G/DL) ALB (G/DL) GLOB (G/DL) a /g Ra t io TBILI (MG/DL) D BJLI (MG/DL) IBILI (MG/DL) CHOL (MG/DL) TRIG (MG/DL) UN/CREAT (RATIO) T LIPIDS (MG/DL) P LIPIDS (MG/DL) HDL (MG/DL) LDL (MG/DL) UA (MG/DL) AST/SGOT (IU/L) ALT/SGPT (IU/L) ALK PHOS (IU/L) GGT (IU/L) SDH (IU/L) LDH (IU/L) CK (IU/L) AMYLASE (IU/L) LIPASE (IU/L) PCOAO (IU/G) CA (MG/DL) ION CA (MG/DL) I PHOS (MG/DL) NA (MMOL/L) K (MMOL/L) CL (MMOL/L) MG (MEQ/L or MG/DL) ZN (MG/L or PPM) SR (MG/L or PPM) FE (UG/DL) 002444 37 Covance 6329-222 3M T-6295.6 Abbreviations and Units for Clinical Chemistry (Continued) Test Excess iron Total iron binding capacity Unbound iron binding capacity Percent iron saturation Plasma cholinesterase Red blood cell cholinesterase Brain cholinesterase Caudate putamen Hippocampus Frontal cortex Cerebellum Bicarbonate Serum hemoglobin Serum bile acids Fecal bile acids Average fecal weight Fecal bile acids (calculation) Osmolality Electrophoresis Albumin Alpha-1-globulin Alpha-2-globulin Beta globulin Gamma globulin High-density lipoprotein Low-density lipoprotein Very-low-density lipoprotein Insulin Adrenocorticotropic hormone Cortisol Glucagon Triiodothyronine Thyroxine Pancreatic-specific amylase Creatine kinase isoenzymes BB MB MM Abbreviation (Units) EX FE (UG/DL) TIBC (UG/DL) UIBC (UG/DL) FE %SAT (%) CHEP (MU/ML) CHER (MU/ML) CHEB (MU/ML) CAUD PUT (UMOL/G) HIPPOCAM (UMOL/G) F CORTEX (UMOL/G) CEREBELL (UMOL/G) BICARB (MMOL/L) SER HGB (MG/DL) SBA (UMOL/L or MG/DL) FBA (UG/ML) FCC WGT (G) FBA (MG/Day) OSMO (MOSM/KG) E ALB (G/DL) E A-l (G/DL) E A-2 (G/DL) E BETA (G/DL) E GAMMA (G/DL) E-HDL (%) E-LDL (%) E-VLDL (%) INSULIN (UU/ML) ACTH (PG/ML) CORTISOL (UG/ML) GLUCAGON (PG/ML) T3 (NG/DL) T4 (UG/DL) P AMYL (U/L) CK-BB (U/L) CK-MB (U/L) CK-MM (U/L) 002445 38 Covance 6329-222 3M T-6295.6 Codes for Anatomical Pathology MICROSCOPIC CODES Distribution of Findings Focal Diffuse Multifocal Grades for Severity or Amount 1 Minimal - the least amount of change that can be observed with the light microscope 2 Slight - less than average amount of change, but readily discernible as abnormal 3 Moderate - the average amount of change that is expected for a lesion 4 Moderately severe (marked) - a marked amount of change with possible loss of function of the affected cells or organs 5 Severe - a great amount of change with probable loss of function of the affected cell or organs and frequently involves large areas of the organ 002446 39 002447 Table 1 Summary of Clinical Observations A.M./Weekly 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS DAYS 1-30 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** APPEARANCE SWOLLEN LIP(SJ DISCHARGE VOMITUS CONTAINING FOOD APPEARS TO BE MENSTRUATING DISCHARGE UNKNOWN SOURCE FOUND IN PAN RED IN COLOR EXCRETION FEW FECES NON-FORMED FECES SKIN & PELAGE RED SKIN LIP(S) SCAB(S) MOUTH QUALITATIVE FOOD CONSUMPTION LOW *** END OF LIST *** SEX: GROUP : DOSE: NUMBER: NUMBER OF ANIMALS AFFECTED --MALE- -- 123 0 0.02 2 -- -FEMALE-123 0 0.02 2 231231 000100 001000 000010 001000 000001 000200 000100 000100 010101 40 Covance 6329-222 3M T-6295.6 PAGE: 1 DAYS 1-29 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** APPEARANCE SWOLLEN LIP(S) EXCRETION NON-FORMED FECES SKIN & PELAGE RED SKIN LIP(S) SCAB (S ) MOUTH *** END OF LIST *** Table 2 Summary of Clinical Observations 30 Minutes Postdose 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS SEX: GROUP: DOSE: NUMBER: NUMBER OF ANIMALS AFFECTED --MALE- -- 123 0 0.02 2 -- -FEMALE-123 0 0.02 2 231231 000100 000100 000100 000100 Covance 6329-222 3M T-6295.6 PAGE: 1 002448 41 DAYS 1-29 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** APPEARANCE SWOLLEN LIP(S) EXCRETION MUCOID FECES SKIN & PELAGE RED SKIN L I P {S) SCAB(S ) MOUTH *** END OF LIST *** Table 3 Summary of Clinical Observations 60 Minutes Postdose 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS SEX: GROUP : DOSE: NUMBER: NUMBER OF ANIMALS AFFECTED --MALE- -- 123 0 0.02 2 -- -FEMALE-123 0 0.02 2 23 123 1 000100 100000 000100 000100 Covance 6329-222 3M T-6295.6 PAGE: 1 002449 42 DAYS 1-29 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** APPEARANCE SWOLLEN LIP (S) SKIN & PELAGE RED SKIN LIP(S) SCAB(S) MOUTH *** END OF LIST *** Table 4 Summary of Clinical Observations 90 Minutes Postdose 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLU0R00CTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS SEX: GROUP: DOSE: NUMBER: NUMBER OF ANIMALS AFFECTED --MALE- -- i23 0 0.02 2 -- -FEMALE-123 0 0.02 2 231231 000100 000100 000100 Covance 6329-222 3M T-6295.6 PAGE: 1 002450 43 DAYS 1-30 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** DISCHARGE VOMITUS CONTAINING FOOD *** END OF LIST *** Table 5 Summary of Clinical Observations Unscheduled 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS SEX: GROUP: DOSE: NUMBER: NUMBER OF ANIMALS AFFECTED --MALE- -- 123 0 0.02 2 -- -FEMALE-123 0 0.02 2 231231 010000 Covance 6329-222 3M T-6295.6 PAGE: 1 002451 44 002452 Table 6 Summary of Body Weight Data (kg) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC-ACID POTASSIUM SALT (PFOS;T--6295) IN CYNOMOLGUS MONKEYS SEX: GROUP : DOSE: 1 0 2 0.02 3 2 12 0 0.02 3 2 DAY UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY -14 N MEAN S.D. -10 N MEAN S.D. -7 N MEAN S.D. -3 N MEAN S.D. -1 N MEAN S.D. 1N MEAN S.D. 5N CAM MEAN S.D. 2 2.3 0.00 2 2.3 0.07 2 2.3 0.07 2 2.3 0.07 2 2.3 0.00 2 2.3 0.14 2 2.3 2.3 0.07 3 2.3 0.21 3 2.3 0.21 3 2.3 0.21 3 2.3 0.21 3 2.4 0.25 3 2.3 0.21 3 2.3 2.3 0.17 1 2.2 1 2.2 1 2.2 1 2.2 1 2.2 1 2.2 1 2.2 2 2.1 0.07 2 2.1 0.07 2 2.1 0.00 2 2.1 0.00 2 2.1 0.00 2 2.1 0.00 2 2.0 2.0 0.00 3 2.1 0.17 3 2.1 0.10 3 2.1 0.15 3 2.1 0.15 3 2.1 0.20 3 2.2 0.15 3 2.1 2.1 0.15 1 2.2 1 2.1 1 2.2 1 2.1 1 2.2 1 2.2 1 2.1 45 Covance 6329-222 3M T-6295.6 PAGE: 1 frzoo Table 6 Summary of Body Weight Data (kg) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T--6295) IN CYNOMOLGUS MONKEYS SEX: GROUP: DOSE: 1 0 2 0.02 3 2 12 0 0.02 3 2 DAY UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY 8N CAM MEAN S.D. 12 N CAM MEAN S.D. 15 N CAM MEAN S.D. 19 N CAM MEAN S.D. 22 N CAM MEAN S.D. 26 N CAM MEAN S.D. 29 N CAM MEAN S.D. 2 2.5 2.5 0.07 2 2.5 2.5 0.07 2 2.4 2.4 0.14 2 2.5 2.5 0.07 2 2.5 2.5 0.07 2 2.5 2.5 0.07 2 2.4 2.4 0.07 3 2.4 2.4 0.12 3 2.3* 2.3 0.12 3 2.4 2.4 0.06 3 2.4 2.4 0.0 3 2.4 2.4 0.10 3 2.4 2.4 0.10 3 2.4 2.4 0.06 1 2.3 1 2.2 1 2.3 1 2.3 1 2.1 1 2.1 1 2.0 2 2.2 2.2 0.07 2 2.1 2.1 0.00 2 2.2 2.2 0.07 2 2.1 2.1 0.00 2 2.2 2.2 0.07 2 2.2 2.2 0.07 2 2.1 2.1 0.00 3 2.2 2.2 0.20 3 2.1 2.2 0.15 3 2.2 2.2 0.20 3 2.3 2.3 0.17 3 2.2 2.2 0.15 3 2.2 2.2 0.15 3 2.1 2.1 0.15 1 2.2 1 2.2 1 2.1 1 2.3 1 2.1 1 2.1 1 2.1 46 Covance 6329-222 3M T-6295.6 PAGE: 2 Table 7 Summary of Rectal Body Temperature Data (C) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS T-6295) IN CYNOMOLGUS MONKEYS SEX: GROUP: DOSE: DAY UNITS: 1 0 MG/KG/DAY 2 0.02 MG/KG/DAY 3 2 MG/KG/DAY 1 0 MG/KG/DAY 2 0.02 MG/KG/DAY 3 2 MG/KG/DAY -14 N MEAN S.D. -10 N MEAN S.D. -7 N MEAN S.D. -3 N MEAN S.D. 1N MEAN S.D. 5N MEAN S.D. 8N MEAN S.D. 2 39.8 0.28 2 40.0 0.35 2 39.8 0.57 2 39.6 0.28 2 39.0 0.57 2 38.9 0.07 2 38.5 0.35 3 39.2 0.57 3 39.2 0.40 3 39.0 0.72 3 39.2 0.45 3 39.4 0.30 3 39.1 0.59 3 39.2 0.40 1 39.6 1 39.5 1 39.1 1 39.2 1 39.4 1 39.9 1 39.6 2 40.2 0.28 2 39.8 0.49 2 39.9 0.21 2 39.8 0.49 2 39.6 0.35 2 39.0 0.35 2 39.1 0.42 3 40.1 0.50 3 39.7 0.55 3 40.0 0.38 3 39.8 0.10 3 39.9 0.29 3 39.8 0.25 3 39.8 0.21 1 40.0 1 39.8 1 39.9 1 39.7 1 39.5 1 39.7 1 39.9 Covance 6329-222 3M T-6295.6 PAGE: 1 002454 47 Table 7 Summary of Rectal Body Temperature Data (C) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS T-6295) IN CYNOMOLGUS MONKEYS SEX: ---MALE----- --FEMALE--- GROUP: i 2 3 1 2 3 DOSE: 0 0.02 2 0 0.02 2 DAY UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY 12 N MEAN S.D. 15 N MEAN S.D. 19 N MEAN S.D. 22 N MEAN S.D. 26 N MEAN S.D. 29 N MEAN S.D. 2 39.0 0.07 2 39.7 0.00 2 38.7 0.21 2 39.4 0.21 2 38.8 0.07 2 38.5 0.42 3 39.1 0.47 3 39.7 0.42 3 38.7 0.64 3 39.5 0.57 3 39.2 0.38 3 38.8 0.35 1 40.0 1 39.7 1 38.9 1 39.4 1 39.2 1 38.9 2 39.2 0.14 2 39.7 0.57 2 39.0 0.35 2 39.6 0.42 2 39.0 0.35 2 38.8 0.14 3 39.8 0.25 3 40.0 0.20 3 39.3 0.21 3 39.8 0.25 3 39.6 0.15 3 39.1 0.38 1 39.7 1 39.8 1 39.3 1 39.4 1 39.1 1 39.2 Covance 6329-222 3M T-6295.6 PAGE: 2 002455 48 Table 8 Summary of Clinical Hematology Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC mg/kg/day XlOVfiL G/DL % FL PG % XIOV^L % xioV ul 0 MEAN S.D. N 0.02 MEAN S.D. N 5.64 .332 2 5.18 .272 3 14.0 1.41 2 12.6 .31 3 42.6 3.82 2 39.1 .90 3 75.4 2.26 2 75.4 2.21 3 24.8 1.06 2 24.4 1.10 3 32.9 .42 2 32.4 .91 3 502 138.6 2 454 88.1 3 .9 .00 2 .9 .53 3 51 2.8 2 46 26.1 3 to o MEAN 5.91 12.8 41.0 69.4 21.7 31.2 531 .7 41 N 111 111111 002456 49 Table 8 Summary of Clinical Hematology Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE WBC mg/kg/day X103/|1L N-SEG XIOVuL LYMPH xioV ul MONO XlOVnL EOSIN BASO XIO'/JIL X103/|1L N-SEG% LYMPH% MONO% EOSIN% BASO% 0 MEAN 8.4 3.4 4.6 .4 .1 .0 40 54 4 1 0 S.D. .99 1.06 .07 .07 .14 .00 7.8 7.1 .7 1.4 .0 N 22222222222 0.02 MEAN 9.2 2.9 5.8 .4 .1 .0 31 63 4 1 0 S.D. 1.00 1.33 1.46 .20 .10 .00 16.5 14.6 2.0 1.0 .0 N 33333333333 2.0 MEAN 8.2 2.8 4.8 .6 .0 .0 34 58 8 0 0 N 11111111111 002457 50 Table 8 Summary of Clinical Hematology Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC mg/kg/day XlOVjtL G/DL % FL PG % XIO3/ ^ % x i o 3/m l 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 5.25 .325 2 5.00 .241 3 5.53 1 13.3 1.34 2 12.8 .21 3 13.4 1 40.4 3.96 2 39.1 .21 3 40.2 1 76.9 2.69 2 78.2 3.30 3 72.7 1 25.4 .92 2 25.6 1.55 3 24.2 1 33.1 .00 2 32.7 .56 3 33.3 1 478 180.3 2 430 121.3 3 505 1 .8 .21 2 .7 .17 3 .8 1 45 14.1 2 35 8.5 3 44 1 002458 51 Table 8 Summary of Clinical Hematology Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLU0R00CTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-629S) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE mg/kg/day 0 MEAN S.D. N 0.02 MEAN S.D. N WBC XlOVnL 9.0 1.48 2 10.2 1.97 3 N-SEG xioV ul LYMPH X103/|iL 3.6 1.91 2 5.1 .14 2 3.5 3.29 3 6.2 4.05 3 MONO X10 3/ \ ih EOSIN XioVjiL BASO x i o 3/h l N-SEG% LYMPH% MONO% EOSIN% BASO% .2 .0 .0 38 58 20 0 .28 .07 .00 14.8 11.3 3.5 .7 .0 22 222 222 .4 .1 .0 36 59 41 0 .12 .10 .00 34.2 32.9 1.5 1.0 .0 33333 333 MEAN 11.7 6.2 4.8 .4 .2 .0 53 42 410 N 11 111111 111 to o 002459 52 Table 9 Summary of Clinical Hematology Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC mg/kg/day XlOVflL G/DL % FL PG % X103/|1L % XlOVjlL 0 MEAN S.D. N 0.02 MEAN S.D. N MEAN N 6.02 .035 2 14.0 .64 2 5.12 * .262 3 12.6 .78 3 5.69 1 13.2 1 44.0 1.84 2 39.1 2.18 3 41.5 1 72.9 2.69 2 76.4 1.69 3 73.1 1 23.3 .99 2 24.6 .61 3 23.1 1 31.9 .21 2 32.2 .26 3 31.7 1 440 116.7 2 392 92.1 3 503 1 .8 .14 2 .5 .35 3 .2 1 48 8 2 28 19 3 11 1 o CM 002460 53 Table 9 Summary of Clinical Hematology Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE WBC mg/kg/day XlOVfiL N-SEG XIOVjlL LYMPH XlOVnL MONO XlOVnL EOSIN xioV ml BASO XlOVjiL N-SEG% LYMPH% MONO% EOSIN% BASO% 0 MEAN 9.2 1.6 6.8 .6 .2 .0 18 74 62 0 S.D. .21 .49 .78 .21 .14 .00 5.7 7.1 2.8 1.4 .0 N 22222222222 0.02 MEAN 8.8 1.0 6.9 .6 .2 .0 13 78 6 2 0 S.D. 2.44 .15 2.27 .38 .10 .00 6.1 5.5 2.3 1.0 .0 N 33333333333 2.0 MEAN 5.8 .9 4.4 .4 .0 .0 16 77 7 0 0 N 11111111111 002461 54 Table 9 Summary of Clinical Hematology Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC mg/kg/day XloVnL G/DL % FL PG % XlOVflL % Xl03/)iL 0 MEAN S.D. N 0,02 MEAN S.D. N MEAN N 5,14 .170 2 5.13 .116 3 4.81 1 13.2 .78 2 13.1 .87 3 12.3 1 40.5 2.33 2 41.1 1.74 3 36.7 1 78.9 2.12 2 80.1 3.93 3 76.4 1 25.6 .71 2 25.5 1.80 3 25.6 1 32.5 .00 2 31.9 .81 3 33.6 1 511 182.4 2 425 116.7 3 529 1 1.2 .21 2 .8 .26 3 1.0 1 59 12.7 2 41 14.0 3 48 1 002462 55 Table 9 Summary of Clinical Hematology Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE WBC mg/kg/day XIOVjlL N-SEG X103/HL LYMPH XloVjiL MONO X10V|IL EOSIN x i o 3/h l BASO X103/JlL N-SEG% LYMPH% MONO% EOSIN% BASO% 0 MEAN 11.1 3.8 6.2 1.0 .0 .0 36 54 10 0 0 S.D. 2.69 .14 2.55 .21 .00 .00 10.6 10.6 .7 .0 .0 N 22222222222 0.02 MEAN S.D. N 10.0 2.55 3 2.2 * .45 3 7.1 2.67 3 .6 * .06 3 .1 .00 3 .0 22 70 6 .00 7.6 9.2 2.1 3333 10 .0 .0 33 2.0 MEAN 15.7 7.2 7.9 .5 .1 .0 46 50 3 1 0 N 11111111111 002463 56 DOSE mg/kg/day GLU MG/DL Table 10 Summary of Clinical Chemistry Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S.D. N 82 19.1 2 24 1.4 2 1.0 .07 2 8.2 .00 2 5.2 .00 2 3.0 .00 2 .2 .07 2 8 155 .7 62.2 22 64 24 2 0.02 MEAN S.D. N 61 13.2 3 29 2.0 3 1.0 .06 3 7.7 .06 3 4.8 .29 3 3.0 .32 3 .3 .06 3 9 161 1.5 35.4 33 85 22 3 2.0 MEAN 54 28 1.0 8.2 5.0 3.2 .4 10 150 68 N 1111111111 002464 57 Table 10 Summary of Clinical Chemistry Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 48 4.9 2 50 7.6 3 54 1 40 9.2 2 612 36.1 2 58 13.0 3 681 81.1 3 50 1086 11 88 4.9 2 101 36.7 3 117 1 4 228 424 .7 102.5 99.7 222 6 214 315 1.2 17.2 63.1 333 5 220 244 111 64 37.5 2 62 61.2 3 7 1 291 69.3 2 223 50.1 3 144 1 29^200 58 Table 10 Summary of Clinical Chemistry Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.7 .14 2 10.6 .52 3 11.4 1 7.2 .57 2 7.7 .71 3 8.7 1 162 2.1 2 159 5.0 3 162 1 5.8 .07 2 5.6 .47 3 5.9 1 110 .0 2 112 4.6 3 111 1 Covance 6329-222 3M T-6295.6 002466 59 DOSE mg/kg/day GLU MG/DL Table 10 Summary of Clinical Chemistry Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S.D. N 0.02 MEAN S.D. N 76 8.5 2 64 9.0 3 24 .0 2 26 4.6 3 1.0 .14 2 .9 .06 3 8.0 .49 2 7.9 .30 3 5.1 .42 2 4.9 .26 3 2.8 .07 2 3.0 .10 3 .5 .28 2 .4 .06 3 4 142 5.7 15.6 22 9 154 2.1 34.6 33 76 14 2 69 35 3 MEAN N 71 1 27 1.0 8.2 4.9 3.3 11111 .3 12 141 111 67 1 to o 002467 60 Table 10 Summary of Clinical Chemistry Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 99 76.4 2 58 6.7 3 53 1 53 21.2 2 58 14.2 3 55 1 593 66.5 2 828 65.5 3 683 1 80 2.1 2 74 10.1 3 110 1 6 1907 4.9 2286.8 22 4 385 1.0 163.0 33 3 1094 11 334 31.1 2 324 44.1 3 315 1 10 10.6 2 64 81.8 3 89 1 232 21 2 215 19 3 224 1 002468 61 Table 10 Summary of Clinical Chemistry Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 11.0 .49 2 11.0 .59 3 11.3 1 7.4 1.27 2 8.0 1.72 3 6.8 1 159 2.8 2 158 6.7 3 165 1 7.2 1.91 2 5.8 .64 3 6.0 1 113 2.8 2 114 4.0 3 115 1 Covance 6329-222 3M T-6295.6 002469 62 DOSE mg/kg/day GLU MG/DL Table 11 Summary of Clinical Chemistry Data Males Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T -6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 57 25 .9 7.4 5.0 2.4 7.1 5. 7 .00 .07 .07 .00 222222 62 24 .8 7.0 * 4.5 * 2.6 6.0 2. 3 .06 .12 .12 .23 333333 58 21 .9 7.3 4.7 2.6 1 11 1 11 .4 16 142 80 .07 4.,2 64.3 48 222 2 .3 10 * 163 69 .06 .6 18.3 18 3333 .4 9 151 50 111 1 002470 63 Table 11 Summary of Clinical Chemistry Data Males Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 75 14.1 2 41 2.5 3 54 1 56 21.2 2 726 48.8 2 56 14.8 3 599 82.7 3 55 1028 11 84 6.4 2 88 31.8 3 105 1 2 ,7 2 2 .0 3 2 1 899 5.7 2 579 391.1 3 219 1 412 69.3 2 289 51.3 3 302 1 31 5.7 2 40 19.6 3 11 1 256 40.3 2 180 30.7 3 139 1 002471 64 Table 11 Summary of Clinical Chemistry Data Males Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.2 .14 2 9.5 * .26 3 10.0 1 6.8 1.06 2 6.7 .31 3 7.0 1 152 1.4 2 147 2.5 3 152 1 5.2 .07 2 4.7 .25 3 5.0 1 106 .7 2 108 4.0 3 104 1 Covance 6329-222 3M T-6295.6 frZOO w 65 DOSE mg/kg/day GLU MG/DL Table 11 Summary of Clinical Chemistry Data Females Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLU0R00CTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S.D. N 70 19 .8 7.4 4.9 2.5 14.1 .0 .07 .42 .28 .14 222222 .4 .07 2 8 145 .7 2.8 22 42 11.3 2 0.02 MEAN 57 24 .8 7.3 4.7 2.6 .5 16 * 133 69 S.D. 3.5 3.5 .06 .15 .30 .23 .06 1.0 28.2 33.7 N 3333333333 MEAN 68 27 1.0 7.5 4.7 2.8 .4 17 136 47 N 1111111111 to o 002473 66 Table 11 Summary of Clinical Chemistry Data Females Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 58 18.4 2 54 4.5 3 46 1 72 43.1 2 57 16.9 3 55 1 578 123.0 2 805 65.3 3 672 1 81 5.7 2 69 8.1 3 100 1 2 523 502 .7 15.6 138.6 222 2 426 351 .6 133.3 46.2 333 2 308 291 111 39 5.7 2 31 9.2 3 84 1 324 96.9 2 208 24.7 3 184 1 002474 67 Table 11 Summary of Clinical Chemistry Data Females Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.2 .71 2 10.0 .25 3 10.0 1 6.7 .28 2 7.6 .85 3 6.5 1 153 4.2 2 151 6.2 3 151 1 5.4 .64 2 4.9 .21 3 4.7 1 108 .0 2 105 2.3 3 106 1 Covance 6329-222 3M T-6295.6 002475 68 DOSE mg/kg/day GLU MG/DL Table 12 Summary of Clinical Chemistry Data Males Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN 81 20 .8 7.8 4.8 3.0 .2 10 138 52 S.D. 4.2 .0 .07 .28 .21 .07 .07 4.9 65.8 7.1 N 2222222222 0.02 MEAN 68 * 21 .8 7.5 4.5 * 3.1 .3 10 156 51 S.D. 3.1 1.5 .06 .25 .06 .25 .00 1.2 19.3 1.5 N 3333333333 2.0 MEAN 63 18 .8 7.5 4.6 2.9 .4 N 1111111 7 137 11 50 1 002476 69 Table 12 Summary of Clinical Chemistry Data Males Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 51 15.6 2 39 3.8 3 46 1 46 13.4 2 770 78.5 2 57 15.0 3 556 106.4 3 49 1012 11 80 .0 2 85 34.6 3 98 1 0 249 .0 79.2 22 0 399 .0 415.4 33 0 27 0 11 397 67.9 2 327 35.6 3 260 1 33 7.1 2 31 13.5 3 0 1 272 48.1 2 225 24.1 3 139 1 002477 70 Table 12 Summary of Clinical Chemistry Data Males Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N MEAN N 10.2 .35 2 9.8 .32 3 10.3 1 7.0 .49 2 7.0 .35 3 6.6 1 156 3.5 2 152 3.6 3 156 1 5.2 .21 2 4.8 .29 3 5.1 1 112 .0 2 112 2.5 3 112 1 to o Covance 6329-222 3M T-6295.6 002478 71 DOSE mg/kg/day GLU MG/DL Table 12 Suinmary of Clinical Chemistry Data Females Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S-D. N 86 20 .8 8.0 4.6 3.5 9.2 6.4 .00 .07 .49 .42 222222 .2 .07 2 7 130 1.4 2.1 22 32 13.4 2 0.02 MEAN S.D. N 73 4.6 3 19 1.5 3 .8 8.0 .10 .17 33 4.8 .31 3 3.2 .15 3 .3 .06 3 8 147 .0 31.3 33 38 6.8 3 2.0 MEAN 73 18 .8 7.9 4.6 3.3 .3 12 117 44 N 1111111 111 002479 72 Table 12 Summary of Clinical Chemistry Data Females Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 46 .7 2 49 8.1 3 45 1 52 13.4 2 57 6.9 3 57 1 558 94.0 2 775 108.2 3 674 1 69 8.5 2 68 9.6 3 90 1 0 142 434 .7 55.2 26.9 222 30 10.6 2 303 26.9 2 0 218 356 * .6 27.8 18.9 333 25 5.1 3 231 34.1 3 0 166 349 101 238 11111 002450 73 Table 12 Summary of Clinical Chemistry Data Females Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 11.0 .78 2 10.7 .40 3 10.6 1 6.1 .57 2 7.3 .78 3 6.4 1 156 2.1 2 155 6.1 3 155 1 6.4 .92 2 5.5 .20 3 5.3 1 112 .7 2 113 1.5 3 113 1 Covance 6329-222 3M T-6295.6 002481 74 DOSE mg/kg/day GLU MG/DL Table 13 Summary of Clinical Chemistry Data Males Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 80 13.4 2 19 1.4 2 .8 7.7 .07 .42 22 5.0 .28 2 2.7 .14 2 63 19 .7 7.2 4.5 2.7 3.8 1.0 .23 .45 .17 .32 333333 64 15 11 .7 7.4 4.8 2.6 1111 .4 .00 2 .4 .00 3 .4 1 8 141 2.1 58.0 22 8 150 2.1 12.2 33 6 132 11 38 7.1 2 44 9.5 3 27 1 02482 75 Table 13 Summary of Clinical Chemistry Data Males Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 47 7.1 2 36 5.7 3 39 1 40 9.2 2 49 8.0 3 45 1 761 33.9 2 519 131.9 3 908 1 80 7.8 2 77 37.0 3 89 1 4 162 394 2.1 43.8 30.4 222 3 111 306 .6 35.2 40.8 333 2 245 242 111 35 8.5 2 35 18.6 3 2 1 262 20.5 2 203 28.9 3 123 1 002453 76 Table 13 Summary of Clinical Chemistry Data Males Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.2 .21 2 7.6 1.63 2 9.7* .15 3 6.7 .64 3 10.1 1 6.4 1 151 1.4 2 4.8 .28 2 106 .7 2 148 1.0 3 4.5 .30 3 107 1.0 3 153 4.8 108 111 Covance 6329-222 3M T-6295.6 0024S4 77 DOSE mg/kg/day GLU MG/DL Table 13 Summary of Clinical Chemistry Data Females Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T -6295 ) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 80 3.5 2 58 9.0 3 59 1 19 4.2 2 20 2.5 3 18 1 .6 7.5 4.6 2.8 .07 .14 .21 .35 2222 .7 7.7 4.8 2.9 .20 .25 .30 .06 3333 .8 7.8 4.6 3.2 1111 .4 .07 2 .5 .15 3 .4 1 7 119 .0 11.3 22 8 139 1.5 24.1 33 8 107 11 24 4 2 35 7 3 41 1 C024SS 78 Table 13 Summary of Clinical Chemistry Data Females Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLU0R00CTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 46 8.5 2 47 7.5 3 40 1 46 7.8 2 55 11.3 3 51 1 499 58.0 2 800 * 68.6 3 727 1 64 .7 2 63 10.4 3 86 1 4 259 428 .7 144.2 40.3 222 30 16.3 2 288 36.1 2 3 307 320 * .6 97.5 27.2 333 39 24.6 3 200 * 18.8 3 3 462 440 309 283 11111 002436 79 Table 13 Summary of Clinical Chemistry Data Females Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.4 .49 2 10.4 .46 3 10.4 1 6.8 .28 2 6.7 .69 3 6.1 1 154 3.5 2 151 6.8 3 152 1 6.0 .71 2 5.2 .25 3 5.4 1 110 2 108 3 3 108 1 Covance 6329-222 3M T-6295.6 0024S7 80 DOSE mg/kg/day GLU MG/DL Table 14 Summary of Clinical Chemistry Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL 0 MEAN S.D. N 81 24 .8 7.6 4.6 3.0 8.5 .0 .07 .14 .00 .14 222222 .2 .07 2 7 140 1.4 65.8 22 36 6.4 2 0.02 MEAN 73 24 .8 7.5 4.3 3.2 .2 10 151 53 * S.D. 7.0 4.0 .15 1.04 .44 .65 .06 3.1 21.5 4.7 N 3333333333 2.0 MEAN N 80 1 15 1.1 8.2 4.8 3.4 1 11 1 1 .3 1 8 91 25 111 002438 81 Table 14 Summary of Clinical Chemistry Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 52 12.7 2 42 7.5 3 31 1 46 14.1 2 62 26.6 3 38 1 755 60.8 2 564 127.2 3 815 1 96 9.2 2 94 42.9 3 88 1 4 410 424 2.8 93.3 87.0 222 3 314 334 1.2 255.2 57.7 333 1 202 285 111 37 .0 2 35 33.9 3 3 1 285 62 2 228 39 3 156 1 0024S9 82 Table 14 Summary of Clinical Chemistry Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L O' MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.5 .14 2 10.2 .29 3 11.0 1 7.5 .99 2 6.3 .40 3 6.4 1 154 2.1 2 152 3.0 3 156 1 5.6 .92 2 5.1 .79 3 6.0 1 111 1.4 2 110 2.0 3 107 1 Covance 6329-222 3M T-6295.6 002490 83 DOSE mg/kg/day GLU MG/DL Table 14 Summary of Clinical Chemistry Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T -6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL MEAN S.D. N 0.02 MEAN S.D. N 86 .7 2 25 1.4 2 .8 7.6 4.4 3.3 .07 .35 .07 .42 2222 62 24 .9 7.9 4.6 3.3 10.8 3.8 .12 .57 .38 .20 333333 .2 .00 2 .3 .10 3 9 121 2.8 19.8 22 9 143 1.7 24.8 33 38 3.5 2 46 6.0 3 MEAN 78 24 1.0 8.2 4.6 3.6 .2 17 62 27 N 1111111111 002491 84 Table 14 Suinmary of Clinical Chemistry Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covanee 6329-222 3M T-6295.6 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L 1? AMYL U/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 53 9.9 2 45 7.1 3 36 1 46 9.2 2 54 5.7 3 47 1 467 69.3 2 908 * 68.8 3 637 1 72 3.5 2 76 7.6 3 93 1 6 298 538 130 370 3.5 51.6 133.6 157.7 99 22222 3 273 340 1.2 79.2 46.1 333 23 14.7 3 218 34 3 2 341 326 11 1 18 221 11 002492 85 Table 14 Summary of Clinical Chemistry Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN N 10.4 .21 2 10.9 .46 3 11.1 1 6.4 1.06 2 6.9 .89 3 6.5 1 152 1.4 2 155 4.4 3 158 1 5.7 .42 2 5.5 .10 3 5.7 1 111 2.8 2 111 2.1 3 110 1 Covance 6329-222 3M T-6295.6 002493 86 Table 15 Summary of Clinical Chemistry Data Males Day 30 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day PCOAO IU/G 0 MEAN S.D. N 0.02 MEAN S.D. N MEAN S.D. N 0 .7 2 4* .6 3 1 .0 1 to o Covance 6329-222 3M T-6295.6 002494 87 Table 15 Summary of Clinical Chemistry Data Females Day 30 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day PCOAO IU/G 0 MEAN S.D. N 0.02 MEAN S.D. N 2.0 MEAN S.D. N 2 2.8 2 3 3.5 3 1 .0 1 Covance 6329-222 3M T-6295.6 002495 88 TABLE 16 Incidence of Macroscopic Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL; GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL ORGAN AND KEYWORD(S) OR PHRASE ** TOP OF LIST ** GENERAL COMMENT (GC) ..................... BONE MARROW SMEAR TAKEN EYES - DAVIDSONS STAINS -PERINEUM/ PERIANAL NO MACROSCOPIC LESIONS ** END OF LIST ** N UM BER -0F -An : SEX: --MALE- FEMALE- GROUP: -1- -2- -3- -1- -2- --3- NUMBER: 2 3 1 2 3 1 231231 231231 231231 000010 231221 Covance 6329-222 3M T-6295.6 PAGE: 1 A F F E C T E D -- 002496 89 TABLE 17 Incidence of Microscopic Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS ;T-6295 ) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION ** TOP OF LIST ** EYE (EY) ............................................ NUM BER -0F-An : SEX: --MALE--- -- FEMALE--- GROUP: -1- -2- -3- -1- -2- --3- NUMBER: 2 3 1 2 3 1 231231 NOT REMARKABLE: 2 3 1 2 3 1 BONE, FEMUR (FE) ................................... ... NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 3 1 2 3 1 MARROW, FEMUR (FM) ................................. ... NUMBER EXAMINED: 0 1 0 1 2 1 NOT REMARKABLE: 0 1 0 1 2 1 KIDNEY (KD) ........................................ ... NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 2 1 1 1 1 --INFILTRATE, LYMPHOPLASMACYTIC 010120 LUNG (LU) .......................................... ... NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 3 1 2 3 1 LIVER (LI) ......................................... ... NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 2 1 0 1 1 --INFILTRATE, LYMPHOPLASMACYTIC --INFLAMMATION, LYMPHOHISTIOCYTIC --LIPIDOSIS, SUBCAPSULAR (TENSION LIPIDOSIS) 010120 000100 000100 Covance 6329-222 3M T-6295.6 PAGE: 1 A F F E C T E D -- 002497 90 TABLE 17 Incidence of Microscopic Observations Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 2 TABLE INCLUDES: SEX=ALL ;GROUP=ALL ;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- N U M B E R - O F - A N I M A L S S E X : ----- MALE---- --- FEMALE GROUP: -1- -2- -3- -1- -2- -3NUMBER: 2 3 1 2 3 1 SPLEEN (SP) .............................. 231231 NOT REMARKABLE: 2 3 1 2 3 1 PANCREAS (PA) ............................ ............. NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 3 1 2 3 1 ADRENAL, CORTEX (AC) .................... ............. NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 3 1 2 2 1 --HEMORRHAGE --THROMBUS 000010 000010 ADRENAL, MEDULLA (MA) ................... ............. NUMBER EXAMINED: 2 3 1 2 3 1 NOT REMARKABLE: 2 3 1 2 3 1 THYMUS (TH) .............................. 231231 NOT REMARKABLE: 2 3 1 2 3 1 TESTIS (TE) .............................. ............. NUMBER EXAMINED: 2 3 1 0 0 0 NOT REMARKABLE: 0 0 0 0 0 0 --IMMATURE 231000 ** END OF LIST ** A F F E C T E D -- C02498 91 APPENDIX 1 Protocol Deviations Protocol Protocol Amendment No. 1 Protocol Amendment No. 2 Protocol Amendment No. 3 Material Safety Data Sheet Covance 6329-222 3M T-6295.6 C02499 92 Covance 6329-222 3M T-6295.6 Protocol Deviations Protocol. Group Designations and Dosage Levels. Dose levels were 0, 0.02, and 2.0 mg/kg/day. The control group (Group 1) was to receive an equivalent amount of lactose in gelatin capsules as the total material administered to Group 3. The total material was 20.0 mg/kg/day for each group; however, the low- and high-dose groups were to receive test material triturated with lactose (1:999, w:w, and 1:9, w:w, respectively). Actual Procedure. Because the capsule broke during dose administration, the following animals may not have received the full amount of dose preparation: Animal No. 105350 (Group 1 male) on Day 1; Animal No. 105367 (Group 1 female) on Days 2, 7, and 14; Animal No. 105344 (Group 2 male) on Day 7; and Animal No. 105369 (Group 3 female) on Day 2. Protocol. Observation of Animals. Rectal Body Temperatures. "Beginning 2 weeks before initiation of treatment, rectal body temperatures will be taken at approximately 11:00 on two days/week (Monday and Thursday)." Actual Procedure. Rectal body temperatures were recorded between 12:50 and 13:30 on Day -14 and between 08:17 and 08:40 on Day -10. Protocol. Serum PFOS Level Determination. Frequency. "Before initiation of treatment (Day -7 or -6), and prior to treatment on Days 2 (approximately 24 hours after the first dose), 7,14, and 29." Actual Procedure. On Day 2, incorrect blood collection tubes were used for the collection of blood for clinical chemistry test; therefore, blood collected for serum PFOS level determinations was used for clinical chemistry tests. Remaining serum from clinical chemistry tests was used as the Day 2 sample for serum PFOS level determinations. In addition, whole blood (approximately 2 mL) was collected from a femoral vein of each animal before treatment on Day 3 (approximately 24 hours after the second dose). 002500 93 Protocol Deviations (Continued) Covance 6329-222 3M T-6295.6 Protocol. Additional Blood Collection. "At scheduled and unscheduled necropsies, blood (as much as possible, up to 20 mL) will be collected from animals at the time of exsanguination." Actual Procedure. Additional blood was not collected from Animal Nos. 105364 (Group 2 female), 105365 (Group 2 female), and 105369 (Group 3 female). Protocol. Postmortem Procedures. Tissue Preservation. "The following tissues (when present) from each animal will be preserved in 10% neutral-buffered formalin, unless otherwise specified, for possible future microscopic examination:" Actual Procedure. Femoral bone marrow from Animal Nos. 105349 and 105350 (Group 1 males), 105344 and 105348 (Group 2 males), 105345 (Group 3 male), 105366 (Group 1 female), and 105364 (Group 2 female) were insufficient; therefore, these tissues were not examined microscopically. This tissue is listed with the appropriate comments in the pathology data sheets for each individual animal. Summary tables do not include it as having been examined. These deviations are not expected to have affected the results of the study. C0Z501 94 Covance 6329-222 --------------------------------- -- --------------------- -------------------------------------------------------- 3M T-6295.6 Protocol 1 of 18 002502 95 002503 002504 002505 002506 Covance 6329-222 3M T-6295.6 002507 002508 Covance 6329-222 3M T-6295.6 002509 002510 Covance 6329-222 3M T-6295.6 C02511 C02512 Covance 6329-222 3M T-6295.6 12 002513 106 00251 002515 002516 002517 Covance 6329-222 3M T-6295.6 17 COSAIS 111 Covance 6329-222 3M T-6295.6 18 002519 112 Protocol Amendment No. 1 Page 1 of 2 Covance 6329-222 3M T-6295.6 002520 113 Page 2 of 2 Covance 6329-222 3M T-6295.6 002521 114 Protocol Amendment No. 2 1 of 2 Covance 6329-222 _____3M T-6295.6 115 C02522 2 of 2 Covance 6329-222 3M T-6295.6 116 002523 Protocol Amendment No. 3 1 of 3 Covance 6329-222 3M T-6295.6 002524 117 Q0Z5S Covance 6329-222 3M T-6295.6 119 002526 Material Safety Data Sheet Page 1 of 6 Covance 6329-222 3M T-6295.6 002527 120 Page 2 of 6 Covance 6329-222 3M T-6295.6 002528 121 Page 3 of 6 Covance 6329-222 3M T-6295.6 002529 122 Page 4 of 6 Covance 6329-222 3M T-6295.6 123 002530 Page 5 of 6 Covance 6329-222 3M T-6295.6 124 002531 Page 6 of 6 Covance 6329-222 3M T-6295.6 125 002532 APPENDIX 2 Individual Animal Fate Data Individual Clinical Observations Individual Rectal Body Temperature Data (C) Covance 6329-222 3M T-6295.6 002533 126 APPENDIX 2 Individual Animal Fate Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS ;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 1 ANIMAL DOSE NUMBER GROUP SEX 105349 1 MALE 105350 1 MALE 105344 2 MALE 105347 2 MALE 105348 2 MALE 105345 3 MALE 105366 1 FEMALE 105367 1 FEMALE 105364 2 FEMALE 105365 2 FEMALE 105370 2 FEMALE 105369 3 FEMALE DEATH CODE T T T T T T T T T T T T TYPE OF DEATH SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED DESCRIPTION OF DEATH TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE DATE OF DAY OF DEATH STUDY 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 05/22/98 30 30 30 30 30 30 30 30 30 30 30 30 WEEK OF STUDY 5 5 5 5 5 5 5 5 5 5 5 5 I 01 05 127 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 PAGE: 1 CATEGORY GROUP: Ml DOSE: 0 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER DAYS 1-30 'C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP AM OBS 30MIN 90MIN UNSCHED DAY PM CHECK 60MIN DISPATCH 105349 T 5 NORMAL NO REMARKABLE OBSERVATIONS 105350 T EXCRETION MUCOID FECES NORMAL NO REMARKABLE OBSERVATIONS 1P- - - - - - 8P- - - _ - - 15 P - - - - - _ 22 P - - - - - - 29 P - - - - _ - 30 P - - - - P- 12 - - - P - - - 1P- - - - - _ 8P- - - - 15 P - - - - - - 22 P - - - - - 29 P - -- - _ - 30 P - - - - P- C02535 128 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS Covatrice 6329-222 3M T-6295.6 PAGE: 2 CATEGORY GROUP: M2 DOSE: 0.02 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER DAYS 1-30 DAY 'C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP AM OBS 30MIN 90MIN UNSCHED PM CHECK 60MIN DISPATCH 105344 T 5 NORMAL NO REMARKABLE OBSERVATIONS 105347 T DISCHARGE VOMITUS CONTAINING FOOD NORMAL NO REMARKABLE OBSERVATIONS 105348 T NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 1P - - - - - - 8P- - - - - - 15 P - - - - - - 22 P - - - - - - 29 P - - - - - - 30 P - - - ~ P- 4 P- - - - - - 1P- - - - - - 8P - - - - - - 15 P - - - - - _ 22 P - - - - - _ 29 P - - - - - - 30 P P- - - - 1P- - - - - - 8P- - - - - - 15 P - - - - - 22 P - - - - - 29 P - - - - - - 30 P - - - - P- 15 P - - - - - - 002536 129 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295 ) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 PAGE: 3 CATEGORY GROUP: M3 DOSE: 2 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER DAYS 1-30 105345 T 5 DISCHARGE VOMITUS CONTAINING FOOD DISCHARGE UNKNOWN SOURCE FOUND IN PAN RED IN COLOR NORMAL NO REMARKABLE OBSERVATIONS 'C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP AM OBS 30MIN 90MIN UNSCHED DAY PM CHECK 60MIN DISPATCH 24 P - - - - - _ 15 P - - - - _ _ 1P- - - - - - 8P- - -_ - 22 P - - - - - - 29 P - - - - - - 30 P - - - - P- N in lo 130 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295 ) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 PAGE: 4 CATEGORY GROUP: FI DOSE: 0 MG/KG/DAY C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP ANIMAL DEATH WK OF KEYWORD AM OBS 30MIN 90MIN UNSCHED NUMBER CODE DEATH QUALIFIER DAYS 1-30 DAY PM CHECK 60MIN DISPATCH 105366 T 5 EXCRETION NON-FORMED FECES NORMAL NO REMARKABLE OBSERVATIONS 105367 T 5 APPEARANCE SWOLLEN LIP(S) EXCRETION NON-FORMED FECES 23 P - P_ _ _ _ 27 P - - - _ - _ 29 P - - - - - - 1P_ _ 8P - - 15 P - - 22 P - - 30 P - - __ ----- _ __ __ __ -_ P- 11 13 14 P 15 P 19 P 20 P 21 P 22 P 23 P 24 25 26 P 30 P 15 P 27 P - - PPP PPP - _ _ P- - - PPP - PPP - PPP- PPP- PP P - _ - ----- PPP- - - PPPPP_ - - -" P- _ __ _ ---- 002538 131 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 PAGE: 5 CATEGORY GROUP: FI DOSE: 0 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER DAYS 1-30 (CONTINUED FROM PREVIOUS PAGE) 105367 T 5 SKIN & PELAGE RED SKIN LIP (S) SCAB(S ) MOUTH NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 'C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP AM OBS 30MIN 90MIN UNSCHED DAY PM CHECK 60MIN DISPATCH 11 13 14 P 15 P 19 P 20 P - PP P - PPP - P- - - PPP - PPP - PPP - _ - 29 P - P P P - 1P - - - - 8P - - _ - - - 4P - - - - - - 002539 132 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 PAGE: 6 CATEGORY GROUP: F2 DOSE: 0.02 MG/KG/DAY 'C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP ANIMAL DEATH WK OF KEYWORD AM OBS 30MIN 90MIN UNSCHED NUMBER CODE DEATH QUALIFIER DAYS 1-30 DAY PM CHECK 60MIN DISPATCH 105364 T 5 NORMAL NO REMARKABLE OBSERVATIONS 105365 T 105370 T DISCHARGE APPEARS TO BE MENSTRUATING NORMAL NO REMARKABLE OBSERVATIONS NORMAL NO REMARKABLE OBSERVATIONS 1P - - - - _ - 8P - - - - - - 15 P - - - _ - - 22 P - '- - - _ - 29 P - - - - - - 30 P - - - - P- 29 P - - - - - _ 30 P - - - - P- 1P- - - - _ - 8P - - - - - _ 15 P - - - - _ 22 P - *- - - - 1P - - - _ - _ 8P - - - - - _ 15 P - - - - - _ 22 P - - - - - 29 P - - - - - 30 P - - - - P _ 002540 133 Appendix 2 Individual Clinical Observations 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS ;T-6295 ) IN CYNOMOLGUS MONKEYS Covance 6329-222 3M T-6295.6 PAGE: 7 CATEGORY GROUP: F3 DOSE: 2 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER DAYS 1-30 105369 T 5 EXCRETION FEW FECES NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 'C' - COMMENTS LISTED AT END OF OBSERVATIONS FOR SEX/GROUP AM OBS 30MIN 90MIN UNSCHED DAY PM CHECK 60MIN DISPATCH 17 P - - - - - 1P - - - - - - 8P - - - - - 15 P - - - - _ _ 22 P - - - - - _ 29 P - - - - - - 30 P - - - - P- 26 P - - - - - - 002541 134 Appendix 2 Individual Rectal Body Temperature Data !C) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS ANIMAL DAY DAY DAY DAY NUMBER -14 -10 -7-3 GROUP: MALE 1 - 0 MG/KG/DAY 105349 105350 40.0 39.6 40.2 39.7 40.2 39.4 GROUP : MALE 2 - 0.02 MG/KG/DAY 105344 105347 105348 39.0 39.8 38.7 39.0 39.7 39.0 38.4 39.8 38.8 GROUP: MALE 3 - 2 MG/KG/DAY 105345 39.6 39.5 39.1 GROUP: FEMALE 1 - 0 MG/KG/DAY 105366 105367 40.0 40.4 39.4 40.1 39.7 40.0 GROUP : FEMALE 2 - 0 . 02 MG/KG/DAY 105364 105365 105370 40.6 39.6 40.1 40.1 39.1 40.0 40.3 39.6 40.2 GROUP : FEMALE 3 - 2 MG/KG/DAY 105369 40.0 39.8 39.9 39.8 39.4 39.2 39.7 38.8 39.2 39.4 40.1 39.9 39.7 39.8 39.7 DAY 1 39.4 38.6 39.7 39.4 39.1 39.4 39.3 39.8 40.2 39.7 39.7 39.5 DAY 5 38.8 38.9 39.3 39.5 38.4 39.9 38.7 39.2 40.0 39.5 39.8 39.7 DAY 8 38.2 38.7 39.4 39.4 38.7 39.6 38.8 39.4 40.0 39.6 39.9 39.9 DAY 12 38.9 39.0 39.3 39.5 38.6 40.0 39.1 39.3 40.0 39.5 39.8 39.7 Covance 6329-222 3M T-6295.6 PAGE: 1 DAY DAY 15 19 39.7 39.7 39.8 40.0 39.2 39.7 39.3 40.1 40.2 40.0 39.8 39.8 38.5 38.8 39.2 39.0 38.0 38.9 38.7 39.2 39.5 39.1 39.4 39.3 002542 135 Appendix 2 Individual Rectal Body Temperature Data (C) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295! IN CYNOMOLGUS MONKEYS ANIMAL DAY DAY DAY NUMBER 22 26 29 GROUP: MALE 1 - 0 MG/KG/DAY 105349 105350 39.2 39.5 38.7 38.8 38.2 38.8 GROUP: MALE 2 - 0.02 MG/KG/DAY 105344 105347 105348 40.0 39.7 38.9 39.4 39.5 38.8 38.8 39.1 38.4 GROUP: MALE 3 - 2 MG/KG/DAY 105345 39.4 39.2 38.9 GROUP: FEMALE 1 - 0 MG/KG/DAY 105366 105367 39.3 39.9 38.7 39.2 38.7 38.9 GROUP: FEMALE 2 - 0.02 MG/KG/DAY 105364 105365 105370 40.1 39.6 39.8 39.8 39.5 39.6 39.3 38.7 39.4 GROUP: FEMALE 3 - 2 MG/KG/DAY 105369 39.4 39.1 39.2 Covance 6329-222 3M T-6295.6 PAGE: 2 002543 136 APPENDIX 3 Individual Body Weight Data (kg) Covance 6329-222 3M T-6295.6 002544 137 Appendix 3 Individual Body Weight Data (kg) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL DAY DAY DAY DAY DAY NUMBER -14 -10 -7-3-1 GROUP: MALE 1 - 0 MG/KG/DAY 105349 105350 2.3 2.2 2.2 2.2 2.3 2.3 2.3 2.3 2.3 2.3 GROUP: MALE 2 - 0.02 MG/KG/DAY 105344 105347 105348 2.4 2.4 2.4 2.4 2.4 2.1 2.1 2.1 2.1 2.1 2.5 2.5 2.5 2.5 2.6 GROUP: MALE 3 - 2 MG/KG/DAY 105345 2.2 2.2 2.2 2.2 2.2 GROUP: FEMALE 1 - 0 MG/KG/DAY 105366 105367 2.0 2.0 2.1 2.1 2.1 2.1 2.1 2.1 2.1 2.1 GROUP : FEMALE 2 - 0. 02 MG/KG/DAY 105364 105365 105370 2.2 2.1 2.1 2.1 2.1 2.2 2.2 2.2 2.2 2.3 1.9 2.0 1.9 1.9 1.9 GROUP: FEMALE 3 - 2 MG/KG/DAY 105369 2.2 2.1 2.2 2.1 2.2 DAY 1 2.2 2.4 2.4 2.1 2.5 2.2 2.1 2.1 2.2 2.3 2.0 2.2 DAY 5 2.2 2.3 2.4 2.1 2.4 2.2 2.0 2.0 2.1 2.3 2.0 2.1 DAY 8 2.4 2.5 2.5 2.3 2.5 2.3 2.2 2.1 2.2 2.4 2.0 2.2 Covance 6329-222 3M T-6295.6 PAGE: 1 DAY DAY 12 15 2.4 2.3 2.5 2.5 2.4 2.4 2.2 2.3 2.4 2.4 2.2 2.3 2.1 2.1 2.1 2.2 2.2 2.2 2.3 2.4 2.0 2.0 2.2 2.1 002545 138 Appendix 3 Individual Body Weight Data (kg) 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER DAY 19 DAY 22 DAY 26 GROUP: MALE 1 - 0 MG/KG/DAY 105349 105350 2.4 2.4 2.5 2.5 GROUP : MALE 2 - 0..02I MG/KG/DAY 105344 105347 105348 2.4 2.5 2.3 2.3 2.4 2.4 GROUP : MALE 3 - 2 MG/KG/DAY 105345 2.3 2.1 GROUP: FEMALE 1 - 0 MG/KG/DAY 105366 105367 2.1 2.1 2.1 2.2 GROUP: FEMALE 2 - 0. 02 MG/KG/DAY 105364 105365 105370 2.2 2.2 2.5 2.4 2.2 2.1 GROUP: FEMALE 3 - 2 MG/KG/DAY 105369 2.3 2.1 2.4 2.5 2.4 2.3 2.5 2.1 2.1 2.2 2.2 2.4 2.1 2.1 DAY 29 2.3 2.4 2.4 2.3 2.4 2.0 2.1 2.1 2.1 2.3 2.0 2.1 Covance 6329-222 3M T-6295.6 PAGE: 2 002546 139 APPENDIX 4 Individual Clinical Hematology Data Individual Clinical Chemistry Data Covance 6329-222 3M T-6295.6 002547 140 ANIMAL NUMBER RBC X106/HL Appendix 4 Individual Clinical Hematology Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC G/DL % FL PG % X103/|IL % XIOVuL Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 5.41 5.88 13.0 15.0 5.64 .332 2 14.0 1.41 2 Dose Level: 0.02 4.97 5.49 5.09 12.3 12.7 12.9 5.18 .272 3 12.6 .31 3 Dose Level : 2.0 5.91 12.8 Dosage Unit: mg/kg/day 39.9 45.3 73.8 77.0 24.0 25.5 42.6 3.82 2 75.4 2.26 2 24.8 1.06 2 Dosage Unit : mg/kg/day 38.5 40.1 38.6 77.5 73.1 75.7 24.8 23.2 25.3 39.1 .90 3 75.4 2.21 3 24.4 1.10 3 Dosage Unit : mg/kg/day 41.0 69.4 21.7 32.6 33.2 32.9 .42 2 32.0 31.7 33.4 32.4 .91 3 31.2 404 600 502 138.6 2 .9 .9 .9 .00 2 473 358 531 454 88.1 3 1.3 .3 1.1 .9 .53 3 531 .7 49 53 51 2.8 2 65 16 56 46 26.1 3 41 Covance 6329-222 3M T-6295.6 002548 141 ANIMAL NUMBER WBC X10V(1L Appendix 4 Individual Clinical Hematology Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS N-SEG XloVflL LYMPH XloVftL MONO EOSIN XlOVfJL XloVjlL BASO N-SEG% XIOVUL LYMPH% MONO% EOSIN% Covanee 6329-222 3M T-6295.6 BASO% Group : 1 Dose Level : 0 Dosage Unit: mg/kg/day 105349 105350 9.1 4.1 4.5 .4 .0 .0 45 49 5 0 0 7.7 2.6 4.6 .3 .2 .0 34 59 4 2 0 MEAN S.D. N 8.4 3.4 4.6 .4 .1 .0 40 54 4 1 0 .99 1.06 .07 .07 .14 .00 7 .,8 7.1 .7 1.4 .0 22222222222 Group : 2 Dose Level : 0.02 Dosage Unit : mg/kg/day 105344 10.3 3.2 6.3 .6 .2 .0 31 61 6 2 0 105347 8.8 1.4 7.0 .4 .1 .0 15 79 4 1 0 105348 8.4 4.0 4.2 .2 .0 .0 48 50 2 0 0 MEAN S.D. N 9.2 2.9 5.8 .4 .1 .0 31 63 4 1 0 1.00 1.33 1.46 .20 .10 .00 16..5 14.6 2.0 1.0 .0 33333333333 Group : 3 Dose Level : 2.0 Dosage Unit: mg/kg/day 105345 8.2 2.8 4.8 .6 .0 .0 34 58 8 0 0 002549 142 Appendix 4 Individual Clinical Hematology Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Covance 6329-222 3M T-6295.6 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day l 105349 - - - - 105350 - Group: 2 Dose Level: 0.02 Dosage Unit: mg/kg/day 105344 - - - - - 105347 - - - - - 105348 - - - - - Group: 3 Dose Level: 2.0 Dosage Unit: mg/kg/day 105345 - - - - - 002550 143 ANIMAL NUMBER Appendix 4 Individual Clinical Hematology Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS RBC HGB HCT MCV MCH MCHC PLT RETIC X10s/|iL G/DL % FL PG % XlOVjlL % Covance 6329-222 3M T-6295.6 RETIC xioV ml Group: 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group: 3 105369 Dose Level : 0 5.02 5.48 12.4 14.3 5.25 .325 2 13.3 1.34 2 Dose Level : 0.02 4.77 4.98 5.25 13.0 12.7 12.6 5.00 .241 3 12.8 .21 3 Dose Level: 2.0 5.53 13.4 Dosage Unit: mg/kg/day 37.6 43.2 75.0 78.8 24.8 26.1 40.4 3.96 2 76.9 2.69 2 25.4 .92 2 Dosage Unit: mg/kg/day 38.9 39.0 39.3 81.5 78.3 74.9 27.2 25.5 24.1 39.1 .21 3 78.2 3.30 3 25.6 1.55 3 Dosage Unit: mg/kg/day 40.2 72.7 24.2 33.1 33.1 33.1 .00 2 33.3 32.6 32.2 32.7 .56 3 33.3 351 606 478 180.3 2 .7 1.0 .8 .21 2 355 365 570 430 121.3 3 .6 .9 .6 .7 .17 3 505 .8 35 55 45 14.1 2 29 45 32 35 8.5 3 44 002551 144 ANIMAL NUMBER WBC X103/|1L Appendix 4 Individual Clinical Hematology Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS N-SEG LYMPH XIO'/HL XlOVjlL MONO EOSIN X103/)1L X103/HL BASO N-SEG* XlOVflL LYMPH* MONO* EOSIN* Covance 6329-222 3M T-6295.6 BASO* Group: 1 Dose Level : 0 Dosage Unit : mg/kg/day 105366 7.9 2.2 5.2 .4 .1 .0 28 66 5 1 0 105367 10.0 4.9 5.0 .0 .0 .0 49 50 0 0 0 MEAN S.D. N 9.0 3.6 5.1 .2 .0 .0 38 58 2 0 0 1.48 1.91 .14 .28 .07 .00 14.8 11.3 3.5 .7 1 2 22 22 2 222 22 Group : 2 Dose Level : 0.02 Dosage Unit: mg/kg/day 105364 8.6 1.6 6.2 .5 .2 .0 19 73 6 2 0 105365 12.4 1.6 10.2 .5 .1 .0 13 82 4 1 0 105370 9.6 7.3 2.1 .3 .0 .0 75 21 3 0 0 MEAN S.D. N 10.2 3.5 6.2 .4 .1 .0 36 59 4 1 0 1.97 3.29 4.05 .12 .10 .00 34.2 32.9 1.5 1.0 33333333333 Group : 3 Dose Level : 2.0 Dosage Unit : mg/kg/day 105369 11.7 6.2 4.8 .4 .2 .0 53 42 4 1 0 002552 145 Appendix 4 Individual Clinical Hematology Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 105366 105367 Dose Level: 0 ___ ___ Group: 2 Dose Level: 0.02 105364 _ _ _ 105365 - 105370 _ _ _ Group: 3 Dose Level: 2.0 105369 - Dosage Unit: mg/kg/day __ __ Dosage Unit: mg/kg/day __ __ Dosage Unit: mg/kg/day Covance 6329-222 3M T-6295.6 002553 146 ANIMAL NUMBER Appendix 4 Individual clinical Hematology Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS RBC HGB HCT MCV MCH MCHC PLT RETIC XIOV^L G/DL % FL PG % XioVjlL % Covance 6329-222 3M T-6295.6 RETIC XIOV^L Group : 1 105349 105350 MEAN S.D. N Group - 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 6.00 6.05 13.6 14.5 6.02 .035 2 14.0 .64 2 Dose Level: 0.02 4.90 5.05 5.41 12.2 12.1 13.5 5.12 .262 3 12.6 .78 3 Dose Level : 2.0 5.69 13.2 Dosage Unit: mg/kg/day 42.7 45.3 71.0 74.8 22.6 24.0 44.0 1.84 2 72.9 2.69 2 23.3 .99 2 Dosage Unit: mg/kg/day 38.1 37.6 41.6 77.8 74.5 76.8 24.9 23.9 25.0 39.1 2.18 3 76.4 1.69 3 24.6 .61 3 Dosage Unit: mg/kg/day 41.5 73.1 23.1 31.8 32.1 31.9 .21 2 32.0 32.1 32.5 32.2 .26 3 31.7 357 522 440 116.7 2 448 286 443 392 92.1 3 503 .9 .7 .8 .14 2 .5 .2 .9 .5 .35 3 .2 54 42 48 8.5 2 24 10 49 28 19.8 3 11 002554 147 ANIMAL NUMBER WBC x i o V ul Appendix 4 Individual Clinical Hematology Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS N-SEG X10V|1L LYMPH XIOVUL MONO XlOVtlL EOSIN XIOVUL BASO N -SEG% XIO'/HL LYMPH% MONO% EOSIN% Covance 6329-222 3M T-6295.6 BASO% Group : 1 Dose Level : 0 Dosage Unit: mg/kg/day 105349 105350 9.1 2.0 6.3 .7 .1 .0 22 69 8 1 0 9.4 1.3 7.4 .4 .3 .0 14 79 4 3 0 MEAN S.D. N 9.2 1.6 6.8 .6 .2 .0 18 74 6 2 0 .21 .49 .78 .21 .14 .00 5.7 7.1 2.8 1.4 0 22 222 22222 2 Group : 2 Dose Level -. 0.02 Dosage Unit: mg/kg/day 105344 10.9 .9 8.8 1.0 .2 .0 9 81 9 1 0 105347 9.3 1.0 7.6 .4 .3 .0 10 82 5 3 0 105348 6.1 1.2 4.4 .3 .1 .0 20 72 5 2 0 MEAN S.D. N 8.8 1.0 6.9 .6 .2 .0 13 78 62 0 2.44 .15 2.27 .38 .10 .00 6.1 5.5 2.3 1.0 .0 33333333333 Group: 3 Dose Level : 2.0 Dosage Unit: mg/kg/day 105345 5.8 .9 4.4 .4 .0 .0 16 77 7 0 0 002555 148 Appendix 4 Individual Clinical Hematology Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Covance 6329-222 3M T-6295.6 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day 1 105349 - - - - - 105350 - - - - - Group: 2 Dose Level: 0.02 Dosage Unit: mg/kg/day 105344 105347 - - - - - 105348 - - - - - Group: 3 Dose Level: 2.0 Dosage Unit: mg/kg/day 105345 002556 149 ANIMAL NUMBER Appendix 4 Individual Clinical Hematology Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS RBC HGB HCT MCV MCH MCHC PLT RETIC X10fi/flL G/DL % FL PG % X103/|iL % Covance 6329-222 3M T-6295.6 RETIC XlOVnL Group : 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level: 0 5.02 5.26 12.6 13.7 5.14 .170 2 13.2 .78 2 Dose Level: 0.02 5.15 5.01 5.24 14.1 12.7 12.5 5.13 .116 3 13.1 .87 3 Dose Level : 2.0 4.81 12.3 Dosage Unit : mg/kg/day 38.9 42.2 77.4 80.4 25.1 26.1 40.5 2.33 2 78.9 2.12 2 25.6 .71 2 Dosage Unit : mg/kg/day 43.1 40.5 39.8 83.7 80.7 75.9 27.4 25.4 23.8 41.1 1.74 3 80.1 3.93 3 25.5 1.80 3 Dosage Unit: mg/kg/day 36.7 76.4 25.6 32.5 32.5 32.5 .00 2 32.8 31.4 31.4 31.9 .81 3 33.6 382 640 511 182.4 2 1.0 1.3 1.2 .21 2 377 340 558 425 116.7 3 1.1 .7 .6 .8 .26 3 529 1.0 50 68 59 12.7 2 57 35 31 41 14.0 3 48 00255 >1 150 ANIMAL NUMBER WBC X103/(lL Appendix 4 Individual Clinical Hematology Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS N-SEG XlOVjlL LYMPH X10'/|!L MONO EOS IN X103/|1L x i o V u l BASO N -SEG% X103/|1L LYMPH* ]MONO* EOSIN* Covan.ce 6329-222 3M T-6295.6 BASO* Group : 1 Dose Level : 0 Dosage Unit: mg/kg/day 105366 9.2 3.9 4.4 .9 .0 .0 43 47 10 0 0 105367 13.0 3.7 8.0 1.2 .0 .0 28 62 9 0 0 MEAN S.D. N 11.1 3.8 6.2 1.0 .0 .0 36 54 10 0 0 2.69 .14 2.55 .21 .00 .00 10.6 10.6 .7 .0 2222222222 2 Group: 2 Dose Level : 0.02 Dosage Unit: mg/kg/day 105364 8.7 1.7 6.2 .6 .1 .0 19 72 7 1 0 105365 12.9 2.2 10.1 .5 .1 .0 17 78 4 1 0 105370 8.3 2.6 5.0 .6 .1 .0 31 60 8 1 0 MEAN S.D. N 10.0 2.2 7.1 .6 .1 .0 22 70 6 1 0 2.55 .45 2.67 .06 .00 .00 7.6 9.2 2.1 .0 3 3 33 333 333 3 Group : 3 Dose Level : 2.0 Dosage Unit: mg/kg/day 105369 15.7 7.2 7.9 .5 .1 .0 46 50 3 1 0 0025 on 00 151 Appendix 4 Individual Clinical Hematology Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT v Group : 1 105366 105367 Group: 2 105364 105365 105370 Group : 3 105369 Dose Level : 0 _ -- Dose Level: 0.02 __ -- -- Dose Level : 2.0 _ Dosage Unit: mg/kg/day _ -- Dosage Unit : mg/kg/day __ -- -- Dosage Unit : mg/kg/day __ Covance 6329-222 3M T-6295.6 002559 152 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group : 1 Dose Level : 0 Dosage Unit: mg/kg/day 105349 105350 95 25 1.0 8.2 5.2 3.0 .2 68 23 1.1 8.2 5.2 3.0 .3 8 111 9 199 46 81 MEAN S.D. N 82 19.1 2 24 1.4 2 1.0 .07 2 8.2 .00 2 5.2 .00 2 3.0 .00 2 .2 .07 2 8 155 .7 62.2 22 64 24.7 2 Group: 2 Dose Level: 0.02 Dosage Unit: mg/kg/day 105344 105347 105348 46 29 .9 7.7 4.6 3.1 .3 11 137 65 71 27 1.0 7.7 5.1 2.6 .4 9 202 82 66 31 1.0 7.8 4.6 3.2 .3 8 145 109 MEAN S.D. N 61 13.2 3 29 2.0 3 1.0 .06 3 7.7 .06 3 4.8 .29 3 3.0 .32 3 .3 .06 3 9 161 1.5 35.4 33 85 22.2 3 Group : 3 Dose Level : 2.0 Dosage Unit: mg/kg/day 105345 54 28 1.0 8.2 5.0 3.2 .4 10 150 68 002560 153 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 52 33 45 46 48 4.9 2 40 9.. 2 2 Dose Level : 0.02 58 45 43 71 48 59 50 7.6 3 58 13..0 3 Dose Level: 2.0 54 50 Dosage Unit: mg/kg/day 638 91 587 84 4 3 612 36.1 2 88 4.9 2 4 .7 2 Dosage Unit: mg/kg/day 606 78 767 143 670 81 7 5 5 681 81.1 3 101 36.7 3 6 1.2 3 Dosage Unit: mg/kg/day 1086 117 5 156 301 228 102.5 2 200 208 233 214 17.2 3 220 353 494 424 99.7 2 376 318 250 315 63.1 3 244 37 90 64 37.5 2 132 38 17 62 61.2 3 7 242 340 291 69 2 275 220 175 223 50 3 144 002561 154 Appendix 4 Individual Clinical Chemistry Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 105349 105350 MEAN S.D. N Group: 2 105344 105347 105348 MEAN S.D. N Group: 3 105345 Dose Level : 0 10.6 10.8 7.6 6.8 10.7 .14 2 7.2 .57 2 Dose Level : 0.02 10.3 11.2 10.3 7.8 6.9 8.3 10.6 .52 3 7.7 .71 3 Dose Level : 2.0 11.4 8.7 Dosage Unit : mg/kg/day 161 5.7 110 164 5.8 110 162 2.1 2 5.8 .07 2 110 2 Dosage Unit: mg/kg/day 159 5.1 111 164 5.8 117 154 6.0 108 159 5.0 3 5.6 .47 3 112 4 3 Dosage Unit : mg/kg/day 162 5.9 111 Covance 6329-222 3M T-6295.6 002562 155 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group: 1 Dose Level : 0 Dosage Unit: mg/kg/day 105366 70 24 .9 7.6 4.8 2.8 105367 SH 82 24 1.1 8.3 5.4 2.9 .3 .7 8 131 0 153 66 86 MEAN S.D. N 76 8.5 2 24 .0 2 1.0 .14 2 8.0 .49 2 5.1 .42 2 2.8 .07 2 .5 .28 2 4 142 5.7 15.6 22 76 14.1 2 Group: 2 Dose Level : 0.02 Dosage Unit : mg/kg/day 105364 105365 105370 55 23 .9 8.2 5.2 3.0 .4 7 114 47 73 23 .8 7.9 4.8 3.1 .4 8 169 49 64 31 .9 7.6 4.7 2.9 .3 11 178 110 MEAN S.D. N 64 26 .9 7.9 4.9 3.0 9.0 4.6 .06 .30 .26 .10 333333 .4 .06 3 9 154 2.1 34.6 33 69 35.8 3 Group: 3 Dose Level : 2.0 Dosage Unit: mg/kg/day 105369 71 27 1.0 8.2 4.9 3.3 .3 12 141 67 002563 156 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105366 105367 SH MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 45 38 153 68 99 76.4 2 53 21.,2 2 Dose Level : 0.02 60 45 64 73 51 55 58 6.7 3 58 14..2 3 Dose Level : 2.0 53 55 Dosage Unit: mg/kg/day 546 81 3 640 78 10 593 66.5 2 80 2.1 2 6 4.9 2 Dosage Unit: m g /kg /day 755 62 849 80 881 79 5 4 3 828 65.5 3 74 10.1 3 4 1.0 3 Dosage Unit: mg/kg/day 683 110 3 290 3524 1907 2286.8 2 253 567 334 385 163.0 3 1094 356 312 334 31.1 2 281 369 321 324 44.1 3 315 17 2 10 10.6 2 21 158 12 64 81.8 3 89 247 216 232 21.9 2 193 228 225 215 19.4 3 224 002564 157 Appendix 4 Individual Clinical Chemistry Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group : 1 105366 105367 SH MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group -. 3 105369 Dose Level : 0 10.6 11.3 6.5 8.3 11.0 .49 2 7.4 1.27 2 Dose Level : 0.02 10.6 10.8 11.7 6.4 7.7 9.8 11.0 .59 3 8.0 1.72 3 Dose Level: 2.0 11.3 6.8 Dosage Unit : mg/kg/day 161 5.9 111 157 8.6 115 159 2.8 2 7.2 1.91 2 113 2.8 2 Dosage Unit: mg/kg/day 154 5.1 110 155 6.1 114 166 6.3 118 158 6.7 3 5.8 .64 3 114 4.0 3 Dosage Unit: mg/kg/day 165 6.0 115 Covance 6329-222 3M T-6295.6 zoo U1 a (A 158 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group : 1 105349 105350 MEAN .D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 52 29 62 21 57 25 7.1 5.7 22 Dose Level: 0.02 56 21 68 25 62 25 62 6.0 3 24 2.3 3 Dose Level: 2.0 58 21 Dosage Unit: mg/kg/day .9 7.4 5.0 .9 7.3 4.9 .9 7.4 5.0 .00 .07 .07 222 Dosage Unit: mg/kg/day .8 7.1 4.4 .8 6.9 4.6 .9 7.1 4.4 .8 7.0 4.5 .06 .12 .12 333 Dosage Unit: mg/kg/day .9 7.3 4.7 2.4 2.4 2.4 .00 2 2.7 2.3 2.7 2.6 .23 3 2.6 .4 .3 .4 .07 2 .3 .3 .4 .3 .06 3 .4 19 97 45 13 188 114 16 142 80 4.2 64.3 48.8 222 10 9 10 10 .6 3 149 184 157 163 18.3 3 60 56 90 69 18.6 3 9 151 50 002566 159 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 2 4 -WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 65 41 85 71 75 14.1 2 56 21.2 2 Dose Level : 0.02 44 40 39 69 41 60 41 2.5 3 56 14.8 3 Dose Level : 2.0 54 55 Dosage Unit: m g /Kg/day 692 88 761 79 2 3 726 48.8 2 84 6.4 2 2 .7 2 Dosage Unit: mg/kg/day 531 68 691 125 575 72 2 2 2 599 82.7 3 88 31.8 3 2 .0 3 Dosage Unit: mg/kg/day 1028 105 2 903 895 899 5.7 2 139 888 709 579 391.1 3 219 363 461 412 69.3 2 325 311 230 289 51.3 3 302 35 27 31 5.7 2 227 284 256 40.3 2 62 35 24 40 19.6 3 205 190 146 180 30.7 3 11 139 002567 160 Appendix 4 Individual Clinical Chemistry Data Males Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level: 0 10.1 10.3 7.6 6.1 10.2 .14 2 6.8 1.06 2 Dose Level : 0.02 9.7 7.0 9.6 6.6 9.2 6.4 9.5 .26 3 6.7 .31 3 Dose Level : 2.0 10.0 7.0 Dosage Unit: mg/kg/day 151 5.2 107 153 5.1 106 152 1.4 2 5.2 .07 2 106 2 Dosage Unit : mg/kg/day 147 5.0 110 150 4.5 110 145 4.7 103 147 2.5 3 4.7 .25 3 108 4 3 Dosage Unit: mg/kg/day 152 5.0 104 Covance 6329-222 3M T-6295.6 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Females Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA \invol/Li CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group: 1 Dose Level : 0 Dosage Unit: mg/kg/day 105366 105367 80 19 60 19 .8 7.1 4.7 2.4 .9 7.7 5.1 2.6 .4 .5 8 143 9 147 34 50 MEAN S.D. N 70 19 .8 7.4 4.9 2.5 14.1 .0 .07 .42 .28 .14 222222 .4 .07 2 8 145 .7 2..8 22 42 11.3 2 Group: 2 Dose Level: 0.02 Dosage Unit: mg/kg/day 105364 105365 105370 60 24 57 28 53 21 .9 7.5 5.0 2.5 .8 7.3 4.4 2.9 .8 7.2 4.7 2.5 .5 15 102 42 .5 16 140 59 .4 17 157 107 MEAN S.D. N 57 24 .8 7.3 4.7 2.6 3.5 3.5 .06 .15 .30 .23 333333 .5 16 133 69 .06 1.0 28..2 33.7 3333 Group: 3 Dose Level : 2.0 Dosage Unit: mg/kg/day 105369 68 27 1.0 7.5 4.7 2.8 .4 17 136 47 002569 162 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Females Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group: 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level:: 0 45 42 71 103 58 18.4 2 72 43.1 2 Dose Level:: 0.02 54 43 59 76 50 53 54 4.5 3 57 16.9 3 Dose Level :: 2.0 46 55 Dosage Unit: mg/"kg/day 491 77 665 85 1 2 578 123.0 2 81 5.7 2 2 ,7 2 Dosage Unit: mg/kg/day 730 60 833 74 851 74 2 3 2 805 65.3 3 69 8.1 3 2 .6 3 Dosage Unit: mg/kg/day 672 100 2 534 512 523 15.6 2 281 543 455 426 133.3 3 308 404 600 502 138.6 2 298 376 380 351 46.2 3 291 43 35 39 5.7 2 256 393 324 96.9 2 21 33 39 31 9.2 3 185 204 234 208 24.7 3 84 184 002570 163 Appendix 4 Individual Clinical Chemistry Data Females Day 2 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 9.7 10.7 6.5 6.9 10.2 .71 2 6.7 .28 2 Dose Level : 0.02 10.2 9.7 10.0 6.7 7.6 8.4 10.0 .25 3 7.6 .85 3 Dose Level: 2.0 10.0 6.5 Dosage Unit: mg/kg/day 150 5.0 108 156 5.9 108 153 4.2 2 5.4 .64 2 108 2 Dosage Unit: mg/kg/day 146 5.1 104 149 4.7 104 158 4.8 108 151 6.2 3 4.9 .21 3 105 2 3 Dosage Unit: mg/kg/day 151 4.7 106 Covance 6329-222 3M T-6295.6 eo cNn 164 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3m T-6295.6 TRIG MG/DL Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 84 20 78 20 81 4.2 2 20 .0 2 Dose Level: 0.02 67 20 71 21 65 23 68 3.1 3 21 1.5 3 Dose Level : 2.0 63 18 Dosage Unit: mg/kg/day .8 7.6 4.7 .9 8.0 5.0 .8 7.8 4.8 .07 .28 .21 222 Dosage Unit : mg/kg/day .8 7.5 4.4 .7 7.3 4.5 .8 7.8 4.5 .8 7.5 4.5 .06 .25 .06 333 Dosage Unit: mg/kg/day .8 7.5 4.6 2.9 3.0 3.0 .07 2 3.1 2.8 3.3 3.1 .25 3 2.9 .3 7 92 47 .2 14 185 57 .2 10 138 52 .07 4.9 65.8 7.1 2222 .3 11 134 49 .3 9 171 51 .3 9 162 52 .3 10 156 51 .00 1.2 19.3 1.5 3333 .4 7 137 50 002572 165 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105349 105350 MEAN S.D. N Group: 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 62 37 40 56 51 15. 6 2 46 13.4 2 Dose Level: 0.02 42 40 41 66 35 66 39 3.8 3 57 15.0 3 Dose Level : 2.0 46 49 Dosage Unit: mg/kg/day 714 80 825 80 0 0 770 78.5 2 80 .0 2 0 .0 2 Dosage Unit: mg/kg/day 477 65 677 125 514 65 0 0 0 556 106.4 3 85 34.6 3 0 .0 3 Dosage Unit : mg/kg/day 1012 98 0 305 193 249 79.2 2 110 875 212 39 9 415.4 3 270 349 445 397 67.9 2 361 330 290 327 35.6 3 260 28 38 33 7.1 2 238 306 272 48 2 42 35 16 31 13.5 3 250 222 202 225 24 3 0 139 002573 166 Appendix 4 Individual Clinical Chemistry Data Males Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level: 0 10.0 10.5 7.3 6.6 10.2 .35 2 7.0 .49 2 Dose Level : 0.02 9.4 9.9 10.0 7.3 7.0 6.6 9.8 .32 3 7.0 .35 3 Dose Level: 2.0 10.3 6.6 Dosage Unit: mg/kg/day 153 5.0 112 158 5.3 112 156 3.5 2 5.2 .21 2 112 2 Dosage Unit: mg/kg/day 151 4.5 112 156 5.0 114 149 5.0 109 152 3.6 3 4.8 .29 3 112 2 3 Dosage Unit: mg/kg/day 156 5.1 112 Covance 6329-222 3M T-6295.6 002574 167 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Females Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group : 1 Dose Level : 0 Dosage Unit: mg/kg/day 105366 105367 80 25 93 16 .8 8.1 4.9 3.2 .8 8.0 4.2 3.8 .3 .2 6 128 8 131 42 23 MEAN S.D. N 86 9.2 2 20 6.4 2 .8 8.0 4.6 .00 .07 .49 222 3.5 .42 2 .2 .07 2 7 130 1.4 2.1 22 32 13.4 2 Group : 2 Dose Level : 0.02 Dosage Unit: mg/kg/day 105364 105365 105370 74 18 68 21 77 19 .8 8.1 5.1 3.0 .7 7.8 4.5 3.3 .9 8.1 4.9 3.2 .3 .4 .3 8 111 8 162 8 168 30 43 40 MEAN S.D. N 73 4.6 3 19 1.5 3 .8 8.0 4.8 3.2 .10 .17 .31 .15 3333 .3 .06 3 8 147 .0 31.3 33 38 6.8 3 Group : 3 Dose Level : 2.0 Dosage Unit : mg/kg/day 105369 73 18 .8 7.9 4.6 3.3 .3 12 117 44 002575 168 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Females Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 Dose Level: 0 Dosage Unit mg/kg/day 1 105366 45 43 492 75 1 181 415 23 284 105367 46 62 625 63 0 103 453 38 322 MEAN S.D. N 46 .7 2 52 13.4 2 558 94.0 2 69 8.5 2 0 142 434 .7 55.2 26.9 222 30 10.6 2 303 26.9 2 Group : 2 Dose Level : 0.02 Dosage Unit mg/kg/day 105364 105365 105370 58 65 655 57 45 53 805 72 43 53 865 75 0 240 364 1 228 334 0 187 369 21 251 31 192 24 251 MEAN S.D. N 49 8.1 3 57 6.9 3 775 108.2 3 68 9.6 3 0 218 356 .6 27.8 18.9 333 25 5.1 3 231 34.1 3 Group : 3 Dose Level : 2.0 Dosage Unit mg/kg/day 105369 45 57 674 90 0 166 349 101 238 002576 169 Appendix 4 Individual Clinical Chemistry Data Females Day 7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group : 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 10.4 11.5 6.5 5.7 11.0 .78 2 6.1 .57 2 Dose Level : 0.02 10.7 10.3 11.1 6.8 6.9 8.2 10.7 .40 3 7.3 .78 3 Dose Level : 2.0 10.6 6.4 Dosage Unit : mg/kg/day 155 5.7 112 158 7.0 113 156 2.1 2 6.4 .92 2 112 2 Dosage Unit: mg/kg/day 151 5.7 111 152 5.3 113 162 5.5 114 155 6.1 3 5.5 .20 3 113 1 3 Dosage Unit: mg/kg/day 155 5.3 113 Covance 6329-222 3M T-6295.6 002577 170 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day 105349 105350 89 18 .9 8.0 5.2 2.8 .4 70 20 .8 7.4 4.8 2.6 .4 6 100 9 182 33 43 MEAN S.D. N 80 13.4 2 19 1.4 2 .8 7.7 .07 .42 22 5.0 .28 2 2.7 .14 2 .4 .00 2 8 141 2.1 58.0 22 38 7 2 Group: 2 Dose Level : 0.02 Dosage Unit: mg/kg/day 105344 105347 105348 60 18 .6 7.2 4.4 2.8 61 20 .6 6.7 4.4 2.3 67 19 1.0 7.6 4.7 2.9 .4 10 136 .4 7 158 .4 6 156 37 55 41 MEAN S.D. N 63 19 .7 7.2 4.5 2.7 3.8 1.0 .23 .45 .17 .32 333333 .4 .00 3 8 150 2.1 12.2 33 44 9 3 Group: 3 Dose Level : 2.0 Dosage Unit : mg/kg/day 105345 64 15 .7 7.4 4.8 2.6 .4 6 132 27 CG2578 171 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 52 34 42 47 47 7.1 2 40 9.2 2 Dose Level : 0.02 42 41 34 48 31 57 36 5.7 3 49 8.0 3 Dose Level : 2.0 39 45 Dosage Unit: mg/Jcg/day 785 86 737 75 6 3 761 33.9 2 80 7.8 2 4 2.1 2 Dosage Unit: mg/kg/day 431 58 671 120 456 54 3 4 3 519 131.9 3 77 37.0 3 3 .6 3 Dosage Unit : mg/kg/day 908 89 2 131 193 162 43.8 2 97 85 151 111 35.2 3 245 372 415 394 30.4 2 351 294 272 306 40.8 3 242 41 29 35 8.5 2 248 277 262 20 2 52 37 15 35 18.6 3 236 188 184 203 28 3 2 123 002579 172 Appendix 4 Individual Clinical Chemistry Data Males Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 10.1 10.4 8.8 6.5 10.2 .21 2 7.6 1.63 2 Dose Level : 0.02 9.7 7.4 9.5 6.4 9.8 6.2 9.7 .15 3 6.7 .64 3 Dose Level: 2.0 10.1 6.4 Dosage Unit: mg/kg/day 152 4.6 105 150 5.0 106 151 1.4 2 4.8 .28 2 106 2 Dosage Unit : mg/kg/day 148 4.5 108 149 4.2 107 147 4.8 106 148 1.0 3 4.5 .30 3 107 1 3 Dosage Unit: mg/kg/day 153 4.8 108 Covance 6329-222 3M T-6295.6 CG25S0 173 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Females Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group: 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group: 3 105369 Dose Level: 0 77 22 82 16 80 3.5 2 19 4.2 2 Dose Level : 0.02 49 20 57 22 67 17 58 9.0 3 20 2.5 3 Dose Level : 2.0 59 18 Dosage Unit : mg/kg/day .7 7.4 4.8 .6 7.6 4.5 .6 7.5 4.6 .07 .14 .21 222 Dosage Unit: mg/kg/day .9 7.9 5.1 .5 7.4 4.5 .7 7.7 4.8 .7 7.7 4.8 .20 .25 .30 333 Dosage Unit: mg/kg/day .8 7.8 4.6 2.6 3.1 2.8 .35 2 2.8 2.9 2.9 2.9 .06 3 3.2 .4 .3 .4 .07 2 .5 .7 .4 .5 .15 3 .4 7 127 7 111 7 119 .0 11.3 22 6 111 8 150 9 155 8 139 1.5 24.1 33 8 107 27 20 24 4.9 2 28 42 36 35 7.0 3 41 0025S1 174 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Females Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 40 41 52 52 46 8.5 2 46 7.8 2 Dose Level : 0.02 46 48 55 68 40 49 47 7.5 3 55 11.3 3 Dose Level: 2.0 40 51 Dosage Unit: mg/kg/day 458 64 540 63 5 4 499 58.0 2 64 .7 2 4 .7 2 Dosage Unit : mg/kg/day 722 51 852 69 825 69 3 3 4 800 68.6 3 63 10.4 3 3 .6 3 Dosage Unit: mg/kg/day 727 86 3 157 361 259 144.2 2 341 383 197 307 97.5 3 462 399 456 428 40.3 2 289 335 337 320 27.2 3 440 18 41 30 16.3 2 31 67 20 39 24.6 3 309 262 313 288 36 2 190 189 222 200 18 3 283 002582 175 Appendix 4 Individual Clinical Chemistry Data Females Day 14 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group: 3 105369 Dose Level : 0 10.1 10.8 6.6 7.0 10.4 .49 2 6.8 .28 2 Dose Level : 0.02 10.5 9.9 10.8 6.3 6.3 7.5 10.4 .46 3 6.7 .69 3 Dose Level : 2.0 10.4 6.1 Dosage Unit: mg/kg/day 152 5.5 110 157 6.5 109 154 3.5 2 6.0 .71 2 110 2 Dosage Unit: mg/kg/day 146 5.2 105 149 5.0 107 159 5.5 112 151 6.8 3 5.2 .25 3 108 3 3 Dosage Unit : mg/kg/day 152 5.4 108 Covance 6329-222 3M T-6295.6 0025S3 176 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group : 1 Dose Level : 0 Dosage Unit: mg/kg/day 105349 105350 75 24 87 24 .8 7.5 4.6 2.9 .9 7.7 4.6 3.1 .3 .2 6 93 8 186 40 31 MEAN S.D. N 81 24 .8 7.6 4.6 3.0 8.5 .0 .07 .14 .00 .14 222222 .2 .07 2 7 140 1.4 65.8 22 36 6.4 2 Group : 2 Dose Level: 0.02 Dosage Unit: mg/kg/day 105344 105347 105348 66 22 .8 7.2 4.0 3.2 73 22 .7 6.7 4.1 2.6 80 29 1.0 8.7 4.8 3.9 .2 9 129 .2 7 151 .3 13 172 48 55 57 MEAN S.D. N 73 24 .8 7.5 4.3 3.2 .2 10 151 53 7.0 4.0 .15 1.04 .44 .65 .06 3.1 21.5 4.7 3333333333 Group : 3 Dose Level : 2.0 Dosage Unit : mg/kg/day 105345 80 15 1.1 8.2 4.8 3.4 .3 8 91 25 C025S4 177 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level:; 0 61 36 43 56 52 12.7 2 46 14.1 2 Dose Level : 0.02 42 45 34 49 49 93 42 7.5 3 62 26.6 3 Dose Level : 2.0 31 38 Dosage Unit: mg/kg/day 798 103 712 90 6 2 755 60.8 2 96 9.2 2 4 2.8 2 Dosage Unit: mg/kg/day 477 73 710 143 505 65 2 4 2 564 127.2 3 94 42.9 3 3 1.2 3 Dosage Unit: mg/kg/day 815 88 1 476 344 410 93.3 2 134 202 606 314 255.2 3 202 362 485 424 87.0 2 382 350 270 334 57.7 3 285 37 37 37 .0 2 241 329 285 62.2 2 73 24 8 35 33.9 3 263 235 185 228 39.5 3 3 156 0025 00 178 Appendix 4 Individual Clinical Chemistry Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group : 1 105349 105350 MEAN S-D. N Group : 2 105344 105347 105348 MEAN S.D. N Group: 3 105345 Dose Level : 0 10.4 10.6 8.2 6.8 10.5 .14 2 7.5 .99 2 Dose Level : 0.02 10.0 10.0 10.5 6.7 5.9 6.3 10.2 .29 3 6.3 .40 3 Dose Level : 2.0 11.0 6.4 Dosage Uni t : mg/kg/day 152 6.3 112 155 5.0 110 154 2.1 2 5.6 .92 2 111 1 2 Dosage Unit: mg/kg/day 149 4.8 108 152 4.5 112 155 6.0 110 152 3.0 3 5.1 .79 3 110 2 3 Dosage Unit : mg/kg/day 156 6.0 107 Covance 6329-222 3M T-6295.6 0025S6 179 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS UN MG/DL CREAT MG/DL T PRO G/DL ALB G/DL GLOB G/DL T BILI MG/DL SBA umol/L CHOL MG/DL Covance 6329-222 3M T-6295.6 TRIG MG/DL Group : 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level: 0 87 26 86 24 86 .7 2 25 1.4 2 Dose Level: 0.02 50 28 71 22 65 21 62 10.8 3 24 3.8 3 Dose Level : 2.0 78 24 Dosage Unit: mg/kg/day .8 7.4 4.4 .9 7.9 4.3 .8 7.6 4.4 .07 .35 .07 222 Dosage Unit: mg/kg/day 1.0 8.5 5.0 .8 7.7 4.4 .8 7.4 4.3 .9 7.9 4.6 .12 .57 .38 333 Dosage Unit: mg/kg/day 1.0 8.2 4.6 3.0 3.6 3.3 .42 2 3.5 3.3 3.1 3.3 .20 3 3.6 .2 11 107 41 .2 7 135 36 .2 9 121 38 .00 2.8 19.8 3 2222 .4 8 114 45 .3 8 156 40 .2 11 158 52 .3 9 143 46 .10 1.7 24.8 6 3333 .2 17 62 27 C025S7 180 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS AST/SGOT ALT/SGPT ALK PHOS IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE LIPASE IU/L IU/L P AMYL U/L Covance 6329-222 3M T-6295.6 Group : 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level :: 0 46 39 60 52 53 9.9 2 46 9..2 2 Dose Level !: 0.02 53 49 44 60 39 52 45 7.1 3 54 5..7 3 Dose Level : 2.0 36 47 Dosage Unit : mg/kg/day 418 70 516 75 9 4 467 69.3 2 72 3.5 2 6 3.5 2 Dosage Unit: mg/kg/day 926 67 966 79 832 81 4 2 2 908 68.8 3 76 7.6 3 3 1.2 3 Dosage Unit : mg/kg/day 637 93 2 335 262 298 51.6 2 215 363 240 273 79.2 3 341 444 633 538 133.6 2 290 348 381 340 46.1 3 326 18 241 130 157.7 2 10 39 20 23 14.7 3 18 300 440 370 99.0 2 193 205 257 218 34.0 3 221 002538 181 Appendix 4 Individual Clinical Chemistry Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group : 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 10.3 10.6 5.6 7.1 10.4 .21 2 6.4 1.06 2 Dose Level: 0.02 11.2 10.4 11.2 7.9 6.6 6.2 10.9 .46 3 6.9 .89 3 Dose Level : 2.0 11.1 6.5 Dosage Unit: mg/kg/day 151 5.4 109 153 6.0 113 152 1.4 2 5.7 .42 2 111 2.8 2 Dosage Unit: mg/kg/day 152 5.5 109 153 5.4 112 160 5.6 113 155 4.4 3 5.5 .10 3 111 2.1 3 Dosage Unit : mg/kg/day 158 5.7 110 Covance 6329-222 3M T-6295.6 002589 182 Appendix 4 Individual Clinical Chemistry Data Males Day 30 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER PCOAO IU/G Group: 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level: 0 0 1 0 .7 2 Dose Level: 0.02 4 4 3 4 .6 3 Dose Level : 2.0 1 Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day Covance 6329-222 3M T-6295.6 Appendix 4 Individual Clinical Chemistry Data Males Day 30 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER PCOAO IU/G Group : 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 0 4 2 2.8 2 Dose Level : 0.02 7 0 3 3 3.5 3 Dose Level : 2.0 1 Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day Covance 6329-222 3M T-6295,6 002591 184 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 002592 185 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 1 ANIMAL NUMBER: 105349 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2235.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 9:44 PROSECTOR: JILL PAUS RECORDER: WENDY CHERRY POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE NECROPSY OBSERVATIONS HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : SECTION EXAMINED; TISSUE NOT PRESENT TESTIS (TE) : -IMMATURE, -PRESENT THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , TESTIS (TE) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR), SPINAL CORD (SC), NERVE, SCIATIC (SN), HEART (HT), MUSCLE, SKELETAL (SM), TRACHEA (TR), ESOPHAGUS (ES), GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG), SKIN (SK), MAMMARY, MALE (MM), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , PROSTATE (PR), SEMINAL VESICLES (SV) , EPIDIDYMIDES (EP) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY), BONE, FEMUR (FE), KIDNEY (KD), LUNG (LU), LIVER (LI), SPLEEN (SP), PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 2 ANIMAL NUMBER: 105350 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2295.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 11:00 PROSECTOR: JILL PAUS RECORDER: DONIA MEYER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE NECROPSY OBSERVATIONS HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : >SECTION EXAMINED; TISSUE NOT PRESENT TESTIS (TE) : -IMMATURE, -PRESENT THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , TESTIS (TE) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN), HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK) , MAMMARY, MALE (MM), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS PAGE: 3 ANIMAL NUMBER: 105344 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2330.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 10:25 PROSECTOR: DAVID SCHUETTE RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE \ OBSERVATIONS NECROPSY HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : >SECTION EXAMINED; TISSUE NOT PRESENT TESTIS (TE) : -IMMATURE, -PRESENT THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , TESTIS (TE) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG), SKIN (SK) , MAMMARY, MALE (MM), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , PROSTATE (PR), SEMINAL VESICLES (SV) , EPIDIDYMIDES (EP) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY), BONE, FEMUR (FE) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) 0025 188 01 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 4 ANIMAL NUMBER: 105347 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2125.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 11:00 PROSECTOR: DAVID SCHUETTE RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE 1 OBSERVATIONS NECROPSY HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS LIVER (LI) : -INFILTRATE, LYMPHOPLASMACYTIC,-MINIMAL TESTIS (TE) : -IMMATURE, -PRESENT THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC) , ADRENAL, MEDULLA (MA) , THYMUS (TH) , TESTIS (TE) , MARROW, STERNUM (SE) , BONE, STERNUM (SB) , BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK) , MAMMARY, MALE (MM), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE), COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , PROSTATE (PR), SEMINAL VESICLES (SV) , EPIDIDYMIDES (EP) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC) , ADRENAL, MEDULLA (MA) , THYMUS (TH) 002596 189 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 5 ANIMAL NUMBER: 105348 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2285.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 10:19 PROSECTOR: DENNIS HOFFMAN RECORDER: DONIA MEYER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE NECROPSY OBSERVATIONS HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : SECTION EXAMINED; TISSUE NOT PRESENT KIDNEY (KD) : -INFILTRATE, LYMPHOPLASMACYTIC,-SLIGHT, TESTIS (TE) : -IMMATURE, -PRESENT FOCAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP), PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , TESTIS (TE) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG), SKIN (SK) , MAMMARY, MALE (MM), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO) , RECTUM (RE) , URINARY BLADDER (UB) , PROSTATE (PR) , SEMINAL VESICLES (SV) , EPIDIDYMIDES (EP) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 6 ANIMAL NUMBER: 105345 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 1870.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 11:10 PROSECTOR: WENDY CHERRY RECORDER: DENNIS HOFFMAN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE 1 OBSERVATIONS NECROPSY HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : SECTION EXAMINED; TISSUE NOT PRESENT TESTIS (TE) : -IMMATURE, -PRESENT THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , TESTIS (TE) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK) , MAMMARY, MALE (MM), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , PROSTATE (PR), SEMINAL VESICLES (SV) , EPIDIDYMIDES (EP) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) 002598 191 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 7 ANIMAL NUMBER: 105366 SEX: FEMALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2000.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 9:40 PROSECTOR: DENNIS HOFFMAN RECORDER: DONIA MEYER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE 1 OBSERVATIONS NECROPSY HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : >SECTION EXAMINED; TISSUE NOT PRESENT LIVER (LI) : -INFLAMMATION, LYMPHOHISTIOCYTIC,-SLIGHT, FOCAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK) , MAMMARY, FEMALE (MF) , STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE), COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , OVARY (OV) , UTERUS (UT) , CERVIX (CV) , VAGINA (VA) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , KIDNEY (KD) , LUNG (LU) , SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) 002599 192 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 8 ANIMAL NUMBER: 105367 SEX: FEMALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2085.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 9:47 PROSECTOR: DAVID SCHUETTE RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE 1 OBSERVATIONS NECROPSY HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS KIDNEY (KD) : -INFILTRATE, LYMPHOPLASMACYTIC,-MINIMAL LIVER (LI) : -INFILTRATE, LYMPHOPLASMACYTIC, -MINIMAL -LIPIDOSIS, SUBCAPSULAR (TENSION LIPIDOSIS),-SLIGHT, FOCAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK), MAMMARY, FEMALE (MF) , STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO) , RECTUM (RE) , URINARY BLADDER (UB) , OVARY (OV) , UTERUS (UT) , CERVIX (CV) , VAGINA (VA) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , LUNG (LU) , SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) 003200 193 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295 ) IN CYNOMOLGUS MONKEYS PAGE: 9 ANIMAL NUMBER: 105364 SEX: FEMALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2080.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 8:09 PROSECTOR: DENNIS HOFFMAN RECORDER: DONIA MEYER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE NECROPSY OBSERVATIONS HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MARROW, FEMUR (FM) : SECTION EXAMINED; TISSUE NOT PRESENT KIDNEY (KD) : -INFILTRATE, LYMPHOPLASMACYTIC,-SLIGHT ADRENAL, CORTEX (AC) : -HEMORRHAGE,-MODERATE, FOCAL -THROMBUS,-PRESENT NOTE: UNILATERAL MICROSCOPIC FINDINGS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN), HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK) , MAMMARY, FEMALE (MF) , STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO) , RECTUM (RE) , URINARY BLADDER (UB) , OVARY (OV) , UTERUS (UT) , CERVIX (CV) , VAGINA (VA) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, MEDULLA (MA) , THYMUS (TH) 002601 194 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 10 ANIMAL NUMBER: 105365 SEX: FEMALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 2245.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 8:08 PROSECTOR: DAVID SCHUETTE RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE 1 OBSERVATIONS NECROPSY HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -STAINS -PERINEUM /PERIANAL ; DARK RED AND MOIST KIDNEY (KD) : -INFILTRATE, LYMPHOPLASMACYTIC,-MODERATE LIVER (LI) : -INFILTRATE, LYMPHOPLASMACYTIC, -MINIMAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP), PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN), HEART (HT), MUSCLE, SKELETAL (SM), TRACHEA (TR), ESOPHAGUS (ES), GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG! , SKIN (SK) , MAMMARY, FEMALE (MF) , STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL), CECUM (CE) , COLON (CO) , RECTUM (RE) , URINARY BLADDER (UB) , OVARY (OV) , UTERUS (UT) , CERVIX (CV) , VAGINA (VA) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , LUNG (LU) , SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) 002S02 195 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS;T-6295) IN CYNOMOLGUS MONKEYS PAGE: 11 ANIMAL NUMBER: 105370 SEX: FEMALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 1940.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 10:18 PROSECTOR: JILL PAUS RECORDER: WENDY CHERRY POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE NECROPSY OBSERVATIONS HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS LIVER (LI) : -INFILTRATE, LYMPHOPLASMACYTIC,-SLIGHT THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) , MARROW, STERNUM (SE) , BONE, STERNUM (SB), BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG), SKIN (SK) , MAMMARY, FEMALE (MF) , STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO), RECTUM (RE), URINARY BLADDER (UB) , OVARY (OV) , UTERUS (UT) , CERVIX (CV) , VAGINA (VA) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC) , ADRENAL, MEDULLA (MA) , THYMUS (TH) C02603 196 APPENDIX 5 Individual Animal Pathology Data Covance 6329-222 3M T-6295.6 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLU0R00CTANE SULFONIC ACID POTASSIUM SALT (PFOS ;T-6295 ) IN CYNOMOLGUS MONKEYS PAGE: 12 ANIMAL NUMBER: 105369 SEX: FEMALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 05/22/98 STUDY DAY OF DEATH: 30 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 1970.0 GRAMS DATE AND TIME OF NECROPSY: 05/22/98 8:08 PROSECTOR: JILL PAUS RECORDER: WENDY CHERRY POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: DR. TOM PALMER WEIGHER: NOT AVAILABLE NECROPSY OBSERVATIONS HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: EYE (EY), BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC) , ADRENAL, MEDULLA (MA) , THYMUS (TH) , MARROW, STERNUM (SE) , BONE, STERNUM (SB) , BRAIN (BR) , SPINAL CORD (SC), NERVE, SCIATIC (SN) , HEART (HT) , MUSCLE, SKELETAL (SM) , TRACHEA (TR) , ESOPHAGUS (ES) , GALLBLADDER (GB) , PITUITARY (PI), AORTA (AO), LN, MESENTERIC (MS), THYROID (TY) , PARATHYROID (PT) , SALIV GL, MANDIB (SG) , SKIN (SK) , MAMMARY, FEMALE (MF) , STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE) , ILEUM (IL) , CECUM (CE) , COLON (CO) , RECTUM (RE) , URINARY BLADDER (UB) , OVARY (OV) , UTERUS <UT) , CERVIX (CV) , VAGINA (VA) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: EYE (EY) , BONE, FEMUR (FE) , MARROW, FEMUR (FM) , KIDNEY (KD) , LUNG (LU) , LIVER (LI), SPLEEN (SP) , PANCREAS (PA), ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA) , THYMUS (TH) 002604 197 Covance 6329-222 3MT-6295.6 APPENDIX 6 Summary and Individual Hormone Analyses Data Figure 1 - Mean Estradiol Data - Males Figure 2 - Mean Estradiol Data - Females Figure 3 - Mean Triiodothyronine Data - Males Figure 4 - Mean Triiodothyronine Data - Females NOTE: This appendix of the report contains information supplied by Ani Lyrics Inc. and has been reviewed by the Quality Assurance Unit of Ani Lyrics Inc. 002605 198 Appendix 6 Summary and Individual Hormone Analyses Data Males Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH FERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ESTRADIOL ESTRONE ESTRIOL THYROID STIMULATING TRIIODOTHYRONINE THYROXIN pg/mL pg/mL pg/mL <$U/mL ng/dL <I>g/dL Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level : 0 34.86 29.20 38.62 17.83 32.03 4.002 2 28.23 14.701 2 Dose Level: 0.02 24.95 34.14 26.73 18.44 17.74 15.79 28.61 4.874 3 17.32 1.373 3 Dose Level : 2.0 28.71 13.98 Dosage Unit: mg/kg/day 0.00 0.00 2.33 3.30 0.00 0.000 2 2.82 0.686 2 Dosage Unit: mg/kg/day 0.00 0.00 0.00 2.62 2.49 1.21 0.00 0.000 3 2.11 0.779 3 Dosage Unit : mg/kg/day 0.00 1.71 160.41 119.07 139.74 29.232 2 152.65 148.40 66.41 122.49 48.610 3 97.61 4.01 6.84 5.43 2.001 2 3.90 4.43 4.52 4.28 0.335 3 3.86 Covance 6329-222 3M T-6295.6 C02G06 199 Appendix 6 Summary and Individual Hormone Analyses Data Females Day -7 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ESTRADIOL ESTRONE ESTRIOL THYROID STIMULATING TRI IODOTHYRONINE THYROXIN pg/mL pg/mL pg/mL <t>U/mL ng/dL C>g/dL Group : 1 105366 105367 MEAN S.D. N Group: 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 45.43 45.13 25.12 32.42 45.28 0.212 2 28.77 5.162 2 Dose Level: 0.02 28.17 70.25 45.95 21.98 26.58 42.65 48.12 21.124 3 30.40 10.852 3 Dose Level : 2.0 37.37 29.50 Dosage Unit: mg/kg/day 0.00 0.00 1.26 7.48 0.00 0.000 2 4.37 4.398 2 Dosage Unit: mg/kg/day 0.00 0.00 0.00 3.07 3.65 0.80 0.00 0.000 3 2.51 1.506 3 Dosage Unit: mg/kg/day 0.00 1.41 172.31 92.99 132.65 56.088 2 148.92 176.45 67.89 131.09 56.434 3 122.38 5.55 4.21 4.88 0.948 2 5.71 4.94 3.62 4.76 1.057 3 3.60 Covance 6329-222 3M T-6295.6 002607 200 Appendix 6 Summary and Individual Hormone Analyses Data Males Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ESTRADIOL ESTRONE ESTRIOL THYROID STIMULATING TRIIODOTHYRONINE THYROXIN pg/mL pg/mL pg/mL OU/mL ng/dL <>g/dL Group : 1 105349 105350 MEAN S.D. N Group : 2 105344 105347 105348 MEAN S.D. N Group : 3 105345 Dose Level: 0 33.04 32.75 25-02 18.84 32.90 0.205 2 21.93 4.370 2 Dose Level: 0-02 25.19 37.25 40.32 10.24 14.20 19.73 34.25 7.998 3 14.72 4.767 3 Dose Level: 2.0 18.16 20.12 Dosage Unit: mg/kg/day 0.00 0.00 0.73 3.57 0.00 0.000 2 2.15 2.008 2 Dosage Unit: mg/kg/day 0.00 0.00 0.00 3.27 3.58 2.45 0.00 0.000 3 3.10 0.584 3 Dosage Unit: mg/kg/day 0.00 0.95 181.44 191.25 186.35 6.937 2 195.89 209.96 159.16 188.34 26.229 3 90.73 3.32 5.31 4.32 1.407 2 3.86 3.82 4.90 4.19 0.612 3 3.18 Covance 6329-222 3M T-6295.6 C02Q8 201 Appendix 6 Summary and Individual Hormone Analyses Data Females Day 29 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ESTRADIOL ESTRONE ESTRIOL THYROID STIMULATING TRIIODOTHYRONINE THYROXIN pg/mL pg/mL pg/mL <I>U/mL ng/dL <t>g/dL Group: 1 105366 105367 MEAN S.D. N Group : 2 105364 105365 105370 MEAN S.D. N Group : 3 105369 Dose Level : 0 67.67 39.27 24.46 27.47 53.47 20.082 2 25.97 2.128 2 Dose Level: 0.02 31.90 87.09 57.17 32.66 30.94 31.23 58.72 27.628 3 31.61 0.921 3 Dose Level: 2.0 19.82 25.85 Dosage Unit: mg/kg/day 0.00 0.00 2.57 3.32 0.00 0.000 2 2.95 0.530 2 Dosage Unit : mg/kg/day 0.00 0.00 0.00 2.50 4.64 1.14 0.00 0.000 3 2.76 1.764 3 Dosage Unit : mg/kg/day 0.00 3.92 141.93 183.46 162.70 29.366 2 179.61 196.25 165.89 180.58 15.203 3 90.17 4.57 3.95 4.26 0.438 2 5.26 3.79 3.09 4.05 1.108 3 3.38 Covance 6329-222 3M T-6295.6 002G09 202 Figure 1 GRAPH - Mean Estradiol Data - Males 203 C02G10 o o & p p Figure 2 GRAPH - Mean Estradiol Data - Females 204 oo o N Figure 3 GRAPH - Mean Triiodothyronine Data - M ales 205 Figure 4 GRAPH - Mean Triiodothyronine Data - Females 206 002613 APPENDIX 7 Dose Analysis Covance 6329-222 3M T-6295.6 NOTE: This appendix of the report contains information supplied by the Sponsor and has been reviewed by the Quality Assurance Unit of 3M. 002614 207 Dose Analysis (to be provided by the Sponsor) Covance 6329-222 3M T-6295.6 002615 208 Covance 6329-222 3M T-6295.6 APPENDIX 8 Serum and Liver PFOS Level Determinations NOTE: This appendix of the report contains information supplied by the Sponsor and has been reviewed by the Quality Assurance Unit of 3M. 002616 209 Serum and Liver PFOS Level Determinations (to be provided by the Sponsor) Covance 6329-222 3M T-6295.6 002S17 210 APPENDIX 9 Cell Proliferation Evaluation Covance 6329-222 3M T-6295.6 NOTE: This appendix of the report contains information supplied by Pathology Associates International and has been reviewed by the Quality Assurance Unit of Pathology Associates International. C02S1S 211 Covance 6329-222 3M T-6295.6 Cell Proliferation Evaluation (to be provided by Pathology Associates International) 002619 212 Pathology Associates International A Company of Science Applications International _____________ Corporation______________ A i Empioyttt-OwnaeiCompany DRAFT CELL PROLIFERATION REPORT i-($-%.(o 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS COVANCE STUDY NUMBER 6329-222 PREPARED FOR: 3M TOXICOLOGY SERVICES BUILDING 220-2E-02, 3M CENTER ST. PAUL, MN 55144-1000 PREPARED BY: PATHOLOGY ASSOCIATES INTERNATIONAL 15 WORMAN'S MILL COURT, SUITE I FREDERICK, MD 21701 SEPTEMBER 30, 1998 15 Worman's Mill Court, Suite I * Frederick, Maryland 21701 * (301) 663-1644 * (301) 663-8994 FAX 002G20 Draft Cell Proliferation Report Covance Study Number 6329-222 Page 2 CELL PROLIFERATION REPORT 4-WEEK CAPSULE TOXICITY STUDY WITH PERFLUOROOCTANE SULFONIC ACID POTASSIUM SALT (PFOS; T-6295) IN CYNOMOLGUS MONKEYS COVANCE STUDY NUMBER 6329-222 PURPOSE The purpose of the study was to provide data for determining an estimated maximum-tolerated dose and lower dose levels to be used in a chronic toxicity study and to assess the effect of the test material on critical enzyme levels, hormones, and other selected biochemical parameters. This report, submitted by Pathology Associates International (PAI) to the study Sponsor, 3M, represents the cell proliferation findings and interpretation for Covance Study Number 6329-222 entitled "4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys". All aspects of the tasks associated with PAI's portion of this study were conducted in compliance with the Environmental Protection Agency Good Laboratory Practice (GLP) Regulations as set forth in Title 40 of the US Code of Federal Regulations, Part 792, issued November 29, 1983 (effective December 29, 1983), and with any applicable amendments. MATERIALS AND METHODS Tissue Collection for Cell Proliferation Two animals per sex in control group 1, three animals per sex in dose group 2 (0.02 mg/kg/day) and one animal per sex in dose group 3 (2.0 mg/kg/day) were sacrificed after four weeks on diet. A representative sample of the liver, testes (males only) and pancreas from each animal was fixed in zinc formalin, processed and embedded to paraffin block by Covance per protocol specifications. Tissue blocks were then shipped to PAI for sectioning and staining. From each block, a slide was prepared for H&E evaluation and immunohistochemical detection of proliferating cell nuclear antigen (PCNA), a marker of cell proliferation. Immunohistochemistry for Cell Proliferation Sections of paraffin-embedded tissues were cut at 5 (im and placed on positively charged slides (Superfrost Plus, Fisher Scientific, Pittsburgh, PA) to ensure adhesion during processing for PCNA. Standard immunohistochemical methods were used to stain tissues for PCNA (PAI's Standard Operating Procedure for Immunohistochemical Staining (SOP #707). Briefly, tissue sections were incubated with a monoclonal antibody to PCNA (DAKO, lot #016, PAI No. A 1723) and reagents required for the avidin-biotin peroxidase (ABC Kit, lot #PK-6100, PAI No. K 324) method for the detection of the antigen-antibody complex. PCNA expression in cells was localized by the chromagen 3,3'-diaminobenzidine (DAB; Sigma Chemical Co., lot #18H8201). Tissue sections were counterstained with hematoxylin. Cell Proliferation Measurements The percentage of proliferating cells (proliferating index, PI) was determined by scoring at least 3000 hepatocytes in 10 fields of liver, at least 500 Leydig cells of the testes (males only), and at least 2000 acinar cells of the pancreas per animal. A negative control slide was included in the staining run and consisted of study tissue that was not incubated with the primary antibody. 002621 Draft Cell Proliferation Report Covance Study Number 6329-222 Page 3 For cell proliferation evaluations, slides were first perused at low magnification (100X) to judge quality of staining, processing and sectioning, potential patterns of cellular proliferation, and histomorphologic changes. Cell proliferation was then quantified at higher magnification (200X for liver, and 400X for testes and pancreas) as described above. Histomorphology was further assessed by evaluating the H&E slide prepared from the same tissue block for each animal evaluated for cell proliferation. Statistical Analysis Due to the small sample size, statistical analysis was not performed. RESULTS Cell Proliferation Individual animal cell proliferation data are presented in Section II (Table 1). Cell proliferation in the liver, testes and pancreas of control and test material-treated animals was similar. H istop ath ology Sections from the same tissue blocks used for preparation of PCNA-stained slides were stained with hematoxylin and eosin (H&E) for histopathologic evaluation to facilitate the interpretation of the immunostained slides. Individual animal findings are presented in Appendix I. Single sections of liver, pancreas, and testes from 6 young adult male monkeys and single sections of liver and pancreas from 6 young adult female monkeys representing control, low-dose (0.02 mg/kg/day), and high-dose (2.0 mg/kg/day) treatment groups were evaluated histologically. Each tissue section was stained with hematoxylin and eosin. The purpose of this evaluation was to determine whether or not morphologic changes were occurring in these tissues which may alter or confound the specificity of the PCNA staining observed in these animals. The results showed that no significant changes were observed in either the liver, pancreas, or testicular tissues from male monkeys or the liver and pancreas tissues from female monkeys, which would alter the interpretation of the PCNA staining in this study. DISCUSSION In the present study, cell proliferation was measured within the liver, testes and pancreas of male monkeys, and the liver and pancreas of female monkeys from control (0 mg/kg/day), low dose (0.02 mg/kg/day), and high dose (2.0 mg/kg/day) groups after four weeks on study to determine an estimated maximun-tolerated dose and lower dose levels to be used in a chronic toxicity study and to assess the effect of the test material on critical enzyme levels, hormones, and other selected biological parameters, to include cell proliferation. There did not appear to be a cell proliferative response to the test material in the liver, testes or pancreas, as determined by proliferating indices which were similar in all animals. SUMMARY In the present study, cell proliferation, as determined by measuring the proliferating index, was not increased in the liver, testes or pancreas of monkeys. CQ2G22 Draft Cell Proliferation Report Covance Study Number 6329-222 o . TABLE C02623 COVANCE STUDY NO. 6329-222 TABLE 1. CELL PROLIFERATION IN MONKEYS Group 1 - 0 mg/kg/day (Control) 1 - 0 mg/kg/day (Control) 2 - 0.02 mg/kg/day (Low dose) 2 - 0.02 mg/kg/day (Low dose) 2 - 0.02 mg/kg/day (Low dose) 3 - 2.0 mg/kg/day (High dose) 1 - 0 mg/kg/day (Control) 1 - 0 mg/kg/day (Control) 2 - 0.02 mg/kg/day (Low dose) 2 - 0.02 mg/kg/day (Low dose) 2 - 0.02 mg/kg/day (Low dose) 3 - 2.0 mg/kg/day (High dose) Sex M M M M M M F F F F F F Animal Number I05349 IO5350 I05344 I05347 I05348 I05345 I05366 I05367 I05364 I05365 IO5370 I05369 Proliferating Index Liver 0.025% 0.087% 0.056% 0.298% 0.106% 0.026% 0.000% 0.086% 0.000% 0.083% 0.143% 0.000% Proliferating Index Testes 20.3% 22.9% 18.5% 33.6% 16.5% 17.6% NA NA NA NA NA NA Proliferating Index Pancreas 62.30% 50.30% 66.30% 55.50% 63.90% 44.90% 50.20% 65.60% 39.60% 43.60% 60.20% 40.90% C02S24 Draft Cell Proliferation Report Covance Study Number 6329-222 APPENDIX I C02625 Covance Study Number 6329-222 Individual Animal Histopathology Findings - Male Monkeys 4-week Capsule Toxicity Study Animal Number 105349 105350 105344 105347 105348 105345 Liver Testes Pancreas No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings Individual Animal Histopathology Findings - Female Monkeys 4-week Capsule Toxicity Study 105366 105367 105364 105365 105370 105369 Animal Number Liver No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings Pancreas No significant findings No significant findings No significant findings No significant findings No significant findings No significant findings 002626 Draft Cell Proliferation Report Covance Study Number 6329-222 III. SIGNATURE PAGE 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys (Covance Study Number 6329- 222) Submitted by: PAI Project Manager: PAI Project Pathologist: Date 002627 Draft Cell Proliferation Report Covance Study Number 6329-222 IV. QUALITY ASSURANCE STATEMENT CG2628 PathologyAssociates International A Company of Science Applications International Corporation AnEmployde-OwnedCompany Cell Proliferation Report 4-Week Capsule Toxicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Cynomolgus Monkeys Covance Study Number 6329-222 QUALITY ASSURANCE STATEMENT This cell proliferation project has been inspected and audited by the PAI Quality Assurance Unit (QAU) as required by the Good Laboratory Practice (GLP) regulations promulgated by the U.S. Environmental Protection Agency. The pathology report is an accurate reflection of the recorded data. The following table is a record of the inspections/audits performed and reported by the QAU. Date of Inspection Phase Inspected Date Findings Reported to Management/ Study Analyst 06/24/98 08/27/98;09/08,10/98 08/27/98:09/08,10/98 Labeling Study Data and Related Documentation Draft Cell Proliferation Report 06/26/98 08/27/98:09/10/98 08/27/98:09/10/98 -C = ^ - Rose A. Bishop Quality Assurance Auditor Date 002629 15 Worman's Mill Court, Suite I Frederick, Maryland 21701 (301) 663-1644 (301) 663-8994 FAX 3M E nvironm ental L aboratory Protocol- Analytical Study QuantitativeAnalysisofPerfluorooctaneSulfonicAcidPotassiumSalt (PFOS, T-6295)inCynomolgusMonkeysFollowingAdministrationofa4- WeekCapsuleToxicityStudy 3M ET & SS Study Number: AMDT-041598.1 In-Vivo Study Reference Number: Covance 6329-222 Test Substance: Perfluorooctane Sulfonic Acid Potassium Salt (Potassium Perfluorooctane Sulfonate) C8F17S 03-K+ (PFOS, T-6295) Name and Address of Sponsor: 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, MN 55144-1000 Name and Address of Biological-Phase Facility: Covance Laboratories Inc. P.O. Box 7545 Madison, WI 53707-7545 Name and Address of Analytical Testing Facility: 3M Environmental Technology and Services 935 Bush Avenue St. Paul, MN 55106 Date of Approval by Sponsor: 4/21/98 Proposed Analytical Initiation Date: 7/15/98 Proposed Analytical Completion Date: 7/15/99 002630 1.0 Purpose This study is designed to quantitatively determine the extent of absorption of PFOS and various metabolites in cynomolgus monkeys orally administered PFOS. 2.0 Regulatory Compliance________________________________________ _ This study will be conducted in accordance with the EPA Good Laboratory Practice regulations 40 CFR part 792 and applicable current Environmental Testing & Safety Services (ET&SS) SOP's and methods (see sections 8.0 and 9.0for specific SOP's and methods related to this protocol). 3.0 Test Materials__________________________________________________ 3.1 Test, Control, and Reference Substances and Matrices 3.1.1 Analytical Reference Substance: Perfluorooctane Sulfonic Acid Potassium Salt (C8FnS 03-K+ (PFOS, T-6295)) 3.1.2 Analytical Reference Substance Matrix: Cynomolgus monkey serum and liver tissue 3.1.3 Analytical Control Substance Matrix: Cynomolgus monkey serum and liver tissue (Control tissue, 105346). 3.2 Source of Materials 3.2.1 Analytical Reference Substance: 3MICP/PCP Division 3.2.2 Analytical Reference Substance Matrix: Covance Research Products (The source of the monkeys will be documented in the raw data) 3.2.3 Analytical Control Substance Matrix: Covance Research Products. The tissue was from a control animal, 105346. 3.3 Number of Test and Control Samples 3.3.1 Test samples Number Dose Level Group & Route PFOS Collections1 Sex (mg/kg/day) 1 (Control) 2 Male Orally by 2 Female gel capsules 0 Blood predose (-6 days from dosing), and on Days 2, 7, 14,and 29. Liver tissue on Day 29. 2 3 Male Orally by (low-dose) 3 Female gel capsules 0.02 Blood predose (-6 days from dosing), and on Days 2, 7, 14,and 29. Liver tissue on Day 29. 3 1 Male Orally by 2.0 Blood predose (-6 days from dosing), and (high-dose) 1 Female gel capsules on Days 2, 7, 14,and 29 Liver tissue on Day 29. 1-Blood collected from animals will be centrifuged by Covance, serum harvested, and serum shipped to 3M ET&SS for analysis 3.4 Identification of Test and Control Samples. Test samples will be identified by Covance at the time of collection. 002631 2 3.5 Purity and Identity of Materials. Characterization of the test materials is the responsibility of the Sponsor. 3.6 Stability of Reference Material. Testing for the stability of the test material under the conditions of administration is the responsibility of the Sponsor. 3.7 Storage Conditions for Test Materials. Analytical reference substance will be stored at ambient temperature. Analytical reference matrices will be stored at or below approximately -20 C, until extraction. All extracts will be stored nominally at 4 C until analyzed. Test and Control samples will be received according to AMDT-S-10. 3.8 Disposition of Specimens. Biological tissues and fluids will be retained for the required time period as per GLP regulation 40 CFR part 792.195 for studies longer than 28 days. 3.9 Safety Precautions. Refer to the Material Safety Data Sheets for the substances used for associated safety information. Exercise caution when handling knives for cutting the sample matrices. Safety glasses, protective clothing and appropriate hand protection should always be worn when working in the Environmental Laboratory. 4.0 Experimental - Overview___________________________________________________ Animals were administered gel capsules orally, daily (7 days/week) for 28 days. Dose levels of PFOS in the capsule varied (0, 0.02, and 2.0 mg/kg) between groups (control, low-dose, and high-dose respectively). Blood samples were collected at regular intervals (see 3.3.1). Liver tissue samples were collected at the time of sacrifice (Day 29). Sera and liver tissue were shipped to 3M ET&SS for the analytical portion of this study. See Covance Study #CHW 6329222 for information regarding the in-life portion of the study. The sera and liver tissue will be extracted via an ion pairing method, or other method as appropriate, and then analyzed via Electrospray Ionization/Mass Spectrometry (Tandem Mass Spectrometry) ESI/MS(MS), or other appropriate technique, for PFOS and other fluorochemical metabolites. 5.0 Experimental- Analytical Methods___________________________________________ Liver tissue and sera will be targeted for analysis. Methods are available for extraction and analysis of fluorochemicals from sera and liver tissue various animal matrices (see attachments). The methods will be validated for cynomolgus monkey matrices prior to or concurrently with sample analysis. 6.0 Data Analysis Data will be reported as the milligrams (mg) of PFOS or metabolite per unit of tissue, or as a concentration of fluoride per tissue, or in other clearly defined units, as appropriate. Quantitation 3 002632 will be performed using calibration curves. These curves will be determined using linear regression analysis. Statistics used, at the discretion of the Principal Investigator, may include averages and standard deviations of concentrations for different dose groups. If necessary, simple statistical tests such as Student's t-test may be applied to determine statistical difference. No final report will be prepared for this study. A data package will be provided to Covance for inclusion in their final report for CHW 6329-222. 7.0 Maintenance of Raw Data and Records 7.1 The following raw data and records will be retained in the study folder in the archives according to AMDT-S-8. 7.1.1 Approved protocol and amendments 7.1.2 Study correspondence 7.1.3 Shipping records 7.1.4 Raw data 7.1.5 Approved final report (original signed copy) 7.1.6 Electronic copies of data 7.2 Supporting records to be retained separately from the study folder in the archives according to AMDT-S-8 will include, but not necessarily be limited to, the following: 7.2.1 Training records 7.2.2 Calibration records 7.2.3 Instrument maintenance logs 7.2.4 Standard Operating Procedures, Equipment Procedures, and Methods 7.2.5 Appropriate specimens 8.0 References 8.1 AMDT-S-1, Chemical Tracking 8.2 AMDT-S-2, Solutions and Standards Making 8.3 AMDT-S-3, Personnel Training 8.4 AMDT-S-4, General Lab Documentation Systems 8.5 AMDT-S-5, GLP-related Documentation Systems 8.6 AMDT-S-6, General Lab Records 8.7 AMDT-S-7, GLP-related Records 8.8 AMDT-S-8, Archives 8.9 AMDT-S-9, GLP Program and Responsibilities 8.10 AMDT-S-10, Sample Tracking System 8.11 AMDT-S-12, Analytical Method Validation 8.12 AMDT-S-15, Laboratory Practices and Data Management 8.13 AMDT-S-16, Quality Assurance Unit 8.14 AMDT-S-17, Analytical Equipment Systems Documentation 002633 4 8.15 AMDT-S-18, Routine Calibration Checks of Balances 8.16 AMDT-S-20, Daily Calibration Checks of Automatic Pipettors 8.17 AMDT-S-21, Annual Calibration Checks of Automatic Pipettors 9.0 Attachments______________________________________________________________ 9.1 FACT-M-1.0 Extraction of PFOS or Other Anionic Fluorochemical Surfactants from Liver Using Analysis Using HPLC Electrospray Mass Spectrometry 9.2 FACT-M-2.0 Analysis of Fluorochemicals in Liver Extracts using HPLC Electrospray/Mass Spectrometry 9.3 FACT-M-3.0 Extraction of PFOS or Other Anionic Fluorochemical Surfactants from Serum Using Analysis Using HPLC Electrospray Mass Spectrometry 9.4 FACT-M-4.0 Analysis of Fluorochemicals in Serum Extracts using HPLC Electrospray/Mass Spectrometry 002634 5 3M MEDICAL DEPARTMENT TOXICOLOGY SERVICES cc: John Butenhoff From: Marv Case Subject: Covance Study 6329-222 Date: 27 July 1998 On 22 July 1998 when I was at Covance Madison, I reviewed the microscopic liver tissue sections of the monkeys on the 4-week oral rangefinder study of PFOS (Covance study 6329-222). There was no evidence of compound-related effects in the liver even in the high dose animals. Our toxicology consultants had asked the question whether the high dose monkeys had any evidence of liver necrosis or any other microscopic evidence adverse liver effects. The answer is negative. 002635