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COVAH^ THE DEVELOPMENT SERVICES COMPANY Sponsors: APME Ad-Hoc APFO Toxicology Working Group FINAL REPORT Study Title: 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Author: Peter J. Thomford, PhD Study Completion Date: December 18, 2001 Testing Facility: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification: Covance 6329-231 Sponsor Study Identification: 3M T-6889.3 Page 1 o f 463 Covance 6329-231 3M T-6889.3 COMPLIANCE STATEMENT 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys All aspects of this study were in accordance with the Environmental Protection Agency Good Laboratory Practice Standards, 40 CFR 792, except that bile acid and palmitoyl CoA oxidase determinations done by the University of Dundee were not done in compliance with GLPs and will be reported separately by the University of Dundee. 2 Covance 6329-231 3M T-6889.3 QUALITY ASSURANCE STATEMENT This report, with exception of appendices 6, 7, and 8, 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 following inspections were conducted and findings reported to the study director and study director management. Inspection Dates_______ From To Phase 09/24/98 09/24/98 Protocol Review 10/07/98 10/07/98 Analytical Laboratory Inspection 01/05/99 01/05/99 Body Weight 04/01/99 04/01/99 Protocol Amendment Review 05/03/99 05/03/99 Clinical Laboratory Inspection 06/18/99 06/18/99 Data Review 07/29/99 07/29/99 Protocol Amendment Review 08/11/99 08/11/99 Protocol Amendment Review 09/02/99 10/01/99 Data Review 09/13/99 10/01/99 Report Review 11/15/99 11/15/99 Protocol Amendment Review 01/15/01 01/15/01 Protocol Amendment Review 02/26/01 02/27/01 Report Review 12/04/01 12/04/01 Report Review Date Reported to Study Director and Study Director Management 09/24/98 10/07/98 01/05/99 04/01/99 05/03/99 06/23/99 07/29/99 08/11/99 10/01/99 10/01/99 11/18/99 01/15/01 03/01/01 12/05/01 Representative Quality Assurance Unit 3 Covance 6329-231 3M T-6889.3 STUDY IDENTIFICATION 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Test Material Ammonium Perfluorooctanoate (APFO) Sponsors APME Ad-Hoc APFO Toxicology Working Group Study Monitor Paul Lieder, PhD, DABT 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 612.737.2678 Alternate Study Monitor John Butenhoff, PhD, DABT 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota 55144-1000 612.733.1962 Sponsor's Representative David Farrar, PhD ICI Chemicals & Polymers Limited Occupational Health The Heath, Runcorn, PO Box 13 Cheshire, WA7 4QF 01928.513953 Study Location Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Study Director Peter J. Thomford, PhD Covance Laboratories Inc. PO Box 7545 Madison, Wisconsin 53707-7545 608.241.7207 4 Covance 6329-231 3M T-6889.3 STUDY IDENTIFICATION (Continued) 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Study Timetable Study Initiation Date In-Life (Experimental) Start Date In-Life Termination Date Experimental Termination Date September 23, 1998 September 29, 1998 July 2, 1999 December 18, 2001 5 Covance 6329-231 3M T-6889.3 KEY PERSONNEL 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Study Director Study Toxicologist Study Coordinator Supervisor, Large Animal Toxicology Supervisor, Dose Formulation Associate Director, Laboratory Animal Medicine Clinical Pathologist Supervisor, Clinical Pathology Anatomic Pathologist Supervisor, Anatomic Pathology Supervisor, Anatomic 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) Johnnie J. Eighmy, DVM, MS Diplomate, ACVP Diplomate, ABT Kimberly W. Durland, BS, HT Laurie J. Schuller, BA, LAT 6 Covance 6329-231 3M T-6889.3 CONTENTS Page ABSTRACT...................................................................................................................... 11 PURPOSE..........................................................................................................................15 REGULATORY COMPLIANCE..................................................................................... 15 TEST MATERIAL............................................................................................................ 15 Test Material.................................................................................................................. 15 Reserve (Archive) Samples........................................................................................... 15 Disposition..................................................................................................................... 15 TEST ANIMALS AND HUSBANDRY...........................................................................16 Animals...........................................................................................................................16 Identification.................................................................................................................. 16 Justification.................................................................................................................... 16 Husbandry...................................................................................................................... 16 Acclimation.................................................................................................................... 17 PROCEDURES................................................................................................................. 17 Group Designations and Dose Level.............................................................................. 17 Dosing Procedures......................................................................................................... 18 Dose Analyses................................................................................................................ 19 Observation of Animals..................................................................................................19 Blood Hormone Determination..................................................................................... 19 Serum APFO Level Determination................................................................................20 Urine and Feces APFO Level Determination................................................................ 20 Clinical Pathology..........................................................................................................21 Additional Blood Collection.......................................................................................... 22 Anatomic Pathology...................................................................................................... 23 Palmitoyl CoA Oxidase Determinations....................................................................... 23 Cell Proliferation Evaluation......................................................................................... 23 Bile Acid Determination................................................................................................ 24 Receptor Level Determination.......................................................................................24 Liver APFO Determination........................................................................................... 24 Statistical Analyses........................................................................................................26 Record Retention............................................................................................................27 RESULTS......................................................................................................................... 27 Observation of Animals................................................................................................. 27 Blood Hormone Determination.....................................................................................30 Clinical Pathology..........................................................................................................30 Cell Proliferation Evaluation......................................................................................... 31 Anatomic Pathology.......................................................................................................31 7 Covance 6329-231 3M T-6889.3 CONTENTS (Continued) Page DISCUSSION AND CONCLUSIONS.............................................................................32 SIGNATURES.................................................................................................................. 33 REFERENCES.................................................................................................................. 34 OPHTHALMOLOGY REPORT...................................................................................... 35 PATHOLOGY REPORT.................................................................................................. 36 COMMENTS ON THE DATA........................................................................................ 43 CODES, ABBREVIATIONS, AND UNITS.................................................................... 45 General Codes and Abbreviations..................................................................................46 Codes for Clinical Pathology......................................................................................... 47 Abbreviations and Units for Clinical Hematology........................................................50 Abbreviations and Units for Clinical Chemistry........................................................... 52 Abbreviations and Units for Clinical Urinalysis............................................................ 54 Codes for Anatomic Pathology...................................................................................... 55 TABLES 1 Summary of Clinical Observations..........................................................................56 2 Summary of Clinical Observations - Recovery.......................................................58 3 Summary of Ophthalmic Observations................................................................... 59 4 Summary of Ophthalmic Observations - Recovery................................................ 61 5 Summary of Body Weight Data (kg)...................................................................... 62 6 Summary of Body Weight Data (kg) - Recovery.....................................................67 7 Summary of Body Weight Change Data (kg)..........................................................69 8 Summary of Body Weight Change Data (kg)- Recovery........................................ 73 9 Summary of Clinical Hematology Data - Day -11................................................... 75 10 Summary of Clinical Hematology Data - Day 31.................................................... 77 11 Summary of Clinical Hematology Data - Day 63............................................79 12 Summary of Clinical Hematology Data - Day 91.................................................... 81 13 Summary of Clinical Hematology Data - Day 182..........................................83 14 Summary of Clinical Hematology Data - Day 217 (Recovery)................................85 15 Summary of Clinical Hematology Data - Day 245 (Recovery)................................87 16 Summary of Clinical Hematology Data - Day 275 (Recovery)................................89 17 Summary of Clinical Chemistry Data - Day -11.............................................. 91 18 Summary of Clinical Chemistry Data - Day 31............................................... 94 19 Summary of Clinical Chemistry Data - Day 63....................................................... 97 20 Summary of Clinical Chemistry Data - Day 91......................................................100 21 Summary of Clinical Chemistry Data - Day 182....................................................103 22 Summary of Clinical Chemistry Data - Day 217 (Recovery).................................106 8 Covance 6329-231 3M T-6889.3 CONTENTS (Continued) Page TABLES 23 Summary of Clinical Chemistry Data - Day 245 (Recovery)............................... 109 24 Summary of Clinical Chemistry Data - Day 275 (Recovery)............................... 112 25 Summary of Clinical Urinalysis Data - Day -11.................................................... 115 26 Summary of Clinical Urinalysis Data - Day 31..................................................... 116 27 Summary of Clinical Urinalysis Data - Day 63..................................................... 117 28 Summary of Clinical Urinalysis Data - Day 91..................................................... 118 29 Summary of Clinical Urinalysis Data - Day 182................................................... 119 30 Summary of Clinical Urinalysis Data - Day 217 (Recovery)............................... 120 31 Summary of Clinical Urinalysis Data - Day 245 (Recovery)............................... 121 32 Summary of Clinical Urinalysis Data - Day 275 (Recovery)............................... 122 33 Summary of Organ Weight Data - Week 27 Sacrifice...........................................123 34 Summary of Organ Weight Data - Week 40 Recovery Sacrifice.......................... 136 35 Incidence of Macroscopic Observations - Week 27 Sacrifice.............................. 149 36 Incidence of Macroscopic Observations - Week 40 Recovery Sacrifice............. 151 37 Incidence of Microscopic Observations - Week 27 Sacrifice.............................. 152 38 Incidence of Microscopic Observations - Week40 Recovery Sacrifice.................161 APPENDIX 1.................................................................................................................. 168 Protocol Deviations...................................................................................................... 169 Protocol........................................................................................................................172 Protocol Amendment No. 1......................................................................................... 190 Protocol Amendment No. 2 ......................................................................................... 200 Material Safety Data Sheet.......................................................................................... 202 Certificate of Analysis................................................................................................. 209 APPENDIX 2 .................................................................................................................. 211 Individual Animal Fate D ata....................................................................................... 212 Individual Clinical Observations.................................................................................213 Individual Ophthalmic Observations.......................................................................... 226 APPENDIX 3.................................................................................................................. 230 Individual Body Weight Data (kg)..............................................................................231 Individual Body Weight Change Data (kg)................................................................. 237 APPENDIX 4 .................................................................................................................. 243 Individual Clinical Hematology D ata......................................................................... 244 Individual Clinical Chemistry D ata.............................................................................278 Individual Clinical Urinalysis Data..............................................................................317 APPENDIX 5.................................................................................................................. 346 Individual Anatomic Pathology Data...........................................................................347 9 Covance 6329-231 3M T-6889.3 CONTENTS (Continued) Page APPENDIX 6.................................................................................................................. 405 Quality Assurance Statements.....................................................................................406 Summary of Hormone Analyses Data......................................................................... 410 Summary of Testosterone Analyses Data (ng/mL)......................................................420 Individual Hormone Analyses Data.............................................................................421 Individual Testosterone Analyses Data (ng/mL).........................................................431 APPENDIX 7.................................................................................................................. 433 Quality Assurance Documentation..............................................................................434 Hormonal Measurements Report (cholecystokinin analyses data)..............................435 APPENDIX 8.................................................................................................................. 442 Cell Proliferation Evaluation....................................................................................... 443 10 ABSTRACT Covance 6329-231 3M T-6889.3 The purpose of this study was to assess the effect of the test material, ammonium perfluorooctanoate (APFO), on critical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus monkeys for at least 26 weeks. Male cynomolgus monkeys were assigned to four groups (six animals/group in Groups 1, 3, and 4, and four animals in Group 2). Animals in Group 1 received empty gelatin capsules. Animals in Groups 2 and 3 received gelatin capsules containing 3 and 10 mg APFO/kg of weight/day (mg/kg/day), respectively. Animals in Group 4 received gelatin capsules containing 30 mg APFO/kg/day on Days 1 through 11; dose administration was discontinued for Days 12 through 21 due to signs of toxicity. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg APFO/kg/day with the exception that dosing for three animals was discontinued between Days 43 and 81; hereafter, the high dose will be referred to as 30/20 mg/kg/day. Animals were administered APFO daily for at least 26 weeks; two animals in Groups 1 and 3 were treated for 26 weeks, then treatment was discontinued and the animals were observed for reversibility, persistence, or delayed occurrence of toxic effects for 13 weeks posttreatment. 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. Ophthalmic examinations were done before initiation of treatment and during Weeks 27 and 40. Body weight data were collected weekly before initiation of treatment, on the first day of treatment, and weekly thereafter. Blood samples for hormone analyses were collected at selected intervals during treatment and recovery. Blood, urine, and fecal samples were collected during Week 2 and every 2 weeks thereafter during treatment and recovery for APFO concentration analyses. Blood and urine samples were collected for clinical hematology, coagulation, clinical chemistry, and urinalysis tests at selected intervals during treatment and recovery. After 26 weeks of treatment, four animals/group in Groups 1through 3, and all surviving animals in Group 4 were anesthetized, weighed, exsanguinated, and necropsied. After 26 weeks of treatment and 13 weeks without treatment, two animals/group in Groups 1 and 3 were anesthetized, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, selected organs were weighed, and selected 11 Covance 6329-231 3M T-6889.3 tissues were collected and preserved. In addition, the right lateral lobe ofliver was collected from each animal for palmitoyl CoA oxidase activity analyses. Representative samples of liver, right and left testes, and pancreas were collected from each animal for cell proliferation evaluation using proliferation cell nuclear antigen (PCNA). Bile was collected from each animal for bile acid determination. A sample of liver was collected from each animal for APFO concentration analyses. Microscopic examinations were done on tissues from each animal. One male given 30/20 mg/kg/day and one male given 3 mg/kg/day were sacrificed in moribund condition on Days 29 and 137, respectively. Test material-related observations noted for the male given 30/20 mg/kg/day included hypoactive behavior, entire body cold to the touch, few or no feces, low or no food consumption, and weight loss. Clinical observations noted for the male given 3 mg/kg/day included limited use and paralysis of the hind limbs, ataxic and hypoactive behavior, few feces, and no food consumption. During Week 1, males given 30 mg/kg/day had observations of few feces, low food consumption, and lost weight. Based on decreased food consumption and body weight loss, the dose level was lowered to 20 mg/kg/day beginning on Day 22. After the dose level was lowered, only two animals tolerated the dose level for remaining 23 weeks of dose administration; one of these animals continued to have test material-related observations of few feces and low food consumption. Dose administration was discontinued for three males given 30/20 mg/kg/day between Days 43 (Week 7) and 81 (Week 12). Test material-related observations noted for these animals included thin appearance, few or no feces, low or no food consumption, and weight loss (17.5 to 23.1%). These animals appeared to recover from the test material-related effects within 3 weeks after dose administration was discontinued. There were no effects on estrone, estradiol, estriol, thyroid stimulating hormone, or testosterone that were clearly dose-related or consistent in their effects over time. Thyroid hormones in general were decreased beginning on Day 35 in animals administered 10 or 20 mg APFO/kg and in general exhibited recovery in the last 3 months of dosing or during the recovery phase. No alterations in cholecystokinin concentrations were observed at any of the time points. Administration of APFO at dose levels of 3 or 10 mg/kg/day had no apparent effects on hematology, coagulation, clinical chemistry, or urinalysis results. Of uncertain relationship to administration of APFO at 30/20 mg/kg/day were mildly increased 12 Covance 6329-231 3M T-6889.3 triglyceride concentration and mildly to moderately decreased absolute neutrophil count, total protein concentration, and albumin concentration. In addition, two animals given APFO at 30/20 mg/kg/day exhibited moderately to markedly increased serum enzyme activities (i.e., aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, and creatine kinase) and mildly increased serum bile acid concentration prior to the unscheduled sacrifice of one of the animals and the cessation of treatment for the other animal because of poor health. These findings, although not observed for most of the animals given 30/20 mg/kg/day, may also have been caused by the test material. During recovery, there was no evidence of persistent or delayed toxic effects on clinical pathology test results. After up to 26 weeks on study, enhanced cell proliferation was not evident in the pancreas or testes of male monkeys, whereas in the liver the findings were equivocal. Test material-related and statistically significant increases were seen in mean absolute liver weights and mean liver-to-body weight percentages in animals in all dose groups at the terminal sacrifice. In addition, mean liver-to-brain weight significantly increased in animals in the 10 mg/kg/day group; this was also considered test material-related. However, no test material-related macroscopic or microscopic changes were seen in any organs at the terminal sacrifice, including liver, adrenal, spleen, pancreas, and testis. At the recovery sacrifice, there were no test material-related effects on terminal body weights or on absolute or relative organ weights, indicating that the liver weight increases seen at the termination of dosing were reversible. There were no macroscopic or microscopic findings attributed to test material administration at the recovery sacrifice. Two animals were sacrificed in a moribund condition during the course of the study, a male given 30/20 mg/kg/day (Day 29) and a male given 3 mg/kg/day (Day 137). The male given 30/20 mg/kg/day had esophageal and gastric lesions indicative of a dosing injury, and liver lesions presumed to be due to the test material. The cause of the moribund condition of the male given 3 mg/kg/day was unclear. Based on the results of this study in which ammonium perfluorooctanoate (APFO) was administered orally by capsule to cynomolgus monkeys at doses of 0, 3, 10, or 30/20 mg/kg/day for 26 weeks, the no-observable-adverse-effect level (NOAEL) was 13 Covance 6329-231 3M T-6889.3 10 mg/kg/day. Effects seen in animals administered 10 mg/kg/day were not evident after 13 weeks of recovery. 14 PURPOSE Covance 6329-231 3M T-6889.3 The purpose of this study was to assess the effect of the test material, ammonium perfluorooctanoate, on critical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus monkeys for at least 26 weeks. REGULATORY COMPLIANCE All aspects of this study were done in accordance with the Environmental Protection Agency Good Laboratory Practice Standards, 40 CFR 792, except that bile acid and palmitoyl CoA oxidase determinations done by the University of Dundee were not done in compliance with GLPs and will be reported separately by the University of Dundee. TEST MATERIAL Test Material The test material, ammonium perfluorooctanoate (APFO), Lot No. 332 (expiration date: December 15, 2001), is a white powder and is 95.2% pure. It was received at Covance on June 10, and October 22, 1998. The test material was stored at room temperature. Information on synthesis methods, composition, or other characteristics that define the test material is on file with the Sponsor. The Certificate of Analysis is in Appendix 1. Reserve (Archive) Samples A reserve sample (1 g) of the test material was taken before initiation of treatment and stored at room temperature. This sample was transferred to the Sponsor on May 2, 2001. Disposition The remaining test material was returned on May 2, 2001. 15 TEST ANIMALS AND HUSBANDRY Covance 6329-231 3M T-6889.3 Animals Young adult to adult cynomolgus monkeys were obtained from Covance Research Products Inc. (Denver, Pennsylvania) on August 25, 1998. The animals were approximately 3 to 7 years old and weighed 3.2 to 4.5 kg at initiation of treatment. Identification Each animal was assigned a permanent number upon arrival and identified with a collar tag before initiation of treatment. All data for an animal are recorded under this number. Justification APFO 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. Husbandry Animal Rooms 253 and 227 were used for this study. Recovery animals were transferred to Animal Room 227 on April 15, 1999 (Day 15 of recovery). Environmental controls for the animal rooms were set to maintain 18 to 29C, 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 suspended, 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. During the study, animals in the high-dose group were offered Gatorade as well as other supplements to rehydrate and to stimulate food consumption. The lot numbers of the Gatorade are recorded in the data. 16 Covance 6329-231 3M T-6889.3 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. Acclimation Twenty-four males were received on August 25, 1998, and acclimated in Animal Room 253 for 35 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 test for parasites were performed on each animal. PROCEDURES This study was conducted in accordance with the Protocol dated September 23, 1998, and Protocol Amendment Nos. 1 and 2. The protocol, protocol amendments, and protocol deviations are in Appendix 1. Group Designations and Dose Level Selection of animals for the study was based on data collected during acclimation. Animals were assigned to treatment groups using a computerized blocking procedure designed to achieve body weight balance with respect to treatment group. 17 Covance 6329-231 3M T-6889.3 Dose Level Group (mg/kg/day) No. of Males 1 (Control) 0a 6b 2 (Low) 3 4c 3 (Mid) 10 6b 4 (High)d 30/20 6 a The control group (Group 1) received empty gelatin capsules. b Two animals in Groups 1 and 3 designated as recovery animals were treated for 26 weeks, then treatment was discontinued, and the animals were observed for reversibility, persistence, or delayed occurrence of toxic effects for 13 weeks posttreatment. c Animal No. I05723 was replaced with Animal No. I05721. Dosing for Animal No. I05721 began on Day 17 (October 15, 1998). d Dosing for Group 4 was suspended on Day 12 (October 10, 1998) and reinitiated at 20 mg/kg/day on Day 22 (October 20, 1998). Dosing Procedures Gelatin capsules (Torpac, Inc., Fairfield, New Jersey), Size No. 2, Lot No. 122932 were used for dose administration. Expiration dates for the empty gelatin capsules are maintained in the raw data. The test material was dispensed into capsules at least weekly. The dose levels were based on the test material as supplied. For Groups 2 through 4, the specified amount of test material was weighed and transferred into the gelatin capsules. The top and bottom halves of each capsule were joined, and the capsules were placed into the appropriately labeled container. The prepared capsules were stored at room temperature. Method of Administration. Gelatin capsules were administered orally to compare with previously conducted toxicology studies using the oral route. The dose preparations were administered orally in gelatin capsules once daily, 7 days/week, for at least 26 weeks (183 days) except that Animal No. I05721 (Group 2 replacement animal) initiated dose administration on Day 17 and the animals in Group 4 were not dosed on Days 12 through 21; dose administration was also discontinued for Animal Nos. I05711, I05722, and I05703 (Group 4) on Days 43 (Week 7), 66 (Week 10), and 81 (Week 10), respectively (see Protocol Deviations for exceptions). Individual daily 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. 18 Covance 6329-231 3M T-6889.3 Dose Analyses Because the test material was not mixed with a vehicle, dose analyses were not required. Observation of Animals Clinical Observations. The animals were observed twice daily (a.m. and p.m.) for mortality and moribundity. Animals were observed at least once daily (a.m.) for signs of poor health or abnormal behavior and food consumption was assessed qualitatively; only abnormal findings were recorded. Animals were observed once weekly; abnormal findings or an indication of normal was recorded (see Protocol Deviations for exceptions). Ophthalmology. Ophthalmic examinations were done on each animal before initiation of treatment and during Weeks 27 and 40 (recovery). The pupils were dilated with 1% Mydriacyl and the anterior portion of the eye, optic media, and ocular fundus were examined with an indirect ophthalmoscope. Body Weights. Individual body weight data were recorded weekly before initiation of treatment, on the first day of treatment, and weekly thereafter. An additional body weight was recorded on Day -1 for the Day 1 dose calculations. Blood Hormone Determination Blood was collected from a femoral vein of each animal three times before initiation of treatment (Days -18, -8, and -4) and on Days 35, 66, 94, and 183 of treatment and on Days 220, 248, and 276 during recovery. Animals were not fasted before collections. Approximately 6 mL of blood for plasma samples was collected into tubes with potassium EDTA as the anticoagulant. Blood samples for plasma were maintained chilled until plasma was harvested (see Protocol Deviations for exceptions). Approximately 6 mL of blood for serum samples was collected without anticoagulant and allowed to clot. Blood samples for serum were maintained at room temperature until serum was harvested. Samples for serum were centrifuged within 1 hour after collection, and serum was harvested. Serum was divided into two approximately equal aliquots 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 serum samples were analyzed for estradiol (E2), estrone (E1), estriol (E3), thyroid stimulating hormone (TSH), total and free 19 Covance 6329-231 3M T-6889.3 triiodothyronine (T3 and FT3, respectively), total and free thyroxin (T4 and FT4, respectively). Results of these analyses provided by Ani Lytics Inc. are in Appendix 6. Samples for plasma were centrifuged within 1 hour after collection. Plasma was harvested and stored in a freezer, set to maintain -60 to -80C, until packed on dry ice and shipped to DuPont for analyses. The plasma samples were analyzed by DuPont for cholecystokinin. Results of these analyses provided by DuPont are in Appendix 7. Because the decision to analyze blood for testosterone (TESTOS) was made after the terminal sacrifice, an aliquot of plasma from prestudy and Days 35, 66, 94, and 183 collection intervals was transferred from DuPont to Ani Lytics Inc. for analysis of testosterone. In addition, serum samples collected during recovery (Days 220, 248, and 276) were also analyzed for testosterone. Results of these analyses provided by Ani Lytics Inc. are in Appendix 6. Serum APFO Level Determination Approximately 2 mL of whole blood were collected from a femoral vein of each animal during Week 2 (after 7 days of treatment) and every 2 weeks thereafter during treatment and recovery. In addition, blood was collected from Animal No. I05724 (Group 4) that was sacrificed in moribund condition. Animals were not fasted before collections. All samples were collected without anticoagulant, maintained at room temperature, and allowed to clot. Samples were centrifuged within 1 hour after collection, serum was harvested and stored in a freezer, set to maintain -10 to -30C, until packed on dry ice and shipped to 3M for analyses. The samples were analyzed for APFO. Results of the analyses will be reported separately by 3M. Urine and Feces APFO Level Determination Samples of urine (at least 2 mL) and feces (at least 5 grams, see Protocol Deviations for exceptions) were collected from each animal during Week 2 (after 7 days of treatment) and every 2 weeks thereafter during treatment and recovery (concurrent with serum APFO sample collection). Animals were not fasted before collections. Urine (collected on wet ice) and feces were collected overnight. Urine and fecal samples were stored in a freezer, set to maintain -10 to -30C, until packed on dry ice and shipped to 3M for 20 Covance 6329-231 3M T-6889.3 analyses. The samples were analyzed for APFO. Results of the analyses will be reported separately by 3M. Clinical Pathology Blood and urine samples were collected from each animal before initiation of treatment; before the daily dose on Days 31, 63, 91, and 182; and on Days 217, 245, and 275 during recovery. Animals were fasted overnight, and urine was collected on wet ice overnight (approximately 16 hours) before blood sampling; water was provided ad libitum. Blood was collected from a femoral vein. Anticoagulants were sodium citrate for coagulation tests and potassium EDTA for hematology tests. Samples for clinical chemistry were collected without anticoagulant. Blood samples were collected from animals sacrificed at an unscheduled interval. Animals were bled in random order. The following were evaluated. Hematology red blood cell (erythrocyte) count differential blood cell count hemoglobin segmented neutrophil count hematocrit lymphocyte count mean corpuscular volume monocyte count mean corpuscular hemoglobin eosinophil count mean corpuscular hemoglobin basophil count concentration blood cell morphology platelet count reticulocyte count white blood cell (leukocyte) count Coagulation prothrombin time fibrinogen activated partial thromboplastin time 21 glucose urea nitrogen creatinine total protein albumin globulin total bilirubin cholesterol triglycerides aspartate aminotransferase alanine aminotransferase alkaline phosphatase Covance 6329-231 3M T-6889.3 Clinical Chemistry gamma glutamyltransferase sorbitol dehydrogenase creatine kinase calcium inorganic phosphorus sodium potassium chloride bile acids amylase lipase pancreatic-specific amylase volume (approximately 16 hours) specific gravity pH protein glucose ketones Urinalysis bilirubin blood urobilinogen microscopic examination of sediment appearance Additional Blood Collection Whole blood (approximately 19 mL) was collected from the vena cava of each animal at the time of exsanguination (scheduled and unscheduled sacrifices). Approximately equal sized samples of serum [approximately 7 mL (collected without anticoagulant)], whole blood (approximately 5 mL), and plasma (approximately 7 mL) using potassium EDTA as the anticoagulant were transferred into containers and stored in a freezer, set to maintain -60 to -80C, until packed on dry ice and shipped to 3M for possible future analysis. In addition to the required blood samples, additional whole blood (approximately 40 to 80 mL/animal) was collected from the animals in the control group at the terminal sacrifice using sodium heparin as an anticoagulant. One-half of this sample was transferred into cryotubes and pooled. The remaining half of the sample was centrifuged and the plasma and red blood cells were transferred into cryotubes and pooled. The pooled samples were stored in a freezer, set to maintain -60 to -80C, until packed on dry ice and shipped to 3M for possible future analysis. 22 Covance 6329-231 3M T-6889.3 Anatomic Pathology Necropsy. A necropsy was done on each animal that was sacrificed at an unscheduled interval. After 26 weeks of treatment, four animals/group in Groups 1through 3 and all surviving animals in Group 4 were fasted overnight, then anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsied (see Protocol Deviations for exceptions). After 26 weeks of treatment and 13 weeks without treatment, two animals/group in Groups 1 and 3 were fasted overnight, then anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsied. Animals were necropsied in random order. The necropsy included a macroscopic examination of the external surface of the body; all orifices; 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. Organ Weights. At each scheduled and unscheduled sacrifice, the following organs (when present) were weighed; paired organs were weighed separately. adrenal (2) brain epididymis (2) kidney (2) liver pancreas testis (2) thyroid (2) with parathyroid Organ-to-body weight percentages and organ-to-brain weight ratios were calculated. Palmitoyl CoA Oxidase Determinations The right lateral lobe of liver was collected from each animal at the scheduled and unscheduled sacrifices. The sample was weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C these samples will be packed on dry ice and shipped to the University of Dundee for palmitoyl CoA oxidase activity analyses. Results of palmitoyl CoA oxidase activity analyses will be reported separately by the University of Dundee. Cell Proliferation Evaluation Representative samples of the left lateral lobe of the liver, left and right testes, and pancreas were collected from each animal at the scheduled and unscheduled sacrifices 23 Covance 6329-231 3M T-6889.3 and preserved in zinc formalin (unscheduled sacrifices and for animals sacrificed during Week 27) or formalin [animals sacrificed during Week 40 (see Protocol Deviations for exceptions)]. After fixation, samples for proliferation cell nuclear antigen (PCNA) evaluation were embedded in paraffin and maintained at ambient temperature (with slides stained with hematoxylin and eosin) until shipped to Pathology Associates, A Charles River Company for PCNA analyses. Results of the evaluation provided by Pathology Associates, A Charles River Company are in Appendix 8. Bile Acid Determination All available bile (up to 5 mL) was collected from each animal at the scheduled and unscheduled sacrifices, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C; these samples were packed on dry ice and shipped to the University of Dundee for bile acid determination. Results of the bile acid determination will be reported separately by the University of Dundee. Receptor Level Determination Samples (approximately 2 g each) of the liver (left median lobe) and pancreas were collected from each animal at the scheduled and unscheduled sacrifices, flash-frozen in liquid nitrogen, and stored in a freezer, set to maintain -60 to -80C until packed on dry ice and shipped to DuPont for possible analysis. Results of receptor level determination, if any, will be reported separately. Liver APFO Determination A section of liver (a non-formalin treated liver sample) was collected from each animal at the scheduled sacrifice and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in a freezer, set to maintain -60 to -80C, until packed on dry ice and shipped to 3M for APFO analyses. Results of the analyses will be reported separately by 3M. Tissue Preservation. The following tissues (when present) or representative samples were collected and preserved in 10% neutral-buffered formalin, unless otherwise specified. 24 adrenal (2) aorta brain cecum 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) lesions liver lung lymph node (mesenteric) Covance 6329-231 3M T-6889.3 mammary gland pancreas pituitary prostate rectum salivary gland [mandibular (2)] sciatic nerve seminal vesicle (2) skeletal muscle (thigh) skin spinal cord (cervical, thoracic, and lumbar) spleen sternum with bone marrow stomach testis [(2) preserved in Bouin's solution] thymus thyroid (2) with parathyroid trachea urinary bladder Three samples (approximately 5 g each) of the liver and all remaining pancreas and left and right testes tissue (divided into three approximately equal samples) were collected from each animal at the scheduled and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in a freezer, set to maintain -60 to -80C, for possible future analysis. In addition, after all other required samples were taken, remaining kidney tissue was collected from the control animals at the terminal sacrifice (Week 27). These tissues were weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C. Testes and kidney tissue samples collected from control animals were packed on dry ice and shipped to 3M for possible future analysis. Bone marrow smears from the sternum of each animal at the unscheduled and scheduled sacrifices were prepared, stained with Wright's stain, and retained for possible examination. Histopathology. Tissues (as appropriate) were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically from each animal including the Group 2 male that was replaced, Animal No. I05723 (see Protocol Deviations for exceptions). Pathology findings and histopathology tissue slides from specified animals 25 Covance 6329-231 3M T-6889.3 in the control, low-, and high-dose groups were transferred to Sierra Biomedical, Inc for a pathology peer review. Statistical Analyses 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. One-way analysis of variance [ANOVA (Winer, 1971a)] was used to analyze initial body weights, body weight changes, continuous clinical pathology values, and organ weight data. 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, covariate-adjusted means were used for control versus treated group comparisons. Groups 2 through 4 were compared with Group 1 (Control). Group comparisons were evaluated at the 5.0%, two-tailed probability level. Only data collected on or after the first day oftreatment were analyzed statistically. Data collected before the first day of treatment or during recovery (except for blood hormone analyses data) were not analyzed statistically. Blood hormone levels, excluding estriol and cholecystokinin, were analyzed by repeated measures analysis ofcovariance (ANCOVA) procedure with average pretreatment measurements for the parameters as covariates. Treatment effects under ANOVA or ANCOVA procedures were evaluated at p = 0.05 level. All post hoc control-versus-treated-group mean comparisons (including values during recovery) were conducted using Dunnett's many-on-one t procedure. Analyses were carried out with SAS procedure PROC MIXED (SAS, 1996) or BMDP (BMDP, 1992), or both. 26 Covance 6329-231 3M T-6889.3 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 at least one 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, the protocol, study correspondence, and the 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 from the Sponsor's designees (Ani Lytics Inc., DuPont, 3M E.T. & S, and the University of Dundee) will be sent to the Sponsor (Paul Lieder, PhD, DABT, 3M). Pathology Associates, A Charles River Company (PAI) is responsible for the maintenance of any raw data or specimens produced by PAI. RESULTS Observation of Animals Clinical Observations. Clinical observations are summarized in Tables 1 and 2; individual data are in Appendix 2. Individual animal fate data are also in Appendix 2. One male (Animal No. I05724) given 30/20 mg/kg/day was sacrificed in moribund condition on Day 29 (Week 5). Test material-related observations noted for Animal No. I05724 included hypoactive behavior, entire body cold to the touch, few or no feces, and low or no food consumption; this animal lost 12.5% (0.5 kg) of its body weight from Week 1 to Week 5. One male given 3 mg/kg/day (Animal No. I05721) was sacrificed in moribund condition on Day 137. Clinical observations noted for Animal No. I05721 on Day 137 (Week 20) included limited use and paralysis of the hind limbs, ataxic and hypoactive behavior, few feces, and no food consumption; this animal lost 9.5% (0.4 kg) of its body weight from Week 19 to Week 20. During Week 1, all males given 30 mg/kg/day had low food consumption and lost from 3.1 to 7.5% of their body weight; four of the six animals also had observations of few feces. Based on decreased food consumption and body weight loss, the dose level was lowered to 20 mg/kg/day beginning on Day 22. After the dose level was lowered, only two animals (Animal Nos. I05704 and I05713) tolerated the dose level for the remaining 23 weeks of dose administration. After Week 2, test material-related observations noted 27 Covance 6329-231 3M T-6889.3 for Animal No. I05713 included few feces and low food consumption. After Week 2, there were no clinical observations considered to be test material-related noted for Animal No. I05704. During the study, dose administration was discontinued for three males given 30/20 mg/kg/day based on test material-related observations. Dose administration for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. Test material-related observations noted for Animal No. I05711 prior to the suspension of dosing included few or no feces and low or no food consumption; this animal lost 17.5% (0.7 kg) of its body weight from Week 1 to Week 7. Test material-related observations noted for Animal No. I05722 prior to the suspension of dosing included thin appearance, few or no feces, and low or no food consumption; this animal lost 23.1% (0.9 kg) of its body weight from Week 1 to Week 10. Test material-related observations noted for Animal No. I05703 prior to the suspension of dosing included thin appearance, few or no feces, and low or no food consumption; this animal lost 18.7% (0.6 kg) of its body weight from Week 1 to Week 12. These animals appeared to recover from the test material-related effects within 3 weeks after dose administration was discontinued. During the study, several animals developed physical conditions that required examination by a laboratory animal veterinarian and administration of treatments. On Day 11 (Week 2), Animal No. I05724 (Group 4) had observations of no feces and no food consumption; this animal was treated with Lactated Ringers solution (Abbott Laboratories) on Days 11 through 13. During Weeks 5 and 6, Animal No. I05713 (Group 4) had observations of liquid feces and low food consumption; this animal was treated with erythromycin (Distal Products Co.) on Days 36 through 46. On Day 134 (Week 20), Animal No. I05721 (Group 2) had observations of few feces and low food consumption. Animal No. I05721 was treated with Ensure (Abbott Laboratories) and Lactated Ringers solution (Abbott Laboratories) on Day 137; however, because the animal had observations of paralysis and limited use of the hind limbs, it was subsequently sacrificed. During Weeks 21 and 26, Animal No. I05719 (Group 3) had liquid feces; this animal was treated with erythromycin (Distal Products Co. or Barre) on Days 143 through 151 and on Days 179 through 183. The condition of these animals improved with treatment except for Animal No. I05721. Ophthalmology. Ophthalmic observations are summarized in Tables 3 and 4; individual data are in Appendix 2. The Ophthalmology Report contains a discussion of the data. 28 Covance 6329-231 3M T-6889.3 There were no ophthalmic findings for any animal during the baseline or the Weeks 27 or 40 examinations. Body Weights. Body weight data are summarized in Tables 5 and 6; individual data are in Appendix 3. Covariate-adjusted mean body weights were notably lower throughout the study (statistically significant during Weeks 2 through 5 and Week 10) for males given 30/20 mg/kg/day. The lower body weights for the males given 30/20 mg/kg/day were considered test material-related. All animals maintained body weights during recovery; there were no marked changes in body weight for each individual animal between the treatment and recovery phases. Differences in mean body weights between the mean body weights of the animals given 10 mg/kg/day and those of the controls during recovery can be attributed to biological variation. Body Weight Changes. Body weight change data are summarized in Tables 7 and 8; individual data are in Appendix 3. During the first 2 weeks of the study, mean body weight changes were notably lower (significantly lower during Week 2) for males initially given 30 mg/kg/day. After the dose level was lowered to 20 mg/kg/day, mean body weight changes were significantly lower than those of controls during Weeks 7, 9, and 24. Overall mean body weight changes (Weeks 1 through 27) were notably lower for the males given 30/20 mg/kg/day (14.3% of those of the control males). Food Consumption. Food consumption data are summarized in Tables 1 and 2 (Summary of Clinical Observations); individual data are included in the individual clinical observations in Appendix 2. There was an increased incidence of low or no food consumption for animals given 30/20 mg/kg/day. The decreased food consumption was considered to be test material-related. 29 Covance 6329-231 3M T-6889.3 Blood Hormone Determination Summary and individual hormone analyses data provided by Ani Lytics Inc. or DuPont, are in Appendices 6 and 7 (cholecystokinin), respectively. There were no effects on estrone, estradiol, estriol, thyroid stimulating hormone, or testosterone that were clearly dose-related or consistent in their effects over time. Total triiodothyronine was decreased beginning on Day 35 in animals administered 10 or 30/20 mg APFO/kg/day. While the low number of animals that remained on treatment in the group administered 30/20 mg/kg/day makes interpretation difficult, it appears that the level of triiodothyronine remained depressed through Day 183 in this group. Total thyroxin was decreased beginning on Day 35 in animals administered 10 or 30/20 mg/kg/day. While the low number of animals that remained on treatment in the group administered 30/20 mg/kg/day makes the interpretation difficult, it appears that the effect on thyroxin was most pronounced at Days 35 and 66 in animals administered 10 or 30/20 mg/kg/day, after which the effect began to diminish and there appeared to be recovery by the end of the study. Free triiodothyronine and free thyroxin were decreased beginning on Day 35 in animals administered 10 or 30/20 mg/kg/day. While the low number of animals that remained on treatment in the group administered 30/20 mg/kg/day makes the interpretation difficult, it appears that the level of triiodothyronine remained depressed through Day 183 in animals administered 10 or 30/20 mg/kg/day and that recovery occurred in animals administered 10 mg/kg during the recovery phase. No alterations in cholecystokinin concentrations were observed at any of the time points. Clinical Pathology Hematology, coagulation, clinical chemistry, and urinalysis data are summarized in Tables 9 through 32; individual data are in Appendix 4. The Pathology Report contains a discussion of the data. Administration of APFO at dose levels of 3 or 10 mg/kg/day had no apparent effects on hematology, coagulation, clinical chemistry, or urinalysis results. Of uncertain relationship to administration of APFO at 30/20 mg/kg/day were mildly increased triglyceride concentration and mildly to moderately decreased absolute neutrophil count, total protein concentration, and albumin concentration. In addition, two animals given APFO at 30/20 mg/kg/day exhibited moderately to markedly increased serum enzyme 30 Covance 6329-231 3M T-6889.3 activities (i.e., aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, and creatine kinase) and mildly increased serum bile acid concentration prior to the unscheduled sacrifice of one of the animals and the cessation of treatment for the other animal because of poor health. These findings, although not observed for most of the animals given 30/20 mg/kg/day, may also have been caused by the test material. During recovery, there was no evidence of persistent or delayed toxic effects on clinical pathology test results. Cell Proliferation Evaluation Results of cell proliferation evaluation provided by Pathology Associates, A Charles River Company are in Appendix 8. After up to 26 weeks on study, enhanced cell proliferation was not evident in the pancreas or testes of male monkeys, whereas in the liver the findings were equivocal. Anatomic Pathology Terminal body weight and organ weight data are summarized in Tables 33 and 34; incidences of macroscopic and microscopic observations are summarized in Tables 35 through 38. Individual data are in Appendix 5. The Pathology Report contains a discussion of the data. Test material-related and statistically significant increases were seen in mean absolute liver weights and mean liver-to-body weight percentages in animals in all dose groups at the terminal sacrifice. In addition, mean liver-to-brain weight significantly increased in animals in the 10 mg/kg/day group; this was also considered test material-related. However, no test material-related macroscopic or microscopic changes were seen in any organs at the terminal sacrifice, including liver, adrenal, spleen, pancreas, and testis. At the recovery sacrifice, there were no test material-related effects on terminal body weights or on absolute or relative organ weights, indicating that the liver weight increases seen at the termination of dosing were reversible. There were no macroscopic or microscopic findings attributed to test material administration at the recovery sacrifice. 31 Covance 6329-231 3M T-6889.3 Two animals were sacrificed in a moribund condition during the course of the study, a male given 30/20 mg/kg/day (Day 29) and a male given 3 mg/kg/day (Day 137). The male given 30/20 mg/kg/day had esophageal and gastric lesions indicative of a dosing injury and liver lesions presumed to be due to the test material. The cause of the moribund condition of the male given 3 mg/kg/day was unclear. DISCUSSION AND CONCLUSIONS Based on the results of this study in which ammonium perfluorooctanoate (APFO) was administered orally by capsule to cynomolgus monkeys at doses of 0, 3, 10, or 30/20 mg/kg/day for 26 weeks, the no-observable-adverse-effect level (NOAEL) was 10 mg/kg/day. Effects seen in animals administered 10 mg/kg/day were not evident after 13 weeks of recovery. 32 SIGNATURES Covance 6329-231 3M T-6889.3 33 Covance 6329-231 3M T-6889.3 REFERENCES BMDP, Biomedical Data Processing, BMDP Inc., Los Angeles, California, 1992. 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). SAS (Statistical Analysis System), SAS Institute, Release 6.12, Cary, North Carolina, 1996. 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). 34 OPHTHALMOLOGY REPORT Covance 6329-231 3M T-6889.3 Ophthalmic examinations were done on each animal before initiation of treatment and during Weeks 27 and 40 (recovery). The pupils were dilated with 1% Mydriacyl, and the anterior portion of the eye, optic media, and ocular fundus were examined with an indirect ophthalmoscope. There were no ophthalmic findings for any animal during the baseline or the Weeks 27 or 40 examinations. n DEC r. I Date 35 PATHOLOGY REPORT Covance 6329-231 3M T-6889.3 SUMMARY The purpose of the study was to assess the effect of the test material, ammonium perfluorooctanoate (APFO), on critical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus monkeys for at least 26 weeks. The test material was initially administered at dose levels of 3, 10, and 30 mg/kg/day. Administration of the highest dose was stopped on Day 12 because of signs of toxicity and then resumed on Day 22 at a lower dose level, 20 mg/kg/day. Administration of APFO at dose levels of 3 or 10 mg/kg/day had no apparent effects on hematology, coagulation, clinical chemistry, or urinalysis results. Of uncertain relationship to administration of APFO at 30/20 mg/kg/day were mildly increased triglyceride concentration and mildly to moderately decreased absolute neutrophil count, total protein concentration, and albumin concentration. In addition, two animals given APFO at 30/20 mg/kg/day exhibited moderately to markedly increased serum enzyme activities (i.e., aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, and creatine kinase) and mildly increased serum bile acid concentration prior to the unscheduled sacrifice of one of the animals and the cessation of treatment for the other animal because of poor health. These findings, although not observed for most of the animals given 30/20 mg/kg/day, may also have been caused by the test material. During recovery, there was no evidence of persistent or delayed toxic effects on clinical pathology test results. Test material-related and statistically significant increases were seen in mean absolute liver weights and mean liver-to-body weight percentages in animals in all dose groups at the terminal sacrifice. In addition, mean liver-to-brain weight significantly increased in animals in the 10 mg/kg/day group; this was also considered test material-related. However, no test material-related macroscopic or microscopic changes were seen in any organs at the terminal sacrifice, including liver, adrenal, spleen, pancreas, and testis. At the recovery sacrifice, there were no test material-related effects on terminal body weights or on absolute or relative organ weights, indicating that the liver weight increases 36 Covance 6329-231 3M T-6889.3 seen at the termination of dosing were reversible. There were no macroscopic or microscopic findings attributed to test material administration at the recovery sacrifice. Two animals were sacrificed in a moribund condition during the course of the study, a male given 30/20 mg/kg/day (Day 29) and a male given 3 mg/kg/day (Day 137). The male given 30/20 mg/kg/day had esophageal and gastric lesions indicative of a dosing injury, and liver lesions presumed to be due to the test material. The reason for the moribund condition of the male given 3 mg/kg/day was unclear. METHODS Four groups of male cynomolgus monkeys were administered the test material daily by capsule at a dose level of 0 (control group; received empty capsules), 3, 10, or 30 mg/kg of body weight/day (mg/kg/day). Treatment of the animals given the highest dose level was stopped on Day 12 because of signs of toxicity. The highest dose level was then reduced to 20 mg/kg/day, and treatment of these animals was resumed on Day 22. One animal given 30/20 mg/kg/day was sacrificed on Day 29 because of poor health, and dosing was permanently stopped for three additional animals given 30/20 mg/kg/day, one on each of Days 43, 66, and 81. At study initiation, there were six animals in the control group and the groups given 10 or 30 mg/kg/day; two animals in each of these groups were designated as recovery animals to be observed for approximately 13 weeks posttreatment. Because only two animals were given 30/20 mg/kg/day for the duration of the treatment period (approximately 26 weeks), there were no high-dose recovery animals. There were four animals in the group given 3 mg/kg/day; one of these animals was sacrificed on Day 137 because of poor health. Blood and urine were collected for hematology, coagulation, clinical chemistry, and urinalysis tests once before initiation of treatment (Day -11), on Days 31, 63, 91, and 182, and on Days 217, 245, and 275 (recovery animals). Blood for hematology, coagulation, and clinical chemistry tests was also collected from animals prior to unscheduled sacrifices. The terminal and recovery sacrifices occurred on Days 184 and 277, respectively. All animals were necropsied; macroscopic observations were recorded, organ weights were obtained, and tissues were placed in fixative as specified by the protocol. The right lateral lobe of the liver was collected and frozen for analysis of palmitoyl CoA oxidase activity. Samples of pancreas, left and right testes, and the left lateral lobe of the liver were collected and preserved for cell proliferation evaluation 37 Covance 6329-231 3M T-6889.3 using proliferation cell nuclear antigen. Samples of bile were collected and frozen for bile acid determination. Samples of liver and pancreas were collected and frozen for receptor level determinations. A sample of liver was collected and frozen for APFO determination. Additional samples of the liver and all remaining pancreas and left and right testes tissue were collected and frozen for possible future analysis. Microscopic examinations were done on collected tissues from all animals, including the replaced animal. Statistically significant differences cited in the Results and Discussion Section are based on comparisons between the control and treated groups. RESULTS AND DISCUSSION Mortality One animal given 30/20 mg/kg/day (Animal No. I05724) was sacrificed on Day 29 because of poor health, and one animal given 3 mg/kg/day (Animal No. I05721) was sacrificed on Day 137 because of poor health. All other animals survived to the respective scheduled sacrifice. Animal No. I05724, the male given 30/20 mg/kg/day that was sacrificed in a moribund condition on Day 29, had multiple significant microscopic findings. Edema and inflammation of the esophagus and erosions and ulcerations in both the esophagus and stomach suggested that a dosing injury was the immediate cause of the animal's death. However, lesions in the liver, including centrilobular and midzonal hepatocellular degeneration and necrosis, diffuse hepatocellular vacuolation, and hepatocyte basophilia in centrilobular areas (liver regeneration) probably contributed to the animal's moribund condition and were likely to be test material-related. Other important findings included involution of the thymus, a relatively common finding in stressed animals, and degeneration and necrosis in the heart, which were probably agonal changes. The cause of death for Animal No. 105721, the male given 3 mg/kg/day that was sacrificed in a moribund condition on Day 137, was not apparent. The clinical history suggested that the blood supply to the animal's hind limbs was severely compromised, as the rear limbs were noticeably cold at the time of the final medical examination, and ketamine injected into the thigh muscles apparently failed to reach the systemic circulation (sedation did not occur). However, the macroscopic and microscopic findings 38 Covance 6329-231 3M T-6889.3 for this animal were minimal and incidental (i.e., evidence for spinal cord injury or impaired blood circulation was not uncovered in the post-life evaluations). Therefore, the role of test material-related toxicity in the animal's declining condition was unclear. Clinical Pathology Day -11. Results of clinical pathology tests indicated no obvious group or individual health abnormalities. Animal No. I05721 (Group 2) had a notably high hematocrit (49.7%) and albumin concentration (5.6 g/dL) that may have been an indication of mild dehydration. It also had the lowest absolute neutrophil count of all the animals (1,600/pL). Whether these findings were directly or indirectly related to the animal's illness requiring early sacrifice on Day 137 could not be determined. Days 31, 63, 91, and 182. There were relatively few statistically significant or otherwise notable differences for clinical pathology test results between the control and treated animals, especially those animals given 3 or 10 mg/kg/day. None of the differences were consistent over time. Comparisons with the animals given 30/20 mg/kg/day were compromised by the unscheduled sacrifice of one animal in this group on Day 29 and the cessation of treatment for three others by Day 80. For the clinical pathology testing intervals on Days 91 and 182, there were only two animals in this group still receiving treatment. Of uncertain relationship to administration of the test material were mildly increased triglyceride concentration and mildly to moderately decreased absolute neutrophil count, total protein concentration, and albumin concentration for animals given 30/20 mg/kg/day. The difference for triglyceride concentration was statistically significant on Days 31 and 91. The other differences were not statistically significant but were relatively consistent over time. Prior to stopping their treatment, absolute neutrophil count and albumin concentration were mildly decreased for each of the three animals given 30/20 mg/kg/day that had their treatment stopped prematurely because of poor health. All of these findings are generally nonspecific and can be associated with poor health for a variety of reasons. Specific mechanisms related to direct actions of the test material were not apparent. Animal No. I05722, the animal in the high-dose group whose treatment was stopped on Day 66, had moderately high serum activities for aspartate aminotransferase, alanine aminotransferase, and creatine kinase and moderately high serum bile acid concentration 39 Covance 6329-231 3M T-6889.3 on Day 63. The relationship of these findings to administration of the test material is not known. Statistically significant differences for other test results were considered incidental and unrelated to administration of the test material. These differences were inconsistent over time, and in some cases, were similar to differences that existed before the initiation of treatment. Days 217, 245, and 275 (Recovery animals). There was no evidence of persistent or delayed toxic effects on clinical pathology test results. Unscheduled Sacrifice Animals. Animal No. I05724, an animal in the high-dose group, was sacrificed on Day 29. Its most notable clinical pathology findings were a mild neutrophilia (13,700 neutrophils/^L); mild hypoglycemia (glucose = 53 mg/dL); mild azotemia (urea nitrogen = 29 mg/dL); moderate to marked hypoproteinemia (total protein = 5.6 g/dL; albumin = 2.9 g/dL; globulin = 2.7 g/dL); moderate hypocalcemia (calcium = 8.0 mg/dL; likely due to low albumin concentration); marked hypocholesterolemia (cholesterol = 14 mg/dL); marked serum enzyme activities (e.g., aspartate aminotransferase = 1,974 IU/L; alanine aminotransferase = 1,463 IU/L; sorbitol dehydrogenase = 59 IU/L; and creatine kinase = 68,850 IU/L); mild hyperbilirubinemia (total bilirubin =1.8 mg/dL); mildly increased serum bile acid concentration (49 p,mol/L); and moderate to marked hyponatremia (sodium = 133 mmol/L) and hypochloridemia (89 mmol/L). Although many of these findings are nonspecific and are commonly observed in animals that are very ill, the serum enzyme activities were indicative of substantial liver and muscle injury, and the hypocholesterolemia was unusually severe. Animal No. I05721, an animal in the low-dose group, was sacrificed on Day 137. Its most notable clinical pathology findings were marked hyperfibrinogenemia (fibrinogen = 702 mg/dL); moderate lymphopenia (1,700 lymphocytes/^L); moderate hypoalbuminemia (albumin = 3.3 g/dL); and mild hypocholesterolemia (94 mg/dL). These findings were also nonspecific, and with the exception of low albumin concentration, were not typical of the findings observed in the animals in the high-dose group that had to be withdrawn from treatment. Although the findings for this animal in the low-dose group did not indicate a specific cause for its poor health, they were not considered to be directly related to administration of the test material. 40 Covance 6329-231 3M T-6889.3 Anatomic Pathology/Terminal Sacrifice (Week 27) Terminal Body Weights and Organ Weights. Mean absolute liver weights and mean liver-to-body weight percentages were statistically significantly increased in animals that were dosed until Week 27 in the 3, 10, and 30/20 mg/kg/day dose groups. In addition, mean liver-to-brain weight ratio was statistically significantly increased in animals in the 10 mg/kg/day group only. Although no correlative macroscopic or microscopic changes were seen in livers in any of the animals from the terminal sacrifice, the increased liver weights in all dose groups may indicate a test material effect, given the nature of the test material and the liver lesions seen in the male in the high-dose group sacrificed on Day 29. Absolute left kidney weight was statistically significantly increased in animals in the 30/20 mg/kg/day group, but this was considered an incidental finding because there were no test material-related macroscopic or microscopic findings in the kidney. There were no other statistically significant or toxicologically significant organ weight variations in treated animals. Macroscopic Findings. There were no test material-related macroscopic findings. All macroscopic findings were of low incidence, were randomly distributed among treated and control animals, and were considered to be spontaneous or incidental changes that were of no toxicological significance. Microscopic Findings. There were no test material-related microscopic findings in any of the tissues that were examined, including liver, adrenal, spleen, pancreas, and testis. All microscopic findings were considered to be spontaneous or incidental changes and typical of findings seen in monkeys on toxicity studies. Anatomic Pathology/Recovery Sacrifice (Week 40) Terminal Body Weights and Organ Weights. There were no test material-related effects on terminal body weights or on absolute or relative organ weights. Absolute organ weights and organ-to-brain weight ratios were consistently higher in the control males, but these elevations were attributed to higher terminal body weights in the control animals (one was even noted as being obese at necropsy). Mean organ-to-body weight percentages, including mean liver-to-body weight, showed only slight variations that were considered unremarkable. These findings indicated that the liver weight increases were reversible. 41 Covance 6329-231 3M T-6889.3 Macroscopic Findings. There were no test material-related macroscopic findings. In fact, no macroscopic lesions of any kind were seen in one control animal or in either of the 10 mg/kg/day animals. The remaining control male was considered to be obese and had liver adhesions, an incidental change. Microscopic Findings. There were no test material-related microscopic findings at the recovery sacrifice. All microscopic findings were incidental, occurred randomly in control animals and in animals given 10 mg/kg/day, and were typical of findings seen in cynomolgus monkeys on toxicity studies. 42 Covance 6329-231 3M T-6889.3 COMMENTS ON THE DATA 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 Excel Version 7.0 software. The units for the dose levels on the data collection system (PTS) summary tables are mg/kg/day. The number of animals listed in the heading of the summary of clinical observations table (Table 1) reflects the number of animals assigned to each group at the start of the study. 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 level of severity for observations of ataxic and hypoactive behavior was not specified at the time of the observation and is indicated as "UNSPECIFIED" on the summary and individual observations tables. The specific details for comments in the individual clinical observations tables that are indicated with a "C" can be found at the end of each group for each sex. The day of initiation of treatment is "Day 1, Week 1." Body weight data are entered at the start of a study week (e.g., a body weight recorded on Day 1 is considered a Week 1 body weight, a body weight recorded on Day 8 is considered a Week 2 body weight). Body weight change data are calculated from the first day of the study week to the first day of the following study week (e.g., Week 1 values are calculated from Day 1 through 7). Differences in the population size (N) on the summary tables for clinical pathology are explained on the individual data tables. 43 Covance 6329-231 3M T-6889.3 COMMENTS ON THE DATA (Continued) Results of clinical pathology samples collected for animals sacrificed at an unscheduled interval appear on the individual clinical pathology tables for the next scheduled interval. These results are not on the summary tables and are not included in the statistical analyses. Dosing was discontinued for Animal Nos. I05711,105722, and I05703 (Group 4) on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12). Summary tables do not include data from these animals after dosing was discontinued and this data are not included in the statistical analyses. Some animals were observed and treated by the laboratory animal veterinary staff, and the data were recorded on the day the examination was done. These data are referenced in the Request for Veterinary Services and are archived with the raw data but do not appear on the summary or individual clinical observations tables. Data collected for Animal No. I05723 (Group 2) will be maintained in the raw data; this data will not be included in this report. Animal No. I05723 was sacrificed in moribund condition on Day 14; the cause of the moribund condition of this animal was determined to be a bacterial septicemia which was unrelated to the test material. Animal No. I05723 was replaced by Animal No. I05721 on Day 15. 44 CODES, ABBREVIATIONS, AND UNITS Covance 6329-231 3M T-6889.3 General Codes and Abbreviations Codes for Clinical Pathology Abbreviations and Units for Clinical Hematology Abbreviations and Units for Clinical Chemistry Abbreviations and Units for Clinical Urinalysis Codes for Anatomic 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. 45 Covance 6329-231 3M T-6889.3 General Codes and Abbreviations WK N Mean; MEAN CAM SD; S.D.; STAND DEV; STANDARD DEV; sd * -; NA NVL C UNSCHED # Week Number of measurements in a group Arithmetic mean Covariate-adjusted mean Standard deviation Group mean is significantly different from the mean of the control group (Group 1) at p < 0.05 No value; not applicable; not present No visible lesions Comment found at the end of each group for each sex Unscheduled Number Animal Death Codes: T M U Terminal sacrifice Moribund First postrecovery sacrifice 46 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 6329-231 3M T-6889.3 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 47 Covance 6329-231 3M T-6889.3 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 URINE APPEARANCE A Pale B Straw C Yellow D Dark yellow Color E Amber F Brown G Red H Green I Black P Blue/green Q Blue R Orange Clarity J Clear K Hazy L Cloudy Miscellaneous M Debris O Feces 48 Codes for Clinical Pathology (Continued) Covance 6329-231 3M T-6889.3 URINE CHEMISTRY MULTISTIX STRIP Urine Glucose - Negative + 100 mg/dL ++ 250 mg/dL +++ 500 mg/dL ++++ 1,000 mg/dL +++++ >2,000 mg/dL Urine Ketone - Negative + 5 mg/dL ++ 15 mg/dL +++ 40 mg/dL ++++ 80 mg/dL +++++ 160 mg/dL Urine Blood - Negative + Small ++ Moderate +++ Large Urine Urobilinogen - 0.2 mg/dL + 1 mg/dL ++ 2 mg/dL +++ 4 mg/dL ++++ 8 mg/dL (1 mg = approximately 1 Ehrlich unit) Urine Bilirubin - Negative + Small ++ Moderate +++ Large URINE SEDIMENT Cells, Crystals, Casts, and Comments________________ A Amorphous urates Q Sperm B Amorphous phosphates R Fecal contamination C Uric acid S Pinworm ova found D Triple phosphates T Pinworm larvae found E Calcium oxalate U Parasite ova found F Calcium carbonate G Granular casts H Hyaline casts 0 Not present I Cellular casts 1 1-5 per field J Waxy casts 2 6-10 per field K Unknown crystal 3 11-20 per field P Mucous threads 4 >20 per field Bacteria 0 Not present 1 Few 2 Moderate 3 Many 49 Covance 6329-231 3M T-6889.3 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 Abbreviation (Units) RBC (E6/UL or X10%iL) HGB (G/DL) HCT (%) MCV (FL) MCH (PG) MCHC (%) PLT (E3/UL or X103/^L) MPV (FL) RETIC (%) RETIC (e 3/UL or X103/^L) 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/^L) NRBC (/100 WBC) COR WBC (E3/UL or X103/^L) N-SEG (E3/UL or X103/^L) and % N-BAND (E3/UL or X103/^L) and % LYMPH (E3/UL or X103/^L) and % MONO (E3/UL or X103/^L) and % EOSIN (E3/UL or X103/^L) and % BASO (E3/UL or X103/^L) and % ANISO (-,1,2,3) POLY (-,1,2,3) 50 Covance 6329-231 3M T-6889.3 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) 51 Covance 6329-231 3M T-6889.3 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 glutamyltransferase Sorbitol dehydrogenase Lactate dehydrogenase Creatine kinase Amylase Lipase Pancreatic-specific Amylase 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 RATIO T BILI (MG/DL) D BILI (MG/DL) I BILI (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) P AMYL (U/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) 52 Covance 6329-231 3M T-6889.3 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 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-1 (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) CK-BB (U/L) CK-MB (U/L) CK-MM (U/L) 53 Covance 6329-231 3M T-6889.3 Abbreviations and Units for Clinical Urinalysis Test Urine volume 8 hour urine volume Specific gravity Urine osmolality Quantitative urinary/cerebrospinal fluid protein Urine protein excretion Urine chemistry Multistix strip Urine pH Urine protein Urine glucose Urine ketones Urine bilirubin Urine blood Urine urobilinogen Urine reducing substances Microscopic examination of urine sediment Red blood cells per high-power field White blood cells per high-power field Epithelial cells per high-power field Bacteria per high-power field Casts per low-power field Crystals per low-power field Urine appearance Comments Abbreviation (Units) U VOL (ML) 8 HR VOL (ML) SPGR U OSMO (MOSM/KG) QUAN PRO (MG/DL) PRO EXC (MG) UPH U PRO (MG/DL) U GLU UKET UBILI U BLOOD UROBILI U RE SUB RBC (PER HPF) WBC (PER HPF) EPITH (PER HPF) BACT (PER HPF) CASTS (PER LPF) CRYSTALS (PERLPF1 or PER LPF2) URINE APPI or URINE APP2 COMMENTS Miscellaneous Codes and Abbreviations for Clinical Pathology Fecal occult blood Not applicable Fecal parasite detection Not applicable Hemolytic potential Not applicable 54 Code T U M Codes for Anatomic Pathology Definition ANIMAL DEATH CODES Terminal sacrifice First postrecovery sacrifice Moribund Covance 6329-231 3M T-6889.3 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 Abbreviation LF LN LN, TRACHEOBRON RT STOMACH, GL SALIV GL, MANDIB THYROID/PARA TISSUE ABBREVIATIONS Definition Left Lymph node Tracheobronchial lymph node Right Glandular stomach Mandibular salivary gland Thyroid/parathyroid 55 Table 1 Summary of Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 DAYS 1-184 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** APPEARANCE LIMITED USE LIMBS-HIND PARALYSIS HIND QUARTERS THIN BEHAVIOR ATAXIC <UNSPECIFIED> HYPOACTIVE <UNSPECIFIED> DISCHARGE VOMITUS CONTAINING FOOD EXCRETION DISCOLORED URINE BROWN IN COLOR FEW FECES LIQUID FECES MUCOID FECES NO FECES NON-FORMED FECES NUMBER OF ANIMALS AFFECTED SEX: GROUP : DOSE: ---- --MALE--1 2 3 4a 0 3 10 20 NUMBER : 6 4 6 6 0100 0100 0002 0100 0101 4232 0001 5106 2112 1100 0004 1121 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 56 Table 1 Summary of Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 DAYS 1-184 CATEGORY KEYWORD QUALIFIER NUMBER OF ANIMALS AFFECTED SEX: GROUP : DOSE: --MALE------ 1 2 3 4a 0 3 10 20 NUMBER: 6 4 6 6 SKIN & PELAGE ALOPECIA HEAD-CRANIAL LIMB-FRONT-LEFT LIMB-FRONT-RIGHT LIMBS-FRONT COLD TO TOUCH BODY-ENTIRE SCAB(S) PERI-ORBITAL-LEFT PERI-ORBITAL-RIGHT SCAR LIP(S) MASS FACE NEXT TO NOSE QUALITATIVE FOOD CONSUMPTION LOW NONE *** END OF LIST *** 1000 1000 1000 1000 0001 0010 0010 0001 0010 5336 01 04 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 57 DAYS 185-277 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** DISCHARGE VOMITUS CONTAINING FOOD EXCRETION NO FECES QUALITATIVE FOOD CONSUMPTION LOW *** END OF LIST *** Table 2 Summary of Clinical Observations Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS NUMBER OF ANIMALS AFFECTED SEX: GROUP: DOSE: --MALE- 13 0 10 NUMBER: 22 21 01 12 Covance 6329-231 3M T-6889.3 PAGE: 1 58 WEEK -1 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** NO VISIBLE LESIONS NO VISIBLE LESIONS EYES *** END OF LIST *** Table 3 Summary of Ophthalmic Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS NUMBER OF ANIMALS AFFECTED SEX: GROUP: DOSE: ---MALE--1234 0 3 10 20 NUMBER: 6466 6466 Covance 6329-231 3M T-6889.3 PAGE: 1 59 Table 3 Summary of Ophthalmic Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 WEEK 27 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** NO VISIBLE LESIONS NO VISIBLE LESIONS EYES *** END OF LIST *** NUMBER OF ANIMALS AFFECTED SEX: GROUP : DOSE: --MALE-----1234 0 3 10 20a NUMBER: 6 3 6 5 6365 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 60 WEEK 40 CATEGORY KEYWORD QUALIFIER *** TOP OF LIST *** NO VISIBLE LESIONS NO VISIBLE LESIONS EYES *** END OF LIST *** Table 4 Summary of Ophthalmic Observations Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS NUMBER OF ANIMALS AFFECTED SEX: GROUP: DOSE: -- MALE13 0 10 NUMBER: 22 22 Covance 6329-231 3M T-6889.3 PAGE: 1 61 Table 5 Summary of Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 WEEK SEX: GROUP: DOSE: UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY -2 N MEAN S.D. -1b N MEAN S.D. -1c N MEAN S.D. 1N MEAN S.D. 2N CAM MEAN S.D. 3N CAM MEAN S.D. 6 3.7 0.45 6 3.8 0.52 6 3.8 0.54 6 3.8 0.56 6 3.8 3.8 0.59 6 3.9 3.9 0.56 4 4.0 0.24 4 4.0 0.34 4 3.9 0.34 4 4.0 0.36 4 3.9 4.0 0.29 4 3.8 4.0 0.24 6 3.8 0.34 6 3.8 0.37 6 3.7 0.43 6 3.8 0.33 6 3.8 3.7 0.42 6 3.7 3.7 0.46 6 3.8 0.26 6 3.8 0.27 6 3.8 0.29 6 3.9 0.32 6 3.7 * 3.7 0.29 6 3.6 * 3.6 0.29 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. b Day -7. c Day -1. 62 Table 5 Summary of Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 WEEK SEX: GROUP: DOSE: UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 4N CAM MEAN S.D. 5N CAM MEAN S.D. 6N CAM MEAN S.D. 7N CAM MEAN S.D. 8N CAM MEAN S.D. 9N CAM MEAN S.D. 6 4.0 4.0 0.57 6 4.0 4.0 0.63 6 4.0 4.0 0.53 6 4.1 4.1 0.62 6 4.0 4.0 0.51 6 4.0 4.0 0.55 4 3.9 4.0 0.22 4 3.8 3.9 0.24 4 4.0 4.1 0.21 4 3.9 4.1 0.13 4 4.0 4.1 0.14 4 4.0 4.2 0.05 6 3.9 3.8 0.44 6 3.8 3.8 0.45 6 3.9 3.9 0.53 6 4.0 3.9 0.57 6 4.0 3.9 0.52 6 4.0 4.0 0.60 6 3.7 * 3.7 0.27 6 3.7 * 3.7 0.30 5 3.7 3.7 0.30 5 3.7 3.7 0.42 4 3.6 3.6 0.42 4 3.6 3.6 0.44 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 63 Table 5 Summary of Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 3 WEEK SEX: GROUP: DOSE: UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 10 N CAM MEAN S.D. 11 N CAM MEAN S.D. 12 N CAM MEAN S.D. 13 N CAM MEAN S.D. 14 N CAM MEAN S.D. 15 N CAM MEAN S.D. 6 4.0 4.0 0.54 6 4.1 4.1 0.58 6 4.1 4.1 0.53 6 4.1 4.1 0.53 6 4.1 4.1 0.55 6 4.2 4.2 0.53 4 4.0 4.1 0.10 4 4.0 4.2 0.05 4 4.0 4.2 0.06 4 4.1 4.2 0.10 4 4.1 4.2 0.05 4 4.2 4.3 0.06 6 4.0 4.0 0.58 6 4.1 4.0 0.59 6 4.0 4.0 0.60 6 4.2 4.1 0.58 6 4.1 4.0 0.59 6 4.1 4.1 0.59 4 3.5 3.4 0.56 3 3.6 3.5 0.60 3 3.5 3.4 0.76 2 3.8 3.9 0.35 2 3.7 3.9 0.35 2 3.7 3.8 0.49 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 64 Table 5 Summary of Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 4 WEEK SEX: GROUP: DOSE: UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 16 N CAM MEAN S.D. 17 N CAM MEAN S.D. 18 N CAM MEAN S.D. 19 N CAM MEAN S.D. 20 N CAM MEAN S.D. 21 N CAM MEAN S.D. 6 4.2 4.2 0.53 6 4.2 4.2 0.53 6 4.3 4.2 0.57 6 4.3 4.2 0.58 6 4.3 4.3 0.56 6 4.3 4.3 0.59 4 4.1 4.2 0.05 4 4.2 4.3 0.08 4 4.3 4.4 0.10 4 4.3 4.4 0.13 4 4.2 4.3 0.32 3 4.3 4.5 0.06 6 4.2 4.1 0.56 6 4.2 4.1 0.56 6 4.3 4.2 0.58 6 4.3 4.2 0.60 6 4.3 4.2 0.58 6 4.3 4.2 0.58 2 3.7 3.8 0.49 2 3.8 3.9 0.42 2 3.9 4.0 0.42 2 3.8 4.0 0.49 2 3.7 3.9 0.64 2 3.7 3.9 0.64 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 65 Table 5 Summary of Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 5 WEEK SEX: GROUP: DOSE: UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 22 N CAM MEAN S.D. 23 N CAM MEAN S.D. 24 N CAM MEAN S.D. 25 N CAM MEAN S.D. 26 N CAM MEAN S.D. 27 N CAM MEAN S.D. 6 4.3 4.3 0.59 6 4.4 4.3 0.60 6 4.4 4.3 0.59 6 4.4 4.4 0.59 6 4.5 4.4 0.60 6 4.5 4.5 0.64 3 4.3 4.5 0.06 3 4.4 4.5 0.06 3 4.4 4.6 0.00 3 4.5 4.6 0.06 3 4.6 4.7 0.06 3 4.6 4.8 0.06 6 4.3 4.3 0.58 6 4.4 4.3 0.56 6 4.4 4.4 0.58 6 4.4 4.3 0.60 6 4.5 4.4 0.62 6 4.5 4.4 0.60 2 3.7 3.9 0.64 2 3.9 4.0 0.57 2 4.0 4.1 0.57 2 3.9 3.9 0.64 2 3.9 4.0 0.71 2 4.0 4.1 0.71 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 66 Table 6 Summary of Body Weight Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WEEK SEX: ---------MALE GROUP: 1 3 DOSE: 0 10 UNITS: MG/KG/DAY MG/KG/DAY 28 N MEAN S.D. 29 N MEAN S.D. 30 N MEAN S.D. 31 N MEAN S.D. 32 N MEAN S.D. 33 N MEAN S.D. 34 N MEAN S.D. 2 5.1 0.28 2 5.2 0.28 2 5.2 0.21 2 5.2 0.21 2 5.3 0.28 2 5.3 0.42 2 5.5 0.28 2 3.8 0.07 2 3.8 0.00 2 3.7 0.07 2 3.7 0.14 2 3.8 0.07 2 3.8 0.14 2 3.8 0.14 Covance 6329-231 3M T-6889.3 PAGE: 1 67 Table 6 Summary of Body Weight Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WEEK SEX: ---------MALE GROUP: 1 3 DOSE: 0 10 UNITS: MG/KG/DAY MG/KG/DAY 35 N MEAN S.D. 36 N MEAN S.D. 37 N MEAN S.D. 38 N MEAN S.D. 39 N MEAN S.D. 40 N MEAN S.D. 2 5.5 0.28 2 5.6 0.35 2 5.6 0.28 2 5.6 0.28 2 5.7 0.28 2 5.7 0.28 2 3.8 0.14 2 3.8 0.14 2 3.8 0.14 2 3.8 0.14 2 3.8 0.21 2 3.8 0.21 Covance 6329-231 3M T-6889.3 PAGE: 2 68 Table 7 Summary of Body Weight Change Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 SEX: --------------------- MALE GROUP: 1 2 DOSE: 0 3 WEEKS UNITS: MG/KG/DAY MG/KG/DAY 3 10 MG/KG/DAY 4 20a MG/KG/DAY 1-2 N MEAN S.D. 2-3 N MEAN S.D. 3-4 N MEAN S.D. 4-5 N MEAN S.D. 5-6 N MEAN S.D. 6-7 N MEAN S.D. 7-8 N MEAN S.D. 6 -0.1 0.05 6 0.1 0.06 6 0.1 0.04 6 0.0 0.10 6 0.0 0.10 6 0.1 0.10 6 -0.1 0.12 4 0.0 0.08 4 0.0 0.05 4 0.0 0.06 4 -0.1 0.08 4 0.2 0.05 4 0.0 0.08 4 0.0 0.10 6 -0.1 0.12 6 0.0 0.05 6 0.1 0.05 6 -0.1 0.05 6 0.1 0.10 6 0.0 0.10 6 0.0 0.09 6 -0.2 0.08 6 -0.1 * 0.17 6 0.2 0.08 6 -0.1 0.08 5 0.0 0.07 5 0.0 0.15 4 -0.3 * 0.10 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 69 Table 7 Summary of Body Weight Change Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 SEX: GROUP: DOSE: WEEKS UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 8-9 N MEAN S.D. 9-10 N MEAN S.D. 10-11 N MEAN S.D. 11-12 N MEAN S.D. 12-13 N MEAN S.D. 13-14 N MEAN S.D. 14-15 N MEAN S.D. 6 0.0 0.13 6 0.0 0.05 6 0.0 0.05 6 0.0 0.06 6 0.0 0.05 6 0.0 0.04 6 0.1 0.05 4 0.1 0.13 4 0.0 0.06 4 0.0 0.06 4 0.0 0.05 4 0.1 0.05 4 -0.1 0.10 4 0.1 0.05 6 0.1 0.08 6 0.0 0.08 6 0.1 0.10 6 0.0 0.05 6 0.1 0.06 6 -0.1 0.05 6 0.1 0.08 4 0.0 0.08 4 -0.1 0.13 3 0.0 0.00 3 -0.1 0.17 2 0.1 0.00 2 -0.1 0.00 2 0.0 0.14 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 70 Table 7 Summary of Body Weight Change Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 3 SEX: GROUP: DOSE: WEEKS UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 15-16 N MEAN S.D. 16-17 N MEAN S.D. 17-18 N MEAN S.D. 18-19 N MEAN S.D. 19-20 N MEAN S.D. 20-21 N MEAN S.D. 21-22 N MEAN S.D. 6 0.0 0.06 6 0.0 0.00 6 0.1 0.05 6 0.0 0.06 6 0.0 0.05 6 0.0 0.04 6 0.0 0.00 4 0.0 0.05 4 0.1 0.05 4 0.1 0.13 4 0.0 0.10 4 -0.1 0.20 3 0.0 0.06 3 0.0 0.00 6 0.0 0.05 6 0.0 0.05 6 0.0 0.05 6 0.0 0.08 6 0.0 0.04 6 0.0 0.00 6 0.0 0.04 2 0.0 0.00 2 0.0 0.07 2 0.1 0.00 2 0.0 0.07 2 -0.1 0.14 2 0.0 0.00 2 0.0 0.00 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 71 Table 7 Summary of Body Weight Change Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 4 SEX: GROUP: DOSE: WEEKS UNITS: 1 0 MG/KG/DAY --------MALE 23 3 10 MG/KG/DAY MG/KG/DAY 4 20a MG/KG/DAY 22-23 N MEAN S.D. 23-24 N MEAN S.D. 24-25 N MEAN S.D. 25-26 N MEAN S.D. 26-27 N MEAN S.D. 1-27 N MEAN S.D. 6 0.1 0.05 6 0.0 0.06 6 0.0 0.05 6 0.1 0.04 6 0.0 0.05 6 0.7 0.33 3 0.1 0.06 3 0.1 0.06 3 0.0 0.06 3 0.1 0.00 3 0.0 0.06 3 0.7 0.35 6 0.0 0.05 6 0.1 0.05 6 0.0 0.05 6 0.1 0.04 6 0.0 0.06 6 0.6 0.34 2 0.1 0.07 2 0.1 0.00 2 -0.2 0.07 2 0.1 0.07 2 0.1 0.00 2 0.1 0.71 a Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day, except that dosing for Animal Nos. I05711, I05722, and I05703 was discontinued on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. 72 Table 8 Summary of Body Weight Change Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS SEX: ---------MALE GROUP: 1 3 DOSE: 0 10 WEEKS UNITS: MG/KG/DAY MG/KG/DAY 27-28 N MEAN S.D. 28-29 N MEAN S.D. 29-30 N MEAN S.D. 30-31 N MEAN S.D. 31-32 N MEAN S.D. 32-33 N MEAN S.D. 33-34 N MEAN S.D. 2 -0.1 0.07 2 0.1 0.00 2 0.0 0.07 2 0.0 0.00 2 0.2 0.07 2 0.0 0.14 2 0.2 0.14 2 -0.1 0.07 2 0.1 0.07 2 -0.2 0.07 2 0.1 0.07 2 0.0 0.07 2 0.0 0.07 2 0.0 0.00 Covance 6329-231 3M T-6889.3 PAGE: 1 73 Table 8 Summary of Body Weight Change Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS SEX: ---------MALE GROUP: 1 3 DOSE: 0 10 WEEKS UNITS: MG/KG/DAY MG/KG/DAY 34-35 N MEAN S.D. 35-36 N MEAN S.D. 36-37 N MEAN S.D. 37-38 N MEAN S.D. 38-39 N MEAN S.D. 39-40 N MEAN S.D. 27-40 N MEAN S.D. 2 0.0 0.00 2 0.1 0.07 2 0.0 0.07 2 0.0 0.00 2 0.1 0.00 2 0.0 0.00 2 0.5 0.07 2 0.0 0.00 2 0.0 0.00 2 0.0 0.00 2 0.0 0.00 2 0.0 0.07 2 0.0 0.00 2 0.0 0.21 Covance 6329-231 3M T-6889.3 PAGE: 2 74 DOSE RBC mg/kg/day X106/j.iL Table 9 Summary of Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/|.lL % X103/|-iL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 6.60 .405 6 6.88 .433 4 6.70 .268 6 6.84 .302 6 12.4 .26 6 12.9 1.23 4 12.1 .56 6 12.2 .83 6 42.1 .85 6 43.9 4.51 4 40.4 1.92 6 41.2 2.68 6 63.9 3.05 6 63.8 3.80 4 60.4 3.78 6 60.2 2.63 6 18.9 1.21 6 18.8 .95 4 18.1 1.02 6 17.8 .89 6 29.5 1.03 6 29.4 .22 4 30.0 .48 6 29.6 .58 6 513 155.0 6 562 109.5 4 515 98.3 6 547 90.6 6 .7 .36 6 .7 .42 4 .6 .38 6 .7 .22 6 45 26.3 6 48 29.9 4 43 24.7 6 49 16.9 6 9.7 .32 6 9.6 .10 4 9.6 .18 6 9.8 .36 6 18.2 1.23 6 20.5 5.03 4 18.3 1.59 6 20.0 3.76 6 286 32.2 6 345 52.3 4 315 22.2 6 304 44.9 6 75 DOSE WBC mg/kg/day X103/|.iL Table 9 Summary of Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/JiL X103/ iL MONO EOSIN BASO X103/JiL X103/ iL X103/lL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% 0 MEAN 12.7 6.0 5.5 1.0 .2 .0 47 43 8 2 0 S.D. 4.36 2.21 2.06 .46 .12 .05 5.5 6.3 1.9 .5 .4 N 66666666666 3 MEAN 10.7 4.6 5.2 .8 .1 .0 40 51 8 1 0 S.D. 3.62 2.84 1.00 .39 .15 .05 14.0 11.2 5.5 1.0 .6 N 44444444444 10 MEAN 11.4 5.7 4.6 .9 .2 .0 48 42 8 2 0 S.D. 3.03 2.66 1.07 .32 .13 .05 14.4 11.2 2.8 2.0 .4 N 66666666666 30/20 MEAN 13.3 7.3 4.8 1.0 .2 .0 54 36 7 2 0 S.D. 2.25 1.57 1.17 .60 .14 .08 5.0 7.1 4.6 .8 .4 N 66666666666 76 DOSE RBC mg/kg/day X10Vj.iL Table 10 Summary of Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/jlL % X103/jiL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 6.81 .415 6 6.47 .378 4 6.73 .387 6 6.63 .396 5 12.9 .80 6 12.4 .57 4 12.3 .51 6 12.1 .99 5 44.0 1.88 6 41.3 1.76 4 41.8 2.11 6 40.9 3.06 5 64.7 3.01 6 64.0 3.43 4 62.2 3.73 6 61.6 3.23 5 19.0 1.12 6 19.2 1.06 4 18.4 1.09 6 18.2 .54 5 29.3 1.23 6 30.0 .45 4 29.6 .46 6 29.6 1.56 5 428 87.8 6 499 98.7 4 446 107.9 6 516 159.7 5 .3 .11 6 .2 .14 4 .2 .08 6 .3 .26 5 21 8.4 6 13 10.4 4 11 5.2 6 23 19.1 5 10.0 .26 6 9.8 .29 4 10.1 .34 6 10.0 .47 5 19.8 1.26 6 21.9 4.98 4 20.0 2.02 6 24.0 4.22 5 369 187.4 6 334 24.0 4 291 38.8 6 475 250.9 5 77 DOSE WBC mg/kg/day X103/|.iL Table 10 Summary of Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/JiL X103/ iL MONO EOSIN BASO X103/JiL X103/ iL X103/lL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% 0 MEAN 12.8 7.3 4.6 .8 .1 .0 54 40 6 1 0 S.D. 4.48 4.05 .83 .54 .08 .00 14.1 15.0 3.1 .8 .0 N 66666666666 3 MEAN 7.8 2.8 4.2 .6 .2 .0 34 56 8 2 0 S.D. 2.34 1.76 1.01 .36 .30 .05 15.3 11.1 3.5 3.4 .5 N 44444444444 10 MEAN 10.7 6.0 3.9 .6 .2 .0 53 38 6 2 0 S.D. 3.51 3.45 .88 .23 .10 .04 13.6 11.9 2.4 1.2 .0 N 66666666666 30/20 MEAN 9.2 4.0 3.8 1.2 .1 .0 44 42 13 * 1 0 S.D. 1.84 .98 .62 .88 .08 .00 5.0 7.1 6.6 .9 .4 N 55555555555 78 DOSE RBC mg/kg/day X106/jiL Table 11 Summary of Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/|.lL % X103/jiL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 6.66 .641 6 6.75 .485 4 6.78 .323 6 6.77 .600 4 12.5 1.10 6 13.0 .90 4 12.4 .37 6 12.0 1.28 4 42.1 3.75 6 43.0 2.45 4 41.2 1.17 6 40.6 4.58 4 63.3 3.24 6 63.9 4.66 4 60.9 2.86 6 60.0 2.31 4 18.8 1.03 6 19.2 1.27 4 18.3 1.05 6 17.8 .54 4 29.7 .97 6 30.0 .83 4 30.1 .53 6 29.6 .59 4 458 187.7 6 467 104.0 4 436 87.3 6 433 131.4 4 .3 .05 6 .4 .17 4 .2 .11 6 .2 .10 4 18 4.4 6 28 10.4 4 13 6.6 6 12 5.6 4 10.1 .41 6 10.0 .30 4 10.2 .27 6 10.8 .95 4 19.2 1.59 6 21.7 3.83 4 20.0 2.47 6 24.7 * 2.15 4 343 100.1 6 318 33.9 4 257 46.5 6 194 * 85.7 4 79 DOSE WBC mg/kg/day X103/|.iL Table 11 Summary of Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/JiL X103/ iL MONO EOSIN BASO X103/JiL X103/ iL X103/lL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% 0 MEAN 11.1 5.8 4.4 .7 .1 .0 51 41 6 1 0 S.D. 1.78 1.83 1.04 .41 .05 .05 10.4 9.8 3.5 .5 .4 N 66666666666 3 MEAN 10.5 5.5 4.1 .6 .2 .0 50 42 6 2 0 S.D. 3.52 2.91 .76 .17 .35 .06 13.5 12.3 1.0 2.9 .0 N 44444444444 10 MEAN 10.1 5.6 3.6 .7 .2 .0 54 37 7 2 0 S.D. 1.60 1.93 .86 .22 .10 .05 12.6 10.9 2.0 .9 .5 N 66666666666 30/20 MEAN 7.7 2.7 4.2 .6 .2 .0 34 54 92 0 S.D. 1.96 1.44 .95 .13 .17 .00 11.4 7.0 3.2 2.2 .6 N 44444444444 80 DOSE RBC mg/kg/day X106/jiL Table 12 Summary of Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/|.lL % X103/jiL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 6.87 .372 6 6.61 .455 4 6.82 .374 6 6.46 .559 2 12.9 .84 6 12.6 .91 4 12.5 .32 6 11.1 .57 2 44.2 2.83 6 64.4 3.88 6 42.1 3.30 4 63.8 4.08 4 41.6 1.12 6 61.1 3.41 6 37.2 * 2.97 2 57.6 .42 2 18.8 1.35 6 19.1 .98 4 18.4 1.10 6 17.2 .64 2 29.1 1.18 6 30.0 .81 4 30.1 .75 6 29.8 .92 2 435 145.1 6 504 129.5 4 421 42.1 6 406 70.7 2 .3 .11 6 .3 .29 4 .3 .23 6 .2 .07 2 21 8.2 6 22 19.4 4 20 14.3 6 10 3.5 2 10.2 .19 6 10.3 .22 4 10.4 .34 6 10.4 .49 2 18.1 1.31 6 19.6 2.73 4 19.2 1.64 6 22.5 2.05 2 278 15 6 311 49 4 262 36 6 244 57 2 81 DOSE WBC mg/kg/day X103/|.iL Table 12 Summary of Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/JiL X103/ iL MONO EOSIN BASO X103/JiL X103/ iL X103/lL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% 0 MEAN 10.8 4.4 5.5 .7 .2 .0 40 52 6 2 0 S.D. 1.68 1.76 .57 .39 .14 .04 9.4 9.4 3.3 .8 .4 N 66666666666 3 MEAN 10.2 4.3 4.6 .6 .6 .0 42 46 6 5 0 S.D. 2.73 1.91 1.45 .21 .82 .05 15.4 10.1 1.9 6.1 .5 N 44444444444 10 MEAN 10.4 5.4 4.0 * .7 .2 .0 50 40 8 2 0 S.D. 2.58 2.42 .88 .33 .18 .05 14.0 10.4 3.1 1.5 .4 N 66666666666 30/20 MEAN 7.7 3.4 3.6 * .6 .1 .0 40 49 8 2 0 S.D. 2.97 2.69 .35 .14 .00 .00 19.8 14.1 4.9 .7 .7 N 22222222222 82 DOSE RBC mg/kg/day X106/j.iL Table 13 Summary of Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/|.lL % X103/|-iL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 6.69 .263 6 6.91 .928 3 6.76 .470 6 6.18 .841 2 12.6 .55 6 40.6 .82 6 12.7 1.04 3 40.9 4.41 3 12.3 .57 6 39.1 2.19 6 10.6 * 1.13 2 33.9 4.45 2 60.8 3.33 6 59.4 2.56 3 58.1 4.19 6 55.0 .21 2 19.0 1.17 6 18.5 1.01 3 18.3 1.14 6 17.2 .49 2 31.1 .98 6 31.2 1.21 3 31.5 .67 6 31.4 .85 2 408 133.8 6 516 132.3 3 416 103.5 6 378 180.3 2 .6 .41 6 .9 .06 3 .5 .41 6 .2 .21 2 42 27.0 6 60 11.7 3 35 25.5 6 8 12.0 2 10.2 .43 6 10.1 .45 3 10.3 .23 6 10.3 .07 2 17.9 1.53 6 20.6 4.98 3 19.6 1.74 6 25.5 7.00 2 272 30 6 294 7 3 278 66 6 224 69 2 83 DOSE WBC mg/kg/day X103/|.iL Table 13 Summary of Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/JiL X103/ iL MONO EOSIN BASO X103/JiL X103/ iL X103/lL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% 0 MEAN 10.9 5.0 4.8 .8 .2 .0 45 45 7 2 0 S.D. 3.43 2.08 1.40 .48 .13 .05 7.3 9.9 3.6 .5 .5 N 66666666666 3 MEAN 12.5 4.3 6.3 1.3 .5 .1 37 49 10 4 1 S.D. 1.75 2.06 2.35 .85 .64 .06 20.7 11.4 5.0 4.6 .6 N 33333333333 10 MEAN 9.7 4.4 4.1 .8 .3 .1 45 43 93 1 S.D. 2.93 1.84 1.53 .23 .19 .04 12.5 11.2 1.8 1.6 .4 N 66666666666 30/20 MEAN 7.8 2.5 4.1 .9 .2 .1 30 54 11 2 2 S.D. 2.19 1.56 .28 .28 .21 .00 10.6 12.7 .0 2.1 .7 N 22222222222 84 DOSE RBC mg/kg/day X106/ iL Table 14 Summary of Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/|iL % X103/jiL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 10 MEAN S.D. N 7.00 .191 2 7.04 .389 2 13.7 .14 2 12.3 .64 2 44.8 .00 2 39.8 .99 2 64.0 1.84 2 56.5 1.70 2 19.6 .28 2 17.5 .07 2 30.6 .42 2 31.0 .71 2 492 247.5 2 390 78.5 2 .6 .07 2 .3 .28 2 46 6.4 2 20 19.1 2 9.8 .35 2 10.2 .21 2 17.9 .92 2 20.2 1.34 2 305 53.7 2 214 14.8 2 85 DOSE WBC mg/kg/day X103/ iL Table 14 Summary of Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/ iL X103/lL MONO EOSIN BASO X103/ iL X103/lL X103/jiL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 0 MEAN S.D. N 10 MEAN S.D. N 18.7 8.56 2 11.1 1.13 2 7.4 5.87 2 4.6 1.48 2 8.8 2.62 2 4.9 1.56 2 1.7 .00 2 1.1 .57 2 .5 .00 2 .4 .42 2 2 36 49 10 3 1 07 14.8 8.5 4.9 1.4 .0 222222 1 42 43 10 4 0 14 17.7 9.9 3.5 3.5 .7 222222 86 DOSE RBC mg/kg/day X106/ iL Table 15 Summary of Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X103/|iL % X103/jiL SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 10 MEAN S.D. N 6.92 .028 2 7.25 .410 2 13.6 .21 2 12.7 .85 2 44.4 .85 2 40.8 .85 2 64.1 1.56 2 56.3 1.98 2 19.6 .49 2 17.5 .14 2 30.5 .00 2 31.2 1.34 2 529 190.9 2 421 97.6 2 .4 .07 2 .2 .21 2 24 4.9 2 10 14.8 2 9.8 .35 2 10.2 .07 2 18.0 1.77 2 19.2 .21 2 323 4.2 2 227 14.1 2 87 DOSE WBC mg/kg/day X103/ iL Table 15 Summary of Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/ iL X103/lL MONO EOSIN BASO X103/ iL X103/lL X103/jiL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 0 MEAN S.D. N 10 MEAN S.D. N 15.8 2.90 2 10.7 5.09 2 5.7 2.83 2 4.4 1.34 2 8.2 .49 2 4.9 3.11 2 1.4 .21 2 1.0 .35 2 .5 .28 2 .3 .28 2 2 35 52 8 4 1 07 11.3 5.7 3.5 2.1 .0 222222 0 44 44 10 2 0 07 8.5 7.8 .7 1.4 .7 222222 88 DOSE RBC mg/kg/day X106/ iL Table 16 Summary of Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HGB HCT MCV MCH MCHC PLT RETIC RETIC PT G/DL % FL PG % X 1 0 3/h L % X 1 0 3/h L SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 0 MEAN S.D. N 10 MEAN S.D. N 6.96 .714 2 7.20 .325 2 13.8 1.20 2 12.8 .49 2 43.6 3.89 2 41.1 .64 2 62.5 .85 2 57.2 1.63 2 19.8 .35 2 17.7 .14 2 31.6 .14 2 31.0 .64 2 584 244.0 2 446 53.7 2 .2 .07 2 .4 .49 2 10 4.2 2 24 34.6 2 9.8 .57 2 10.2 .21 2 17.6 .49 2 18.3 .71 2 530 173.2 2 300 26.2 2 89 DOSE WBC mg/kg/day X103/ iL Table 16 Summary of Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/ iL X103/lL MONO EOSIN BASO X103/ iL X103/lL X103/jiL N-SEG% lymph% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 0 MEAN S.D. N 10 MEAN S.D. N 15.0 4.31 2 16.2 4.17 2 7.4 2.55 2 9.1 5.94 2 5.6 1.77 2 5.6 1.77 2 1.6 .07 2 1.3 .00 2 .2 .00 2 .1 .00 2 1 49 38 12 2 1 00 2.8 .7 2.8 .7 .0 222222 0 54 38 8 0 0 00 23.3 20.5 2.1 .7 .0 222222 90 DOSE mg/kg/day Table 17 Summary of Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 92 15.3 6 88 11.7 4 92 21.5 6 81 4.6 6 16 2.6 6 14 4.6 4 16 1.6 6 15 2.0 6 1.2 .15 6 1.1 .15 4 1.2 .05 6 1.1 .21 6 9.4 .58 6 9.4 .87 4 9.1 .68 6 9.1 .77 6 4.8 .40 6 5.2 .29 4 4.8 .21 6 4.8 .20 6 4.6 .56 6 4.2 .63 4 4.3 .63 6 4.4 .70 6 .0 9 147 39 .05 2.0 44.3 11.3 6666 .1 10 174 50 .15 4.6 53.7 10.2 4444 .2 9 145 61 .23 1.7 22.0 18.0 6666 .2 8 140 56 .15 4.7 26.3 13.2 6666 91 Table 17 Summary of Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 35 9.6 6 40 3.9 4 40 7.3 6 39 8.3 6 58 28.8 6 42 8.1 4 77 52.6 6 66 41.8 6 455 202.2 6 556 180.3 4 604 173.8 6 521 231.6 6 126 32.4 6 135 24.3 4 120 38.0 6 117 49.1 6 3 145 516 .8 77.2 214.2 666 5 142 377 2.7 19.1 41.6 444 5 128 369 2.1 45.0 98.5 666 3 142 380 1.4 56.6 89.3 666 25 9.1 6 38 27.3 4 14 8.7 6 37 29.6 6 237 79.8 6 183 30.4 4 195 70.6 6 187 46.0 6 92 Table 17 Summary of Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 11.4 .45 6 11.4 .70 4 10.9 .45 6 10.7 .57 6 5.8 .69 6 6.7 .53 4 6.3 1.37 6 6.1 .96 6 163 2.9 6 162 5.7 4 158 2.4 6 159 4.2 6 5.8 .50 6 5.9 .78 4 5.4 .48 6 5.6 .56 6 114 1 6 110 1 4 112 1 6 112 2 6 Covance 6329-231 3M T-6889.3 93 DOSE mg/kg/day Table 18 Summary of Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN S.D. N 78 22.9 6 15 2.4 6 1.3 .17 6 9.2 .58 6 4.7 .42 6 4.6 .56 6 .2 .12 6 8 146 2.9 19.1 66 44 22.9 6 3 MEAN S.D. N 78 9.3 4 16 4.4 4 1.2 .17 4 8.6 .37 4 4.9 .24 4 3.7 .45 4 .1 .14 4 7 151 1.4 60.4 44 51 24.1 4 10 MEAN 72 17 1.3 8.9 4.8 4.1 .2 10 142 76 S.D. 8.5 1.5 .15 .75 .27 .55 .12 3.3 25.9 26.6 N 6666666666 30/20 MEAN S.D. N 75 9.3 5 16 2.4 5 1.3 .13 5 8.8 .49 5 4.5 .38 5 4.3 .37 5 .1 .09 5 8 158 108 * 1.9 20.8 57.3 555 94 Table 18 Summary of Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 34 6.7 6 39 10.9 4 36 7.0 6 33 6.6 5 48 16.7 6 29 6.4 4 55 22.6 6 36 13.5 5 577 232.0 6 629 193.9 4 704 165.2 6 571 313.5 5 121 29.3 6 107 24.5 4 107 29.6 6 98 34.1 5 4 115 551 1.6 51.3 177.3 666 3 157 396 2.6 88.3 58.3 444 2 144 372 1.4 36.4 109.2 666 1 128 434 1.3 66.4 109.7 555 39 20.2 6 46 21.0 4 19 10.6 6 34 28.5 5 255 87.1 6 181 33.5 4 197 85.8 6 205 49.0 5 95 Table 18 Summary of Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 11.0 .45 6 10.1 .14 4 10.4 .34 6 10.7 .81 5 5.9 1.12 6 5.8 .88 4 5.9 .75 6 4.9 .63 5 158 3.3 6 152 2.5 4 153 5.1 6 157 6.2 5 5.8 .37 6 5.3 .22 4 5.0 .55 6 5.8 .90 5 113 2 6 111 1 4 110 2 6 112 3 5 Covance 6329-231 3M T-6889.3 96 DOSE mg/kg/day Table 19 Summary of Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 78 21.1 6 68 7.0 4 71 10.7 6 76 7.0 4 17 3.8 6 18 4.3 4 17 1.5 6 20 5.0 4 1.2 .19 6 1.1 .10 4 1.2 .16 6 1.2 .13 4 9.0 .39 6 8.9 .48 4 8.6 .67 6 8.1 1.20 4 4.6 .42 6 5.0 .25 4 4.6 .35 6 3.9 .75 4 4.4 .39 6 3.8 .31 4 4.0 .54 6 4.2 .67 4 .4 5 151 43 .18 3.7 36.9 13.5 6666 .3 9 161 59 .08 5.1 61.3 20.4 4444 .2 9 158 76 .10 3.2 46.2 27.4 6666 .3 22 146 66 .21 25.8 12.2 39.0 4444 97 Table 19 Summary of Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 36 8.0 6 35 10.4 4 36 6.9 6 141 187.4 4 62 23.9 6 45 26.7 4 53 19.4 6 192 269.7 4 582 193.3 6 612 169.9 4 668 190.3 6 484 159.5 4 123 31.2 6 121 15.9 4 114 29.7 6 110 55.7 4 4 139 481 2.9 78.9 147.1 666 2 131 396 1.0 16.2 58.5 444 3 143 347 1.5 65.6 106.2 666 9 379 352 8.6 496.0 71.3 444 28 16.2 6 86 81.3 4 13 12.2 6 8 13.6 4 262 81.8 6 220 45.4 4 211 83.4 6 204 49.5 4 98 Table 19 Summary of Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 10.6 .32 6 10.6 .33 4 10.4 .38 6 9.8 .93 4 5.9 .44 6 6.2 1.07 4 5.7 .69 6 4.9 .48 4 156 3.4 6 154 3.9 4 150 * 1.8 6 152 3.9 4 5.1 .31 6 5.0 .13 4 4.6 .45 6 5.8 .94 4 111 2 6 111 2 4 110 2 6 111 2 4 Covance 6329-231 3M T-6889.3 99 DOSE mg/kg/day Table 20 Summary of Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN 79 19 1.3 9.5 4.9 4.6 .2 11 167 40 S.D. 11.7 1.8 .23 .52 .33 .27 .17 4.5 45.3 8.5 N 6666666666 3 MEAN 78 18 1.2 8.9 4.9 4.0 .3 12 157 56 S.D. 9.8 3.5 .14 .12 .19 .17 .10 4.0 51.3 25.2 N 4444444444 10 MEAN 77 20 1.3 9.1 4.7 4.3 .2 11 155 88 * S.D. 8.9 2.9 .12 .70 .33 .53 .12 5.2 30.6 36.8 N 6666666666 30/20 MEAN 84 17 1.0 9.0 4.4 4.6 .1 13 142 99 * S.D. 19.1 1.4 .21 1.13 .64 .49 .14 5.7 9.2 55.2 N 2222222222 100 Table 20 Summary of Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 38 7.8 6 40 6.7 4 40 6.8 6 38 7.1 2 63 22.7 6 47 25.2 4 53 15.5 6 48 17.7 2 529 240.3 6 585 177.6 4 656 208.6 6 432 306.2 2 128 31.4 6 118 22.5 4 113 30.8 6 120 88.4 2 10 3.7 6 10 1.0 4 11 2.9 6 10 .0 2 143 55.8 6 126 35.3 4 133 34.4 6 156 31.8 2 515 148.7 6 378 63.6 4 367 100.7 6 318 67.9 2 20 17.4 6 50 32.0 4 9 12.6 6 11 15.6 2 270 66.1 6 207 47.2 4 219 77.0 6 184 62.9 2 101 Table 20 Summary of Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 11.3 .20 6 10.8 * .44 4 10.8 * .34 6 10.1 * .71 2 6.4 .60 6 6.3 1.10 4 6.1 .80 6 5.0 .42 2 167 3.0 6 162 2.5 4 160 * 3.7 6 158 * 2.8 2 5.3 .38 6 5.1 .46 4 4.8 .37 6 5.4 .85 2 117 2 6 118 1 4 117 1 6 114 3 2 Covance 6329-231 3M T-6889.3 102 DOSE mg/kg/day Table 21 Summary of Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN 71 20 1.1 8.6 4.7 3.9 .3 18 156 44 S.D. 14.5 3.1 .17 .50 .32 .41 .12 3.6 35.0 8.7 N 6666666666 3 MEAN 63 22 1.1 8.4 4.9 3.5 .2 17 142 51 S.D. 8.1 5.8 .25 .51 .35 .35 .15 2.5 47.4 24.4 N 3333333333 10 MEAN 66 20 1.1 8.4 4.6 CO ro .2 16 154 72 S.D. 19.7 2.4 .19 .71 .26 .62 .23 1.4 30.6 24.5 N 6666666666 30/20 MEAN 80 16 .9 8.3 4.2 4.2 .2 18 150 92 S.D. 27.6 .7 .14 .14 .49 .35 .35 .7 15.6 40.3 N 2222222222 103 Table 21 Summary of Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 37 4.8 6 46 1.5 3 44 11.6 6 40 3.5 2 68 15.7 6 43 5.8 3 53 26.7 6 48 7.8 2 444 190.8 6 574 290.4 3 544 181.0 6 384 260.9 2 124 30.5 6 130 39.2 3 110 24.1 6 122 95.5 2 5 140 2.3 28.8 66 6 139 2.0 37.6 33 7 922 2.2 1902.1 66 2 169 .7 58.0 22 500 144.3 6 457 105.5 3 362 114.7 6 305 55.2 2 39 25.0 6 106 63.8 3 11 * 9.1 6 8 12.0 2 328 91.9 6 313 72.0 3 268 107.9 6 215 65.1 2 104 Table 21 Summary of Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 10.0 .23 6 10.3 1.29 3 9.7 .52 6 9.2 .21 2 5.8 .44 6 6.0 2.12 3 5.8 1.16 6 4.8 .00 2 152 2.0 6 154 10.4 3 148 3.9 6 150 2.8 2 4.9 .33 6 4.9 .96 3 4.3 .57 6 5.0 1.20 2 106 1.3 6 109 1.7 3 106 2.3 6 108 1.4 2 Covance 6329-231 3M T-6889.3 105 DOSE mg/kg/day Table 22 Summary of Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN S.D. N 10 MEAN S.D. N 101 36.8 2 61 9.9 2 17 .0 2 21 1.4 2 1.4 .07 2 1.4 .14 2 9.2 .28 2 8.0 .21 2 4.8 .35 2 4.6 .21 2 4.4 .07 2 3.3 .42 2 .4 .07 2 .2 .07 2 6 194 .0 48.8 22 7 159 .0 39.6 22 40 .7 2 80 43.8 2 106 Table 22 Summary of Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 10 MEAN S.D. N 34 7.8 2 29 2.8 2 42 17.0 2 18 8.5 2 247 18.4 2 548 196.6 2 140 51.6 2 120 31.1 2 5 92 612 1.4 14.1 221.3 222 6 140 477 1.4 3.5 94.8 222 20 13.4 2 22 7.1 2 415 192.3 2 392 133.6 2 107 Table 22 Summary of Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 MEAN S.D. N 10.9 .00 2 9.9 .00 2 6.3 .28 2 6.2 1.41 2 156 4.2 2 146 1.4 2 5.8 .35 2 4.6 .14 2 108 3.5 2 108 .7 2 Covance 6329-231 3M T-6889.3 108 DOSE mg/kg/day Table 23 Summary of Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN S.D. N 10 MEAN S.D. N 95 1.4 2 80 2.1 2 15 .0 2 20 2.8 2 1.3 .14 2 1.3 .14 2 9.1 .00 2 8.1 .14 2 4.8 .35 2 4.8 .21 2 4.2 .35 2 3.2 .35 2 .2 .07 2 .2 .07 2 4 203 .0 67.9 22 5 164 1.4 30.4 22 49 2 2 92 64 2 109 Table 23 Summary of Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 10 MEAN S.D. N 35 7.1 2 28 3.5 2 44 1.4 2 44 9.2 2 245 58.0 2 635 206.5 2 134 65.8 2 120 32.5 2 4 508 604 .7 559.3 219.2 222 2 164 490 .7 53.0 70.0 222 46 2.1 2 56 13.4 2 420 186.0 2 394 112.4 2 110 Table 23 Summary of Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 10 MEAN S.D. N 10.7 .00 2 10.3 .00 2 6.8 .21 2 6.4 1.06 2 158 .0 2 153 2.8 2 5.6 1.27 2 5.3 .42 2 110 7 2 114 7 2 Covance 6329-231 3M T-6889.3 111 DOSE mg/kg/day Table 24 Summary of Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS GLU MG/DL 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 6329-231 3M T-6889.3 TRIG MG/DL 0 MEAN 84 18 1.2 9.2 4.7 4.5 .3 10 194 38 S.D. 12.0 2.1 .42 .57 .85 .28 .14 .7 88.4 12.0 N 2222222222 10 MEAN S.D. N 90 4.2 2 21 .0 2 1.3 .00 2 8.2 .00 2 4.9 .42 2 3.3 .42 2 .3 .00 2 8 150 .7 39.6 22 48 36.8 2 112 Table 24 Summary of Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS 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 Covance 6329-231 3M T-6889.3 0 MEAN S.D. N 10 MEAN S.D. N 60 6.4 2 50 4.9 2 108 63.6 2 76 7.8 2 270 75.7 2 603 210.7 2 112 21.2 2 116 31.1 2 2 1024 2.1 533.9 22 826 224.2 2 2 1524 1074 1.4 563.6 813.2 222 164 61.5 2 357 422.8 2 574 168 2 903 787 2 113 Table 24 Summary of Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 10 MEAN S.D. N 10.9 .42 2 10.2 .00 2 4.9 .99 2 5.2 1.91 2 154 .7 2 150 2.8 2 6.0 .78 2 4.4 .00 2 107 4.2 2 103 .0 2 Covance 6329-231 3M T-6889.3 114 Table 25 Summary of Clinical Urinalysis Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day U VOL ML SP GR U PH 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 136.8 131.02 6 231.0 220.83 4 141.0 157.36 6 88.3 66.52 6 1.016 .0073 6 1.010 .0086 4 1.014 .0060 6 1.014 .0081 6 8.2 .41 6 7.9 .25 4 8.2 .41 6 8.2 .42 6 Covance 6329-231 3M T-6889.3 115 Table 26 Summary of Clinical Urinalysis Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE /day U VOL ML SP GR U PH 0 MEAN S.D. N 3 MEAN S.D. N MEAN S.D. N 30/20 MEAN S.D. N 166.5 158.98 6 241.8 141.01 4 155.3 111.19 6 223.2 99.35 5 1.015 .0066 6 1.010 .0092 4 1.014 .0067 6 1.007 .0056 5 7.9 .38 6 7.8 .50 4 8.1 .20 6 7.5 .50 5 Covance 6329-231 3M T-6889.3 116 Table 27 Summary of Clinical Urinalysis Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day U VOL ML SP GR U PH 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 189.0 191.82 6 253.0 145.45 4 190.0 188.04 6 83.0 22.89 4 1.013 .0078 6 1.010 .0097 4 1.012 .0057 6 1.016 .0048 4 8.1 .20 6 7.5 * .41 4 8.2 .26 6 7.5 .58 4 Covance 6329-231 3M T-6889.3 117 Table 28 Summary of Clinical Urinalysis Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day U VOL ML SP GR U PH 0 MEAN S.D. N 3 MEAN S.D. N 10 MEAN S.D. N 30/20 MEAN S.D. N 186.0 182.11 6 272.0 218.99 4 222.0 174.10 6 71.0 9.90 2 1.017 .0083 6 1.012 .0088 4 1.012 .0054 6 1.020 .0000 2 8.2 .27 6 7.8 * .29 4 7.9 .20 6 8.2 .35 2 Covance 6329-231 3M T-6889.3 118 Table 29 Summary of Clinical Urinalysis Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE /day U VOL ML SP GR U PH 0 MEAN S.D. N 3 MEAN S.D. N MEAN S.D. N 30/20 MEAN S.D. N 159.5 67.63 6 172.3 71.07 3 208.5 159.04 6 197.0 154.15 2 1.015 .0063 6 1.016 .0060 3 1.013 .0067 6 1.014 .0113 2 7.7 .41 6 7.8 .29 3 7.2 .27 6 7.8 .35 2 Covance 6329-231 3M T-6889.3 119 Table 30 Summary of Clinical Urinalysis Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day U VOL ML SP GR U PH 0 MEAN 392.5 1.008 S.D. 215.67 .0071 N 22 10 MEAN 290.0 1.006 S.D. 233.35 .0035 N 22 8.0 .0 0 2 7.8 .3 5 2 Covance 6329-231 3M T-6889.3 120 Table 31 Summary of Clinical Urinalysis Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day U VOL ML SP GR U PH 0 MEAN 196.0 1.013 S.D. 166.88 .0099 N 22 10 MEAN 341 5 1.005 S.D. 246 .78 .0028 N 22 8.0 .00 2 7.5 .00 2 Covance 6329-231 3M T-6889.3 121 Table 32 Summary of Clinical Urinalysis Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DOSE mg/kg/day U VOL ML SP GR U PH 0 MEAN 115.0 1.018 S.D. 60.81 .0042 N 22 MEAN S.D. N 135.5 61.52 2 1.012 .0028 2 7.0 .00 2 .0 .00 2 Covance 6329-231 3M T-6889.3 122 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL LF ADRENAL SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 0.3085 0.0462 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.0078 0.0003 4 0.0048 0.0004 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 0.3720 0.0460 3 0.0083 0.0010 3 0.0056 0.0009 M3 NUMBER IN GROUP: MEAN: STANDARD DEV 4 4447.5 498.5 4 0.3030 0.0940 4 0. 0069 0. 0024 4 0. 0048 0. 0017 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 0.3320 0.0311 2 0. 0087 0. 0006 2 0. 0045 0. 0002 123 Covance 6329-231 3M T-6889.3 PAGE: 1 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL RT ADRENAL SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 0.2513 0.0503 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.0063 0.0008 4 0.0039 0.0006 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 0.3573 0.0492 3 0.0080 0.0010 3 0.0054 0.0009 M3 NUMBER IN GROUP: MEAN: STANDARD DEV 4 4447.5 498.5 4 0.2328 0.0512 4 0. 0054 0. 0016 4 0. 0036 0. 0009 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 0.2620 0.0891 2 0. 0067 0. 0012 2 0. 0035 0. 0010 124 Covance 6329-231 3M T-6889.3 PAGE: 2 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL BRAIN SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) ORGAN WEIGHT (g) 4 3947.5 591.1 4 64.5708 7.6823 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 1.6471 0.1763 4 1.0000 0.0000 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 66.5134 2.3695 3 1.4827 0.0614 3 1.0000 0.0000 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 64.2743 4.2590 4 1.4622 0.2194 4 1.0000 0.0000 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 74.2460 3.6416 2 1.9603 0.2309 2 1.0000 0.0000 125 Covance 6329-231 3M T-6889.3 PAGE: 3 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL LF EPIDIDYMIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 1.6380 0.5473 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.0410 0.0112 4 0.0256 0.0095 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 2.3627 0.6805 3 0.0526 0.0151 3 0.0355 0.0100 M3 NUMBER IN GROUP: MEAN: STANDARD DEV 4 4447.5 498.5 4 1.7010 0.5692 4 0. 0382 0. 0127 4 0. 0268 0. 0094 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 1.8945 0.3345 2 0. 0510 0. 0172 2 0. 0257 0. 0058 126 Covance 6329-231 3M T-6889.3 PAGE: 4 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL RT EPIDIDYMIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 1.7750 0.4542 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.0449 0.0100 4 0.0278 0.0086 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 2.3617 0.5749 3 0.0526 0.0127 3 0.0356 0.0087 M3 NUMBER IN GROUP: MEAN: STANDARD DEV 4 4447.5 498.5 4 1.6640 0.5738 4 0. 0375 0. 0133 4 0. 0261 0. 0091 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 1.7740 0.2489 2 0. 0476 0. 0144 2 0. 0240 0. 0045 127 Covance 6329-231 3M T-6889.3 PAGE: 5 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL LF KIDNEY SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 6.5898 0.9070 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.1674 0.0133 4 0.1023 0.0110 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 8.0123 1.1567 3 0.1785 0.0245 3 0.1209 0.0216 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 8.0508 0.6366 4 0.1818 0.0136 4 0.1260 0.0168 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 9.1090 * 1.0041 2 0.2437 0.0668 2 0.1232 0.0196 128 Covance 6329-231 3M T-6889.3 PAGE: 6 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL RT KIDNEY SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 6.5520 1.0155 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.1660 0.0085 4 0.1014 0.0092 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 7.7810 1.2850 3 0.1733 0.0274 3 0.1175 0.0237 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 7.8853 0.7930 4 0.1777 0.0124 4 0.1235 0.0191 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 9.1500 0.9772 2 0.2447 0.0663 2 0.1237 0.0192 129 Covance 6329-231 3M T-6889.3 PAGE: 7 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL LIVER SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) ORGAN WEIGHT (g) 4 3947.5 591.1 4 60.1698 6.9386 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 1.5303 0.0769 4 0.9344 0.0736 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 81.7917 * 2.8112 3 1.8228 * 0.0502 3 1.2317 0.0856 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 83.1743 * 9.6617 4 1.8700 * 0.0616 4 1.3042 0.2255 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 90.3925 * 4.2208 2 2.4057 * 0.5106 2 1.2203 0.1167 130 Covance 6329-231 3M T-6889.3 PAGE: 8 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11 1 1 1 11 2 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL PANCREAS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 5.6195 1.0600 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.1427 0.0212 4 0.0872 0.0136 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 6.1023 1.2194 3 0.1359 0.0262 3 0.0922 0.0214 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 5.2703 1.0885 4 0.1194 0.0281 4 0. 0828 0. 0206 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 6.2610 0.3168 2 0.1653 0.0192 2 0. 0843 0. 0001 131 Covance 6329-231 3M T-6889.3 PAGE: 9 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL LF TESTIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 9.9312 3.9350 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.2516 0.0984 4 0.1580 0.0783 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 15.1513 3.7198 3 0.3375 0.0822 3 0.2279 0.0552 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 12.1860 4.6403 4 0.2728 0.1022 4 0.1915 0.0740 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 10.2960 2.1680 2 0.2777 0.1029 2 0.1396 0.0360 132 Covance 6329-231 3M T-6889.3 PAGE: 10 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL RT TESTIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 9.6432 3.8907 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.2453 0.1000 4 0.1540 0.0788 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 16.1067 4.2181 3 0.3588 0.0930 3 0.2425 0.0641 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 4 4447.5 498.5 4 11.5203 3.9126 4 0.2584 0.0867 4 0.1810 0.0633 M4 NUMBER IN GROUP: MEAN: STANDARD DEV: 5 3925.0 583.0 2 9.8880 2.0633 2 0.2667 0.0983 2 0.1340 0.0344 133 Covance 6329-231 3M T-6889.3 PAGE: 11 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL LF THYROID/PARA SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 0.2205 0.0617 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.0058 0.0023 4 0.0035 0.0011 M2 NUMBER IN GROUP: MEAN: STANDARD DEV: 3 4486.7 30.6 3 0.1677 0.0422 3 0.0037 0.0009 3 0.0025 0.0007 M3 NUMBER IN GROUP MEAN STANDARD DEV 4 4447.5 498.5 4 0.3340 0.1502 4 0. 0074 0. 0028 4 0. 0053 0. 0025 M4 NUMBER IN GROUP MEAN STANDARD DEV 5 3925.0 583.0 2 0.2435 0.0700 2 0. 0063 0. 0008 2 0. 0033 0. 0008 134 Covance 6329-231 3M T-6889.3 PAGE: 12 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11 Ol 1 1 1 11 2 TABLE 33 Summary of Organ Weight Data Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL RT THYROID/PARA SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 4 3947.5 591.1 ORGAN WEIGHT (g) 4 0.2225 0.0654 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 4 0.0058 0.0023 4 0.0035 0.0011 NUMBER IN GROUP: MEAN: STANDARD DEV: M3 NUMBER IN GROUP MEAN STANDARD DEV M4 NUMBER IN GROUP MEAN STANDARD DEV 3 4486.7 30.6 4 4447.5 498.5 5 3925.0 583.0 3 0.1850 0.0305 4 0.3135 0.1146 2 0.2150 0.1273 3 0.0041 0.0007 4 0. 0070 0. 0023 2 0. 0054 0. 0024 3 0.0028 0.0004 4 0. 0049 0. 0019 2 0. 0029 0. 0016 135 Covance 6329-231 3M T-6889.3 PAGE: 13 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL LF ADRENAL SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 0.3990 0.0438 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.0074 0.0005 2 0.0061 0.0000 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 0.2770 0.0509 2 0.0072 0.0024 2 0.0041 0.0004 Covance 6329-231 3M T-6889.3 PAGE: 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 136 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL RT ADRENAL SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 0.2465 0.0389 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.0045 0.0005 2 0.0037 0.0002 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 0.1920 0.0382 2 0.0050 0.0018 2 0.0029 0.0003 Covance 6329-231 3M T-6889.3 PAGE: 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 137 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL BRAIN SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) ORGAN WEIGHT (g) 2 5410.0 240.4 2 65.7115 7.2811 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 1.2128 0.0807 2 1.0000 0.0000 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 66.8240 6.1559 2 1.7330 0.4292 2 1.0000 0.0000 Covance 6329-231 3M T-6889.3 PAGE: 3 138 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL LF EPIDIDYMIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 2.6085 0.2963 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.0481 0.0033 2 0.0397 0.0001 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 1.6595 0.0955 2 0.0425 0.0043 2 0.0250 0.0037 Covance 6329-231 3M T-6889.3 PAGE: 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 139 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL RT EPIDIDYMIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 2.7290 0.0382 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.0505 0.0015 2 0.0418 0.0040 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 1.5995 0.1605 2 0.0415 0.0106 2 0.0239 0.0002 Covance 6329-231 3M T-6889.3 PAGE: 5 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 140 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL LF KIDNEY SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 9.0575 1.0232 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.1680 0.0264 2 0.1396 0.0310 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 5.8750 0.9942 2 0.1493 0.0018 2 0.0890 0.0231 Covance 6329-231 3M T-6889.3 PAGE: 6 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 141 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL RT KIDNEY SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 8.8620 0.9730 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.1644 0.0253 2 0.1365 0.0299 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 5.6370 0.6449 2 0.1438 0.0062 2 0.0852 0.0175 Covance 6329-231 3M T-6889.3 PAGE: 7 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 142 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL LIVER SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) ORGAN WEIGHT (g) 2 5410.0 240.4 2 90.1885 2.4816 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 1.6697 0.1201 2 1.3831 0.1910 M3 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 66.0390 5.2212 2 1.6898 0.1331 2 0.9961 0.1699 Covance 6329-231 3M T-6889.3 PAGE: 8 143 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL PANCREAS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV: TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 8.4993 0.7025 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.1570 0.0060 2 0.1295 0.0037 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 5.4815 0.0955 2 0.1409 0.0197 2 0.0824 0.0090 Covance 6329-231 3M T-6889.3 PAGE: 9 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 144 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL LF TESTIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) ORGAN WEIGHT (g) 2 5410.0 240.4 2 16.0235 2.4600 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.2975 0.0587 2 0.2474 0.0649 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 10.0800 0.1329 2 0.2598 0.0443 2 0.1514 0.0120 Covance 6329-231 3M T-6889.3 PAGE: 10 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 145 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL RT TESTIS SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) ORGAN WEIGHT (g) 2 5410.0 240.4 2 16.3235 2.3553 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.3030 0.0570 2 0.2519 0.0638 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 10.2370 0.4454 2 0.2627 0.0300 2 0.1542 0.0209 Covance 6329-231 3M T-6889.3 PAGE: 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 146 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL LF THYROID/PARA SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 0.2545 0.0134 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.0047 0.0005 2 0.0039 0.0006 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 0.3165 0.1732 2 0.0085 0.0057 2 0.0046 0.0022 Covance 6329-231 3M T-6889.3 PAGE: 12 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 147 TABLE 34 Summary of Organ Weight Data Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=U;SUBSET=ALL RT THYROID/PARA SEX DOSE GROUP M1 NUMBER IN GROUP: MEAN: STANDARD DEV TERMINAL BODY WT (g) 2 5410.0 240.4 ORGAN WEIGHT (g) 2 0.2570 0.0127 ORGAN-TOBODY WT (%) ORGAN-TOBRAIN WT RATIO 2 0.0048 0.0004 2 0.0039 0.0006 NUMBER IN GROUP: MEAN: STANDARD DEV: 2 3932.5 618.7 2 0.3000 0.1937 2 0.0081 0.0062 2 0.0044 0.0025 Covance 6329-231 3M T-6889.3 PAGE: 13 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ro 1 1 1 1 11 2 148 TABLE 35 Incidence of Macroscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: -- MALE GROUP: -1- -2- -3- -4- ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 4 3 4 5 -- ------------------------------------------- -=- -=- -=- -=- ** TOP OF LIST ** GENERAL COMMENT (GC) ......... ....................... NUMBER EXAMINED : 4 3 4 5 BONE MARROW SMEAR TAKEN EYES - DAVIDSONS NO MACROSCOPIC LESIONS ANIMAL OBESE 4345 4345 3014 0100 LIVER (LI) ................... ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 DIFFUSELY DARK 0010 KIDNEY (KD) .................. ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 4 CYST(S) 0001 LUNG (LU) .................... ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 2 3 5 MOTTLED RED FOCUS(I)/AREA(S) 0010 0100 149 TABLE 35 Incidence of Macroscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 4 3 4 5 -------------------------------- ------------------------------------------- -=- -=- -=- -=- PARATHYROID (PT) ............. ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 CYST(S) 0010 CECUM (CE) ................... ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 2 4 5 RED FOCUS(I)/AREA(S) 1100 SKIN (SK) .................... ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 CRUSTED AREA(S) 0010 LN, TRACHEOBRON (TB) ........ ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 DIFFUSELY DARK 0010 LN, MANDIBULAR (MN) ......... ........................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 4 LARGE ** END OF LIST 0001 150 TABLE 36 Incidence of Macroscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---SEX: --MALE -GROUP: -1- -3- ORGAN AND KEYWORD(S) OR PHRASE NUMBER: 2 2 ** TOP OF LIST ** GENERAL COMMENT (GC) ..................... ............ NUMBER EXAMINED: 2 2 BONE MARROW SMEAR TAKEN EYES - DAVIDSONS NO MACROSCOPIC LESIONS ANIMAL OBESE 22 22 12 10 LIVER (LI) ................................ ............ NUMBER EXAMINED: NOT REMARKABLE: 2 1 2 2 ADHESION(S) ** END OF LIST 10 151 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION NUMBER: 4 3 4 5 -------------------------------------------- ------------------------------- -=- -=- -=- -=- ** TOP OF LIST ** ADRENAL, CORTEX (AC) .................... ............. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 1 2 3 --CORTICAL TISSUE, EXTRACAPSULAR --ECTOPIC ZONA GLOMERULOSA-LIKE CELLS, ZONA FASCICULATA --HYPERTROPHY, CORTICAL CELL --MINERALIZATION 1101 0001 1121 1010 ADRENAL, MEDULLA (MA) ................... ............. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 LIVER (LI) ............................... ............. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 1 1 0 0 --INFILTRATE, LYMPHOHISTIOCYTIC --PIGMENT, HEPATOCELLULAR --PIGMENT, KUPFFER CELL 3245 0100 01 02 SPLEEN (SP) .............................. ............. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 PANCREAS (PA) ............................ ............. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 --INFILTRATE, LYMPHOHISTIOCYTIC 0010 152 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- NUMB E R -< SEX: --- MALE GROUP: -1- -2- -3- -4- NUMBER: 4 3 4 5 TESTIS (TE) --ATROPHY/DEGENERATION BONE, FEMUR (FE) ........ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 4 0001 NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 --INFILTRATE, LYMPHOHISTIOCYTIC, CONJUNCTIVAL NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 0010 Covance 6329-231 3M T-6889.3 PAGE: 2 153 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 3 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION -- -- NUMBER: 4 3 4 5 -=- -=- -=- -=- BRAIN (BR) ............................ ................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 3 --INFILTRATE, LYMPHOHISTIOCYTIC --MINERALIZATION 0001 0001 KIDNEY (KD) .......................... ................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 2 2 1 2 --CYST --INFILTRATE, LYMPHOHISTIOCYTIC --MINERALIZATION, TUBULAR 0001 1101 2 032 LUNG (LU) ............................. ................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 0 0 0 0 --CONGESTION --INFILTRATE, EOSINOPHILIC --INFILTRATE, MACROPHAGE, ALVEOLAR --MINERALIZATION, ALVEOLAR --PIGMENT 0100 1000 0031 1000 4345 HEART (HT) ............................ ................ NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 2 2 4 --INFILTRATE, LYMPHOHISTIOCYTIC --PIGMENT 0121 0100 154 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 4 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION -- -- NUMBER: 4 3 4 5 -=- -=- -=- -=- GALLBLADDER (GB) .................. ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 THYMUS (TH) ....................... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 2 2 5 --INVOLUTION 012 0 LN, MESENTERIC (MS) ............... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 2 3 3 --INFILTRATE, EOSINOPHILIC --INFLAMMATION, GRANULOMATOUS --PARASITISM --PIGMENT 1001 1000 1000 1111 TRACHEA (TR) ...................... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 ESOPHAGUS (ES) .................... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 155 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 5 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION -- -- NUMBER: 4 3 4 5 -=- -=- -=- -=- THYROID (TY) ...................... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 3 0 2 --ECTOPIC THYMUS --INFILTRATE, LYMPHOHISTIOCYTIC --ONE EXAMINED --CYST, THYROGLOSSAL 0022 0 02 1 1000 0010 PARATHYROID (PT) .................. ................... NUMBER EXAMINED: 3 3 4 5 NOT REMARKABLE: 3 2 3 5 --CYST, GLANDULAR 0110 AORTA (AO) ........................ ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 PITUITARY (PI) .................... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 3 4 5 --CYST 1000 SALIV GL, MANDIB (SG) ............. ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 2 2 3 4 --INFILTRATE, LYMPHOHISTIOCYTIC 2111 156 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 6 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION -- -- NUMBER: 4 3 4 5 -=- -=- -=- -=- MUSCLE, SKELETAL (SM) .......... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 --DEGENERATION/NECROSIS --INFLAMMATION, ACUTE 0010 0010 SPINAL CORD (SC) ................ ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 NERVE, SCIATIC (SN) ............. ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 STOMACH, GL (ST) ................ ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 4 --INFLAMMATION, GRANULOMATOUS --PARASITISM 0001 0001 DUODENUM (DU) ................... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 --PARASITISM 0010 JEJUNUM (JE) .................... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 157 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 7 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION -- -- NUMBER: 4 3 4 5 -=- -=- -=- -=- ILEUM (IL) ...................... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 --INFILTRATE, EOSINOPHILIC 0010 CECUM (CE) ...................... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 3 3 5 --INFLAMMATION, GRANULOMATOUS --PARASITISM 1010 1000 COLON (CO) ...................... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 3 4 5 --INFLAMMATION, CHRONIC 1000 RECTUM (RE) ..................... ..................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 --INFLAMMATION, GRANULOMATOUS 0010 SKIN (SK) ....................... ..................... NUMBER EXAMINED: 3 3 4 5 NOT REMARKABLE: 3 3 3 5 --ACANTHOSIS --INFLAMMATION, CHRONIC 0010 0010 158 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 8 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION -- -- NUMBER: 4 3 4 5 -=- -=- -=- -=- MAMMARY, MALE (MM) ................ ................... NUMBER EXAMINED: 3 3 3 5 NOT REMARKABLE: 3 3 3 5 URINARY BLADDER (UB) .............. ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 2 2 1 1 --INFILTRATE, EOSINOPHILIC --INFILTRATE, LYMPHOHISTIOCYTIC 1000 2134 PROSTATE (PR) ..................... ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 2 2 1 2 --INFILTRATE, LYMPHOHISTIOCYTIC --INFLAMMATION, SUBACUTE 2123 0010 SEMINAL VESICLES (SV) ............. ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 2 5 --MINERALIZATION 002 0 EPIDIDYMIDES (EP) ................. ................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 3 4 4 --INFILTRATE, LYMPHOHISTIOCYTIC 1001 159 TABLE 37 Incidence of Microscopic Observations Week 27 Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 9 TABLE INCLUDES: SEX=ALL;GROUP=ALL;WEEKS=ALL DEATH=T;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---- SEX: ---MALE GROUP: -1- -2- -3- -4- ORGAN AND FINDING DESCRIPTION NUMBER: 4 3 4 5 -- ------------------------------------------- -=- -=- -=- -=- LN, MANDIBULAR (MN) ......... ........................ NUMBER EXAMINED: 0 0 0 1 NOT REMARKABLE: 0 0 0 1 LN, TRACHEOBRON (TB) ........ ........................ NUMBER EXAMINED: 0 0 1 0 NOT REMARKABLE: 0 0 0 0 --PIGMENT 0010 ** END OF LIST 160 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL -- N U M B E R - O F - A N I M A L S - A F F E C T E D SEX: --MALE-GROUP: -1- -3 ORGAN AND FINDING DESCRIPTION NUMBER: 2 2 ** TOP OF LIST ** ADRENAL, CORTEX (AC) .................................. NUMBER EXAMINED: NOT REMARKABLE: 2 1 2 0 --CORTICAL TISSUE, EXTRACAPSULAR 12 ADRENAL, MEDULLA (MA) ................................. NUMBER EXAMINED: NOT REMARKABLE: LIVER (LI) --FIBROSIS, CAPSULAR/SUBCAPSULAR --INFILTRATE, LYMPHOHISTIOCYTIC --PIGMENT, HEPATOCELLULAR SPLEEN (SP) ........................ NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: PANCREAS (PA) NUMBER EXAMINED: NOT REMARKABLE: TESTIS (TE) NUMBER EXAMINED: NOT REMARKABLE: 161 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---SEX: --MALE -GROUP: -1- -3NUMBER: 2 2 BONE, FEMUR (FE) .................................. .... NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 MARROW, FEMUR (FM) ................................ ... NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 MARROW, STERNUM (SE) .............................. ... NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 BONE, STERNUM (SB) ................................ ... NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 EYE (EY) .......................................... ... NUMBER EXAMINED: NOT REMARKABLE: --INFILTRATE, LYMPHOHISTIOCYTIC, CHOROIDAL BRAIN (BR) ........................................ ... NUMBER EXAMINED: NOT REMARKABLE: --INFILTRATE, LYMPHOHISTIOCYTIC --MINERALIZATION 2 0 2 2 0 2 1 2 2 0 2 1 1 0 162 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 3 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---SEX: --MALE-GROUP: -1- -3NUMBER: 2 2 KIDNEY (KD) --INFILTRATE, LYMPHOHISTIOCYTIC --INFLAMMATION, VASCULAR --THICKENING, INTIMAL, VASCULAR LUNG (LU) ........................ --PIGMENT HEART (HT) . --INFILTRATE, LYMPHOHISTIOCYTIC GALLBLADDER (GB) ................. NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: 2 1 1 1 1 2 0 2 2 2 0 2 2 2 2 0 0 0 2 0 2 2 1 1 2 2 THYMUS (TH) --INVOLUTION NUMBER EXAMINED: NOT REMARKABLE: 2 0 2 2 2 0 163 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 4 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---SEX: --MALE -GROUP: -1- -3NUMBER: 2 2 LN, MESENTERIC (MS) ........................ ......... NUMBER EXAMINED: NOT REMARKABLE: --PIGMENT TRACHEA (TR) ................................ ......... NUMBER EXAMINED: NOT REMARKABLE: --INFLAMMATION, ACUTE ESOPHAGUS (ES) .............................. ......... NUMBER EXAMINED: NOT REMARKABLE: 2 0 2 2 1 1 2 2 2 2 0 2 2 0 2 2 THYROID (TY) ................................ ......... NUMBER EXAMINED: NOT REMARKABLE: --CYST, GLANDULAR PARATHYROID (PT) ............................ ......... NUMBER EXAMINED: NOT REMARKABLE: --INFILTRATE, LYMPHOHISTIOCYTIC AORTA (AO) .................................. ......... NUMBER EXAMINED: NOT REMARKABLE: --THICKENING, INTIMAL 2 2 0 1 1 0 2 2 0 2 1 1 2 1 1 2 1 1 164 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 5 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---SEX: --MALE-GROUP: -1- -3 NUMBER: 2 2 PITUITARY (PI) ................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 SALIV GL, MANDIB (SG) ............ --INFILTRATE, LYMPHOHISTIOCYTIC MUSCLE, SKELETAL (SM) ............ --PARASITISM SPINAL CORD (SC) ................. NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: 22 00 22 22 21 01 22 22 NERVE, SCIATIC (SN) .............. --FIBROSIS --INFILTRATE, LYMPHOHISTIOCYTIC STOMACH, GL (ST) ................. --INFLAMMATION, CHRONIC NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: 22 12 10 10 22 11 01 165 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 6 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION ** FROM PREVIOUS PAGE ** STOMACH, GL (ST) ..... --PARASITISM --THICKENING, INTIMAL, VASCULAR DUODENUM (DU) .................... --PARASITISM JEJUNUM (JE) ..................... -- N U M B E R SEX: --MALE- GROUP: -1- -3NUMBER: 2 2 NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: 22 11 01 10 22 12 10 22 22 O F A N I M A L S A F F E C T E D -- ILEUM (IL) ....................... NUMBER EXAMINED: 2 NOT REMARKABLE: 2 2 2 CECUM (CE) NUMBER EXAMINED: 2 NOT REMARKABLE: 2 2 2 COLON (CO) --INFLAMMATION, EOSINOPHILIC NUMBER EXAMINED: NOT REMARKABLE: 22 12 10 166 TABLE 38 Incidence of Microscopic Observations Week 40 Recovery Sacrifice 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 7 TABLE INCLUDES: SEX=ALL;GROUP=1,3;WEEKS=ALL DEATH=U;FIND=ALL;SUBSET=ALL ORGAN AND FINDING DESCRIPTION -- N U M B E R - O F - A N I M A L S - A F F E C T E D ---SEX: --MALE -GROUP: -1- -3NUMBER: 2 2 RECTUM (RE) ...................... NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 SKIN (SK) ........................ NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 MAMMARY, MALE (MM) ............... NUMBER EXAMINED: NOT REMARKABLE: 2 2 2 2 URINARY BLADDER (UB) ............. --INFILTRATE, LYMPHOHISTIOCYTIC PROSTATE (PR) .................... --INFILTRATE, LYMPHOHISTIOCYTIC SEMINAL VESICLES (SV) ............ EPIDIDYMIDES (EP) ................ ** END OF LIST NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: NUMBER EXAMINED: NOT REMARKABLE: 2 0 2 2 0 2 2 2 2 2 2 0 2 2 0 2 2 2 2 2 167 APPENDIX 1 Protocol Deviations Protocol Protocol Amendment No. 1 Protocol Amendment No. 2 Material Safety Data Sheet Certificate of Analysis Covance 6329-231 3M T-6889.3 168 Protocol Deviations Covance 6329-231 3M T-6889.3 Protocol. Husbandry. Diet. "Certified primate diet (#8726C, Harlan Teklad) once or twice daily." Actual Procedure. All animals were fasted beginning in the afternoon on November 15, 1998 (Day 48); animals were provided with food in the morning on November 16, 1998 (Day 49). Protocol. Dosing Procedures. Method of Administration. "Orally by gelatin capsules, daily (7 days/week) for at least 26 weeks." Actual Procedure. There were several occasions when the test material was not administered to animals due to the condition of the animal or at the recommendation of a laboratory animal veterinarian. Dose administration was discontinued for Animal No. I05724 (Group 4) on Day 28; this animal was subsequently sacrificed in moribund condition on Day 29. Dose administration was discontinued for Animal Nos. I05711, I05722, and I05703 (Group 4) on Days 43 (Week 7), 66 (Week 10), and 81 (Week 12), respectively. Dose administration was discontinued for Animal No. I05721 (Group 2) for Days 135 and 136; this animal was subsequently sacrificed in moribund condition on Day 137. On Day 44, Animal No. I05703 (Group 4) did not receive its amount of dose preparation because the capsule broke during dose administration procedures. Protocol. Observation of Animals. Clinical Observations. "Once weekly, each animal will be observed; abnormal findings, or an indication that the animal is normal will be recorded." 169 Protocol Deviations (Continued) Covance 6329-231 3M T-6889.3 Actual Procedure. The following animals did not have a weekly observation recorded on the following days: Animal No. I05714 (Group 1) on Days 1 and 22; Animal No. I05725 (Group 1) on Day 1; Animal No. I05717 (Group 2) on Day 57; Animal No. I05719 (Group 3) on Days 1 and 29; Animal No. I05703 (Group 4) on Days 8 and 15; Animal No. I05704 (Group 4) on Day 15; Animal No. I05711 (Group 4) on Days 8 and 15; Animal No. I05713 (Group 4) on Days 15, 43, and 64; and Animal No. I05724 (Group 4) on Day 8. Protocol. Blood Hormone Determination. Method of Collection. "Blood samples will be maintained chilled until plasma is harvested." Actual Procedure. Blood samples collected for blood hormone determination on Days 35, 66, and 94 were stored at room temperature during harvesting. Protocol. Urine and Feces APFO Level Determination. Sample Handling. "Samples of urine (at least 2 mL) and feces (at least 5 grams) will be stored in a freezer set to maintain -10 to -30C" Actual Procedure. Approximately 3 grams of feces were collected from Animal Nos. I05711 and I05724 (Group 4) during Week 2 for feces APFO level Determination. Protocol. Termination. Scheduled Sacrifices. "After at least 26 weeks of treatment, four animals/sex/group will be fasted overnight, then anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsied." Actual Procedure. Animal No. I05709 (Group 1) was weighed incorrectly at the terminal sacrifice (Week 27, Day 184). The body weight collected for this animal on Day 183 was entered into the computer system for organ-to-body weight weight percentage calculations. 170 Protocol Deviations (Continued) Covance 6329-231 3M T-6889.3 Protocol. Termination. Postmortem Procedures. Cell Proliferation Evaluation. "Representative samples of the left lateral lobe of the liver, left and right testes, and pancreas will be collected from each animal at the scheduled and unscheduled sacrifices and preserved in formalin." Actual Procedure. The fixative used for the tissue samples collected from the left lateral lobe of the liver, left and right testes, and pancreas of the recovery animals for cell proliferation evaluation was documented incorrectly. Protocol. Experimental Design. Postmortem Procedures. Histopathology. "Tissues from each animal (including Animal No. I05723) will be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically." Actual Procedure. Some tissues, required by the protocol, were not available for histopathologic examination. Missing tissues or insufficient tissue samples are listed with appropriate comments in the pathology data sheets for individual animals. Summary tables do not include them as having been examined. These deviations are not expected to have affected the results of the study. 171 COVA-ffCEL^ THE DEVELOPMENT SERVICES COMPANY Sponsors: APME Ad-Hoc APFO Toxicology Working Group PROTOCOL Study Title: 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Date: September 23, 1998 Performing Laboratory: Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704-2595 Laboratory Study Identification: Proposal No. w6806a Covance 6329-231 172 Covance 6329-231 __________ _________________________________________________________________ Page 2 Study 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Purpose To assess the effect of the test material on critical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus monkeys for at least 26 weeks Sponsors APME Ad-Hoc APFO Toxicology Working Group Study Monitor Paul Lieder, PhD, DABT 3M Toxicology Services Building 220-2E-02, 3M Center St. Paul, Minnesota, 55144-1000 Telephone No.: 612.737.2678 Facsimile No.: 612.733.1773 Alternate Study Monitor John Butenhoff, PhD, DABT 3M Telephone No.: 612.733.1962 Facsimile No.: 612.733.1733 Sponsor's Representative David Farrar, PhD ICI Chemicals & Polymers Limited Occupational Health The Heath, Runcorn, PO Box 13 Cheshire, WA7 4QF Telephone No.: 01928.513953 Facsimile No.: 01928.515146 Study Location Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 173 Covance 6329-231 ______________________________________ ___________________________________ Page 3 Mailing Address: PO Box 7545-2595 Madison, Wisconsin 53707-7545 Study Director Peter J. Thomford, PhD Covance Laboratories Inc. Telephone No.: 608.241.7207 Facsimile No.: 608.242.2736 Toxicologist Dale Aldridge, BS Covance Laboratories Inc. Proposed Study Timetable Experimental Start Date: September 29, 1998 In-Life Start Date: September 29, 1998 In-Life End Date: July 2, 1999 Audited Draft Report Date: October 22, 1999 Experimental Termination Date: To be determined Regulatory Compliance This study will be conducted in compliance with the Environmental Protection Agency Good Laboratory Practice 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 except that bile acid determinations done by University of Dundee will not be done in compliance with GLPs. Animal Care and Use Statement All procedures in this protocol are in compliance with the Animal Welfare Act Regulations, 9 CFR 1-4. In the opinion of the Sponsor and study director, the study does not unnecessarily duplicate any previous work. Quality Assurance The protocol, study conduct, and final report will be audited by the Covance Quality Assurance Unit (QAU). The proliferation cell nuclear antigen evaluation data and report will be audited by the QAU of Pathology Associates International. The serum, urine, feces, and liver APFO analysis and report will be audited by the QAU of 3M Environmental Laboratories. The blood hormone determinations and report will be audited by the QAU of Ani Lytics Inc and DuPont, as appropriate. The receptor level determinations and report will be audited by the QAU of DuPont. Bile acid determinations done by the University of Dundee will not be audited. 174 Covance 6329-231 _________________________________________________________________________________ Page4 Test Material Identification Ammonium Perfluorooctanoate (APFO) Lot Number The lot number will be maintained in the raw data. Purity Responsibility of the Sponsor Stability Responsibility of the Sponsor Storage Conditions At room temperature Characteristics Information on synthesis methods, composition, or other characteristics that define the test material is on file with the Sponsor. Gelatin Capsules Capsules (Size No. 2) obtained from Torpac, Inc. (Fairfield, New Jersey); lot number will be supplied by the manufacturer. Gelatin capsules will be stored at room temperature. A copy of the Certificate of Analysis provided by the manufacturer will be maintained in the data. Reserve (Archive) Samples A reserve sample of each lot of test material (1 g each) will be taken and stored at room temperature. These samples will be transferred to the Sponsor after completion of the in-life phase. Disposition of Test Material Any remaining test material will be returned after authorization from the Sponsor. Animals Species Cynomolgus monkey 175 Covance 6329-231 ________________________________________________ _________________________________ Page 5 Source Covance Research Products Inc. Age at Initiation of Treatment Young adult/adult Weight at Initiation of Treatment 3 to 5 kg Number and Sex 22 males Identification Collar tag Husbandry Housing Individual; animals will be housed in suspended, stainless steel cages. Diet Certified primate diet (#8726C, Harlan Teklad) once or twice daily. The diet is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Results of specified nutrient and contaminant analyses are on file at Covance-Madison. Fruit, vegetables, or other supplements may be provided but will not require analysis. Water Ad libitum. Samples of the water are routinely analyzed for specified microorganisms and environmental contaminants. The results are on file at Covance-Madison. Contaminants There are no known contaminants in the diet or water at levels that might interfere with this study. Environment Environmental controls for the animal room will be set to maintain 18 to 29C, a relative humidity of 30 to 70%, and a 12-hour light/12-hour dark cycle. Acclimation Minimum of 4 weeks 176 Covance 6329-231 __________Page 6 Randomization Animals will be weighed, stratified by body weight, and allocated to the number of blocks equal to the number of animals to be selected for each group. Animals in each block will then be assigned to groups using computer-generated random numbers. Justification APFO 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. Group Designations and Dosage Levels a The control group (Group 1) will receive empty gelatin capsules, b Two animals in Groups 1,3, and 4 designated as recovery animals will be treated for 26 weeks, then treatment will be discontinued, and the animals will be observed for reversibility, persistence, or delayed occurrence of toxic effects for at least 13 weeks posttreatment. Based on plasma test material levels and clinical pathology findings, the recovery may be reduced or extended at the discretion of the study director after consultation with the Sponsors. Dosing Procedures Method of Administration Orally by gelatin capsules, daily (7 days/week) for at least 26 weeks Reason for Dosing Route To compare with previously conducted toxicology studies using the oral route 177 Covance 6329-231 _________________________________________________ ________________________________ Page 7 Dose Preparation Capsules will be prepared at least weekly. The size and number of capsules will depend on the physical characteristics of the test material, the dose level, and the weight of the monkey. Dose levels will be based on the test material as supplied. Individual daily doses will be based on the most recent individual body weights, with the exception of body weight collection days when the previous body weight will be used. All dose preparations will be stored at room temperature until dosed. Dose Analysis Because the test material is not being mixed with a vehicle, dose analyses are not required. Observation of Animals Clinical Observations Each animal will be observed twice daily (a.m. and p.m.) for mortality and moribundity; findings will be recorded as they are observed. Each animal will be observed daily and food consumption will be assessed qualitatively; abnormal findings will be recorded. Once weekly, each animal will be observed; abnormal findings, or an indication that the animal is normal will be recorded. Additional findings will be recorded as they are observed. Body Weights Weekly before initiation of treatment, Day -1 (for the Day 1 dose calculations),on the first day of treatment, and weekly thereafter Ophthalmic Examinations Before initiation of treatment and before each scheduled sacrifice. The anterior portion of the eye, optic media, and ocular fundus will be examined using an indirect ophthalmoscope. Clinical Pathology Frequency Unscheduled Collections When possible, blood will be collected for clinical pathology tests from animals sacrificed at unscheduled intervals 178 Covance 6329-231 ____________________________________________________________________________ Page 8 Scheduled Collections Before initiation of treatment; and (before the daily dose) after at least 30, 60, 90, and 180 days of treatment; and after at least 30, 60, and 90 days of recovery Number of Animals All Method of Collection Animals will be fasted overnight; blood will be collected from a femoral vein. Anticoagulants will be sodium citrate for coagulation tests and potassium EDTA for hematology tests. No anticoagulant is required for clinical chemistry tests. Urine will be collected on wet ice overnight (approximately 16 hours). Tests Hematology red blood cell (erythrocyte) count platelet count hemoglobin white blood cell (leukocyte) count hematocrit differential blood cell count mean corpuscular volume blood cell morphology mean corpuscular hemoglobin reticulocyte count mean corpuscular hemoglobin concentration Coagulation activated partial thromboplastin time prothrombin time fibrinogen Clinical Chemistry glucose aspartate aminotransferase urea nitrogen gamma glutamyltransferase creatinine sorbitol dehydrogenase total protein creatine kinase albumin calcium globulin inorganic phosphorus total bilirubin sodium direct bilirubin (if total bilirubin is potassium greater than 2.0 mg/dL) chloride cholesterol bile acids triglycerides amylase alanine aminotransferase lipase alkaline phosphatase pancreatic-specific amylase 179 Frequency Three times before initiation of treatment; after at least 30, 60, 90, and 180 days of treatment; and after at least 30, 60, and 90 days of recovery Number of Animals All Method of Collection Animals will not be fasted; blood will be collected from a femoral vein (an alternative vein may be used if necessary). Approximately 6 mL of blood for plasma samples will be collected into tubes with potassium EDTA as the anticoagulant. Approximately 6 mL of blood for serum samples will be collected without anticoagulant and allowed to clot. Blood samples will be maintained at room temperature until serum is harvested. Blood samples will be maintained chilled until plasma is harvested. Serum Sample Handling Samples for serum will be centrifuged within 1 hour after collection, and serum will be harvested. Serum will be divided into two approximately equal aliquots and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped to: Dr. Saroj Das Ani Lytics Inc. 200 Girard Street, Suite 200 Gaithersburg, Maryland 20877 Telephone No.: 301.921.0168 Facsimile No.: 301.977.0433 Ani Lytics Inc. will be notified regarding shipment of samples. 180 Covance 6329-231 ______________________________________________________________ __________ Page 10 Serum Tests Samples will be analyzed by Ani Lytics Inc., for estradiol, estrone, estriol, thyroid stimulating hormone, total and free triiodothyronine (T3), and total and free thyroxin (T4). Results will be provided for inclusion in the final report. Plasma Sample Handling Samples for plasma will be centrifuged within 1hour after collection. Plasma will be harvested and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped to: Jon C. Cook, PhD, DABT E. I. du Pont de Nemours & Company, Inc. Haskell Laboratory for Toxicology and Industrial Medicine Building 11 Room 1325 1090 Elkton Road Newark, Delaware 19711-0500 Telephone No.: 302.366.5495 Facsimile No.: 302.366.5003 DuPont will be notified regarding shipment of samples. Plasma Analysis Samples will be analyzed by DuPont Haskell Company for cholecystokinin. Results will be provided for inclusion in the final report. Serum APFO Level Determination Frequency After 7 days of treatment and every 2 weeks thereafter during treatment and recovery Number of Animals All Method of Collection Animals will not be fasted; blood (approximately 2 mL) will be collected from a femoral vein (an alternative vein may be used if necessary) without an anticoagulant. Sample Handling Samples will be centrifuged within 1hour after collection, and serum will be harvested. Serum samples will be stored in a freezer set to maintain -10 to -30 C. 181 Covance 6329-231 _______________________________________________________________________ Page 11 Sample Shipping Serum samples will be packed on dry ice and shipped to: Kris J. Hansen, PhD 3M E.T. & S Bldg. 2-3E-09 935 Bush Avenue St. Paul, Minnesota 55106 Kris J. Hansen, PhD or her alternate will be notified regarding the shipment of the samples. Analysis of serum for APFO will be done on the samples. Results will be provided for inclusion in the final report. Additional Blood Collection At scheduled and unscheduled sacrifices, blood (as much as possible, up to 20 mL) will be collected from animals at the time of exsanguination. Approximately equally sized samples of serum (collected without anticoagulant) and whole blood and plasma (both collected using EDTA as an anticoagulant) from each animal will be transferred into containers (approximately 5 mL each). Whole blood, serum, and plasma samples will be stored in a freezer set to maintain -60 to -80C until shipped to 3M (Kris Hansen) for possible future analysis. Urine and Feces APFO Level Determination Frequency After 7 days of treatment and every 2 weeks thereafter during treatment and recovery (concurrent with serum APFO sample collection) Number of Animals All Method of Collection Animals will not be fasted; urine (collected on wet ice) and feces will be collected overnight. Sample Handling Samples of urine (at least 2 mL) and feces (at least 5 grams) will be stored in a freezer set to maintain -10 to -30C. 182 Covance 6329-231 _________________________________________________________ ___________________ Page 12 Sample Shipping Samples will be packed on dry ice and shipped to: Kris J. Hansen, PhD 3M E.T. & S Bldg. 2-3E-09 935 Bush Avenue St. Paul, Minnesota 55106 Kris J. Hansen, PhD or her alternate will be notified regarding the shipment of the samples. Analysis of urine and feces for APFO will be done on the samples. Results will be provided for inclusion in the final report. Termination Unscheduled Sacrifices and Deaths Necropsies will be done. Animals to be sacrificed will be anesthetized with ketamine and xylazine, weighed, and exsanguinated. Scheduled Sacrifices After at least 26 weeks of treatment, four animals/sex/group will be fasted overnight, then anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsied. After at least 26 weeks of treatment and at least 13 weeks without treatment, the remaining animals will be fasted overnight, then anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsied. Postmortem Procedures Necropsy The necropsy will include examination of: all orifices cranial cavity external surface of the brain; the external surface of the spinal cord and cut surfaces of the brain and spinal cord will be examined whenever tissue trimming is performed cervical tissues and organs thoracic, abdominal, and pelvic cavities and viscera external surface of the body nasal cavity and paranasal sinuses 183 Covance 6329-231 _________ Page 13 Organ Weights From each animal at scheduled and unscheduled sacrifices, the following organs (when present) will be weighed; paired organs will be weighed separately: adrenal (2) brain epididymis (2) kidney (2) liver pancreas testis (2) thyroid (2) with parathyroid Organ-to-body weight percentages and organ-to-brain weight ratios will be calculated. Palmitoyl CoA Oxidase Determinations The right lateral lobe of liver will be collected from each animal at the scheduled and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80 C until disposition of the samples is determined by the Sponsor. Cell Proliferation Evaluation Representative samples of left lateral lobe of the liver, left and right testes, and pancreas will be collected from each animal at the scheduled and unscheduled sacrifices, and preserved in zinc formalin. After fixation, samples for proliferation cell nuclear antigen (PCNA) evaluation will be embedded in paraffin maintained at ambient temperature until disposition of the samples is determined by the Sponsor. Bile Acid Determination All available bile (up to 5 mL) will be collected from each animal at the scheduled and unscheduled sacrifices, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C. Bile samples will be packed on dry ice and shipped to: 184 Covance 6329-231 _________________________________________________________________ ______________Page 14 Biomedical Research Centre Level 5 Ninewells Hospital and Medical School University of Dundee Dundee DD1 9SY UK Dr. Cliff Elcombe Biomedical Research Centre Ninewells Hospital and Medical School University of Dundee Dundee DD1 9SY, UK Telephone: +44(0)1382-632641 Fax: +44 (0)1382-425586 Results of bile acid determinations analyses will be provided for inclusion in the final report. Receptor Level Determination Samples (approximately 2 g) of liver and pancreas will be collected from each animal at the scheduled and unscheduled sacrifices, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C. Liver and pancreas samples will be packed on dry ice and shipped to: Jon C. Cook, PhD, DABT E. I. du Pont de Nemours & Company, Inc. Haskell Laboratory for Toxicology and Industrial Medicine Building 11 Room 1325 1090 Elkton Road Newark, Delaware 19711-0500 Telephone No.: 302.366.5495 Facsimile No.: 302.366.5003 DuPont will be notified regarding shipment of samples. Results of receptor level determinations will be provided for inclusion in the final report. Tissue Preservation Three samples (approximately 5 g each) of the liver and all remaining pancreas and left and right testes tissue, if any, (divided into three approximately equal samples) will be collected from each animal at the scheduled and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80 C for possible future analysis. 185 Covance 6329-231 ___________________________________________________ _______________________ Page 15 The following tissues (when present) from each animal will be preserved in 10% neutral-buffered formalin, unless otherwise specified, for possible future microscopic examination: adrenal (2) aorta brain cecum colon duodenum epididymis (2) esophagus eye [(2) to be preserved in Davidson's fixative from sacrificed animals only] femur with bone marrow (articular surface of the distal end) gallbladder heart ileum jejunum kidney (2) lesions liver lung mammary gland mesenteric lymph node pancreas pituitary prostate rectum salivary gland [mandibular (2)] sciatic nerve seminal vesicle (2) skeletal muscle (thigh) skin spinal cord (cervical, thoracic, and lumbar) spleen sternum with bone marrow stomach testis [(2) to be preserved in Bouins' solution from sacrificed animals only] thymus thyroid (2) with parathyroid trachea urinary bladder Bone Marrow Smear From the sternum of each animal at unscheduled and scheduled sacrifices (made and held for possible future examination) Liver APFO Determination A sample of liver (any non-formalin treated liver remaining after sampling for histopathology) will be collected from each animal at the scheduled and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C until shipped with serum samples to 3M (Kris Hansen) for analysis. Analysis of liver for APFO will be done on the samples. Results will be provided for inclusion in the final report. 186 Covance 6329-231 ________________________________________________________________ ___________ Page 16 Histopathology Tissues from each animal in the control and high-dose groups and each animal that dies or is sacrificed at unscheduled interval will be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. The adrenals, pancreas, liver, spleen, and testes from each animal in the low- and mid-dose groups will be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. Suspected target organs noted at the high-dose will be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically from all animals (at the Sponsor's request and added by amendment). Reports A draft report which includes the following information will be prepared and submitted: Experimental Design and Methods Results mortality clinical observations body weights body weight gains food consumption ophthalmic examination results clinical pathology results hormone analyses (provided by Ani Lytics, Inc. and the DuPont Haskell Company) serum, urine, feces, and liver APFO levels (provided by 3M) organ weights organ-to-body weight percentages organ-to-brain weight ratios macroscopic observations microscopic observations palmitoyl CoA oxidase activities (provided by the Sponsor's designee) cell proliferation evaluations (provided by Pathology Associates International) bile acid determinations (provided by University of Dundee) receptor determination (provided by DuPont) 187 Covance 6329-231 ________________________________________________ __________________________ Page 17 Statistical Evaluation Levene's test will be done to test for variance homogeneity. In the case of heterogeneity of variance at p < 0.05, transformations will be used to stabilize the variance. Comparison tests will take variance heterogeneity into consideration. One-way analysis of variance (ANOVA) will be used (if applicable) to analyze initial body weights, body weight gains, continuous clinical pathology values, palmitoyl CoA oxidase activities, and organ weight data. If the ANOVA is significant, Dunnett's t-test will be used for control versus treated group comparisons. One-way analysis of covariance (ANCOVA) will be used to analyze body weights, with initial body weights as the covariate. If the ANCOVA is significant, covariate-adjusted means will be used for control versus treated group comparisons. Group comparisons (Groups 2 through 4 versus Group 1) will be evaluated at the 5.0% two-tailed probability level. Only data collected on or after the first day of treatment will be analyzed statistically. Data collected before the first day of treatment or during recovery will not be analyzed statistically. At the end of 1 year after issuance of the audited draft report, if no requested revisions or instructions to finalize have been communicated by the Sponsor, then the audited draft report will be considered 'final' and issued as the final report, signed by the study director, and submitted to the Sponsor. Any modifications or changes to the audited draft report requested 1 year after issuance will be performed at additional cost to the Sponsor. Record Retention All raw data, documentation, records, protocol, specimens, and final report generated as a result of this study will be archived in the storage facilities of Covance-Madison for a period of 1 year following submission of the final report to the Sponsor. One year after submission of the final report, all of the aforementioned materials will be sent to the Sponsor, and a return fee will be charged. The Sponsor may elect to have the materials retained in the Covance archives for an additional period of time, and Covance will charge a storage fee. If the Sponsor chooses to have Covance dispose of the materials, a disposal fee will be charged. All raw data stored on magnetic media will be retained by Covance. Within one year after submission of the final report, all of the aforementioned materials from the Sponsor's designees (Ani Lyrics Inc., E. I. du Pont de Nemours & Company, Inc., 3M E.T. & S, Pathology Associates International, and University of Dundee) will be sent to the Sponsor (Paul Lieder, PhD, DABT, 3M) to be maintained. 188 189 COVAfiCE?^ PROTOCOL AMENDMENT NO. 1 Covance 6329-231 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Sponsor: Study Monitor: Testing Facility: Study Director: APME Ad-Hoc APFO Toxicology Working Group Paul Lieder, PhD, DABT Covance Laboratories Inc., Madison, Wisconsin Peter J. Thomford, PhD This amendment modifies the following portions of the protocol. Effective October 9,1998 1. Page 6, Dosing Procedures, Method of Administration. To reflect suspension of dosing to Group 4, delete the text in this section and replace with the following. Orally by gelatin capsules, daily (7 days/week) for at least 26 weeks unless otherwise specified Effective October 9 and 13,1998, and March 24,1999 2. Page 6, Group Designations and Dosage Levels. To suspend dosing to Group 4 (effective October 9, 1998), to replace Animal No. 105723 with Animal No. 105721 (effective October 13,1998), to designate an initial dosing date for Animal No. 105721 (effective October 13, 1998), to lower the dose level for Group 4 (effective October 13, 1998), and to indicate that all Group 4 animals will be sacrificed at the terminal sacrifice (effective March 24, 1999), delete this table and replace with the following. 190 Covance 6329-231 Protocol Amendment No. 1 _________________ Page 2 a The control group (Group 1) will receive empty gelatin capsules, b Two animals in Groups 1 and 3 designated as recovery animals will be treated for 26 weeks, then treatment will be discontinued, and the animals will be observed for reversibility, persistence, or delayed occurrence of toxic effects for at least 13 weeks posttreatment. Based on plasma test material levels and clinical pathology findings, the recovery may be reduced or extended at the discretion of the Study Director after consultation with the Sponsor, c Animal No. 105723 will be replaced with Animal No. 105721. Dosing for Animal No. 105721 will begin on Day 17 (October 15, 1998). d Dosing for Group 4 will be suspended after Day 11 (October 9, 1998) and reinitiated at 20 mg/kg/day on Day 22 (October 20, 1998). Effective October 21 and December 22,1998 3. Page 10, Blood Hormone Determination, Plasma Sample Handling, Paragraph 1, and Page 14, Receptor Level Determination, Paragraph 1. To reflect that Jon Cook has been replaced at DuPont by John O'Connor (effective October 21, 1998) and to clarify the address (effective December 22, 1998), delete the name and address in this paragraph and replace with the following. John O'Connor E. I. du Pont de Nemours & Company, Inc. Haskell Laboratory for Toxicology and Industrial Medicine Building 1 Room 919 1090 Elkton Road Newark, Delaware 19711-0500 Telephone No.: 302.366.6169 Facsimile No.: 302.366.5003 191 Covance 6329-231 Protocol Amendment No. 1 ______________________________________________________________________________________ Page 3 Effective March 24,1999 4. Page 12, Termination, Scheduled Sacrifices, Paragraph 1. To indicate that all Group 4 animals will be sacrificed at the terminal sacrifice, delete this paragraph and replace with the following. After at least 26 weeks of treatment, four animals/group in Groups 1 through 3 and all surviving animals in Group 4 will be fasted overnight, then anesthetized with ketamine and xylazine, weighed, exsanguinated, and necropsied. Effective March 30,1999 5. Page 14, Postmortem Procedures, Tissue Preservation. To indicate that samples of kidney and testes tissue from animals in the control group at the terminal sacrifice will be collected, frozen, and shipped to 3M, add the following. In addition, after all other required samples, are taken any remaining kidney tissue will be collected from the control animals at the terminal sacrifice. These tissues will be weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C. From animals in the control group at the terminal sacrifice, any available kidney and testes tissues that were flash-frozen in liquid nitrogen and stored in a freezer set to maintain -60 to -80C will be packed on dry ice and shipped to the recipient below for possible future analysis. Kris J. Hansen, PhD 3M E.T. & S Bldg. 2-3E-09 935 Bush Avenue St. Paul, Minnesota 55106 Effective March 31,1999 6. Page 11, Additional Blood Collection. To indicate that an additional heparinized whole blood sample will be collected from animals in the control group at the terminal sacrifice, add the following. 192 Covance 6329-231 Protocol Amendment No. 1 _______________________________________________________________________________ Page 4 In addition to the required blood samples, additional whole blood (as much as possible) will be collected using sodium heparin as an anticoagulant from the animals in the control group at the terminal sacrifice. One-half of this sample will be transferred into cryotubes and pooled. The remaining half of the sample will be centrifuged and the plasma and red blood cells will be transferred into cryotubes and pooled. The pooled samples will be stored in a freezer, set to maintain -60 to -80C, until packed on dry ice and shipped to the recipient below for possible future analysis. Kris J. Hansen, PhD 3M E.T. & S Bldg. 2-3E-09 935 Bush Avenue St. Paul, Minnesota 55106 Effective April 8,1999 7. Page 17, Record Retention, Paragraph 2. To modify the record retention requirements for Pathology Associates International, delete this paragraph and replace with the following. Within 1 year after submission of the final report, all of the aforementioned materials from the Sponsor's designees (Ani Lytics Inc., E. I. du Pont de Nemours & Company, Inc., 3M E.T. & S, and the University of Dundee) will be sent to the Sponsor (Paul Lieder, PhD, DABT, 3M). Pathology Associates International (PAI) is responsible for the maintenance of any raw data or specimens produced by PAL Effective May 4 and July 12 and 21 and November 12,1999 8. Page 17, Reports, Statistical Evaluation. To add statistical analysis of hormone values (effective May 4, 1999), to include statistical analysis of hormone values during recovery (effective July 12, 1999), and to modify the statistical methods (effective July 21, 1999 and November 12, 1999), add the following to the end of this section. Blood hormone levels, excluding estriol and cholecystokinin, will be analyzed by repeated measures analysis of covariance (ANCOVA) procedure with average pretreatment measurements for the parameters as covariates. 193 Covance 6329-231 Protocol Amendment No. 1 ____________________________________________________________________ ___________________ Page 5 Treatment effects under ANOVA or ANCOVA procedures will be evaluated at p=0.05 level. All post hoc control-versus-treated-group mean comparisons (including values during recovery) will be conducted using Dunnett's many-on-one t procedure. Analyses will be carried out with SAS procedure, PROC MIXED or BMDP or both. Effective May 27,1999 9. Page 3, Regulatory Compliance. To define the regulatory compliance requirement for the palmitoyl CoA oxidase determinations, delete the text in this section and replace with the following. This study will be conducted in compliance with the Environmental Protection Agency Good Laboratory Practice 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 except that bile acid and palmitoyl CoA oxidase determinations done by University of Dundee will not be done in compliance with GLPs. 10. Page 3, Quality Assurance, Sentence 6. To define the quality assurance responsibility for palmitoyl CoA oxidase determinations, delete this sentence and replace with the following. Bile acid and palmitoyl CoA oxidase determinations done by the University of Dundee will not be audited 11. Page 3, Quality Assurance. To define the quality assurance responsibility for proliferation cell nuclear antigen (PCNA) evaluations, add the following to the end of the section. Proliferation cell nuclear antigen (PCNA) and report will be audited by the QAU of Pathology Associates International 194 Covance 6329-231 Protocol Amendment No. 1 _______________________________________________________________________________________ Page 6 12. Page 10, Blood Hormone Determination, Serum Tests. To add serum testosterone analysis during recovery, delete the text in this section and replace with the following. Samples will be analyzed by Ani Lytics Inc. for estradiol, estrone, estriol, thyroid stimulating hormone, total and free triiodothyronine (T3), and total and free thyroxin (T4). In addition, samples collected during recovery will be analyzed for testosterone. Results will be provided for inclusion in the final report. 13. Page 10, Blood Hormone Determination, Plasma Analysis. To add plasma testosterone analysis from prestudy, treated, and recovery intervals, add the following to the end of the section. Samples from the pretest, treated, and recovery intervals will be analyzed by Ani Lytics Inc. for testosterone. Results will be provided for inclusion in the final report. 14. Page 13, Postmortem Procedures, Cell Proliferation Evaluation. To designate the laboratory to perform the analysis, to include preparation of slides stained with hematoxylin and eosin in the PCNA evaluation, and to change the fixative from zinc formalin to formalin, delete the text in this section and replace with the following. Representative samples of the left lateral lobe of the liver, left and right testes, and pancreas will be collected from each animal at the scheduled and unscheduled sacrifices and will be preserved in formalin. After fixation, samples for proliferation cell nuclear antigen (PCNA) evaluation will be embedded in paraffin maintained at ambient temperature (with slides stained with hematoxylin and eosin) until shipped to: Sandra R. Eldridge, PhD Pathology Associates International 15 Worman's Mill Court Suite I Frederick, Maryland 21701 Telephone No.: 301.624.2036 Facsimile No.: 301.663.8994 Pathology Associates International will be notified regarding shipment of samples. Results of PCNA analyses will be provided for inclusion in the final report. 195 Covance 6329-231 Protocol Amendment No. 1 ____________________________________________________________________________ Page 7 15. Page 16, Postmortem Procedures, Histopathology. To reflect the decision to evaluate all tissues from all animals microscopically, delete the text in this section and replace with the following. Tissues from each animal (including Animal No. 105723) will be embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. Effective May 27 and July 14,1999 16. Page 13, Postmortem Procedures, Palmitoyl CoA Oxidase Determinations. To designate the laboratory to perform the analysis (effective May 27, 1999) and to change the shipping address (effective July 14, 1999), delete the text in this section and replace with the following. The right lateral lobe of liver will be collected from each animal at the scheduled and unscheduled sacrifices, weighed, flash-frozen in liquid nitrogen, and stored in a freezer set to maintain -60 to -80C until packed on dry ice and shipped to Dr. Cliff Elcombe at the University of Dundee via the following shipping address. Ms. Sara Spencer Shamrock (Great Britain) Ltd. Henfield Road Small Dole West Sussex BN5 9XH United Kingdom Telephone: +44(0)1903-879191 Fax: +44 (0)1903-812532 Results of analyses will be provided for inclusion in the final report. Effective May 27 and August 2,1999 17. Page 10, Blood Hormone Determination, Plasma Sample Handling. To add plasma testosterone analysis, add the following to the end of the section. An aliquot of plasma from prestudy and treatment intervals will be transferred from DuPont to Ani Lytics Inc. for analysis of testosterone. 196 Covance 6329-231 Protocol Amendment No. 1 ________________________________________________________________________________ Page 8 Effective May 27 and October 21,1999 18. Page 16, Reports, Results. To identify the laboratory to conduct the palmitoyl CoA oxidase activities assays (effective May 27, 1999) and to reflect the Sponsor's decision to report the results of specified analyses separately (effective October 21, 1999), delete the text in this section and replace with the following. mortality clinical observations body weights body weight gains food consumption ophthalmic examination results clinical pathology results hormone analyses (provided by Ani Lytics Inc. and the DuPont Haskell Company) organ weights organ-to-body weight percentages organ-to-brain weight ratios macroscopic observations microscopic observations palmitoyl CoA oxidase activities (provided by the University of Dundee) cell proliferation evaluations (provided by Pathology Associates International) Effective October 13,1999 19. Page 16, Postmortem Procedures, Histopathology. To reflect the decision to do an external pathology peer review, add the following after this section. Pathology Peer Review Pathology findings and histopathology tissue slides from specified animals in the control, low-, and high-dose groups will be transferred to the recipient below for a pathology peer review. Craig Schmidt Sierra Biomedical, Inc 587 Dunn Circle Sparks, Nevada 89431 Upon completion of the peer review, these materials will be returned to Covance. 197 Covance 6329-231 Protocol Amendment No. 1 __________________________________________________________________ ____________________ Page 9 Effective October 21,1999 20. Page 11, Seram APFO Level Determinations, Sample Shipping, Paragraph 2, Sentence 3. To reflect the Sponsor's decision to report the results of specified analyses separately, delete this sentence and replace with the following. Results will be reported separately. 21. Page 12, Urine and Feces APFO Level Determinations, Sample Shipping, Paragraph 2, Sentence 3. To reflect the Sponsor's decision to report the results of specified analyses separately, delete this sentence and replace with the following. Results will be reported separately. 22. Page 14, Postmortem Procedures, Bile Acid Determination, Paragraph 2. To reflect the Sponsor's decision to report the results of specified analyses separately, delete this paragraph and replace with the following. Results of bile acid determinations will be reported separately. 23. Page 14, Postmortem Procedures, Receptor Level Determination, Paragraph 2, Sentence 2. To reflect the Sponsor's decision to report the results of specified analyses, if done, separately, delete this sentence and replace with the following. Results of receptor level determination, if any, will be reported separately. 24. Page 15, Postmortem Procedures, Liver APFO Determination, Sentence 3. To reflect the Sponsor's decision to report the results of specified analyses separately, delete this sentence and replace with the following. Results will be reported separately. 198 199 COV/MC> THE DEVELOPMENT SERVICES COMPANY PROTOCOL AMENDMENT NO. 2 Covance 6329-231 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate (APFO) in Cynomolgus Monkeys Sponsor: Study Monitor: Testing Facility: Study Director: APME Ad-Hoc APFO Toxicology Working Group Paul Lieder, PhD, DABT Covance Laboratories Inc., Madison, Wisconsin Peter J. Thomford, PhD__________________________________ This amendment modifies the following portions of the protocol. Effective 22 December 2000 1. Page 13, Postmortem Procedures, Palmitoyl CoA Oxidase Determinations, Paragraph 3. To reflect the sponsor's decision to report the results of the Palmitoyl CoA Oxidase determinations separately, delete this paragraph and replace with the following. Results will be reported separately. 2. Page 16, Reports, Results. To reflect the sponsor's decision to report the results of the Palmitoyl CoA Oxidase determinations separately, delete "palmitoyl CoA oxidase activities (provided by the University of Dundee)." 3. Page 17, Reports, Statistical Evaluation, Paragraph 2. To reflect the sponsor's decision to report the results of the Palmitoyl CoA Oxidase determinations separately, delete this paragraph and replace with the following. One-way analysis of variance (ANOVA) will be used (if applicable) to analyze initial body weights, body weight gains, continuous clinical pathology values, and organ weight data. If the ANOVA is significant, Dunnett's t-test will be used for control versus treated group comparisons. 200 201 Covance 6329-231 3M T-6889.3 MATERIAL SAFETY DATA SHEET 3M 3M Center St. Paul, Minnesota 55144-1000 1-800-364-3577 or (651 737-6501 (24 hours) Copyright, 1998, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless prior agreement is obtained from 3M, and 2) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon. DIVISION: 3M CHEMICALS TRADE NAME: FC-143 FLUORAD Brand Fluorochemical Surfactant ID NUMBER/U.P.C.: 98-0211-0008-0 00-51135-09138-8 98-0211-0891-9 98-0211-5489-7 00-51135-02941-1 98-0211-6581-0 98-0211-7394-7 00-51135-10762-1 ZF-0002-0378-4 ISSUED: January 29, 1998 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3808-2 00-51135-09365-8 00-51135-10405-7 1. INGREDIENT C.A.S. NO. PERCENT AMMONIUM PERFLUOROOCTANOATE....... ..... AMMONIUM PERFLUOROHEPTANOATE...... ..... AMMONIUM PERFLUOROPENTANOATE...... ..... AMMONIUM PERFLUOROHEXANOATE....... ..... 3825-26-1 6130-43-4 68259-11-0 21615-47-4 93 1 1 0.1 - 97 -3 -3 -1 2. PHYSICAL DATA BOILING POINT:................ VAPOR PRESSURE:............... VAPOR DENSITY:................ EVAPORATION RATE:............. SOLUBILITY IN WATER:.......... SPECIFIC GRAVITY:............. PERCENT VOLATILE:............. p H : ........................... VISCOSITY:.................... MELTING POINT:................ N/A N/A N/A N/A apprec. 0.4 - 0.5 Water=1 (Bulk) N/A ca. 5 (0.5% Aqueous) N/D N/A APPEARANCE AND ODOR: Light colored powder; slight odor. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 202 MSDS: FC-143 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 Covance 6329-231 3M T-6889.3 PAGE 2 3. FIRE AND EXPLOSION HAZARD DATA FLASH POINT:............ FLAMMABLE LIMITS -LEL:.. ......N/A FLAMMABLE LIMITS - UEL :...... N/A AUTOIGNITION TEMPERATURE:..... N/A Non-flammable EXTINGUISHING MEDIA: Water, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around arms, waist and legs, face mask, and protective covering for exposed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion. 4. REACTIVITY DATA \BILITY: Stable INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: Not Applicable HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Nitrogen, Hydrogen Fluoride, Ammonia. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions from other sections. Collect spilled material. Use wet sweeping compound or water to avoid dusting. Clean up residue. Place in a closed container. RECOMMENDED DISPOSAL: Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permitted to accept chemical waste. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 203 Covance 6329-231 3M T-6889.3 MSDS: FC-143 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 PAGE 3 >. ENVIRONMENTAL INFORMATION (continued) ENVIRONMENTAL DATA: SUPPORTING DATA: BIODEGRADATION: Theoretical Oxygen Demand (ThOD): 0.320 g/g Chemical Oxygen Demand (COD): 0.0007 g/g 20-Day Biochemical Oxygen Demand (BOD20): Nil AQUATIC TOXICITY: Fathead minnow (Pimephales promelas) 96-hr LC50: 766 mg/L Water flea (Daphnia magna) 48-hr EC50: 632 mg/L Bluegill sunfish (Lepomis macrochirus) 96-hr EC50: 569 mg/L Green Algae (Selenastrum capricornutum) 14-Day EC50: >1000 mg/L Microtox (Photobacterium phosphoreum) 30-min EC50: 730 mg/L BIONCONCENTRATION: BCF = 1 . 8 REGULATORY INFORMATION: Volatile Organic Compounds: N/A. VOC Less H20 & Exempt Solvents: N/A. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Number = None (Not U.S. EPA Hazardous). The components of this product are in compliance with the chemical registration requirements of TSCA, EINECS, CDSL, AICS, MITI and KTCCL. OTHER ENVIRONMENTAL INFORMATION: This substance did not degrade significantly in a ready biodegradation test. This compound is completely fluorinated (perfluorinated), or it contains perfluorinated portions. Perfluoroalkyl groups resist degradation in most natural environments. This substance has minimal toxicity to aquatic organisms (100 mg/L < Lowest LC50, EC50, or IC50 < or = 1000 mg/L). No data are available on the toxicity effects of this substance on wastewater treatment system organisms. This substance has been found to not bioconcentrate or accumulate significantly in one or more living organisms. cPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 204 MSDS: FC-143 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 Covance 6329-231 3M T-6889.3 PAGE 4 <3. SUGGESTED FIRST AID EYE CONTACT: Immediately flush eyes with large amounts of water for at least 15 minutes. Get immediate medical attention. SKIN CONTACT: Flush skin with large amounts of water. If irritation persists, get medical attention. INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SWALLOWED: Do not induce vomiting. Drink two glasses of water. Call a physician 7. PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid eye contact. Wear vented goggles. _..IN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this material. A pair of gloves made from the following material(s) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective garments (other than gloves) should be made of either of the following materials: polyethylene/polyvinylidene chloride (Saranex). RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Provide sufficient ventilation to maintain emissions below recommended exposure limits. If exhaust ventilation is not adequate, use appropriate respiratory protection. RESPIRATORY PROTECTION: Avoid breathing of airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: full-face high efficiency filter respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and before eating. Abbreviations : N/D - Not Determined N/A - Not Applicable CA - Approximately 205 Covance 6329-231 3M T-6889.3 MSDS: FC-143 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 7. PRECAUTIONARY INFORMATION (continued) PAGE 5 RECOMMENDED STORAGE: Do not store containers on their sides. Store at room temperature. Keep container dry. Keep container closed when not in use. **PREVENT MOISTURE CONTAMINATION TO KEEP POWDER FREE FLOWING.** FIRE AND EXPLOSION AVOIDANCE: Keep container tightly closed. No smoking while handling this material. HMIS HAZARD RATINGS: HEALTH: 3 FLAMMABILITY: 0 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* AMMONIUM PERFLUOROOCTANOATE....... ,.. AMMONIUM PERFLUOROHEPTANOATE.......... AMMONIUM PERFLUOROPENTANOATE...... .. AMMONIUM PERFLUOROHEXANOATE.... . .... 0.01 0.1 0.1 0.1 MG/M3 MG/M3 MG/M3 MG/M3 TWA ACGIH Y TWA 3M Y TWA 3M Y TWA 3M Y >KIN NOTATION: Listed substances indicated with 'Y` under SKIN refer to ine potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - ACGIH: American Conference of Governmental Industrial Hygienists - 3M: 3M Recommended Exposure Guidelines 8. HEALTH HAZARD DATA EYE CONTACT: Moderate Eye Irritation: signs/symptoms can include redness, swelling, pain, tearing, and hazy vision. Airborne product may cause eye injury consisting of corneal opacity. SKIN CONTACT: Product is not expected to be irritating to the skin. Mild Skin Irritation (after prolonged or repeated contact): signs/symptoms can include redness, swelling, and itching. lay be absorbed through the skin and persist in the body for an extended time. Abbreviations : N/D - Not Determined N/A - Not Applicable CA - Approximately 206 Covance 6329-231 3M T-6889.3 MSDS: FC-143 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 PAGE 6 5. HEALTH HAZARD DATA (continued) INHALATION: Illness requiring medical attention may result from a single exposure by inhalation to moderate quantities of this material. May be absorbed by inhalation and persist in the body for an extended time. Single overexposure, above recommended guidelines, may cause: Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing. Prolonged or repeated overexposure, above recommended guidelines, may cause: Liver Effects: signs/symptoms can include yellow skin(jaundice) and tenderness of upper abdomen. Repeated inhalation of airborne product above the exposure guideline can result in elevated organofluoride levels in the blood. tp SWALLOWED: Ingestion is not a likely route of exposure to this product. Illness may result from a single swallowing of a moderate quantity of this material. CANCER: A mixture of ammonium perfluorooctanoate, ammonium perfluoroheptanoate, ammonium perfluoropentanoate and ammonium perfluorohexanoate, that was 93 to 97% AMMONIUM PERFLUOROOCTANOATE (3825-26-1) was fed to albino rats for 2 years, no compound induced carcinogenicity was found in the study. There were statistically significant compound related benign testicular tumors. In a second two-year study there were statistically significant compound related benign tumors in the liver, pancreas, and testis when compared to ad libitum and pair-fed controls. Based on the current knowledge, these findings have no human health implications. (3825-26-1) (1983 and 1993 studies conducted jointly by 3M and DuPont). MUTAGENICITY: Not mutagenic in invitro mutagenicity assays. Did not cause cell transformation in a mammalian cell transformation assay. REPRODUCTIVE/DEVELOPMENTAL TOXINS: Not teratogenic in rabbits by oral administration. Not teratogenic to rats by gavage or inhalation exposures. Abbreviations: N/D - Not Determined N /A - Not Applicable CA - Approximately 207 MSDS: FC-143 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 . HEALTH HAZARD DATA (continued) Covance 6329-231 3M T-6889.3 PAGE 7 OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under California Proposition 65. A Product Toxicity Summary Sheet is available. SECTION CHANGE DATES HEADING SECTION CHANGED SINCE November 05, 1997 ISSUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately The information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application. 3M provides information in electronic form as a service to its customers nue to the remote possibility that electronic transfer may have resulted errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the information in the MSDS available directly from 3M. 208 Covance 6329-231 3M T-6889.3 Purity1 INTERIM CERTIFICATE OF ANALYSIS Centre Analytical Laboratories COA Reference #: 023-033 3M Product: Ammonium Perfluorooctanoate Test Control Reference #: TCR-99131-37, Lot #: 332 ___________________ Purity: 95,2% Test Name Specifications Result 95.2% Appearance Identification NMR Metals (ICP/MS) 1. C alcium 2. Magnesium 3. Sodium 4. Potassium 5. Nickel 6. Iron 7. Manganese Total % Impurity (NM R) Total % Impurity (LC/MS) Total % Impurity (GC/MS) Residual Solvents (TGA) Purity by DSC Inorganic Anions (IC) 1. Chloride 2. Fluoride 3. Bromide 4. Nitrate .5. Nitrite 6. Phosphate 7. Sulfate Organic Acids2 (IC) 1. TFA 2. PFPA 3. HFBA 4. NFPA Elem ental A n alysis1: 1. Carbon 2. Hydrogen 3. Nitrogen 4. Sulfur 5. Fluorine Ammonium Analysis3 Ion Selective Electrode ' White, crystalline solid C onform s .. v: . . ' A- A ' , A' . 'A': A' -/ . , . :'.A;.-./A.-AA," . . ..... . : ,,. : =" A'i; l A 'i;. P o sitiv e 1. 0 .0 0 1 w t/w t.% 2. <0.001 wtAwt.% 3. 0.005 wt./wt.% 4. < 0 .0 0 1 wt./-wt.% 5. <0.001 wt./wt.% 6. <0.001 wt./wt.% 7. <0.001 wt./wt.% 0.34 wt./wt.% 4.49 wt,/wt.% N one Quantified None Detected 99.7% . . : `-.v ' 1. < 0 .0 1 5 w t./w t.% 2. <0.005 wt./wt.% 3. <0.040 wt./wt.% 4. < 0.009 wt./wt.% 5. < 0.006 wt.Avt.% 6. < 0.006 wt.Avt.% 7. <0.040 wt./wt.% : Theoretical Value = 22.3% Theoretical Value = 0.935% Theoretical Value = 3.25% Theoretical Value = 0% Theoretical Value = 66.1% 1. <0.1 wt.Avt.% 2. <0.1 wt.Avt.% 3. <0.1 wt.Avt.% 4. <0.25 wt.Avt.% 1. 18.9 wd.Avt.% 2. 1.31 wt.Avt.% 3. 3.75 wt.Avt.% 4. 4.34 wt.Avt.% 5. 63.2 wt.Avt.% Theoretical Value = 4.18% 3.49 wd./wt. % COA023033-37.doc Page 1 of2 209 Covance 6329-231 3M T-6889.3 210 APPENDIX 2 Individual Animal Fate Data Individual Clinical Observations Individual Ophthalmic Observations Covance 6329-231 3M T-6889.3 211 APPENDIX 2 Individual Animal Fate Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL DOSE NUMBER GROUP I05709 I05714 I05715 I05718 I05720 I05725 I05702 I05706 I05717 I05721 I05707 I05708 I05710 I05712 I05716 I05719 I05703 I05704 I05711 I05713 I05722 I05724 1 1 1 1 1 1 2 2 2 2 3 3 3 3 3 3 4 4 4 4 4 4 SEX MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE MALE DEATH CODE TYPE OF DEATH DESCRIPTION OF DEATH T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE U SCHEDULED FIRST POST-RECOV SAC U SCHEDULED FIRST POST-RECOV SAC T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE M UNSCHEDULED UNSCHEDULED DEATH T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE U SCHEDULED FIRST POST-RECOV SAC U SCHEDULED FIRST POST-RECOV SAC T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE T SCHEDULED TERMINAL SACRIFICE M UNSCHEDULED UNSCHEDULED DEATH DATE OF DAY OF DEATH STUDY 03/31/99 03/31/99 03/31/99 07/02/99 07/02/99 03/31/99 03/31/99 03/31/99 03/31/99 02/12/99 03/31/99 03/31/99 03/31/99 07/02/99 07/02/99 03/31/99 03/31/99 03/31/99 03/31/99 03/31/99 03/31/99 10/27/98 184 184 184 277 277 184 184 184 184 137 184 184 184 277 277 184 184 184 184 184 184 29 WEEK OF STUDY 27 27 27 40 40 27 27 27 27 20 27 27 27 40 40 27 27 27 27 27 27 5 PAGE: 1 212 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: Ml DOSE: 0 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05709 T I05714 T 27 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION FEW FECES SKIN & PELAGE ALOPECIA HEAD-CRANIAL LIMB-FRONT-RIGHT NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 27 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION FEW FECES LIQUID FECES MUCOID FECES NORMAL NO REMARKABLE OBSERVATIONS 184 31 62 9-10, 15-17, 23, 27 1, 8,, 22, 29, 36, 43, 50,, 57, 64, 71, 78, 85,. 92, 99, 106, 113 120, 127, 134,, 141, 148, 155, 162,, 169, 176, 183-184 36 142 56 102 31 8, 15, 29,. 36, 43, 50, 57, 64,, 71, 78, 85, 92, 99, 106, 113, 120 127, 134, 141, 148,, 155, 162, 169, 176, 183-184 213 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: Ml (CONTINUED FROM PREVIOUS PAGE) I05714 T 27 QUALITATIVE FOOD CONSUMPTION LOW I05715 T 27 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION FEW FECES NORMAL NO REMARKABLE OBSERVATIONS U 40 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION FEW FECES NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW DOSE: 0 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS 1, 22, 24, 54-56, 58, 123 184 31, 36 1, 8 , 15, 22, 29, 43, 50,, 57, 64, 71, 78, 85,, 92, 99, 106, 113 120, 127, 134,, 141, 148, 155, 162,. 169, 176, 183-184 275 31, 50-51 1, 8 , 15, 22, 29, 36, 43,, 57, 64, 71, 78, 85,, 92, 99, 106, 113 120, 127, 134,, 141, 148, 155, 162,. 169, 176, 183-184, 190, 197 204, 211, 218,, 225, 232, 239, 246,. 253, 260, 267, 274, 277 50-51 214 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 3 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: Ml DOSE: 0 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS U 40 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION FEW FECES LIQUID FECES NON-FORMED FECES NORMAL NO REMARKABLE OBSERVATIONS I05725 T QUALITATIVE FOOD CONSUMPTION LOW 27 DISCHARGE VOMITUS CONTAINING FOOD SKIN & PELAGE ALOPECIA LIMB-FRONT-LEFT LIMBS-FRONT NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 6 5-6 4, 7-11, 14-15, 17 1, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120 127, 134, 141, 148, 155, 162, 169, 176, 183-184, 190, 197, 204 211, 218, 225, 232, 239, 246, 253, 260, 267, 274, 277 6, 185, 263 184 107, 113, 116 62, 64 8, 15, 22, 29, 36, 43, 50, 57, 71, 78, 85, 92, 99, 106, 120, 127 134, 141, 148, 155, 162, 169, 176, 183-184 1, 122 215 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 4 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M2 DOSE: 3 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05702 T I05706 T I05717 T 27 NORMAL NO REMARKABLE OBSERVATIONS 27 DISCHARGE VOMITUS CONTAINING FOOD NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 27 DISCHARGE VOMITUS CONTAINING FOOD NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 1, 8 , 15, 22, 29, 36, 43 , 50 , 57, 64, 71, 78, 85 , 92, 99, 106 113, 120, 127, 134, 141, 148 , 155, 162, 169, 176 , 183-184 184 1, 8 , 15, 22, 29, 36, 43 , 50 , 57, 64, 71, 78, 85 , 92, 99, 106 113, 120, 127, 134, 141, 148 , 155, 162, 169, 176 , 183-184 10-12, 14 184 1, 8 , 15, 22, 29, 36, 43 , 50 , 64, 71, 78, 85, 92 , 99, 106, 113 120, 127, 134, 141, 148, 155 , 162, 169, 176, 183 -184 14, 16, 34 , 45, 53, 55, 57, 67, 73 , 86, 88, 110- 111, 114 216 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 5 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M2 DOSE: 3 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05721a M 20 APPEARANCE LIMITED USE LIMBS-HIND PARALYSIS HIND QUARTERS BEHAVIOR ATAXIC <UNSPECIFIED> HYPOACTIVE <UNSPECIFIED> EXCRETION FEW FECES LIQUID FECES MUCOID FECES NON-FORMED FECES NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW NONE 137 137 137 136 -137 29- 30, 125, 127, 129, 133-137 16, 18, 27-28 18, 29 18, 21-24, 27-28,, 32, 54 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120 24, 27-30, 32-34, 125, 127, 129, 133-136 16, 137 a Animal No. I05721 replaced Animal No. I05723 on Day 15. Dose administration for this animal initiated on Day 17 (Week 3). 217 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 6 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M3 DOSE: 10 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05707 T I05708 T I05710 T I05712 U 27 NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW 27 DISCHARGE VOMITUS CONTAINING FOOD NORMAL NO REMARKABLE OBSERVATIONS 27 SKIN & PELAGE SCAB(S) PERI-ORBITAL-LEFT PERI-ORBITAL-RIGHT NORMAL NO REMARKABLE OBSERVATIONS 40 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION NO FECES NON-FORMED FECES 1, 8 , 15, 22, 29, 36, 43,, 50, 57, 64, 71, 78, 85, 92, 99, 106 113, 120, 127,, 134, 141, 148, 155,. 162, 169, 176, 183-184 18 184 1, 8 , 15, 22, 29, 36, 43,, 50, 57, 64, 71, 78, 85, 92, 99, 106 113, 120, 127,, 134, 141, 148, 155,. 162, 169, 176, 183-184 9-10 23, 27 1, 8 , 15, 22, 29, 36, 43,, 50, 57, 64, 71, 78, 85, 92, 99, 106 113, 120, 127,, 134, 141, 148, 155,. 162, 169, 176, 183-184 184, 275 275 1 218 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 7 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M3 (CONTINUED FROM PREVIOUS PAGE) I05712 U 40 NORMAL NO REMARKABLE OBSERVATIONS I05716 U QUALITATIVE FOOD CONSUMPTION LOW 40 DISCHARGE VOMITUS CONTAINING FOOD NORMAL NO REMARKABLE OBSERVATIONS I05719 T QUALITATIVE FOOD CONSUMPTION LOW 27 EXCRETION LIQUID FECES NON-FORMED FECES SKIN & PELAGE OTHER NORMAL NO REMARKABLE OBSERVATIONS DOSE: 10 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS 8, 15, 22, 29, 36, 43, 50, 57,, 64, 71, 78, 85, 92, 99, 106, 113 120 , 127, 134, 141, 148, 155, 162, 169, 176 , 183, 190, 197, 204 211 , 218, 225, 232, 239, 246, 253, 260, 267 , 274, 277 185 55, 184 1, 8 , 15 , 22, 29, 36, 43,, 50, 57, 64, 71, 78, 85, 92, 99, 106 113, 120 , 127 , 134 , 141, 148, 155, 162 , 169, 176, 183,. 190, 197 204, 211 , 218 , 225 , 232, 239, 246, 253 , 260, 267, 274, 277 13, 21, 185, 187, 276 140-141, 175-176, 178-180 34, 142-143, 147-151, 174 140-143C, 147-151C, 155C, 161-162C, 164-165C, 16 9C, 174-180C 183-184C 8, 15, 22,, 36, 43, 50, 57,. 64, 71, 78, 85, 92, 99, 106, 113, 120 127, 134 219 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 8 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M3 (CONTINUED FROM PREVIOUS PAGE) I05719 T 27 QUALITATIVE FOOD CONSUMPTION LOW DOSE: 10 MG/KG/DAY DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS 1, 3, 23-24, 29, 33, 55, 177-180 220 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS STUDY ANIMAL GROUP DAY WK CATEGORY KEYWORD QUALIFIER FREE-TEXT COMMENT I05719 M3 140 20 SKIN & PELAGE TO 184 27 OTHER APPROX 1CM X 1CM MASS ON FACE NEXT TO NOSE Covance 6329-231 3M T-6889.3 PAGE: 9 221 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 10 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M4 DOSE: 20 MG/KG/DAYb DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05703c T I05704 T 27 APPEARANCE THIN DISCHARGE VOMITUS CONTAINING FOOD EXCRETION DISCOLORED URINE BROWN IN COLOR FEW FECES LIQUID FECES NO FECES NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW NONE 27 DISCHARGE VOMITUS CONTAINING FOOD EXCRETION FEW FECES NORMAL NO REMARKABLE OBSERVATIONS 76-83 77, 184 79 11, 45-46, 50-52, 54-60, 62, 64-66, 68, 70, 72, 75, 77-80, 82-83 76 43, 61, 71 1, 22, 29, 36, 85, 92, 99, 106,. 113, 120, 127, 134, 141, 148 155, 162, 169, 176, 183-184 3, 8-11, 15-16 , 24, 27-28, 34, 36, 38-40, 43-47, 50-52, 54-59 61-62, 64-66, 68-70 , 72, 77-83, 128 60, 71, 73-76 184 11-12 1, 8, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113 b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. c Dose administration discontinued on Day 81 (Week 12). 222 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 11 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M4 (CONTINUED FROM PREVIOUS PAGE) I05704 T 27 NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW I05711d T 27 EXCRETION FEW FECES NO FECES NORMAL NO REMARKABLE OBSERVATIONS I05713 T QUALITATIVE FOOD CONSUMPTION LOW NONE 27 EXCRETION FEW FECES LIQUID FECES NON-FORMED FECES NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW DOSE: 20 MG/KG/DAYb DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS 120, 127, 134 , 141, 148, 155, 162, 169, 176, 183-184 11-12, 15 11-12, 29-30, 38-46, 121-122, 124-125, 127 31, 35-36 1, 22, 50, 57 , 64, 71, 78, 85, 92, 99, 106, 113, 120,. 134, 141 148, 155, 162 , 169, 176, 183-184 7-12, 14-16, 18, 28-30, 32-34, 38-45, 120-122, 124-125, 127-128 158 35-37 45, 49-51, 66 , 70, 134, 136, 138 34-36 32-33, 37-38, 46 1, 8, 22, 29, 57, 71, 78, 85, 92, 99, 106, 113, 120, 127, 141 148, 155, 162 , 169, 176, 183-184 3, 10-12, 15, 34-35, 37-43, 45-46, 48, 50-51, 59, 62,. 64, 66, 70 129-130, 133- 134, 136, 138 b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. d Dose administration discontinued on Day 43 (Week 7). 223 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 12 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M4 DOSE: 20 MG/KG/DAYb DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05722e T 27 APPEARANCE THIN EXCRETION FEW FECES NO FECES SKIN & PELAGE SCAR LIP(S) I05724 M NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW NONE 5 BEHAVIOR HYPOACTIVE <UNSPECIFIED> EXCRETION FEW FECES NO FECES 65-69, 71-76 29, 35-36, 45-46, 49-52, 56-62, 69 43, 53-55, 64-66 1, 3, 8, 10-12, 15, 22, 28-30, 32-39, 42-43, 45-62, 64-69, 71-76 78, 85, 92, 99, 106, 113 , 120, 127, 134, 141,, 148, 155, 162 , 166 169, 176 , 183-184 8, 22, 78,, 85, 92, 99, 106, 113, 120, 127,, 134, 141, 148 , 155 162, 169, 176, 183-184 3, 10-12, 15, 28-30, 32-35, 37-39 , 42-43, 45-48, 50-59, 61-62 67-69 60, 64-66 28-29 9-10, 18, 28-29 11-17 b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. e Dose administration discontinued on Day 66 (Week 10). 224 Appendix 2 Individual Clinical Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 13 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M4 (CONTINUED FROM PREVIOUS PAGE) I05724 M 5 SKIN & PELAGE COLD TO TOUCH BODY-ENTIRE NORMAL NO REMARKABLE OBSERVATIONS QUALITATIVE FOOD CONSUMPTION LOW NONE DOSE: 20 MG/KG/DAYb DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS 29 1, 22 3, 7-8, 16, 18, 21, 24-25 9-15, 17, 27-29 b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. 225 Appendix 2 Individual Ophthalmic Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M1 DOSE: 0 MG/KG/DAY WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05709 T I05714 T I05715 T I05718 U I05720 U I05725 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 -1, 27 -1, 27 -1, 27, 40 -1, 27, 40 -1, 27 226 Appendix 2 Individual Ophthalmic Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M2 DOSE: 3 MG/KG/DAY WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05702 T I05706 T I05717 T I05721 M 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 20 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1 -1 -1 -1 227 Appendix 2 Individual Ophthalmic Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 3 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M3 DOSE: 10 MG/KG/DAY WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05707 T I05708 T I05710 T I05712 U I05716 U I05719 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 -1, 27 -1, 27 -1, 27, 40 -1, 27, 40 -1, 27 228 Appendix 2 Individual Ophthalmic Observations 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 4 CATEGORY ANIMAL DEATH WK OF KEYWORD NUMBER CODE DEATH QUALIFIER GROUP: M4 DOSE: 20 MG/KG/DAY WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; 'C' - COMMENTS LISTED AT END OF OBSERVATIONS I05703 T I05704 T I05711 T I05713 T I05722 T I05724 M 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 5 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 -1, 27 -1, 27 -1, 27 -1, 27 -1 229 APPENDIX 3 Individual Body Weight Data (kg) Individual Body Weight Change Data (kg) Covance 6329-231 3M T-6889.3 230 Appendix 3 Individual Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 ANIMAL NUMBER WEEK -2 WEEKa -1 WEEKb -1 WEEK 1 WEEK 2 WEEK 3 WEEK 4 WEEK 5 WEEK 6 WEEK 7 GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 4.2 4.4 4.4 4.5 4.5 4.6 4.7 4.8 4.7 4.8 3.2 3.3 3.2 3.2 3.1 3.2 3.3 3.2 3.3 3.2 3.7 3.8 3.7 3.8 3.8 3.8 3.9 3.9 4.0 4.0 4.1 4.4 4.3 4.4 4.3 4.4 4.5 4.4 4.4 4.5 3.8 3.9 3.8 3.9 3.8 3.9 4.1 4.2 4.2 4.4 3.1 3.2 3.1 3.2 3.1 3.3 3.4 3.3 3.5 3.5 GROUP: MALE 2 - 3 MG/KG/DAY I05702 3.8 3.9 3.8 3.9 3.9 3.9 4.0 3.9 4.1 4.1 I05706 4.3 4.5 4.4 4.5 4.4 4.3 4.3 4.2 4.3 4.2 I05717c 3.8 3.8 3.7 3.8 3.8 3.8 3.9 3.9 4.1 4.1 I05721c 3.9 3.7 3.7 3.8 3.6 3.8 3.9 CO ro CO ro CO ro GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 3.9 3.9 3.9 4.0 3.8 3.8 3.9 3.8 4.0 4.0 3.9 3.9 3.8 3.9 3.9 3.9 4.0 4.0 4.2 4.2 4.2 4.3 4.3 4.3 4.4 4.4 4.5 4.5 4.7 4.8 3.4 3.4 3.2 3.4 3.3 3.2 3.4 3.3 3.3 3.3 3.3 3.3 3.2 3.5 3.3 3.2 3.3 3.3 3.4 3.3 3.8 3.7 3.7 3.7 3.6 3.6 3.8 3.7 3.7 3.9 a Day -7. b Day -1. c Animal No. I05721 replaced Animal No. I05723 on Day 15. Dose administration for this animal initiated on Day 17 (Week 3). 231 Appendix 3 Individual Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 ANIMAL NUMBER WEEK -2 WEEKa -1 WEEKb -1 WEEK 1 WEEK 2 WEEK 3 WEEK 4 WEEK 5 WEEK 6 WEEK 7 GROUP: MALE 4 - 20 MG/KG/DAYd I05703 3.3 3.3 3.2 3.2 3.1 3.1 3.3 3.2 3.3 3.3 I05704 4.0 4.0 3.9 4.0 3.9 3.9 4.1 4.1 4.1 4.3 I05711e 3.8 4.0 3.9 4.0 3.7 3.6 3.8 3.6 3.5 3.3 I05713 3.9 3.8 3.9 4.0 3.8 3.7 3.8 3.7 3.7 3.8 I05722 3.7 3.8 3.8 3.9 3.7 3.8 3.8 3.8 3.8 3.8 I05724 4.0 4.0 4.0 4.0 3.8 3.4 3.6 3.5 a Day -7. b Day -1. d Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. e Dose administration was discontinued on Day 43 (Week 7). Beginning 232 Appendix 3 Individual Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 8 WEEK 9 WEEK 10 WEEK 11 WEEK 12 WEEK 13 WEEK 14 WEEK 15 GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 4.6 4.5 4.5 4.6 4.5 4.6 4.6 4.6 3.3 3.1 3.2 3.2 3.3 3.3 3.3 3.4 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.3 4.4 4.5 4.6 4.6 4.6 4.6 4.7 4.3 4.4 4.4 4.4 4.4 4.4 4.4 4.5 3.5 3.6 3.6 3.6 3.6 3.7 3.6 3.7 GROUP: MALE 2 - 3 MG/KG/DAY I05702 I05706 I05717 I05721 4.0 4.1 4.0 4.1 4.1 4.2 4.1 4.2 4.3 4.2 4.2 4.2 4.2 4.3 4.2 4.2 4.1 4.2 4.2 4.2 4.2 4.3 4.2 4.3 4.0 4.2 4.1 4.2 4.1 4.1 4.2 4.3 GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 4.0 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.2 4.2 4.3 4.2 4.3 4.3 4.3 4.8 5.0 4.9 5.0 5.0 5.1 5.0 5.1 3.4 3.4 3.3 3.5 3.4 3.5 3.4 3.6 3.4 3.4 3.5 3.4 3.4 3.6 3.5 3.5 3.8 3.8 3.7 3.8 3.8 3.9 3.8 3.8 GROUP: MALE 4 - 20 MG/KG/DAY I05703f 3.1 3.1 2.9 2.9 2.6 2.8 2.9 3.2 I05704g 4.1 4.1 4.1 4.1 4.1 4.2 4.1 4.2 I05711g 3.3 3.6 3.7 3.9 3.9 3.9 3.9 3.9 I05713h 3.6 3.7 3.6 3.6 3.6 3.7 3.6 3.5 I05722h 3.4 3.3 3.0 3.1 3.3 3.6 3.6 4.0 f Dose administration was discontinued on Day 81 (Week 12) g Dose administration was discontinued on Day 43 (Week 7). h Dose administration was discontinued on Day 66 (Week 10) Covance 6329-231 3M T-6889.3 PAGE: 3 WEEK 16 WEEK 17 4.5 4.5 3.4 3.4 4.0 4.0 4.7 4.7 4.6 4.6 3.7 3.7 4.2 4.3 4.2 4.3 4.3 4.4 4.2 4.2 4.1 4.2 4.3 4.4 5.1 5.1 3.6 3.6 3.6 3.6 3.9 4.0 3.3 3.4 4.2 4.2 3.9 3.9 3.5 3.6 4.1 4.3 233 Appendix 3 Individual Body Weight Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 18 WEEK 19 WEEK 20 WEEK 21 WEEK 22 WEEK 23 WEEK 24 WEEK 25 GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 4.6 4.5 4.6 4.6 4.6 4.6 4.6 4.7 3.4 3.4 3.5 3.5 3.5 3.5 3.6 3.6 4.0 4.0 4.0 4.0 4.0 4.1 4.0 4.1 4.8 4.9 4.9 5.0 5.0 5.1 5.1 5.1 4.7 4.7 4.7 4.7 4.7 4.8 4.8 4.8 3.8 3.8 3.8 3.8 3.8 3.9 3.9 3.9 GROUP: MALE 2 - 3 MG/KG/DAY I05702 I05706 I05717 I05721 4.3 4.4 4.4 4.4 4.4 4.5 4.6 4.7 4.5 4.5 4.5 4.5 4.5 4.6 4.6 4.6 4.3 4.4 4.4 4.5 4.5 4.5 4.6 4.6 4.3 4.2 3.8 GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 4.2 4.2 4.2 4.2 4.2 4.3 4.4 4.3 4.4 4.5 4.5 4.5 4.5 4.5 4.5 4.5 5.2 5.2 5.2 5.2 5.2 5.2 5.3 5.3 3.6 3.6 3.7 3.7 3.7 3.7 3.8 3.7 3.7 3.6 3.6 3.6 3.6 3.7 3.7 3.7 4.1 4.2 4.2 4.2 4.3 4.4 4.5 4.5 GROUP: MALE 4 - 20 MG/KG/DAY I05703f 3.5 3.5 3.5 3.5 3.5 3.6 3.5 3.6 I05704g 4.3 4.3 4.3 4.3 4.3 4.4 4.5 4.4 I05711g 3.9 3.7 3.8 3.9 3.9 4.0 4.0 4.0 I05713h 3.7 3.6 3.4 3.4 3.4 3.6 3.7 3.5 I05722h 4.5 4.5 4.6 4.7 4.7 4.8 4.8 4.8 f Dose administration was discontinued on Day 81 (Week 12) g Dose administration was discontinued on Day 43 (Week 7). h Dose administration was discontinued on Day 66 (Week 10) Covance 6329-231 3M T-6889.3 PAGE: 4 WEEK 26 WEEK 27 4.8 4.8 3.7 3.7 4.1 4.1 5.2 5.3 4.9 5.0 4.0 4.0 4.8 4.8 4.7 4.8 4.7 4.7 4.4 4.3 4.6 4.6 5.4 5.4 3.8 3.8 3.7 3.8 4.6 4.6 3.6 3.7 4.5 4.6 4.0 4.1 3.5 3.6 4.9 4.9 234 Appendix 3 Individual Body Weight Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 28 WEEK 29 WEEK 30 WEEK 31 WEEK 32 WEEK 33 WEEK 34 WEEK 35 GROUP: MALE 1 - 0 MG/KG/DAY I05718 I05720 5.3 5.4 5.3 5.3 5.5 5.6 5.7 5.7 4.9 5.0 5.0 5.0 5.1 5.0 5.3 5.3 GROUP: MALE 3 - 10 MG/KG/DAY I05712 I05716 3.8 3.8 3.7 3.8 3.8 3.9 3.9 3.9 3.7 3.8 3.6 3.6 3.7 3.7 3.7 3.7 Covance 6329-231 3M T-6889.3 PAGE: 5 WEEK 36 WEEK 37 5.8 5.8 5.3 5.4 3.9 3.9 3.7 3.7 235 Appendix 3 Individual Body Weight Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 38 WEEK 39 WEEK 40 GROUP: MALE 1 - 0 MG/KG/DAY I05718 I05720 5.8 5.9 5.4 5.5 GROUP: MALE 3 - 10 MG/KG/DAY I05712 I05716 3.9 4.0 3.7 3.7 Covance 6329-231 3M T-6889.3 PAGE: 6 236 Appendix 3 Individual Body Weight Change Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 ANIMAL NUMBER WEEK 1-2 WEEK 2-3 WEEK 3-4 WEEK 4-5 WEEK 5-6 WEEK 6-7 WEEK 7-8 WEEK 8-9 WEEK 9-10 WEEK 10-11 GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 0.0 -0.1 0.0 -0.1 -0.1 -0.1 0.1 0.1 0.0 0.1 0.1 0.2 GROUP: MALE 2 - 3 MG/KG/DAY I05702 I05706 I05717a I05721a 0.0 -0.1 0.0 0.1 0.0 -0.1 0.0 0.0 GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 -0.2 0.0 0.1 -0.1 -0.2 -0.1 0.0 0.0 0.0 -0.1 -0.1 0.0 0.1 0.1 0.1 0.1 0.2 0.1 0.1 0.0 0.1 0.0 0.1 0.1 0.1 0.2 0.1 0.2 0.1 -0.1 0.0 -0.1 0.1 -0.1 -0.1 -0.1 0.0 -0.2 -0.1 0.0 0.0 -0.1 0.0 -0.1 -0.1 0.1 0.1 0.0 0.0 0.2 0.2 0.1 0.2 0.2 0.2 0.2 0.2 0.0 0.1 0.0 0.1 -0.1 0.0 0.1 0.2 0.0 0.0 -0.1 0.0 0.1 0.0 0.0 0.1 0.0 -0.1 0.2 -0.2 0.1 0.0 -0.2 -0.1 0.0 -0.1 0.1 0.0 0.1 0.0 -0.1 0.0 0.1 0.1 -0.1 -0.1 -0.2 0.0 0.1 0.1 0.1 0.1 -0.1 0.1 0.2 0.1 0.1 0.2 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.0 -0.1 0.0 0.0 -0.1 0.0 0.0 -0.1 -0.1 0.1 -0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.1 0.1 0.2 -0.1 0.1 a Animal No. I05721 replaced Animal No. I05723 on Day 15. Dose administration for this animal initiated on Day 17 (Week 3). 237 Appendix 3 Individual Body Weight Change Data (kg) 26 -WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 ANIMAL NUMBER WEEK 1-2 WEEK 2-3 WEEK 3-4 WEEK 4-5 WEEK 5-6 WEEK 6-7 WEEK 7-8 WEEK 8-9 WEEK 9-10 WEEK 10-11 oo o oo o o o ro ooo o o oo oo oo oo GROUP: MALE 4 - 20 MG/KG/DAYb I05703 I05704 I05711c I05713d I05722d I05724 -0.1 -0.1 -0.3 -0.2 -0.2 -0.2 -0.1 -0.1 O I-1 0.2 0.2 0.2 0.1 0.0 0.2 -0.1 0.0 -0.2 -0.1 0.0 -0.1 0.1 0.0 -0.1 0.0 0.2 -0.2 0.1 -0.2 -0.2 0.0 -0.2 -0.4 0.1 -0.1 -0.2 0.0 0.1 -0.1 -0.3 0.2 0.1 b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. c Dose administration was discontinued on Day 43 (Week 7). d Dose administration was discontinued on Day 66 (Week 10). Beginning 238 Appendix 3 Individual Body Weight Change Data (kg) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 11-12 WEEK 12-13 WEEK 13-14 WEEK 14-15 WEEK 15-16 WEEK 16-17 WEEK 17-18 WEEK 18-19 GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 -0.1 0.1 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.1 GROUP: MALE 2 - 3 MG/KG/DAY I05702 I05706 I05717 I05721 0.0 0.0 0.0 -0.1 0.1 0.1 0.1 0.0 GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 0.0 -0.1 0.0 -0.1 0.0 0.0 0.0 0.1 0.1 0.1 0.2 0.1 GROUP: MALE 4 - 20 MG/KG/DAY I05703e I05704c I05711c I05713d I05722d -0.3 0.0 0.0 0.0 0.2 0.2 0.1 0.0 0.1 0.3 0.0 0.0 0.0 0.0 0.0 -0.1 -0.1 -0.1 -0.1 0.1 0.0 0.0 -0.1 -0.1 -0.1 -0.1 0.1 -0.1 0.0 -0.1 0.0 0.0 0.1 0.0 0.1 0.1 0.1 0.1 0.0 0.1 0.1 0.0 0.0 0.1 0.2 0.0 0.0 0.3 0.1 0.0 -0.1 0.4 -0.1 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 -0.1 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.0 0.0 0.0 0.1 0.0 0.1 -0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.1 0.0 0.0 0.1 0.0 0.1 0.0 0.1 0.1 0.2 0.0 0.1 -0.1 0.1 0.0 0.1 -0.1 0.1 0.0 0.0 0.1 0.0 0.1 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.1 -0.1 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 -0.2 0.1 0.1 -0.1 0.2 0.2 0.0 c Dose administration was discontinued on Day 43 (Week 7). d Dose administration was discontinued on Day 66 (week 10). e Dose administration was discontinued on Day 81 (Week 12). Covance 6329-231 3M T-6889.3 PAGE: 3 WEEK 19-20 WEEK 20-21 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.4 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.1 -0.2 0.1 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 239 Appendix 3 Individual Body Weight Change Data (kg) 26 -WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 21-22 WEEK 22-23 WEEK 23-24 WEEK 24-25 WEEK 25-26 WEEK 26-27 TOTAL 1-27 GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.1 0.0 0.1 GROUP: MALE 2 - 3 MG/KG/DAY I05702 I05706 I05717 0.0 0.1 0.0 0.1 0.0 0.0 GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 GROUP: MALE 4 - 20 MG/KG/DAY I05703e 0.0 0.1 I05704c 0.0 0.1 I05711c 0.0 0.1 105713d 0.0 0.2 I05722d 0.0 0.1 0.0 0.1 -0.1 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.0 0.1 0.1 0.0 0.1 -0.1 0.1 0.0 0.1 0.0 0.1 0.0 0.1 0.0 0.0 0.0 0.1 0.0 0.0 -0.1 0.0 0.0 -0.1 0.0 0.0 0.1 -0.1 0.0 -0.2 0.0 0.1 0.0 0.3 0.1 0.0 0.5 0.0 0.0 0.3 0.1 0.1 0.9 0.1 0.1 1.1 0.1 0.0 0.8 0.1 0.0 0.9 0.1 0.1 0.3 0.1 0.0 0.9 0.1 -0.1 0.1 0.0 0.1 0.0 0.1 0.0 0.0 0.1 0.1 0.0 0.3 0.7 1.1 0.4 0.3 0.9 0.0 0.1 0.5 0.1 0.1 0.6 0.0 0.1 0.1 0.0 0.1 -0.4 0.1 0.0 1.0 c Dose administration was discontinued on Day 43 (Week 7) d Dose administration was discontinued on Day 66 (Week 10). e Dose administration was discontinued on Day 81 (Week 12). 240 Covance 6329-231 3M T-6889.3 PAGE: 4 Appendix 3 Individual Body Weight Change Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 27-28 WEEK 28-29 WEEK 29-30 WEEK 30-31 WEEK 31-32 WEEK 32-33 WEEK 33-34 WEEK 34-35 GROUP: MALE 1 - 0 MG/KG/DAY I05718 I05720 0.0 -0.1 0.1 -0.1 0.1 0.0 0.2 0.1 0.1 -0.1 0.1 0.3 GROUP: MALE 3 - 10 MG/KG/DAY I05712 0.0 0.0 -0.1 0.1 0.0 0.1 I05716 -0.1 0.1 -0.2 0.0 0.1 0.0 oo oo oo oo oo oo oo oo oo oo oo oo Covance 6329-231 3M T-6889.3 PAGE: 5 WEEK 35-36 WEEK 36-37 0.1 0.0 0.0 0.1 241 Appendix 3 Individual Body Weight Change Data (kg) Recovery 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER WEEK 37-38 WEEK 38-39 WEEK 39-40 TOTAL 27-40 oo oo oo oo oo oo oo oo GROUP: MALE 1 - 0 MG/KG/DAY I05718 I05720 0.1 0.1 GROUP: MALE 3 - 10 MG/KG/DAY I05712 I05716 0.1 0.0 0.6 0.5 0.2 -0.1 Covance 6329-231 3M T-6889.3 PAGE: 6 242 APPENDIX 4 Individual Clinical Hematology Data Individual Clinical Chemistry Data Individual Clinical Urinalysis Data Covance 6329-231 3M T-6889.3 243 ANIMAL NUMBER Group: 1 105709 105714 105715 105718 105720 I05725 MEAN S.D. N Group: 2 I05702 105706 I05717 105721 MEAN S.D. N Group: 3 105707 105708 105710 I05712 105716 105719 MEAN S.D. N RBC X106/|iL HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC % FL PG % X103/|iL % X103/|iL PT SEC Dose Level: 0 7.15 6.13 7.04 6.46 6.32 6.52 12.7 12.3 12.0 12.4 12.4 12.7 6.60 .405 6 12.4 .26 6 Dose Level: 3 6.36 7.17 6.70 7.30 12.1 13.3 11.8 14.5 6.88 .433 4 12.9 1.23 4 Dose Level: 10 6.99 6.77 6.43 6.32 6.91 6.80 11.9 12.2 12.9 11.2 12.2 12.3 6.70 .268 6 12.1 .56 6 Dosage Unit: mg/kg/day 42.1 41.6 43.6 41.7 41.2 42.5 59.0 67.8 62.0 64.5 65.2 65.2 17.8 20.1 17.0 19.3 19.6 19.5 42.1 .85 6 63.9 3.05 6 18.9 1.21 6 Dosage Unit: mg/kg/day 41.2 45.2 39.6 49.7 64.9 63.1 59.0 68.1 19.0 18.6 17.6 19.9 43.9 4.51 4 63.8 3.80 4 18.8 .95 4 Dosage Unit: mg/kg/day 40.4 40.6 43.5 37.6 39.6 40.9 57.8 60.0 67.7 59.4 57.2 60.2 17.0 18.1 20.0 17.7 17.6 18.0 40.4 1.92 6 60.4 3.78 6 18.1 1.02 6 30.1 29.6 27.4 29.9 30.0 29.9 29.5 1.03 6 29.3 29.5 29.7 29.2 29.4 .22 4 29.4 30.1 29.6 29.9 30.8 30.0 30.0 .48 6 576 499 362 785 475 380 513 155..0 6 .7 .8 1.3 .5 .3 .4 .7 .36 6 416 677 599 555 562 109..5 4 .8 1.1 .8 .1 .7 .42 4 489 474 692 482 550 404 515 98..3 6 .6 1.2 .4 1.0 .2 .5 .6 .38 6 50 49 92 32 19 26 45 26.3 6 9.8 10.1 10.0 9.4 9.3 9.7 9.7 .32 6 51 79 54 7 48 29.9 4 9.7 9.5 9.6 9.5 9.6 .10 4 42 81 26 63 14 34 43 24.7 6 9.7 9.5 9.4 9.6 9.9 9.7 9.6 .18 6 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 19.2 19.2 17.4 16.1 18.8 18.6 18.2 1.23 6 16.5 27.7 17.7 20.2 20.5 5.03 4 16.2 19.7 19.5 17.8 19.7 16.7 18.3 1.59 6 313 261 299 285 236 320 286 32 6 317 331 309 422 345 52 4 309 309 346 280 315 329 315 22 6 244 ANIMAL NUMBER Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/p,L X103/fJ,L PT SEC Dose Level: 30/20 7.31 6.46 6.73 7.07 6.72 6.74 13.3 10.8 12.4 11.8 12.3 12.5 6.84 .302 6 12.2 .83 6 Dosage Unit: mg/kg/day 44.9 36.8 41.4 40.3 42.6 41.1 61.4 57.0 61.5 57.0 63.4 61.0 18.2 16.7 18.5 16.7 18.3 18.6 41.2 2.68 6 60.2 2.63 6 17.8 .89 6 29.7 29.3 30.0 29.2 28.8 30.4 29.6 .58 6 635 437 639 494 468 608 547 90.6 6 1.1 .7 .5 .5 .7 .8 .7 .22 6 80 45 34 35 47 54 49 16.9 6 9.8 9.6 9.9 10.4 9.4 9.5 9.8 .36 6 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 20.0 20.6 18.8 27.0 17.1 16.6 20.0 3.76 6 310 324 330 339 308 216 304 44 6 245 ANIMAL NUMBER Group: 1 105709 105714 105715 105718 105720 I05725 MEAN S.D. N Group: 2 I05702 105706 I05717 105721 MEAN S.D. N Group: 3 105707 105708 105710 I05712 105716 105719 MEAN S.D. N WBC X103/ iL Appendix 4 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/ iL X103/ iL MONO X103/ iL EOSIN X103/ iL BASO N-SEG% X103/ iL LYMPH% MONO1 EOSIN1 Covance 6329-231 3M T-6889.3 BASO% Dose Level: 0 13.1 9.2 15.5 15.0 17.4 5.8 5.6 4.9 6.6 6.5 9.5 2.8 12.7 4.36 6 6.0 2.21 6 Dose Level: 3 10.6 15.5 10.1 6.7 5.2 8.2 3.2 1.6 10.7 3.62 4 4.6 2.84 4 Dose Level: 10 7.7 8.2 15.0 10.7 13.9 12.9 2.4 2.8 9.4 7.0 6.3 6.3 11.4 3.03 6 5.7 2.66 6 Dosage Unit: mg/kg/day 6.6 7 3.4 7 7.8 9 6.5 1 6 6.0 1 5 2.5 5 .2 .1 .2 .3 .3 .0 5.5 2.06 6 10 46 6 .2 .12 6 Dosage Unit: mg/kg/day 4.9 4 5.9 1 2 6.2 5 4.0 1 0 .0 .2 .3 .0 5.2 1.00 4 8 .1 39 .15 44 Dosage Unit: mg/kg/day 4.4 8 4.0 9 4.3 9 3.1 4 6.0 1 4 5.6 1 0 .1 .4 .3 .1 .1 .1 4.6 1.07 6 9 .2 32 .13 66 .0 42 .0 53 .0 42 .1 43 .1 54 .0 48 .0 47 .05 5 66 .0 50 .1 53 .0 32 .0 24 .0 40 .05 14 44 .0 31 .0 34 .1 63 .0 66 .1 45 .0 49 .0 48 .05 14 66 50 6 2 0 37 8 1 0 50 6 1 0 43 11 2 1 35 9 2 0 43 8 1 0 43 8 2 0 6.3 1.9 .5 .4 6666 46 4 0 0 38 7 1 1 61 5 2 0 60 16 01 51 8 1 0 11.2 5.5 1.0 .6 4444 58 10 1 0 49 11 6 0 29 6 2 1 30 4 1 0 44 10 1 0 43 7 1 0 42 8 2 0 11.2 2.8 2.0 .4 6666 246 ANIMAL NUMBER Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N WBC X103/jiL Appendix 4 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/jlL X103/jlL MONO EOSIN X103/jiL X103/lL BASO N-SEG% X103/jiL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 Dose Level: 30/20 11.3 13.8 14.1 11.5 11.9 17.2 6.1 6.9 6.8 6.4 7.2 10.4 13.3 2.25 6 7.3 1.57 6 Dosage Unit: mg/kg/day 4.2 .6 6.1 .5 5.8 1.1 2.9 1.9 4.4 .3 5.1 1.3 .3 .3 .3 .2 .0 .4 4.8 1.17 6 1.0 .60 6 .2 .14 6 .0 54 38 6 .0 50 44 4 .0 48 41 8 .2 55 25 16 .0 60 37 3 .1 60 30 7 .0 54 36 7 .08 5.0 7.1 4.6 6666 20 20 20 21 00 20 20 .8 .4 66 247 Appendix 4 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 a I05706 I05717 I05721 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 Dose Level: 0 ------- Dose Level: 3 ----- Dose Level: 10 ------- Dose Level: 30/20 ------- - - - - Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ----- Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ------- a Plasmodium was observed. 248 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER RBC X106/p,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/fJ,L X103/fJ,L PT SEC Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 7.25 6.42 6.87 7.29 6.28 6.76 13.3 12.7 11.8 13.8 12.2 13.6 6.81 .415 6 12.9 .80 6 Dose Level : 3 6.06 6.60 6.93 6.29 11.6 12.7 12.4 12.9 6.47 .378 4 12.4 .57 4 Dose Level : 10 7.21 6.58 6.29 6.33 7.03 6.96 12.4 12.3 12.8 11.4 12.4 12.8 6.73 .387 6 12.3 .51 6 Dosage Unit: mg/kg/day 43.4 43.7 43.4 46.9 41.4 45.3 59.8 68.1 63.2 64.3 65.9 67.1 18.4 19.8 17.1 18.9 19.5 20.2 44.0 1.88 6 64.7 3.01 6 19.0 1.12 6 Dosage Unit: mg/kg/day 38.9 41.3 41.8 43.1 64.3 62.6 60.4 68.5 19.1 19.2 17.9 20.5 41.3 1.76 4 64.0 3.43 4 19.2 1.06 4 Dosage Unit: mg/kg/day 42.7 41.5 43.2 38.1 41.1 44.1 59.3 63.0 68.6 60.1 58.5 63.4 17.2 18.7 20.3 18.0 17.6 18.4 41.8 2.11 6 62.2 3.73 6 18.4 1.09 6 30.7 29.1 27.1 29.3 29.5 30.1 29.3 1.23 6 29.7 30.6 29.6 29.9 30.0 .45 4 29.0 29.7 29.7 29.9 30.1 29.0 29.6 .46 6 521 438 273 502 424 411 428 87.8 6 402 626 525 444 499 98.7 4 384 459 644 353 469 370 446 107.9 6 .5 .2 .3 .3 .2 .3 .3 .11 6 .1 .2 .4 .1 .2 .14 4 .1 .3 .2 .2 .1 .1 .2 .08 6 36 13 21 22 13 20 21 8.4 6 10.0 10.0 10.2 10.2 9.5 10.1 10.0 .26 6 6 13 28 6 13 10.4 4 9.9 10.2 9.5 9.8 9.8 .29 4 7 20 13 13 7 7 11 5.2 6 10.1 9.7 10.0 9.9 10.0 10.7 10.1 .34 6 a Dosing was started on Day 17. Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 19.6 20.3 17.8 20.5 19.3 21.5 19.8 1.26 6 17.9 29.0 19.1 21.6 21.9 4.98 4 18.0 20.3 18.5 19.0 20.9 23.5 20.0 2.02 6 339 234 293 745 314 290 369 187.4 6 308 325 338 365 334 24.0 4 306 277 311 229 278 343 291 38.8 6 249 ANIMAL NUMBER RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/p,L X103/fJ,L PT SEC Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 a MEAN S.D. N Dose Level: 30/20 7.24 6.24 6.80 6.47 6.41 6.21 13.3 10.9 12.9 11.7 11.6 11.7 6.63 .396 5 12.1 .99 5 Dosage Unit: mg/kg/day 44.1 37.1 41.9 38.2 43.0 39.1 60.9 59.4 61.6 59.1 67.1 63.0 18.4 17.5 19.0 18.1 18.1 18.8 40.9 3.06 5 61.6 3.23 5 18.2 .54 5 30.1 29.5 30.9 30.6 27.0 29.9 29.6 1.56 5 750 360 598 474 396 361 516 159.7 5 .7 .2 .0 .4 .4 .1 .3 .26 5 51 10.1 23.8 12 10.2 21.5 0 9.3 21.6 26 10.5 31.4 26 9.7 21.9 6 NO COAG NO COAG 23 19.1 5 10.0 .47 5 24.0 4.22 5 325 336 349 451 915 UTD 475 250.9 5 a Unscheduled sacrifice on Day 29. 250 ANIMAL NUMBER WBC X103/fJ,L Appendix 4 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/p,L X103/fJ,L MONO EOSIN X103/fJ,L X103/fJ,L BASO N -SEG% X103/fJ,L LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level 0 19.5 11.0 14.3 15.3 9.6 7.0 13.6 6.7 7.6 9.6 3.9 2.3 12.8 4.48 6 7.3 4.05 6 Dose Level 3 8.8 3.8 9.4 4.8 8.6 1.6 4.3 1.1 7.8 2.34 4 2.8 1.76 4 Dose Level 10 7.6 8.6 16.7 8.0 12.8 10.7 3.2 3.3 12.5 5.0 6.8 5.4 10.7 3.51 6 6.0 3.45 6 Dosage Unit: mg/kg/day 4.9 .8 3.5 .7 5.8 .6 3.9 1.8 5.0 .4 4.3 .3 .2 .1 .1 .0 .2 .1 4.6 .8 .1 .83 .54 .08 666 Dosage Unit: mg/kg/day 4.5 .4 3.9 .6 5.3 1.1 2.9 .3 .0 .0 .6 .0 4.2 .6 .2 1.01 .36 .30 444 Dosage Unit: mg/kg/day 4.0 .4 4.1 .8 3.4 .5 2.4 .5 4.7 1.0 4.7 .6 .1 .3 .2 .0 .2 .1 3.9 .6 .2 .88 .23 .10 666 .0 70 25 4 1 0 .0 61 32 6 0 0 .0 53 41 4 1 0 .0 63 25 12 0 0 .0 41 53 4 2 0 .0 33 61 5 1 0 .0 54 40 6 1 0 .00 14 1 15 0 31 .8 0 666666 .0 43 52 5 0 0 .0 51 42 7 0 0 .1 18 62 13 7 1 .0 25 67 7 1 0 .0 34 56 8 2 0 .05 15 3 11 1 35 3.4 5 444444 .0 42 52 5 1 0 .0 38 48 10 4 0 .0 75 20 3 1 0 .0 62 30 6 1 0 .1 53 36 8 2 0 .0 50 43 6 1 0 .0 53 38 6 2 0 .04 13 6 11 9 24 1.2 0 666666 a Dosing was started on Day 17. 251 ANIMAL NUMBER WBC X103/p,L Appendix 4 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/p,L X103/fJ,L MONO EOSIN X103/fJ,L X103/fJ,L BASO N-SEG% X103/fJ,L LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 a MEAN S.D. N Dose Level : 30/20 7.6 10.0 7.3 9.2 11.8 16.4 3.3 4.4 2.7 4.7 5.0 13.7 9.2 1.84 5 4.0 .98 5 Dosage Unit: mg/kg/day 3.3 .9 4.8 .6 3.6 .9 3.3 1.0 3.9 2.8 2.4 .1 .2 .2 .1 .1 .0 .1 3.8 .62 5 1.2 .88 5 .1 .08 5 .0 43 43 12 .0 44 48 6 .0 37 49 12 .0 51 36 11 .0 43 33 24 .0 84 15 1 .0 44 42 13 .00 5.0 7.1 6.6 5555 20 20 20 11 00 10 10 .9 .4 55 a Unscheduled sacrifice on Day 29. 252 Appendix 4 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 Dose Level: 0 I05709 - - - 105714 - - - 105715 - - - I05718 - - - I05720 - - - I05725 - - - Group: 2 Dose Level: 3 I05702 I05706 I05717 I05721 b - - Group: 3 Dose Level: 10 105707 - - - 105708 - - - I05710 - - - I05712 - - - I05716 - - - I05719 - - - Group: 4 Dose Level: 30/20 105703 105704 I05711 I05713 I05722 I05724 a - - - - - - Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ------ - - a Unscheduled sacrifice on Day 29. b Dosing was started on Day 17. 253 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/fJ,L X103/fJ,L PT SEC Dose Level: 0 7.21 5.54 6.79 6.28 7.10 7.04 13.0 11.1 11.6 11.9 13.6 13.7 6.66 .641 6 12.5 1.10 6 Dose Level: 3 6.19 7.25 7.05 6.52 11.9 13.8 12.5 13.6 6.75 .485 4 13.0 .90 4 Dose Level: 10 7.03 6.53 6.27 6.75 7.02 7.06 12.1 12.1 12.7 12.0 12.5 12.9 6.78 .323 6 12.4 .37 6 Dosage Unit: mg/kg/day 42.1 36.9 41.2 39.7 47.1 45.5 58.4 66.6 60.7 63.2 66.3 64.7 18.0 20.0 17.2 19.0 19.1 19.5 42.1 3.75 6 63.3 3.24 6 18.8 1.03 6 Dosage Unit: mg/kg/day 40.1 44.2 42.1 45.7 64.8 60.9 59.8 70.1 19.2 19.0 17.7 20.8 43.0 2.45 4 63.9 4.66 4 19.2 1.27 4 Dosage Unit: mg/kg/day 40.8 40.3 41.2 40.5 40.9 43.5 58.0 61.8 65.7 60.0 58.2 61.7 17.3 18.5 20.3 17.8 17.8 18.2 41.2 1.17 6 60.9 2.86 6 18.3 1.05 6 30.9 30.1 28.3 30.1 28.8 30.1 29.7 .97 6 29.6 31.3 29.6 29.7 30.0 .83 4 29.8 29.9 30.9 29.7 30.6 29.6 30.1 .53 6 461 631 230 725 342 361 458 187.7 6 385 599 502 383 467 104.0 4 397 403 602 347 434 431 436 87.3 6 .3 .2 .3 .3 .3 .2 .3 .05 6 .5 .2 .4 .6 .4 .17 4 .1 .2 .4 .2 .1 .2 .2 .11 6 22 11 20 19 21 14 18 4.4 6 10.5 9.9 10.4 9.7 9.7 10.6 10.1 .41 6 31 14 28 39 28 10.4 4 10.2 10.2 9.6 9.8 10.0 .30 4 7 13 25 14 7 14 13 6.6 6 10.4 9.8 10.0 10.2 10.4 10.5 10.2 .27 6 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 19.7 21.0 17.4 17.5 18.8 20.9 19.2 1.59 6 19.6 26.8 18.1 22.5 21.7 3.83 4 17.6 19.9 18.1 19.4 20.8 24.5 20.0 2.47 6 338 361 253 530 273 301 343 100.1 6 286 338 294 356 318 33.9 4 309 248 287 191 216 290 257 46.5 6 254 ANIMAL NUMBER Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/p,L X103/fJ,L PT SEC Dose Level: 30/20 7.47 6.01 6.66 6.88 6.73 13.7 10.6 12.8 11.7 12.0 6.77 .600 4 12.0 1.28 4 Dosage Unit: mg/kg/day 46.1 35.1 41.9 39.6 41.8 61.7 58.4 62.9 57.6 62.2 18.4 17.6 19.2 17.1 17.9 40.6 4.58 4 60.0 2.31 4 17.8 .54 4 29.8 30.2 30.6 29.6 28.8 29.6 .59 4 623 325 558 410 374 433 131.4 4 .2 .3 .1 .1 .1 .2 .10 4 15 18 7 7 7 12 5.6 4 10.7 9.8 9.8 10.8 12.1 10.8 .95 4 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 24.6 21.7 20.0 26.4 26.1 24.7 2.15 4 166 279 309 245 87 194 85.7 4 a Dosing was stopped on Day 43; not included in the statistical analyses. 255 ANIMAL NUMBER WBC X103/p,L Appendix 4 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/p,L X103/fJ,L MONO EOSIN X103/fJ,L X103/fJ,L BASO N -SEG% X103/fJ,L LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 10.8 3.9 6.2 .4 .2 .0 36 58 4 2 0 I05714 13.6 8.9 3.9 .6 .1 .0 66 29 51 0 I05715 10.9 6.5 4.1 .2 .1 .0 59 38 2 1 0 I05718 11.7 5.4 5.1 1.0 .1 .1 46 44 81 0 I05720 11.3 5.7 4.0 1.3 .2 .1 50 36 12 21 I05725 8.1 4.1 3.3 .5 .1 .0 51 41 6 1 0 MEAN S.D. N 11.1 5.8 4.4 .7 .1 .0 51 41 6 1 0 1.78 1.83 1.04 .41 .05 .05 10..4 9..8 3..5 .5 4 66666666666 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 13.7 9.0 3.9 .7 .0 .1 66 28 5 0 0 I05706 11.2 5.9 4.4 .8 .0 .1 53 40 7 0 0 I05717 11.7 5.2 5.0 .7 .7 .0 45 43 6 6 0 I05721 5.5 1.9 3.2 .4 .0 .0 34 58 7 1 0 MEAN S.D. N 10.5 5.5 4.1 .6 .2 .0 50 42 6 2 0 3.52 2.91 .76 .17 .35 .06 13..5 12..3 1..0 2..9 0 44444444444 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 8.4 4.5 3.1 .7 .1 .0 54 37 8.9 3.9 3.9 .8 .2 .0 44 44 11.7 7.4 3.3 .6 .3 .1 64 28 11.1 8.3 2.4 .4 .1 .0 74 21 11.8 5.8 4.7 1.0 .3 .1 49 40 8.7 3.6 4.4 .5 .1 .0 41 51 81 93 53 41 82 62 0 0 1 0 0 1 MEAN S.D. N 10.1 5.6 3.6 .7 .2 .0 54 37 7 2 0 1.60 1.93 .86 .22 .10 .05 12..6 10..9 2..0 .9 5 66666666666 256 ANIMAL NUMBER Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N WBC X103/lL Appendix 4 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/lL X103/lL MONO EOSIN X103/hL X103/lL BASO N-SEG% X103/ iL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 Dose Level: 30/20 Dosage Unit: mg/kg/day 7.6 1.5 4.8 .8 .4 .0 20 63 11 5 1 9.3 4.3 4.3 .6 .1 .0 46 46 6 1 0 9.9 4.5 4.2 .9 .2 .0 46 43 92 0 5.0 1.5 2.8 .6 .1 .0 30 55 12 2 1 9.0 3.6 4.8 .5 .0 .0 40 54 6 0 0 7.7 2.7 4.2 .6 .2 .0 34 54 92 0 1.96 1.44 .95 .13 .17 .00 11.4 7.0 3.2 2.2 .6 44444444444 a Dosing was stopped on Day 43; not included in the statistical analyses. 257 Appendix 4 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 I05709 105714 105715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 Group: 3 105707 105708 I05710 I05712 I05716 I05719 Group: 4 105703 105704 I05711 a I05713 I05722 Dose Level: 0 Dose Level: 3 Dose Level: 10 Dose Level: 30/20 Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day Dosage Unit: mg/kg/day a Dosing was stopped on Day 43. 258 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/p,L X103/fJ,L PT SEC Dose Level: 0 6.82 6.15 7.14 6.95 7.05 7.11 12.3 12.6 11.9 12.8 13.5 14.2 6.87 .372 6 12.9 .84 6 Dose Level: 3 6.00 7.06 6.82 6.55 11.5 13.4 12.2 13.3 6.61 .455 4 12.6 .91 4 Dose Level: 10 6.84 6.59 6.24 6.95 7.33 7.00 12.3 12.3 12.8 12.2 13.0 12.6 6.82 .374 6 12.5 .32 6 Dosage Unit: mg/kg/day 40.1 42.6 44.1 43.9 46.5 48.1 58.8 69.2 61.8 63.2 65.9 67.6 18.0 20.4 16.7 18.4 19.2 19.9 44.2 2.83 6 64.4 3.88 6 18.8 1.35 6 Dosage Unit: mg/kg/day 37.9 43.4 41.5 45.7 63.1 61.4 60.8 69.7 19.1 19.0 17.9 20.3 42.1 3.30 4 63.8 4.08 4 19.1 .98 4 Dosage Unit: mg/kg/day 40.1 40.5 42.0 41.9 42.2 43.1 58.6 61.4 67.3 60.2 57.6 61.5 18.0 18.6 20.5 17.5 17.7 18.0 41.6 1.12 6 61.1 3.41 6 18.4 1.10 6 30.6 29.5 27.0 29.1 29.1 29.5 29.1 1.18 6 30.3 30.9 29.5 29.1 30.0 .81 4 30.7 30.4 30.5 29.1 30.7 29.2 30.1 .75 6 441 477 238 680 378 397 435 145.1 6 381 632 599 405 504 129.5 4 388 431 487 383 448 387 421 42.1 6 .3 .1 .4 .3 .3 .4 .3 .11 6 .4 .1 .7 .1 .3 .29 4 .1 .2 .7 .3 .1 .4 .3 .23 6 20 6 29 21 21 28 21 8.2 6 10.5 10.3 10.2 10.2 9.9 10.2 10.2 .19 6 24 7 48 7 22 19.4 4 10.4 10.5 10.0 10.3 10.3 .22 4 7 13 44 21 7 28 20 14.3 6 10.6 10.0 10.1 10.1 10.6 10.8 10.4 .34 6 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 18.3 19.8 16.6 16.6 18.5 19.1 18.1 1.31 6 17.1 23.4 18.3 19.8 19.6 2.73 4 17.1 19.7 17.6 19.2 20.2 21.5 19.2 1.64 6 299 256 267 288 281 279 278 15.2 6 287 329 258 370 311 49.0 4 301 241 263 224 233 310 262 36.2 6 259 ANIMAL NUMBER Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/p,L X103/fJ,L PT SEC Dose Level: 30/20 6.30 6.06 6.92 6.85 6.59 11.8 10.7 13.3 11.5 12.6 6.46 .559 2 11.1 .57 2 Dosage Unit: mg/kg/day 39.3 35.1 42.9 39.3 44.8 62.4 57.9 62.0 57.3 68.0 18.7 17.6 19.2 16.7 19.0 37.2 2.97 2 57.6 .42 2 17.2 .64 2 30.0 30.5 31.0 29.2 28.0 29.8 .92 2 587 356 510 456 436 406 70.7 2 1.8 .2 .1 .1 .3 .2 .07 2 113 12 7 7 20 10 3.5 2 9.7 10.1 10.5 10.8 10.2 10.4 .49 2 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 22.4 21.0 19.5 23.9 19.7 22.5 2.05 2 274 285 283 204 221 244 57 2 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 260 ANIMAL NUMBER Group: 1 105709 105714 105715 105718 105720 I05725 MEAN S.D. N Group: 2 I05702 105706 I05717 105721 MEAN S.D. N Group: 3 105707 105708 105710 I05712 105716 105719 MEAN S.D. N WBC X103/ iL Appendix 4 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/ iL X103/ iL MONO X103/ iL EOSIN X103/ iL BASO N-SEG% X103/ iL LYMPH% MONO1 EOSIN1 Covance 6329-231 3M T-6889.3 BASO% Dose Level: 0 10.4 13.5 10.2 10.5 11.8 8.5 4.1 7.9 3.9 3.8 4.2 2.8 10.8 1.68 6 4.4 1.76 6 Dose Level: 3 10.0 11.1 13.0 6.5 5.7 6.0 3.7 1.9 10.2 2.73 4 4.3 1.91 4 Dose Level: 10 9.2 7.3 15.0 9.5 11.0 10.5 4.8 2.4 9.5 6.2 3.8 5.4 10.4 2.58 6 5.4 2.42 6 Dosage Unit: mg/kg/day 5.8 .4 4.6 .7 5.8 .4 6.1 .4 5.7 1 .4 5.0 .7 .1 .2 .1 .2 .4 .0 5.5 .7 .2 .57 .39 .14 666 Dosage Unit: mg/kg/day 3.8 .3 .1 4.2 .8 .1 6.8 .6 1..8 3.8 .5 .3 4.6 .6 .6 1.45 .21 .82 444 Dosage Unit: mg/kg/day 3.4 .7 3.8 .8 4.0 .8 2.8 .4 5.3 1.3 4.6 .4 .1 .3 .5 .1 .4 .1 4.0 .7 .2 .88 .33 .18 666 .0 40 55 4 1 0 .0 59 34 5 2 0 .0 38 57 4 1 0 .0 36 58 4 2 0 .1 36 48 12 3 1 .0 33 58 8 1 0 .0 40 52 6 2 0 .04 9.4 9.4 3.3 .8 .4 666666 .1 57 38 .0 54 38 .0 28 52 .0 30 58 31 71 5 14 75 1 0 0 0 .0 42 46 6 5 0 .05 15.4 10.1 1.9 6.1 .5 444444 .0 53 38 8 1 0 .0 32 53 10 4 0 .1 64 27 6 3 0 .0 65 29 5 1 0 .1 35 48 12 4 1 .0 52 44 4 1 0 .0 50 40 8 2 0 .05 14.0 10.4 3.1 1.5 .4 666666 261 ANIMAL NUMBER Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N WBC X103/|iL Appendix 4 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/|iL X103/|iL MONO EOSIN X103/|iL X103/|.iL BASO N-SEG% X103/|.iL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 Dose Level: 30/20 10.0 9.8 16.0 5.6 8.2 4.0 5.3 9.8 1.5 1.8 7.7 2.97 2 3.4 2.69 2 Dosage Unit: mg/kg/day 4.2 1.4 3.8 .5 4.3 1.5 3.3 .7 5.3 .7 .3 .1 .4 .1 .4 3.6 .6 .1 .35 .14 .00 222 .0 40 42 14 .0 54 39 5 .1 61 27 9 .0 26 59 12 .0 22 64 8 .0 40 49 8 .00 19.8 14.1 4.9 2222 40 10 20 21 50 20 .7 .7 22 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 262 Appendix 4 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 a I05704 I05711 b I05713 I05722 c Dose Level: 0 ------- Dose Level: 3 ----- Dose Level: 10 ------- Dose Level: 30/20 ------ - - - - Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ----- Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ------ a Dosing was stopped on Day 80 b Dosing was stopped on Day 43 c Dosing was stopped on Day 66 263 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/p,L X103/fJ,L PT SEC Dose Level: 0 7.11 6.33 6.83 6.67 6.56 6.63 12.8 12.6 11.7 12.7 12.7 13.4 6.69 .263 6 12.6 .55 6 Dose Level: 3 5.86 7.23 7.63 5.26 11.5 13.2 13.4 10.7 6.91 .928 3 12.7 1.04 3 Dose Level: 10 7.20 6.24 6.38 6.43 7.36 6.93 12.1 11.7 12.9 11.7 13.0 12.5 6.76 .470 6 12.3 .57 6 Dosage Unit: mg/kg/day 39.7 40.8 39.6 40.9 41.1 41.7 55.7 64.5 58.0 61.3 62.5 63.0 18.0 19.9 17.2 19.0 19.3 20.3 40.6 .82 6 60.8 3.33 6 19.0 1.17 6 Dosage Unit: mg/kg/day 36.4 41.2 45.2 35.4 62.1 57.0 59.2 67.2 19.6 18.3 17.6 20.3 40.9 4.41 3 59.4 2.56 3 18.5 1.01 3 Dosage Unit: mg/kg/day 39.2 36.6 42.0 36.5 40.3 40.2 54.5 58.6 65.9 56.7 54.7 58.0 16.8 18.7 20.2 18.2 17.6 18.1 39.1 2.19 6 58.1 4.19 6 18.3 1.14 6 32.2 30.8 29.6 31.1 30.9 32.2 31.1 .98 6 31.6 32.1 29.8 30.2 31.2 1.21 3 30.9 32.0 30.6 32.1 32.1 31.2 31.5 .67 6 488 390 245 630 346 352 408 133.8 6 .4 .9 .6 1.2 .7 .0 .6 .41 6 366 617 564 399 516 132.3 3 .8 .9 .9 .3 .9 .06 3 409 383 609 322 432 338 416 103.5 6 .5 .6 1.3 .2 .2 .4 .5 .41 6 28 57 41 80 46 0 42 27.0 6 10.3 10.2 10.3 10.2 9.4 10.7 10.2 .43 6 47 65 69 16 60 11.7 3 10.1 10.5 9.6 10.2 10.1 .45 3 36 37 83 13 15 28 35 25.5 6 10.2 10.7 10.1 10.3 10.1 10.4 10.3 .23 6 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 19.3 19.0 16.0 16.3 17.3 19.3 17.9 1.53 6 17.3 26.3 18.1 22.1 20.6 4.98 3 17.1 21.9 18.9 18.8 20.0 21.1 19.6 1.74 6 313 233 277 300 261 251 272 30 6 302 287 293 702 294 7 3 315 243 273 216 226 393 278 66 6 a Unscheduled sacrifice on Day 137. 264 ANIMAL NUMBER Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/fJ,L X103/fJ,L PT SEC Dose Level: 30/20 7.12 5.58 7.00 6.77 6.81 13.4 9.8 13.1 11.4 12.9 6.18 .841 2 10.6 1.13 2 Dosage Unit: mg/kg/day 41.7 30.8 40.6 37.1 42.3 58.6 55.2 58.0 54.9 62.1 18.8 17.6 18.6 16.9 18.9 33.9 4.45 2 55.0 .21 2 17.2 .49 2 32.2 32.0 32.2 30.8 30.4 31.4 .85 2 610 250 428 505 406 378 180.3 2 .8 .3 .3 .0 .2 .2 .21 2 57 17 21 0 14 8 12.0 2 10.3 10.3 10.1 10.4 9.5 10.3 .07 2 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 19.4 20.6 19.1 30.5 17.2 25.5 7.00 2 244 273 338 175 293 224 69 2 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 265 ANIMAL NUMBER WBC X103/p,L Appendix 4 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/p,L X103/fJ,L MONO EOSIN X103/fJ,L X103/fJ,L BASO N -SEG% X103/fJ,L LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 10.5 4.1 5.8 .4 .3 .0 39 55 4 11.5 6.5 3.5 1.3 .1 .1 57 30 11 10.3 4.3 5.6 .3 .1 .0 42 54 2 15.7 8.0 6.0 1.3 .3 .1 51 38 8 12.1 5.2 5.3 1.2 .3 .1 43 44 10 5.1 2.0 2.6 .5 .0 .0 39 51 9 2 1 1 2 2 1 0 1 0 0 1 0 MEAN S.D. N 10.9 5.0 4.8 .8 .2 .0 45 45 7 2 0 3.43 2.08 1.40 .48 .13 .05 7..3 9..9 3..6 .5 5 66666666666 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 11.0 5.9 4.4 .5 .1 .0 54 40 51 0 I05706 12.0 5.1 5.5 1.2 .1 .1 43 46 10 11 I05717 14.4 2.0 8.9 2.2 1.2 .1 14 62 15 91 I05721 a 9.4 6.6 1.7 1.1 .0 .0 70 18 12 0 0 MEAN S.D. N 12.5 4.3 6.3 1.3 .5 .1 37 49 10 4 1 1.75 2.06 2.35 .85 .64 .06 20..7 11..4 5..0 4.6 6 33333333333 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 8.2 4.0 3.0 .9 .1 .1 50 37 11 1 1 I05708 8.2 3.4 3.4 .8 .4 .1 42 42 10 5 1 I05710 12.9 6.9 4.5 1.0 .4 .1 54 35 83 0 I05712 9.3 5.6 3.0 .5 .1 .1 60 32 6 1 1 I05716 13.5 4.9 7.0 1.1 .5 .1 36 52 841 I05719 6.0 1.6 3.6 .6 .1 .0 26 61 10 2 1 MEAN S.D. N 9.7 4.4 4.1 .8 .3 .1 45 43 93 1 2.93 1.84 1.53 .23 .19 .04 12..5 11..2 1..8 1.6 4 66666666666 a Unscheduled sacrifice on Day 137. 266 ANIMAL NUMBER Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N WBC X103/|iL Appendix 4 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/|iL X103/|iL MONO EOSIN X103/|iL X103/|.iL BASO N-SEG% X103/|.iL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 Dose Level: 30/20 Dosage Unit: mg/kg/day 9.5 4.6 3.5 1.2 .2 .0 48 37 13 2 1 9.4 3.6 4.3 1.1 .4 .1 38 45 11 4 1 13.6 8.1 4.3 1.0 .1 .1 60 32 7 1 0 6.3 1.4 3.9 .7 .1 .1 23 63 11 1 2 13.2 7.4 5.2 .6 .1 .0 56 39 4 1 0 7.8 2.5 4.1 .9 .2 .1 30 54 11 2 2 2.19 1.56 .28 .28 .21 .00 10.6 12.7 .0 2.1 .7 22222222222 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 267 Appendix 4 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 - - - - - 105714 - - - - - 105715 - - - - - I05718 - - - - - I05720 - - - - - I05725 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 - I05706 - I05717 - I05721 d - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day 105707 - - - - - 105708 - - - - - I05710 - - - - - I05712 - - - - - I05716 - - - - - I05719 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day 105703 a 105704 I05711 b I05713 I05722 c - - - - - - -- -- - - - - - a Dosing was stopped on Day 81 b Dosing was stopped on Day 43 c Dosing was stopped on Day 66 d Unscheduled sacrifice on Day 137. 268 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N RBC X106/|iL HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC % FL PG % X103/|iL % X103/|iL PT SEC Dose Level: 0 7.14 6.87 13.8 13.6 7.00 .191 2 13.7 .14 2 Dose Level: 10 6.77 7.32 11.9 12.8 7.04 .389 2 12.3 .64 2 Dosage Unit: mg/kg/day 44.8 44.8 62.7 65.3 19.4 19.8 44.8 .00 2 64.0 1.84 2 19.6 .28 2 Dosage Unit: mg/kg/day 39.1 40.5 57.7 55.3 17.6 17.5 39.8 .99 2 56.5 1.70 2 17.5 .07 2 30.9 30.3 30.6 .42 2 30.5 31.5 31.0 .71 2 667 317 492 247.5 2 335 446 390 78.5 2 .7 .6 .6 .07 2 .5 .1 .3 .28 2 50 41 46 6.4 2 10.0 9.5 9.8 .35 2 34 7 20 19.1 2 10.1 10.4 10.2 .21 2 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 17.3 18.6 17.9 .92 2 19.2 21.1 20.2 1.34 2 343 267 305 53 2 203 224 214 14 2 269 ANIMAL NUMBER WBC X103/lL Appendix 4 Individual Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/lL X103/lL MONO EOSIN X103/lL X103/lL BASO N-SEG% X103/ iL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05718 24.7 11.6 10.7 1.7 .5 .2 47 43 7 2 1 I05720 12.6 3.3 7.0 1.7 .5 .1 26 55 14 41 MEAN S.D. N 18.7 7.4 8.8 1.7 .5 .2 36 49 10 3 1 8.56 5.87 2.62 .00 .00 .07 14.8 8.5 4.9 1.4 .0 22222222222 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 10.3 5.7 3.8 .7 .1 .0 55 36 7 1 0 11.9 3.6 6.0 1.5 .7 .2 30 50 12 6 1 MEAN S.D. N 11.1 4.6 4.9 1.1 .4 .1 42 43 10 4 0 1.13 1.48 1.56 .57 .42 .14 17.7 9.9 3.5 3.5 .7 22222222222 270 Appendix 4 Individual Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 --- Dose Level: 10 --- Dosage Unit: mg/kg/day -._ --_ Dosage Unit: mg/kg/day _-_ --_ Covance 6329-231 3M T-6889.3 271 ANIMAL NUMBER Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N RBC X10Vj.lL HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC % FL PG % X103/|aL % X103/lL PT SEC Dose Level: 0 6.94 6.90 13.4 13.7 6.92 .028 2 13.6 .21 2 Dose Level: 10 6.96 7.54 12.1 13.3 7.25 .410 2 12.7 .85 2 Dosage Unit: mg/kg/day 43.8 45.0 63.0 65.2 19.2 19.9 44.4 .85 2 64.1 1.56 2 19.6 .49 2 Dosage Unit: mg/kg/day 40.2 41.4 57.7 54.9 17.4 17.6 40.8 .85 2 56.3 1.98 2 17.5 .14 2 30.5 30.5 30.5 .00 2 30.2 32.1 31.2 1.34 2 664 394 529 190.9 2 352 490 421 97.6 2 .4 .3 .4 .07 2 .3 .0 .2 .21 2 28 21 24 4.9 2 10.0 9.5 9.8 .35 2 21 0 10 14.8 2 10.1 10.2 10.2 .07 2 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 16.7 19.2 18.0 1.77 2 19.0 19.3 19.2 .21 2 326 320 323 4 2 217 237 227 14 2 272 ANIMAL NUMBER WBC X103/lL Appendix 4 Individual Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/lL X103/lL MONO EOSIN X103/lL X103/lL BASO N-SEG% X103/ iL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO1 Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 17.9 13.8 7.7 3.7 15.8 2.90 2 5.7 2.83 2 Dose Level: 10 7.1 14.3 3.5 5.4 10.7 5.09 2 4.4 1.34 2 Dosage Unit: mg/kg/day 8.5 1.2 7.8 1.5 .3 .7 8.2 .49 2 1.4 .21 2 .5 .28 2 Dosage Unit: mg/kg/day 2.7 .7 7.1 1.2 .1 .5 4.9 3.11 2 1.0 .35 2 .3 .28 2 .2 43 48 6 .1 27 56 11 2 5 .2 35 52 8 4 .07 11.3 5.7 3.5 2.1 22222 .0 50 39 10 .1 38 50 9 1 3 .0 44 44 10 2 .07 8.5 7.8 .7 1.4 22222 1 1 1 .0 2 0 1 0 .7 2 273 Appendix 4 Individual Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 --- Dose Level: 10 --- Dosage Unit: mg/kg/day -._ --_ Dosage Unit: mg/kg/day _-_ --_ Covance 6329-231 3M T-6889.3 274 ANIMAL NUMBER Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N RBC X106/fJ,L HGB G/DL Appendix 4 Individual Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS HCT MCV MCH MCHC PLT RETIC RETIC FL PG X103/fJ,L X103/fJ,L PT SEC Dose Level: 0 7.47 6.46 14.6 12.9 6.96 .714 2 13.8 1.20 2 Dose Level: 10 6.97 7.43 12.4 13.1 7.20 .325 2 12.8 .49 2 Dosage Unit: mg/kg/day 46.3 40.8 61.9 63.1 19.5 20.0 43.6 3.89 2 62.5 .85 2 19.8 .35 2 Dosage Unit: mg/kg/day 40.7 41.6 58.3 56.0 17.8 17.6 41.1 .64 2 57.2 1.63 2 17.7 .14 2 31.5 31.7 31.6 .14 2 30.5 31.4 31.0 .64 2 756 411 584 244.0 2 408 484 446 53.7 2 .1 .2 .2 .07 2 .7 .0 .4 .49 2 7 13 10 4.2 2 10.2 9.4 9.8 .57 2 49 0 24 34.6 2 10.1 10.4 10.2 .21 2 Covance 6329-231 3M T-6889.3 PTT SEC FBR MG/DL 17.3 18.0 17.6 .49 2 17.8 18.8 18.3 .71 2 408 653 530 173.2 2 282 319 300 26.2 2 275 ANIMAL NUMBER WBC X103/p,L Appendix 4 Individual Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS N-SEG LYMPH X103/ iL X103/fJ,L MONO EOSIN X103/fJ,L X103/fJ,L BASO N-SEG% X103/|iL LYMPH% MONO% EOSIN% Covance 6329-231 3M T-6889.3 BASO% Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 18.1 12.0 9.2 5.6 15.0 4.31 2 7.4 2.55 2 Dose Level: 10 19.1 13.2 13.3 4.9 16.2 4.17 2 9.1 5.94 2 Dosage Unit: mg/kg/day 6.9 1.7 4.4 1.6 .2 .2 5.6 1.77 2 1.6 .07 2 .2 .00 2 Dosage Unit: mg/kg/day 4.4 1.3 6.9 1.3 .1 .1 5.6 1.77 2 1.3 .00 2 .1 .00 2 1 51 38 10 1 1 1 47 37 14 2 1 1 49 38 12 2 1 00 2.8 .7 2.8 .7 .0 222222 0 70 23 7 0 0 0 37 52 10 1 0 0 54 38 8 0 0 00 23.3 20.5 2.1 .7 .0 222222 276 Appendix 4 Individual Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ANISO POLY POIK HYPO TOXNEUT Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 --- Dose Level: 10 --- Dosage Unit: mg/kg/day -._ --_ Dosage Unit: mg/kg/day _-_ --_ Covance 6329-231 3M T-6889.3 277 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 85 20 96 15 83 15 122 16 82 12 87 17 92 15.3 6 16 2. 6 6 Dose Level : 3 78 13 78 19 96 15 100 8 88 11.7 4 14 4. 6 4 Dose Level : 10 78 15 77 16 134 18 85 17 96 14 84 14 92 21.5 6 16 1. 6 6 Dosage Unit: mg/kg/day 1.3 8.9 1.3 8.8 1.2 10.4 1.2 9.4 .9 9.7 1.3 9.3 4.3 5.0 5.3 5.0 4.4 5.1 1.2 .15 6 9.4 .58 6 4.8 .40 6 Dosage Unit: mg/kg/day 1.0 10.0 1.3 9.2 1.0 8.3 1.2 10.2 5.2 5.2 4.9 5.6 1.1 .15 4 9.4 .87 4 5.2 .29 4 Dosage Unit: mg/kg/day 1.2 8.9 1.2 8.7 1.3 10.1 1.2 8.6 1.3 8.5 1.3 9.8 4.6 4.8 4.9 5.1 4.6 5.0 1.2 .05 6 9.1 .68 6 4.8 .21 6 4.6 3.8 5.1 4.4 5.3 4.2 4.6 .56 6 4.8 4.0 3.4 4.6 4.2 .63 4 4.3 3.9 5.2 3.5 3.9 4.8 4.3 .63 6 .0 11 132 28 .0 7 128 48 .1 8 122 30 .0 12 237 57 .0 8 127 33 .1 10 138 40 .0 9 147 39 .05 2. 0 44. 3 11. 3 6666 .3 4 154 45 .0 11 120 55 .0 9 176 61 .0 15 247 38 .1 10 174 50 .15 4. 6 53. 7 10. 2 4444 .1 11 127 50 .0 7 138 57 .1 9 139 65 .0 7 183 80 .1 10 125 33 .6 10 158 79 .2 9 145 61 .23 1. 7 22. 0 18. 0 6666 278 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Dose Level: 30/20 88 14 79 17 84 14 75 12 78 17 80 16 81 4.6 6 15 2.0 6 Dosage Unit: mg/kg/day 1.4 10.3 1.0 9.9 1.2 8.6 .8 8.8 1.2 8.7 1.2 8.5 4.7 5.1 4.7 4.5 4.8 4.7 1.1 .21 6 9.1 .77 6 4.8 .20 6 5.6 4.8 3.9 4.3 3.9 3.8 4.4 .70 6 .1 3 153 61 .4 2 123 75 .3 9 165 42 .1 6 106 43 .0 14 170 52 .1 11 122 66 .2 8 140 56 .15 4.7 26.3 13.2 6666 279 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 37 42 28 36 24 35 52 96 34 44 36 93 35 9.6 6 58 28. 8 6 Dose Level: 3 44 38 42 52 40 33 35 43 40 3.9 4 42 8. 1 4 Dose Level: 10 42 144 42 45 51 130 38 91 30 40 34 14 40 7.3 6 77 52. 6 6 Dosage Unit: mg/kg/day 290 109 699 99 442 151 300 107 288 181 711 111 4 3 2 4 3 4 455 202.2 6 126 32.4 6 3 8 6 Dosage Unit: mg/kg/day 333 101 514 159 762 141 616 138 3 4 9 4 556 180.3 4 135 24.3 4 5 2. 7 4 Dosage Unit: mg/kg/day 903 136 598 158 468 84 673 167 411 85 572 92 5 6 8 5 3 2 604 173.8 6 120 38.0 6 5 2. 1 6 88 102 128 160 100 294 145 77. 2 6 146 121 134 166 142 19. 1 4 139 129 205 80 126 86 128 45. 0 6 376 320 552 917 420 514 516 214. 2 6 391 358 428 332 377 41. 6 4 409 246 285 374 526 375 369 98. 5 6 26 24 25 21 13 41 25 9. 1 6 194 175 266 387 191 210 237 79 6 31 69 46 4 38 27. 3 4 202 166 214 149 183 30 4 26 0 10 19 13 13 14 8. 7 6 196 129 157 184 331 173 195 70 6 280 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Dose Level: 30/20 42 38 43 98 40 48 25 24 49 56 34 135 39 8. 3 6 66 41. 8 6 Dosage Unit: mg/kg/day 790 72 581 57 266 176 288 139 774 162 427 96 6 3 3 2 3 3 521 231.6 6 117 49.1 6 3 1.4 6 136 200 117 122 213 61 142 56.6 6 448 390 413 331 469 226 380 89.3 6 85 50 41 0 32 15 37 29.6 6 249 215 184 155 200 118 187 46 6 281 Appendix 4 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 11.3 11.5 12.2 11.5 10.9 11.1 6.0 4.6 5.6 6.1 6.2 6.6 11.4 .45 6 5.8 .69 6 Dose Level : 3 11.6 11.5 10.5 12.2 6.9 6.8 5.9 7.1 11.4 .70 4 6.7 .53 4 Dose Level : 10 10.7 10.7 11.8 10.7 10.6 11.0 7.0 6.0 8.1 6.7 4.0 5.9 10.9 .45 6 6.3 1.37 6 Dosage Unit: mg/kg/day 164 6.0 114 164 5.4 113 168 6.0 116 162 6.4 111 159 5.0 113 163 5.8 114 163 2.9 6 5.8 .50 6 114 1 6 Dosage Unit: mg/kg/day 166 6.3 112 164 5.8 112 154 4.9 109 166 6.7 109 162 5.7 4 5.9 .78 4 110 1 4 Dosage Unit: mg/kg/day 158 5.1 113 159 5.4 112 162 6.1 111 155 4.9 109 156 4.9 111 158 5.7 113 158 2.4 6 5.4 .48 6 112 1 6 282 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Dose Level : 30/20 11.5 11.1 10.2 10.1 10.9 10.3 7.0 5.8 5.1 6.3 7.3 5.0 10.7 .57 6 6.1 .96 6 Dosage Unit: mg/kg/day 159 6.3 110 159 5.4 109 157 5.3 113 158 5.7 111 166 6.3 115 153 4.9 113 159 4.2 6 5.6 .56 6 112 2 6 Covance 6329-231 3M T-6889.3 283 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 Dose Level : 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 72 17 1.2 8.6 4.2 4.4 61 14 1.5 8.8 4.9 3.9 63 19 1.4 10.2 5.1 5.1 123 13 1.3 9.6 4.5 5.1 81 13 1.0 9.2 4.2 5.0 71 15 1.3 9.1 5.1 4.0 .3 5 123 .0 10 153 .1 12 126 .3 8 174 .1 5 143 .1 10 154 24 40 36 89 36 36 MEAN S.D. N 78 22.9 6 15 2. 4 6 1.3 .17 6 9.2 .58 6 4.7 .42 6 4.6 .56 6 .2 .12 6 8 146 2. 9 19. 1 66 44 22 6 Group: 2 Dose Level : 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 a 80 18 1.1 9.0 4.7 4.3 64 18 1.2 8.8 5.2 3.6 81 17 1.2 8.4 4.7 3.7 85 9 1.5 8.2 5.0 3.2 .3 .1 .0 .0 7 130 5 76 8 190 8 209 38 37 87 42 MEAN S.D. N 78 9.3 4 16 4. 4 4 1.2 .17 4 8.6 .37 4 4.9 .24 4 3.7 .45 4 .1 .14 4 7 151 1. 4 60. 4 44 51 24 4 Group: 3 Dose Level : 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 70 16 1.4 8.9 4.9 4.0 70 17 1.2 8.5 4.5 4.0 81 16 1.5 9.4 4.7 4.7 84 18 1.1 8.3 4.7 3.6 69 19 1.2 8.1 4.5 3.6 61 15 1.3 10.1 5.2 4.9 .0 8 120 64 .1 8 148 82 .3 11 138 90 .3 16 190 116 .2 7 120 38 .1 9 137 65 MEAN S.D. N 72 17 1.3 8.9 4.8 4.1 .2 10 142 76 8.5 1. 5 .15 .75 .27 .55 .12 3. 3 25. 9 26 6666666666 a Dosing was started on Day 17. 284 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 4 Dose Level : 30/20 I05703 I05704 I05711 I05713 I05722 I05724 SH, a 71 68 70 75 91 53 19 18 17 13 15 29 MEAN S.D. N 75 9.3 5 16 2.4 5 Dosage Unit: mg/kg/day 1.5 9.3 4.9 1.4 9.0 4.9 1.2 8.1 4.1 1.2 8.5 4.4 1.4 9.1 4.2 1.9 5.6 2.9 1.3 .13 5 8.8 .49 5 4.5 .38 5 4.4 4.1 4.0 4.1 4.9 2.7 4.3 .37 5 .1 .2 .2 .0 .2 1.8 .1 .09 5 7 11 6 8 7 49 8 1. 9 5 179 146 181 137 145 14 158 20.8 5 122 129 45 57 185 87 108 57 5 a Unscheduled sacrifice on Day 29. 285 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 40 34 33 53 27 45 30 40 32 39 45 80 34 6.7 6 48 16. 7 6 Dose Level: 3 47 33 25 22 48 26 35 36 39 10.9 4 29 6. 4 4 Dose Level: 10 41 80 47 52 38 74 28 65 33 42 31 19 36 7.0 6 55 22. 6 6 Dosage Unit: mg/kg/day 364 121 810 96 632 151 411 80 363 154 882 122 6 5 2 3 4 6 577 232.0 6 121 29.3 6 4 1. 6 6 Dosage Unit: mg/kg/day 362 85 686 104 824 142 645 98 4 0 6 2 629 193.9 4 107 24.5 4 3 2. 6 4 Dosage Unit: mg/kg/day 906 113 682 149 587 80 811 134 452 78 785 90 2 5 3 2 2 1 704 165.2 6 107 29.6 6 2 1. 4 6 78 112 124 70 93 211 115 51. 3 6 114 77 157 280 157 88. 3 4 162 187 151 88 161 113 144 36. 4 6 429 368 550 838 446 675 551 177. 3 6 354 342 466 421 396 58. 3 4 391 272 272 335 565 397 372 109. 2 6 25 24 43 31 34 78 39 20. 2 6 213 202 244 426 192 251 255 87 6 66 57 42 18 46 21. 0 4 179 156 229 160 181 33 4 30 9 12 27 28 7 19 10. 6 6 181 145 144 164 369 177 197 85 6 a Dosing was started on Day 17. 286 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 4 Dose Level: 30/20 I05703 I05704 I05711 I05713 I05722 I05724 SH,a 36 41 31 23 33 1974 32 60 31 29 28 1463 MEAN S.D. N 33 6.6 5 36 13.5 5 Dosage Unit: mg/kg/day 696 67 738 60 188 130 300 133 931 98 452 90 3 0 0 2 2 59 571 313.5 5 98 34.1 5 1 1.3 5 111 244 78 116 93 68850 128 66.4 5 438 372 409 333 617 180 434 109.7 5 34 79 27 0 30 64 34 28.5 5 241 203 176 142 264 95 205 49.0 5 a Unscheduled sacrifice on Day 29. 287 Appendix 4 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 10.5 11.5 11.0 11.5 10.5 10.9 6.3 6.1 6.1 4.1 5.4 7.5 11.0 .45 6 5.9 1.12 6 Dose Level : 3 10.0 10.3 10.1 10.0 5.3 4.9 6.9 6.0 10.1 .14 4 5.8 .88 4 Dose Level : 10 10.4 10.5 10.7 10.0 9.9 10.7 6.1 6.0 6.8 5.8 4.5 6.0 10.4 .34 6 5.9 .75 6 Dosage Unit: mg/kg/day 157 5.8 117 160 6.3 112 162 5.2 112 158 5.7 109 153 5.9 115 161 6.0 113 158 3.3 6 5.8 .37 6 113 2 6 Dosage Unit: mg/kg/day 150 5.1 111 152 5.6 111 152 5.3 112 156 5.2 109 152 2.5 4 5.3 .22 4 111 1 4 Dosage Unit: mg/kg/day 153 4.6 109 156 5.8 114 157 5.6 110 145 4.7 109 149 4.5 111 158 5.0 108 153 5.1 6 5.0 .55 6 110 2 6 a Dosing was started on Day 17. 288 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 4 Dose Level : 30/20 I05703 I05704 I05711 I05713 I05722 I05724 SH,a 11.6 10.3 10.1 9.9 11.5 8.0 5.6 5.4 4.2 4.8 4.3 4.9 MEAN S.D. N 10.7 .81 5 4.9 .63 5 Dosage Unit: mg/kg/day 164 6.8 115 152 4.5 107 154 6.5 116 151 5.6 110 163 5.8 111 133 5.6 89 157 6.2 5 5.8 .90 5 112 3 5 a Unscheduled sacrifice on Day 29. Covance 6329-231 3M T-6889.3 289 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 Dose Level : 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 61 20 1.2 8.7 4.4 4.3 67 18 1.0 8.5 4.1 4.4 60 23 1.2 9.5 5.1 4.4 115 14 1.3 9.1 4.1 5.0 74 13 .9 9.3 4.7 4.6 88 16 1.4 8.7 4.9 3.8 .5 4 126 30 .3 10 113 61 .7 6 139 33 .2 1 216 59 .5 2 168 42 .5 9 143 35 MEAN S.D. N 78 21.1 6 17 3.8 6 1.2 .19 6 9.0 .39 6 4.6 .42 6 4.4 .39 6 .4 .18 6 5 151 3..7 36. 9 66 43 13.5 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 75 20 1.0 9.3 5.1 4.2 62 23 1.2 9.0 5.3 3.7 73 17 1.1 8.2 4.7 3.5 62 13 1.0 9.1 5.1 4.0 .3 2 132 46 .2 8 91 39 .4 14 191 83 .3 11 229 69 MEAN S.D. N 68 7.0 4 18 4.3 4 1.1 .10 4 8.9 .48 4 5.0 .25 4 3.8 .31 4 .3 .08 4 9 161 5.1 61.3 44 59 20.4 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 76 16 1.2 9.0 4.7 4.3 .1 4 122 69 63 19 .9 8.0 4.2 3.8 .3 10 164 81 78 15 1.2 8.7 4.4 4.3 .2 9 137 80 83 18 1.2 8.2 5.0 3.2 .3 10 246 124 70 17 1.4 8.0 4.5 3.5 .3 13 125 41 54 16 1.2 9.7 5.1 4.6 .1 6 151 64 MEAN S.D. N 71 10.7 6 17 1.5 6 1.2 .16 6 8.6 .67 6 4.6 .35 6 4.0 .54 6 .2 .10 6 9 158 3.2 46.2 66 76 27.4 6 290 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Dose Level: 30/20 81 19 69 20 61 18 83 15 71 27 76 7.0 4 20 5.0 4 Dosage Unit: mg/kg/day 1.4 8.9 3.8 1.2 9.0 4.7 1.2 8.5 4.5 1.2 8.1 4.1 1.1 6.4 2.9 1.2 .13 4 8.1 1.20 4 3.9 .75 4 5.1 4.3 4.0 4.0 3.5 4.2 .67 4 .3 15 143 72 .3 12 138 116 .0 12 166 47 .0 2 139 56 .5 60 164 22 .3 22 146 66 .21 25.8 12.2 39 4444 a Dosing was stopped on Day 43; not included in the statistical analyses. 291 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 31 36 46 63 30 52 31 70 30 46 46 104 36 8.0 6 62 23. 9 6 Dose Level: 3 45 46 21 21 34 31 40 82 35 10.4 4 45 26. 7 4 Dose Level: 10 33 48 45 51 32 52 44 88 32 53 29 28 36 6.9 6 53 19. 4 6 Dosage Unit: mg/kg/day 366 143 729 80 534 126 592 111 400 170 870 107 2 7 2 3 0 7 582 193.3 6 123 31.2 6 4 2. 9 6 Dosage Unit: mg/kg/day 386 104 576 113 757 140 727 128 2 2 0 2 612 169.9 4 121 15.9 4 2 1. 0 4 Dosage Unit: mg/kg/day 880 115 603 154 502 86 908 147 452 91 665 94 2 5 2 4 1 2 668 190.3 6 114 29.7 6 3 1. 5 6 85 118 113 113 105 298 139 78.9 6 114 121 143 147 131 16.2 4 108 256 117 84 187 105 143 65.6 6 426 287 465 729 435 542 481 147.1 6 400 415 455 316 396 58.5 4 334 226 248 364 519 391 347 106.2 6 9 17 17 41 38 49 28 16.2 6 113 187 36 6 86 81.3 4 25 0 5 24 22 0 13 12.2 6 245 176 252 418 226 255 262 81 6 237 228 260 155 220 45 4 188 138 154 212 371 203 211 83 6 292 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Dose Level: 30/20 85 90 37 49 38 42 22 34 419 595 141 187..4 4 192 269. 7 4 Dosage Unit: mg/kg/day 496 70 591 57 186 167 255 175 595 136 11 2 2 2 20 484 159.5 4 110 55.7 4 9 8.6 4 114 167 137 113 1122 379 496. 0 4 418 330 351 262 400 352 71.3 4 0 28 17 0 3 8 13.6 4 262 207 185 141 205 204 49.5 4 a Dosing was stopped on Day 43; not included in the statistical analyses. 293 Appendix 4 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 10.7 10.5 10.9 10.5 10.8 10.0 6.2 5.9 5.9 5.1 6.0 6.4 10.6 .32 6 5.9 .44 6 Dose Level : 3 10.5 10.8 10.1 10.8 5.8 5.2 6.2 7.7 10.6 .33 4 6.2 1.07 4 Dose Level : 10 10.7 9.9 10.2 10.8 10.1 10.7 5.7 5.9 5.9 6.1 4.4 6.4 10.4 .38 6 5.7 .69 6 Dosage Unit: mg/kg/day 158 5.5 112 150 5.3 106 159 5.3 115 155 5.2 110 158 4.8 111 154 4.7 111 156 3.4 6 5.1 .31 6 111 2 6 Dosage Unit: mg/kg/day 156 4.9 109 153 5.2 114 150 5.0 110 159 5.1 111 154 3.9 4 5.0 .13 4 111 2 4 Dosage Unit: mg/kg/day 151 4.3 110 150 4.5 111 149 5.5 112 151 4.5 112 147 4.3 111 152 4.6 105 150 1.8 6 4.6 .45 6 110 2 6 294 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Dose Level : 30/20 10.6 10.4 10.9 9.4 8.6 5.1 5.3 5.0 4.2 4.9 9.8 .93 4 4.9 .48 4 Dosage Unit: mg/kg/day 158 7.0 111 151 4.7 107 155 6.4 116 152 5.8 113 149 5.8 112 152 3.9 4 5.8 .94 4 111 2 4 a Dosing was stopped on Day 43; not included in the statistical analyses. Covance 6329-231 3M T-6889.3 295 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 Dose Level : 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 66 19 1.7 9.0 4.5 4.5 71 20 1.3 9.2 4.7 4.5 68 22 1.2 10.5 5.4 5.1 88 18 1.4 9.5 4.9 4.6 86 18 1.0 9.5 4.9 4.6 93 17 1.3 9.5 5.2 4.3 .2 11 131 33 .1 10 158 55 .3 19 144 32 .0 5 257 43 .5 12 154 40 .2 10 158 36 MEAN S.D. N 79 19 1.3 9.5 4.9 4.6 .2 11 167 40 11.7 1. 8 .23 .52 .33 .27 .17 4. 5 45. 3 8 6666666666 Group: 2 Dose Level : 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 74 22 1.0 9.0 4.8 4.2 68 20 1.3 9.0 5.2 3.8 91 17 1.3 8.8 4.9 3.9 79 14 1.2 8.8 4.8 4.0 .3 17 137 40 .2 8 97 33 .4 14 180 89 .2 10 215 62 MEAN S.D. N 78 18 1.2 8.9 4.9 4.0 .3 12 157 56 9.8 3. 5 .14 .12 .19 .17 .10 4. 0 51. 3 25 4444444444 Group: 3 Dose Level : 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 77 16 1.3 9.3 4.7 4.6 67 21 1.1 8.5 4.3 4.2 84 17 1.4 9.4 4.7 4.7 90 21 1.4 8.6 5.0 3.6 76 24 1.3 8.4 4.5 3.9 68 20 1.2 10.2 5.2 5.0 .2 9 124 66 .3 6 170 83 .0 6 136 112 .2 15 205 148 .1 11 131 46 .3 19 163 70 MEAN S.D. N 77 20 1.3 9.1 4.7 4.3 .2 11 155 88 8.9 2. 9 .12 .70 .33 .53 .12 5. 2 30. 6 36 6666666666 296 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Dose Level:: 30/20 96 20 71 18 63 23 98 16 74 19 84 19.1 2 17 1.4 2 Dosage Unit: mg/kg/day 1.2 8.9 3.8 1.2 9.8 4.9 1.4 8.9 4.8 .9 8.2 4.0 1.1 9.1 4.6 1.0 .21 2 9.0 1.13 2 4.4 .64 2 5.1 4.9 4.1 4.2 4.5 4.6 .49 2 1 12 186 75 2 9 148 138 4 11 159 58 0 17 135 60 2 14 177 41 1 13 142 99 14 5.7 9.2 55.2 2222 a Dosing was stopped on Day 81; not included in the statistical analyses. b Dosing was stopped on Day 43; not included in the statistical analyses. c Dosing was stopped on Day 66; not included in the statistical analyses. 297 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05709 105714 105715 I05718 105720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 105721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 36 47 48 69 26 54 38 65 35 40 45 104 38 7.8 6 63 22. 7 6 Dose Level: 3 48 44 32 27 41 33 38 83 40 6.7 4 47 25. 2 4 Dose Level: 10 32 49 46 48 43 62 48 78 35 50 34 32 40 6.8 6 53 15.5 6 Dosage Unit: mg/kg/day 328 128 637 103 509 126 322 100 424 187 956 121 5 14 9 11 9 15 529 240.3 6 128 31.4 6 10 3.7 6 Dosage Unit: mg/kg/day 344 96 571 107 757 148 667 121 10 10 12 10 585 177.6 4 118 22.5 4 10 1.0 4 Dosage Unit: mg/kg/day 897 115 592 145 410 78 871 154 445 87 720 101 8 16 12 13 10 9 656 208.6 6 113 30.8 6 11 2.9 6 99 144 110 120 131 252 143 55. 8 6 104 90 147 165 126 35. 3 4 99 165 122 118 186 109 133 34.4 6 413 319 520 694 463 679 515 148.7 6 340 378 468 327 378 63.6 4 387 248 261 393 520 395 367 100.7 6 7 12 10 12 26 53 20 17.4 6 238 201 278 384 222 297 270 66 6 21 94 33 50 50 32.0 4 199 197 272 159 207 47 4 3 0 0 33 12 5 9 12.6 6 204 153 164 229 366 200 219 77 6 298 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Dose Level: 30/20 55 58 43 60 46 55 33 35 44 51 38 7..1 2 48 17. 7 2 Dosage Unit: mg/kg/day 347 80 648 57 277 160 215 182 390 133 15 10 8 10 9 432 306.2 2 120 88.4 2 10 .0 2 130 178 151 133 188 156 31.8 2 446 366 389 270 390 318 67.9 2 5 22 21 0 26 11 15.6 2 279 229 209 140 184 184 62 2 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 299 Appendix 4 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 10.9 11.4 11.4 11.2 11.4 11.4 6.1 6.4 5.8 6.0 6.4 7.5 11.3 .20 6 6.4 .60 6 Dose Level : 3 10.2 11.1 11.1 10.6 5.5 5.2 7.3 7.2 10.8 .44 4 6.3 1.10 4 Dose Level : 10 11.2 10.4 10.7 10.9 10.4 11.1 6.0 6.2 6.3 6.6 4.6 6.9 10.8 .34 6 6.1 .80 6 Dosage Unit: mg/kg/day 164 5.5 119 165 5.1 115 170 5.2 118 163 6.0 112 169 4.9 119 169 5.3 117 167 3.0 6 5.3 .38 6 117 2 6 Dosage Unit: mg/kg/day 159 4.6 119 163 5.4 120 162 5.6 119 165 4.9 116 162 2.5 4 5.1 .46 4 118 1 4 Dosage Unit: mg/kg/day 162 4.9 119 160 5.1 119 159 5.2 119 158 4.5 116 155 4.3 115 166 5.1 116 160 3.7 6 4.8 .37 6 117 1 6 300 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Dose Level : 30/20 11.2 10.6 10.8 9.6 10.9 6.3 5.3 4.4 4.7 8.4 10.1 .71 2 5.0 .42 2 Dosage Unit: mg/kg/day 164 7.4 121 156 4.8 112 159 5.3 121 160 6.0 117 169 6.3 119 158 2.8 2 5.4 .85 2 114 3.5 2 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses Covance 6329-231 3M T-6889.3 301 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 60 21 71 22 56 23 95 17 63 15 79 19 71 14.5 6 20 3.1 6 Dose Level : 3 68 19 54 29 68 19 96 6 63 8.1 3 22 5.8 3 Dose Level: 10 54 18 71 23 101 21 67 19 61 20 43 16 66 19.7 6 20 2.4 6 Dosage Unit: mg/kg/day 1.3 8.6 4.3 .9 8.3 4.7 1.2 9.6 5.2 1.2 8.5 4.8 .9 8.5 4.4 1.2 8.2 4.8 1.1 .17 6 8.6 .50 6 4.7 .32 6 Dosage Unit: mg/kg/day .9 8.3 4.6 1.1 8.0 4.9 1.4 9.0 5.3 .8 8.5 3.3 1.1 .25 3 8.4 .51 3 4.9 .35 3 Dosage Unit: mg/kg/day 1.0 8.6 4.5 .9 7.7 4.2 1.3 9.6 4.9 1.1 7.8 4.8 1.4 8.0 4.6 1.1 8.6 4.4 1.1 .19 6 8.4 .71 6 4.6 .26 6 4.3 3.6 4.4 3.7 4.1 3.4 3.9 .41 6 3.7 3.1 3.7 5.2 3.5 .35 3 4.1 3.5 4.7 3.0 3.4 4.2 3.8 .62 6 .5 14 134 34 .2 15 149 52 .3 15 138 31 .2 23 225 48 .4 20 153 47 .4 19 134 49 .3 18 156 44 .12 3. 6 35.0 8.7 6666 .1 14 120 40 .2 17 109 34 .4 19 196 79 .1 6 94 61 .2 17 142 51 .15 2. 5 47.4 24.4 3333 .1 17 128 68 .4 14 174 57 .6 18 157 99 .1 16 203 102 .0 16 134 39 .3 17 126 66 .2 16 154 72 .23 1.4 30.6 24 6666 a Unscheduled sacrifice on Day 137. 302 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Dose Level: 30/20 64 21 61 17 44 21 100 16 82 20 80 27.6 2 16 .7 2 Dosage Unit: mg/kg/day 1.3 8.8 4.6 1.0 8.4 4.5 1.3 8.5 4.7 .8 8.2 3.8 1.2 8.4 4.7 .9 8.3 4.2 .14 .14 .49 222 4.2 3.9 3.8 4.4 3.7 4.2 .35 2 2 16 151 100 0 17 139 120 5 17 162 53 5 18 161 63 4 21 194 56 2 18 150 92 35 .7 15.6 40.3 2222 a Dosing was stopped on Day 81; not included in the statistical analyses. b Dosing was stopped on Day 43; not included in the statistical analyses. c Dosing was stopped on Day 66; not included in the statistical analyses. 303 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 33 55 45 68 33 52 39 88 38 57 33 85 37 4.8 6 68 15. 7 6 Dose Level: 3 48 36 45 46 46 46 21 9 46 1.5 3 43 5. 8 3 Dose Level: 10 41 43 42 48 67 104 39 53 39 46 35 25 44 11.6 6 53 26. 7 6 Dosage Unit: mg/kg/day 291 151 553 110 401 115 280 101 364 173 778 97 3 9 5 3 4 4 444 190.8 6 124 30.5 6 5 2. 3 6 Dosage Unit: mg/kg/day 251 93 659 125 813 171 611 83 6 8 4 4 574 290.4 3 130 39.2 3 6 2. 0 3 Dosage Unit: mg/kg/day 798 115 512 132 339 82 724 142 397 95 496 91 8 10 8 5 8 4 544 181.0 6 110 24.1 6 7 2. 2 6 110 128 122 137 153 191 140 28. 8 6 119 115 182 201 139 37. 6 3 103 206 4804 105 194 122 922 1902. 1 6 402 356 480 745 428 590 500 144. 3 6 350 460 561 361 457 105. 5 3 358 237 258 391 558 371 362 114. 7 6 73 8 30 65 25 31 39 25. 0 6 89 177 53 2 106 63. 8 3 17 0 0 12 22 15 11 9. 1 6 282 270 308 510 271 327 328 91. 9 6 249 299 391 185 313 72. 0 3 241 179 199 273 478 241 268 107. 9 6 a Unscheduled sacrifice on Day 137. 304 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Dose Level: 30/20 45 41 42 54 47 47 37 43 63 70 40 3. 5 2 48 7. 8 2 Dosage Unit: mg/kg/day 1070 568 350 199 833 104 54 156 189 174 10 3 2 2 6 384 260.9 2 122 95.5 2 2 .7 2 117 210 141 128 302 169 58. 0 2 452 344 415 266 531 305 55.2 2 88 17 25 0 46 8 12.0 2 338 261 273 169 333 215 65.1 2 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 305 Appendix 4 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 10.1 10.2 10.0 10.3 9.8 9.7 6.2 6.1 5.6 5.2 5.4 6.2 10.0 .23 6 5.8 .44 6 Dose Level : 3 9.2 9.9 11.7 9.0 4.4 5.2 8.4 4.8 10.3 1.29 3 6.0 2.12 3 Dose Level : 10 9.8 9.3 10.7 9.5 9.5 9.4 5.0 5.3 7.8 6.2 4.5 5.8 9.7 .52 6 5.8 1.16 6 Dosage Unit: mg/kg/day 153 5.1 107 154 4.9 107 153 4.7 107 153 5.4 104 149 4.5 105 150 4.7 105 152 2.0 6 4.9 .33 6 106 1 6 Dosage Unit: mg/kg/day 147 4.0 108 149 4.7 108 166 5.9 111 142 3.9 100 154 10.4 3 4.9 .96 3 109 1 3 Dosage Unit: mg/kg/day 146 3.8 108 146 3.8 108 155 5.2 103 149 4.2 108 145 3.9 105 145 4.7 104 148 3.9 6 4.3 .57 6 106 2 6 a Unscheduled sacrifice on Day 137. 306 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 4 I05703 a I05704 I05711 b I05713 I05722 c Dose Level: 30/20 9.8 9.4 9.8 9.1 10.3 6.7 4.8 3.9 4.8 8.1 Dosage Unit: mg/kg/day 151 5.3 107 148 4.2 107 148 5.5 111 152 5.9 109 155 6.5 112 MEAN S.D. N 9.2 .21 2 4.8 .00 2 150 2.8 2 5.0 1.20 2 108 1.4 2 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses Covance 6329-231 3M T-6889.3 307 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level : 0 127 17 75 17 101 36.8 2 17 .0 2 Dose Level : 10 68 20 54 22 61 9.9 2 21 1.4 2 Dosage Unit: mg/kg/day 1.4 9.4 5.0 1.5 9.0 4.5 1.4 .07 2 9.2 .28 2 4.8 .35 2 Dosage Unit: mg/kg/day 1.3 7.8 4.8 1.5 8.1 4.5 1.4 .14 2 8.0 .21 2 4.6 .21 2 4.4 4.5 4.4 .07 2 3.0 3.6 3.3 .42 2 .3 .4 .4 .07 2 .2 .3 .2 .07 2 6 228 6 159 6 194 .0 48.8 22 40 39 40 .7 2 7 187 111 7 131 49 7 159 .0 39.6 22 80 43.8 2 308 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 40 54 29 30 34 7.8 2 42 17.0 2 Dose Level: 10 31 24 27 12 29 2.8 2 18 8.5 2 Dosage Unit: mg/kg/day 234 103 260 176 6 4 247 18.4 2 140 51.6 2 5 1.4 2 Dosage Unit: mg/kg/day 687 142 409 98 7 5 548 196.6 2 120 31.1 2 6 1.4 2 102 82 92 14.1 2 143 138 140 3.5 2 769 456 612 221.3 2 410 544 477 94.8 2 11 30 20 13.4 2 551 279 415 192.3 2 27 17 22 7.1 2 298 487 392 133.6 2 309 Appendix 4 Individual Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level : 0 10.9 10.9 6.1 6.5 10.9 .00 2 6.3 .28 2 Dose Level : 10 9.9 7.2 9.9 5.2 9.9 .00 2 6.2 1.41 2 Dosage Unit: mg/kg/day 153 6.0 106 159 5.5 111 156 4.2 2 5.8 .35 2 108 3.5 2 Dosage Unit: mg/kg/day 147 4.5 108 145 4.7 107 146 1.4 2 4.6 .14 2 108 .7 2 Covance 6329-231 3M T-6889.3 310 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level : 0 96 15 94 15 95 1.4 2 15 .0 2 Dose Level : 10 82 18 79 22 80 2.1 2 20 2.8 2 Dosage Unit: mg/kg/day 1.4 9.1 5.1 1.2 9.1 4.6 1.3 .14 2 9.1 .00 2 4.8 .35 2 Dosage Unit: mg/kg/day 1.2 8.0 5.0 1.4 8.2 4.7 1.3 .14 2 8.1 .14 2 4.8 .21 2 4.0 4.5 4.2 .35 2 3.0 3.5 3.2 .35 2 .2 .3 .2 .07 2 .2 .3 .2 .07 2 4 251 4 155 4 203 .0 67. 9 22 51 47 49 2.8 2 6 186 138 4 143 47 5 164 1.4 30. 4 22 92 64.3 2 311 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 30 43 40 45 35 7.1 2 44 1. 4 2 Dose Level: 10 25 51 30 38 28 3.5 2 44 9. 2 2 Dosage Unit: mg/kg/day 204 87 286 180 3 4 245 58.0 2 134 65.8 2 4 .7 2 Dosage Unit: mg/kg/day 781 143 489 97 3 2 635 206.5 2 120 32.5 2 2 .7 2 113 904 508 559.3 2 127 202 164 53.0 2 759 449 604 219.2 2 441 540 490 70.0 2 44 47 46 2.1 2 551 288 420 186.0 2 66 47 56 13.4 2 315 474 394 112.4 2 312 Appendix 4 Individual Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level : 0 10.7 10.7 6.6 6.9 10.7 .00 2 6.8 .21 2 Dose Level : 10 10.3 10.3 7.1 5.6 10.3 .00 2 6.4 1.06 2 Dosage Unit: mg/kg/day 158 6.5 111 158 4.7 110 158 .0 2 5.6 1.27 2 110 .7 2 Dosage Unit: mg/kg/day 155 5.0 113 151 5.6 114 153 2.8 2 5.3 .42 2 114 .7 2 Covance 6329-231 3M T-6889.3 313 ANIMAL NUMBER GLU MG/DL Appendix 4 Individual Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 TRIG MG/DL Group: 1 Dose Level : 0 Dosage Unit: mg/kg/day I05718 I05720 93 20 1.5 9.6 5.3 4.3 76 17 .9 8.8 4.1 4.7 .2 10 256 30 .4 9 131 47 MEAN S.D. N 84 18 1.2 9.2 4.7 4.5 .3 10 194 38 12.0 2.1 .42 .57 .85 .28 .14 .7 88.4 12.0 2222222222 Group: 3 Dose Level : 10 Dosage Unit: mg/kg/day I05712 I05716 93 21 1.3 8.2 5.2 3.0 87 21 1.3 8.2 4.6 3.6 .3 .3 8 178 7 122 74 22 MEAN S.D. N 90 4.2 2 21 .0 2 1.3 .00 2 8.2 .00 2 4.9 .42 2 3.3 .42 2 .3 .00 2 8 150 .7 39.6 22 48 36.8 2 314 ANIMAL NUMBER Appendix 4 Individual Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) 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 6329-231 3M T-6889.3 Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 64 153 55 63 60 6.4 2 108 63. 6 2 Dose Level: 10 47 70 54 81 50 4.9 2 76 7. 8 2 Dosage Unit: mg/kg/day 216 97 323 127 4 1 270 75.7 2 112 21.2 2 2 2.1 2 Dosage Unit: mg/kg/day 752 138 454 94 1 3 603 210.7 2 116 31.1 2 2 1.4 2 647 1402 1024 533. 9 2 984 667 826 224.2 2 1922 1125 1524 563. 6 2 499 1649 1074 813.2 2 208 121 164 61.5 2 693 455 574 168 2 58 656 357 422.8 2 346 1460 903 787 2 315 Appendix 4 Individual Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER CA MG/DL I PHOS MG/DL NA MMOL/L K MMOL/L CL MMOL/L Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level : 0 11.2 10.6 5.6 4.2 10.9 .42 2 4.9 .99 2 Dose Level : 10 10.2 10.2 6.6 3.9 10.2 .00 2 5.2 1.91 2 Dosage Unit: mg/kg/day 154 6.6 104 153 5.5 110 154 .7 2 6.0 .78 2 107 4.2 2 Dosage Unit: mg/kg/day 152 4.4 103 148 4.4 103 150 2.8 2 4.4 .00 2 103 .0 2 Covance 6329-231 3M T-6889.3 316 Appendix 4 Individual Clinical Urinalysis Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 100.0 395.0 50.0 128.0 108.0 40.0 1.021 1.002 1.021 1.016 1.019 1.019 136.8 131.02 6 1.016 .0073 6 Dose Level: 3 64.0 129.0 176.0 555.0 1.015 1.019 1.006 1.000 231.0 220.83 4 1.010 .0086 4 Dose Level: 10 50.0 50.0 139.0 455.0 86.0 66.0 1.021 1.012 1.016 1.003 1.014 1.016 141.0 157.36 6 1.014 .0060 6 Dosage 8.5 7.5 8.5 8.0 8.0 8.5 8.2 .41 6 Dosage 8.0 8.0 8.0 7.5 7.9 .25 4 Dosage 8.5 8.5 8.0 7.5 8.0 8.5 8.2 .41 6 mg/kg/day mg/kg/day mg/kg/day 317 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Urinalysis Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Dose Level: 30/20 158.0 19.0 166.0 11.0 73.0 103.0 1.005 1.027 1.010 1.020 1.014 1.009 88.3 66.52 6 1.014 .0081 6 Dosage 8.0 8.5 7.5 8.5 8.5 8.5 8.2 .42 6 mg/kg/day Covance 6329-231 3M T-6889.3 318 Appendix 4 Individual Clinical Urinalysis Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 Dose Level: 0 10 10 10 10 10 10 - Dose Level: 3 10 10 00- Dose Level: 10 10 000010 - Dose Level: 30/20 010 00010 - - - - - Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day -+ ---- Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ------- - - - - Covance 6329-231 3M T-6889.3 319 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS CRYSTALS PER HPF PER: HPF PER HPF PER HPF PER LPF PER LPF1 PER LPF2 URINE APP1 COMMENTS Covance 6329-231 3M T-6889.3 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 0 0 0 2 0 1B4E 0 CK - I05714 0 0 0 2 0 0 0 AJ - I05715 0 0 0 1 0 3B1D 0 CK Q I05718 0 0 0 2 0 2B2E 0 CK - I05720 0 0 0 2 0 2B1E 0 CK - I05725 0 0 0 2 0 2B2D 0 CK - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 0 0 1 3 0 4B4D 0 CK - I05706 0 0 0 3 0 4E4F 0 CK - I05717 0 0 0 3 0 2B1E 0 BK - I05721 0 0 0 2 0 0 0 AJ - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 0 1 3 0 3B2D 1F CK - I05708 0 0 1 3 0 2B1F 0 BK Q I05710 0 0 0 2 0 3B1E 2F BK - I05712 0 0 0 3 0 0 0 AJ - I05716 0 1 0 2 0 2B1D 0 BK - I05719 0 0 0 1 0 3B1E 0 CK - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 0 0 0 3 0 2B 0 AJ - I05704 0 0 0 3 0 3E4F 0 CK Q I05711 0 0 0 3 0 2B1E 0 BK - I05713 0 0 0 3 0 4F 0 GK - I05722 0 0 0 3 0 0 0 CJ - I05724 0 0 0 3 0 1E 0 BK - 320 Appendix 4 Individual Clinical Urinalysis Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 a MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level : 0 89.0 490.0 98.0 90.0 122.0 110.0 1.021 1.002 1.017 1.016 1.018 1.014 166.5 158.98 6 1.015 .0066 6 Dose Level : 3 210.0 64.0 397.0 296.0 1.010 1.023 1.004 1.003 241.8 141.01 4 1.010 .0092 4 Dose Level : 10 84.0 94.0 228.0 350.0 107.0 69.0 1.020 1.018 1.008 1.003 1.014 1.018 155.3 111.19 6 1.014 .0067 6 Dosage 8.0 7.5 8.5 7.5 8.0 8.0 7.9 .38 6 Dosage 8.0 8.0 8.0 7.0 7.8 .50 4 Dosage 8.0 8.0 8.0 8.0 8.0 8.5 8.1 .20 6 mg/kg/day mg/kg/day mg/kg/day a Dosing was started on Day 17. 321 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Urinalysis Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 4 I05703 I05704 I05711 I05713 I05722 MEAN S.D. N Dose Level: 30/20 215.0 282.0 180.0 350.0 89.0 1.005 1.005 1.006 1.003 1.017 223.2 99.35 5 1.007 .0056 5 Dosage 7.5 7.0 7.0 8.0 8.0 7.5 .50 5 mg/kg/day Covance 6329-231 3M T-6889.3 322 Appendix 4 Individual Clinical Urinalysis Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 a Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 I05704 I05711 I05713 I05722 Dose Level: 0 10 010 30 00- Dose Level: 3 0000- Dose Level: 10 000000- Dose Level: 30/20 00000- - - - - Dosage Unit: mg/kg/day -+ ------ Dosage Unit: mg/kg/day - ++ ---- Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day --+ ---- - - - - a Dosing was started on Day 17. 323 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS CRYSTALS PER HPF PER HPF PER HPF PER HPF PER LPF PER LPF1 PER LPF2 URINE APP1 COMMENTS Covance 6329-231 3M T-6889.3 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 0 0 0 3 0 4B3D 0 BK - I05714 0 0 0 3 0 0 0 AJ - I05715 0 0 1 3 0 4B 0 BK - I05718 0 1 1 3 0 0 0 BJ Q I05720 0 0 0 3 0 4B1E 0 BL - I05725 0 0 0 3 0 4B 0 BK - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 0 0 0 3 0 4B 0 AK - I05706 0 0 0 3 0 4B 0 BJ - I05717 0 0 1 3 0 0 0 AJ - I05721 a 0 1 0 3 0 1B 0 AJ Q Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 1 0 3 0 2B2D 0 BJ - I05708 0 0 0 3 0 4B2E 3F BL - I05710 0 1 1 3 0 1E 0 AJ - I05712 0 0 0 2 0 1D 0 AJ - I05716 0 0 0 3 0 4B 0 BL - I05719 0 0 0 3 0 2B1D 0 CJ - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 0 0 1 3 0 0 0 AJ - I05704 0 1 1 2 0 1B 0 AJ Q I05711 0 0 0 3 1H 2B 0 AJ PQ I05713 0 0 1 3 0 3B 0 AJ Q I05722 0 0 0 2 0 2B4D 0 BL - a Dosing was started on Day 17. 324 Appendix 4 Individual Clinical Urinalysis Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 48.0 570.0 124.0 170.0 78.0 144.0 1.024 1.002 1.014 1.009 1.019 1.010 189.0 191.82 6 1.013 .0078 6 Dose Level: 3 240.0 52.0 360.0 360.0 1.006 1.024 1.004 1.004 253.0 145.45 4 1.010 .0097 4 Dose Level: 10 88.0 162.0 96.0 570.0 122.0 102.0 1.019 1.011 1.015 1.002 1.011 1.014 190.0 188.04 6 1.012 .0057 6 Dosage 8.0 8.0 8.0 8.5 8.0 8.0 8.1 .20 6 Dosage 7.5 7.0 7.5 8.0 7.5 .41 4 Dosage 8.5 8.5 8.0 8.0 8.0 8.0 8.2 .26 6 mg/kg/day mg/kg/day mg/kg/day 325 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Urinalysis Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Dose Level : 30/20 114.0 74.0 98.0 60.0 84.0 1.011 1.021 1.015 1.020 1.014 83.0 22.89 4 1.016 .0048 4 Dossaagg<e Unit: mg/kg/day 8.0 8.0 8.0 7.0 7.0 7.5 .58 4 Covance 6329-231 3M T-6889.3 a Dosing was stopped on Day 43; not inc analyses. 326 Appendix 4 Individual Clinical Urinalysis Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 I05704 I05711 a I05713 I05722 Dose Level: 0 10 010 010 0- Dose Level: 3 010 00- Dose Level: 10 010 0000- Dose Level: 30/20 00000- - - - - Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day -+ ---- Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ------ - - - - a Dosing was stopped on Day 43. 327 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS CRYSTALS PER HPF PER: HPF PER HPF PER HPF PER LPF PER LPF1 PER LPF2 URINE APP1 COMMENTS Covance 6329-231 3M T-6889.3 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 0 0 0 3 0 4D 0 CK Q I05714 0 0 1 3 0 0 0 AJ - I05715 0 0 0 3 0 2B1D 0 BK Q I05718 0 0 0 3 0 0 0 BK - I05720 0 0 0 3 0 4B2D 1E CK - I05725 0 1 0 3 0 0 0 BJ Q Group: 2 I05702 I05706 I05717 I05721 Dose Level: 3 00 01 00 00 Dosage Unit: mg/kg/day 130 030 130 130 0 1E 0 2B 0 0 0 0 AK - CK Q AJ Q AK Q Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 0 0 3 0 1B2D 1E CK - I05708 0 0 0 3 0 4B4D 0 BK - I05710 0 0 0 3 0 2E4F 0 CK - I05712 0 0 0 3 0 0 0 AJ - I05716 0 0 0 3 0 4B4D 1E BK - I05719 0 0 0 3 0 2B 0 CK - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 0 0 0 3 0 4B3D 2E BK - I05704 0 0 0 1 0 1B1D 1E CK Q I05711 a 0 0 0 3 0 4B1E 0 BK - I05713 0 0 1 2 0 1D 0 CK PQ I05722 0 1 1 3 0 1B4D 0 CJ - a Dosing was stopped on Day 43. 328 Appendix 4 Individual Clinical Urinalysis Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 I05721 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 69.0 546.0 93.0 137.0 79.0 192.0 1.025 1.004 1.020 1.017 1.025 1.011 186.0 182.11 6 1.017 .0083 6 Dose Level: 3 124.0 74.0 338.0 552.0 1.018 1.021 1.006 1.003 272.0 218.99 4 1.012 .0088 4 Dose Level: 10 88.0 163.0 234.0 564.0 146.0 137.0 1.019 1.015 1.010 1.003 1.012 1.014 222.0 174.10 6 1.012 .0054 6 Dosage 8.5 8.0 8.0 8.5 8.5 8.0 8.2 .27 6 Dosage 8.0 7.5 8.0 7.5 7.8 .29 4 Dosage 8.0 7.5 8.0 8.0 8.0 8.0 7.9 .20 6 mg/kg/day mg/kg/day mg/kg/day 329 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Urinalysis Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 4 105703 a 105704 I05711 b I05713 I05722 c MEAN S..D. N Dose Level: 30/20 402.0 78.0 106.0 64.0 185.0 1.005 1.020 1.018 1.020 1.010 71.0 9.90 2 1.020 .0000 2 Dosage Unit: mg/kg/day 8.0 8.0 7.5 8.5 8.0 .2 .35 2 Covance 6329-231 3M T-6889.3 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 330 Appendix 4 Individual Clinical Urinalysis Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 a I05704 I05711 b I05713 I05722 c Dose Level: 0 10 010 010 0- Dose Level: 3 0000- Dose Level: 10 000000- Dose Level: 30/20 00000- - - - - Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ----- Dosage Unit: mg/kg/day ------- Dosage Unit: mg/kg/day ------ - - - - a Dosing was stopped on Day 81 b Dosing was stopped on Day 43 c Dosing was stopped on Day 66 331 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS CRYSTALS PER HPF PER: HPF PER HPF PER HPF PER LPF PER LPF1 PER LPF2 URINE APP1 COMMENTS Covance 6329-231 3M T-6889.3 Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 I05721 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 I05704 I05711 I05713 I05722 Dose Level: 0 000 001 000 000 001 000 Dose Level: 3 000 001 001 001 Dose Level: 10 000 000 000 001 000 000 Dose Level: 30/20 001 000 000 000 000 Dosage Unit: mg/kg/day 30 20 30 30 20 30 Dosage Unit: mg/kg/day 30 30 30 30 Dosage Unit: mg/kg/day 30 30 20 20 30 30 Dosage Unit: mg/kg/day 20 30 30 30 30 4B4D 0 2B 2B2E 4B4D 3B 4B2D 4B4D 0 1B1E 4B4D 3B2E 1B3E 0 4B 4B4E 2E 3B4D 4B1F 4B4D 4B1E 0 0 0 0 4E3F 0 2E2F 3E 0 0 0 2F 0 0 0 2F 0 1E 0 0 1F BJ AJ BK BJ BK BJ BK BJ AJ AJ BK BK AJ AJ BK BJ AJ BK BK BK BK Q Q PQ - Q - - - a Dosing was stopped on Day 81. b Dosing was stopped on Day 43. c Dosing was stopped on Day 66. 332 Appendix 4 Individual Clinical Urinalysis Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 MEAN S.D. N Group: 2 I05702 I05706 I05717 MEAN S.D. N Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 MEAN S.D. N Dose Level: 0 86.0 218.0 158.0 255.0 90.0 150.0 1.026 1.010 1.013 1.011 1.019 1.011 159.5 67.63 6 1.015 .0063 6 Dose Level: 3 198.0 92.0 227.0 1.015 1.022 1.010 172.3 71.07 3 1.016 .0060 3 Dose Level: 10 66.0 306.0 214.0 473.0 122.0 70.0 1.021 1.006 1.012 1.004 1.015 1.018 208.5 159.04 6 1.013 .0067 6 Dosage 8.0 7.5 8.0 8.0 7.5 7.0 7.7 .41 6 Dosage 8.0 7.5 8.0 7.8 .29 3 Dosage 7.0 7.5 7.5 7.5 7.0 7.0 7.2 .27 6 mg/kg/day mg/kg/day mg/kg/day 333 Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Urinalysis Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Dose Level: 30/20 290.0 88.0 159.0 306.0 49.0 1.005 1.022 1.012 1.006 1.020 197.0 154.15 2 1.014 .0113 2 Dosage Unit mg/kg/day 7.5 8.0 7.0 7.5 8.0 7.8 .35 2 Covance 6329-231 3M T-6889.3 a Dosing was stopped on Day 81; not included in the statistical analyses b Dosing was stopped on Day 43; not included in the statistical analyses c Dosing was stopped on Day 66; not included in the statistical analyses 334 Appendix 4 Individual Clinical Urinalysis Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 a I05704 I05711 b I05713 I05722 c Dose Level: 0 000000- Dose Level: 3 000- Dose Level: 10 000000- Dose Level: 30/20 00000- Dosage Unit: mg/kg/day --- ------+-- --- Dosage Unit: mg/kg/day --+ +-- --- Dosage Unit: mg/kg/day + - ++++ - - - + Dosage Unit: mg/kg/day --- --------- - - - - a Dosing was stopped on Day 81 b Dosing was stopped on Day 43 c Dosing was stopped on Day 66 335 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS CRYSTALS PER HPF PER HPF PER HPF PER HPF PER LPF PER LPF1 PER LPF2 URINE APP1 COMMENTS Covance 6329-231 3M T-6889.3 Group: 1 I05709 I05714 I05715 I05718 I05720 I05725 Group: 2 I05702 I05706 I05717 Group: 3 I05707 I05708 I05710 I05712 I05716 I05719 Group: 4 I05703 a I05704 I05711 b I05713 I05722 c Dose Level: 0 000 001 001 001 000 010 Dose Level: 3 000 001 001 Dose Level: 10 001 001 000 000 001 001 Dose Level: /2 0 001 000 000 000 000 o ro Dosage Unit: mg/kg/day 2 1H 30 30 30 3 1H 30 Dosage Unit: mg/kg/day 20 30 30 Dosage Unit: mg/kg/day 30 30 30 30 30 30 Dosage Unit: mg/kg/day 30 30 30 30 10 3B1D 2B 4B3D 2B 2B4D 0 3B1E 3B1F 0 1B3D 2B 3B2D 0 2B 1D 0 4B4D 1B 0 3B4D 3F 0 0 0 3E 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1E BJ Q BJ BK BJ BJ Q BJ P BK BJ AJ Q BJ AJ Q BJ Q AJ BJM BJ Q AJ Q BK BJ AJ Q BJ Q a Dosing was stopped on Day 81. b Dosing was stopped on Day 43. c Dosing was stopped on Day 66. 336 Appendix 4 Individual Clinical Urinalysis Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 240.0 545.0 1.013 1.003 392.5 215.67 2 1.008 .0071 2 Dose Level: 10 455.0 125.0 1.004 1.009 290.0 233.35 2 1.006 .0035 2 Dosage Unit: mg/kg/day 8.0 8.0 8.0 .00 2 Dosage Unit: mg/kg/day 8.0 7.5 7.8 .35 2 Covance 6329-231 3M T-6889.3 337 Appendix 4 Individual Clinical Urinalysis Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 00- Dose Level: 10 00- Dosage Unit: mg/kg/day --- Dosage Unit: mg/kg/day --- - - Covance 6329-231 3M T-6889.3 338 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS CRYSTALS PER HPF PER HPF PER HPF PER HPF PER LPF PER LPF1 PER LPF2 URINE APP1 COMMENTS Covance 6329-231 3M T-6889.3 Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05718 0 0 0 1 0 3B1D 0 BJ - I05720 0 0 0 2 0 3B1D 1E AJ - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 0 0 0 2 0 1B 0 AJ - I05716 0 0 0 3 0 2B1D 0 AJ - 339 Appendix 4 Individual Clinical Urinalysis Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 78.0 314.0 1.020 1.006 196.0 166.88 2 1.013 .0099 2 Dose Level: 10 516.0 167.0 1.003 1.007 341.5 246.78 2 1.005 .0028 2 Dosage Unit: mg/kg/day 8.0 8.0 8.0 .00 2 Dosage Unit: mg/kg/day 7.5 7.5 7.5 .00 2 Covance 6329-231 3M T-6889.3 340 Appendix 4 Individual Clinical Urinalysis Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD UROBILI Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 00- Dose Level: 10 00- Dosage Unit: mg/kg/day --- Dosage Unit: mg/kg/day --- - - Covance 6329-231 3M T-6889.3 341 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS PER HPF PER HPF PER HPF PER HPF PER LPF PER LPF1 URINE COMMENTS APP1 Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 00 00 Dose Level: 10 00 00 Dosage Unit: mg/kg/day 030 02 0 Dosage Unit: mg/kg/day 130 130 4B1E 1B 1B 2B BL BK AKM BK Q - Q Q Covance 6329-231 3M T-6889.3 342 Appendix 4 Individual Clinical Urinalysis Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U VOL ML SP GR U PH Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Dose Level: 0 158.0 72.0 1.015 1.021 115.0 60.81 2 1.018 .0042 2 Dose Level: 10 179.0 92.0 1.010 1.014 135.5 61.52 2 1.012 .0028 2 Dosage Unit: mg/kg/day 7.0 7.0 7.0 .00 2 Dosage Unit: mg/kg/day 8.0 8.0 8.0 .00 2 Covance 6329-231 3M T-6889.3 343 Appendix 4 Individual Clinical Urinalysis Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER U PRO MG/DL U GLU U KET U BILI U BLOOD Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 10 + 10 + Dose Level: 10 010 + Dosage Unit: mg/kg/day -+ ++ Dosage Unit: mg/kg/day --+ - - Covance 6329-231 3M T-6889.3 344 ANIMAL NUMBER Appendix 4 Individual Clinical Urinalysis Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC WBC EPITH BACT CASTS CRYSTALS PER HPF PER HPF PER HPF PER HPF PER LPF PER LPF1 URINE COMMENTS APP1 Group: 1 I05718 I05720 Group: 3 I05712 I05716 Dose Level: 0 02 00 Dose Level: 10 01 00 Dosage Unit: mg/kg/day 130 030 Dosage Unit: mg/kg/day 110 130 3B 3B1D 1D 3B1D BK CK BJ BK Covance 6329-231 3M T-6889.3 345 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 346 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 1 ANIMAL NUMBER: I05709 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4800.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:13 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3730 .3040 73.9130 2.0600 2.0060 7.5960 7.9230 69.5030 6.9550 10.4110 9.5080 .1850 .2090 .0078 % .0063 % 1.5399 % .0429 % .0418 % .1582 % .1651 % 1.4480 % .1449 % .2169 % .1981 % .0039 % .0044 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0050 .0041 1.0000 .0279 .0271 .1028 .1072 .9403 .0941 .1409 .1286 .0025 .0028 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY KIDNEY (KD) : -MINERALIZATION, TUBULAR,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL PITUITARY (PI) : -CYST,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, EOSINOPHILIC,-MINIMAL -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 347 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 2 ANIMAL NUMBER: I05709 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4800.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:13 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE),BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH),LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE),BONE, STERNUM (SB), EYE (EY), BRAIN (BR), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 348 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 3 ANIMAL NUMBER: I05714 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3445.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:28 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT' (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .2650 .1840 61.7660 .9650 1.1580 5.4390 5.5320 53.0460 5.8810 6.0980 6.1630 .3120 .3150 .0077 % .0053 % 1.7929 % .0280 % .0336 % .1579 % .1606 % 1.5398 % .1707 % .1770 % .1789 % .0091 % .0091 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0043 .0030 1.0000 .0156 .0187 .0881 .0896 .8588 .0952 .0987 .0998 .0051 .0051 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY CECUM (CE) : -RED FOCUS(I)/AREA(S); WITHIN WALL: SINGLE DARK RED AND FIRM AREA, 0.4 CM IN DIAMETER; COLLECTED ON ROUTINE SECTION LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL CECUM (CE) : -INFLAMMATION, GRANULOMATOUS,-MODERATE -PARASITISM,-PRESENT COLON (CO) : -INFLAMMATION, CHRONIC,-MINIMAL 349 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 4 ANIMAL NUMBER: I05714 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3445.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:28 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY SKIN (SK) : >NOTE:>TRIMMING COMMENT: MISSING FROM WET TISSUE MAMMARY, MALE (MM) : >NOTE:>TRIMMING COMMENT: MISSING FROM WET TISSUE GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS SKIN (SK) : >TISSUE MISSING MAMMARY, MALE (MM) : >TISSUE MISSING THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), COLON (CO), RECTUM (RE), SKIN MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), (SK), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), RECTUM (RE), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 350 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 5 ANIMAL NUMBER: I05715 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3835.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:26 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .2900 .2490 55.8000 2.1070 2.2030 6.4160 6.1400 57.6270 5.1700 15.2070 15.1080 .1820 .1610 .0076 % .0065 % 1.4550 % .0549 % .0574 % .1673 % .1601 % 1.5027 % .1348 % .3965 % .3940 % .0047 % .0042 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0052 .0045 1.0000 .0378 .0395 .1150 .1100 1.0327 .0927 .2725 .2708 .0033 .0029 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -CORTICAL TISSUE, EXTRACAPSULAR,-MINIMAL -HYPERTROPHY, CORTICAL CELL,-MINIMAL -MINERALIZATION,-MINIMAL LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL KIDNEY (KD) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -MINERALIZATION, TUBULAR,-MINIMAL LUNG (LU) : -INFILTRATE, EOSINOPHILIC,-MINIMAL -PIGMENT,-MINIMAL 351 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 6 ANIMAL NUMBER: I05715 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3835.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:26 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS LUNG (LU) : >NOTE:>EOSINOPHILS ARE MULTIFOCALLY TRANSMIGRATING THE BRONCHIAL EPITHELIUM. SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL EPIDIDYMIDES (EP) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 352 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 7 ANIMAL NUMBER: I05715 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3835.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:26 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV) 353 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 8 ANIMAL NUMBER: I05718 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 5580.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:01 PROSECTOR: WENDY CHERRY RECORDER: JILL PAUS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JILL PAUS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .4300 .2740 70.8600 2.8180 2.7560 8.3340 8.1740 88.4330 8.9960 14.2840 14.6580 .2450 .2480 .0077 % .0049 % 1.2699 % .0505 % .0494 % .1494 % .1465 % 1.5848 % .1612 % .2560 % .2627 % .0044 % .0044 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0061 .0039 1.0000 .0398 .0389 .1176 .1154 1.2480 .1270 .2016 .2069 .0035 .0035 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -CORTICAL TISSUE, EXTRACAPSULAR,-MINIMAL LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL EYE (EY) : -INFILTRATE, LYMPHOHISTIOCYTIC, CHOROIDAL,-MINIMAL BRAIN (BR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -MINERALIZATION,-MINIMAL KIDNEY (KD) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -INFLAMMATION, VASCULAR,-MODERATE 354 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 9 ANIMAL NUMBER: I05718 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 5580.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:01 PROSECTOR: WENDY CHERRY RECORDER: JILL PAUS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JILL PAUS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS KIDNEY (KD) : -THICKENING, INTIMAL, VASCULAR,-MODERATE >NOTE:>BOTH RENAL ARTERIES AND THEIR BRANCHES HAVE THICKENED INTIMA INFILTRATED BY LOW NUMBERS OF INFLAMMATORY CELLS. SEVERAL ARCUATE ARTERIES OR THEIR BRANCHES ARE THICKENED AND SURROUNDED BY GRANULOMATOUS OR PYOGRANULOMATOUS INFLAMMATION. LUNG (LU) : -PIGMENT,-MINIMAL THYMUS (TH) : -INVOLUTION,-MODERATELY SEVERE LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL STOMACH, GL (ST) : -THICKENING, INTIMAL, VASCULAR,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 355 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 10 ANIMAL NUMBER: I05718 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 5580.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:01 PROSECTOR: WENDY CHERRY RECORDER: JILL PAUS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JILL PAUS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), HEART (HT), GALLBLADDER (GB), TRACHEA (TR), ESOPHAGUS (ES), THYROID PARATHYROID (PT), AORTA (AO), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) (TY), 356 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 11 ANIMAL NUMBER: I05720 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 5240 .0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:45 PROSECTOR: WENDY CHERRY RECORDER: JILL PAUS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JILL PAUS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3680 .2190 60.5630 2.3990 2.7020 9.7810 9.5500 91.9440 8.0025 17.7630 17.9890 .2640 .2660 .0070 % .0042 % 1.1558 % .0458 % .0516 % .1867 % .1823 % 1.7547 % .1527 % .3390 % .3433 % .0050 % .0051 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0061 .0036 1.0000 .0396 .0446 .1615 .1577 1.5182 .1321 .2933 .2970 .0044 .0044 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LIVER (LI) : -ADHESION(S); LEFT AND RIGHT MEDIAN LOBES TO OMENTUM: MULTIPLE GRAY FIBROUS ADHESIONS; COLLECTED LIVER (LI) : -FIBROSIS, CAPSULAR/SUBCAPSULAR,-MODERATE -INFILTRATE, LYMPHOHISTIOCYTIC,-SLIGHT -PIGMENT, HEPATOCELLULAR,-SLIGHT EYE (EY) : -INFILTRATE, LYMPHOHISTIOCYTIC, CHOROIDAL,-MINIMAL BRAIN (BR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYMUS (TH) : -INVOLUTION,-MODERATE 357 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 12 ANIMAL NUMBER: I05720 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 5240.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:45 PROSECTOR: WENDY CHERRY RECORDER: JILL PAUS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JILL PAUS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -ANIMAL OBESE LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL TRACHEA (TR) : -INFLAMMATION, ACUTE,-MINIMAL PARATHYROID (PT) : >SECTION EXAMINED; TISSUE NOT PRESENT SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL NERVE, SCIATIC (SN) : -FIBROSIS,-MODERATELY SEVERE -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL DUODENUM (DU) : -PARASITISM,-PRESENT COLON (CO) : -INFLAMMATION, EOSINOPHILIC,-SLIGHT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 358 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 13 ANIMAL NUMBER: I05720 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 5240.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:45 PROSECTOR: WENDY CHERRY RECORDER: JILL PAUS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JILL PAUS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), ESOPHAGUS (ES), THYROID (TY), AORTA (AO), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), STOMACH, GL (ST), JEJUNUM (JE), ILEUM (IL), CECUM (CE), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 359 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 14 ANIMAL NUMBER: I05725 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3710.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:52 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3060 .2680 66.8040 1.4200 1.7330 6.9080 6.6130 60.5030 4.4720 8.0090 7.7940 .2030 .2050 .0082 % .0072 % 1.8006 % .0383 % .0467 % .1862 % .1782 % 1.6308 % .1205 % .2159 % .2101 % .0055 % .0055 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0046 .0040 1.0000 .0213 .0259 .1034 .0990 .9057 .0669 .1199 .1167 .0030 .0031 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -MINERALIZATION, ALVEOLAR,-MINIMAL -PIGMENT,-MINIMAL LN, MESENTERIC (MS) : -INFILTRATE, EOSINOPHILIC,-MINIMAL -INFLAMMATION, GRANULOMATOUS,-SLIGHT -PARASITISM,-PRESENT -PIGMENT,-MINIMAL >NOTE:>GRANULOMATOUS INFLAMMATION ENCIRCLES A NEMATODE PARASITE IN THE ADJACENT CONNECTIVE TISSUE. 360 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 15 ANIMAL NUMBER: I05725 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3710.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:52 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY THYROID (TY) : >NOTE:>TRIMMING COMMENT: ONLY ONE THYROID FOUND AT TRIMMING PARATHYROID (PT) : >NOTE:>TRIMMING COMMENT: ONLY ONE PARATHYROID FOUND AT TRIMMING GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS THYROID (TY) : -ONE EXAMINED,-PRESENT PARATHYROID (PT) : >SECTION EXAMINED; TISSUE NOT PRESENT 361 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 16 ANIMAL NUMBER: I05725 SEX: MALE DOSE GROUP: 1 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3710.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:52 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), TRACHEA (TR), ESOPHAGUS (ES), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 362 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 17 ANIMAL NUMBER: I05702 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4520.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:48 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .4180 .4140 63.8380 2.4140 2.5390 9.2760 9.2350 84.9350 7.3540 15.7540 17.5050 .2150 .1860 .0092 % .0092 % 1.4123 % .0534 % .0562 % .2052 % .2043 % 1.8791 % .1627 % .3485 % .3873 % .0048 % .0041 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0065 .0065 1.0000 .0378 .0398 .1453 .1447 1.3305 .1152 .2468 .2742 .0034 .0029 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -CORTICAL TISSUE, EXTRACAPSULAR,-SLIGHT LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -PIGMENT, HEPATOCELLULAR,-MINIMAL KIDNEY (KD) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL HEART (HT) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -PIGMENT,-MINIMAL 363 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 18 ANIMAL NUMBER: I05702 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4520.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:48 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY CECUM (CE) : -RED FOCUS(I)/AREA(S); DIFFUSE, WITHIN WALL: MULTIPLE DARK RED AND FIRM AREAS, UP TO 0.4 CM IN DIAMETER; COLLECTED ON ROUTINE SECTION GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS THYMUS (TH) : -INVOLUTION,-SLIGHT LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-SLIGHT CECUM (CE) : ^UNREMARKABLE 364 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 19 ANIMAL NUMBER: I05702 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4520.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:48 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), COLON (CO), RECTUM (RE), SKIN MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), (SK), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), GALLBLADDER (GB), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 365 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 20 ANIMAL NUMBER: I05706 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4480.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 12:05 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3260 .3330 68.3500 3.0160 2.8270 7.7550 7.3100 80.9240 6.0350 18.5330 19.4480 .1540 .2150 .0073 % .0074 % 1.5257 % .0673 % .0631 % .1731 % .1632 % 1.8063 % .1347 % .4137 % .4341 % .0034 % .0048 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0048 .0049 1.0000 .0441 .0414 .1135 .1069 1.1840 .0883 .2711 .2845 .0023 .0031 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LUNG (LU) : -RED FOCUS(I)/AREA(S); ALL LOBES: MULTIPLE LINEAR AREAS, UP TO 2 X LESS THAN 1 MM GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS LUNG (LU) : -CONGESTION,-MINIMAL -PIGMENT,-MINIMAL PARATHYROID (PT) : -CYST, GLANDULAR,-PRESENT 366 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 21 ANIMAL NUMBER: I05706 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4480.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 12:05 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) (FE), 367 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 22 ANIMAL NUMBER: I05717 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4460.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:40 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3720 .3250 67.3520 1.6580 1.7190 7.0060 6.7980 79.5160 4.9180 11.1670 11.3670 .1340 .1540 .0083 % .0073 % 1.5101 % .0372 % .0385 % .1571 % .1524 % 1.7829 % .1103 % .2504 % .2549 % .0030 % .0035 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0055 .0048 1.0000 .0246 .0255 .1040 .1009 1.1806 .0730 .1658 .1688 .0020 .0023 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -HYPERTROPHY, CORTICAL CELL,-SLIGHT LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -PIGMENT, KUPFFER CELL,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 368 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 23 ANIMAL NUMBER: I05717 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4460.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:40 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -ANIMAL OBESE THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 369 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 24 ANIMAL NUMBER: I05721 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: UNSCHEDULED (M) DATE OF DEATH: 02/12/99 STUDY DAY OF DEATH: 137 STUDY WEEK OF DEATH: 20 TERMINAL BODY WEIGHT: 3995.0 GRAMS DATE AND TIME OF NECROPSY: 02/12/99 14:25 PROSECTOR: LAURIE J. SCHULLER RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: AS ASSIGNED WEIGHER: TERRI L. WILLIAMS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3040 .2430 58.4860 1.3310 1.4600 8.9430 9.1420 97.3000 6.5560 8.3940 8.3410 .1220 .1460 .0076 % .0061 % 1.4640 % .0333 % .0365 % .2239 % .2288 % 2.4355 % .1641 % .2101 % .2088 % .0031 % .0037 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0052 .0042 1.0000 .0228 .0250 .1529 .1563 1.6636 .1121 .1435 .1426 .0021 .0025 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LIVER (LI) : -LIGHT FOCUS(I)/AREA(S); ALONG MARGIN OF LEFT LATERAL LOBE: SINGLE TAN AREA, 0.3 CM IN DIAMETER; COLLECTED ON ROUTINE SECTION LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -VACUOLATION, HEPATOCELLULAR, FOCAL,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYMUS (TH) : -INVOLUTION,-MINIMAL PITUITARY (PI) : -INFILTRATE, LYMPHOCYTIC,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 370 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 25 ANIMAL NUMBER: I05721 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: UNSCHEDULED (M) DATE OF DEATH: 02/12/99 STUDY DAY OF DEATH: 137 STUDY WEEK OF DEATH: 20 TERMINAL BODY WEIGHT: 3995.0 GRAMS DATE AND TIME OF NECROPSY: 02/12/99 14:25 PROSECTOR: LAURIE J. SCHULLER RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: AS ASSIGNED WEIGHER: TERRI L. WILLIAMS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY COLON (CO) : -DIVERTICULUM(A); PROXIMAL TO CECUM: SINGLE DIVERTICULUM, 1.0 CM IN DIAMETER; COLLECTED GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS COLON (CO) : ^UNREMARKABLE >NOTE:>THE SECTION FROM THE TISSUE IDENTIFIED AS A DIVERTICULUM IS COMPOSED MICROSCOPICALLY OF NORMAL APPEARING COLONIC TISSUE. URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL CAUSE OF DEATH (CD) : -UNKNOWN,-PRESENT 371 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 26 ANIMAL NUMBER: I05721 SEX: MALE DOSE GROUP: 2 SACRIFICE STATUS: UNSCHEDULED (M) DATE OF DEATH: 02/12/99 STUDY DAY OF DEATH: 137 STUDY WEEK OF DEATH: 20 TERMINAL BODY WEIGHT: 3995.0 GRAMS DATE AND TIME OF NECROPSY: 02/12/99 14:25 PROSECTOR: LAURIE J. SCHULLER RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: AS ASSIGNED WEIGHER: TERRI L. WILLIAMS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), RECTUM (RE), SKIN MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (SK), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 372 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 27 ANIMAL NUMBER: I05707 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4090.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:09 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .2600 .2490 68.6950 .8690 .8850 7.9840 7.7280 73.6910 3.8970 5.7840 6.0340 .1490 .1690 .0064 % .0061 % 1.6796 % .0212 % .0216 % .1952 % .1889 % 1.8017 % .0953 % .1414 % .1475 % .0036 % .0041 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0038 .0036 1.0000 .0127 .0129 .1162 .1125 1.0727 .0567 .0842 .0878 .0022 .0025 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LUNG (LU) : -MOTTLED; ALL LOBES: RED AND GRAY LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -INFILTRATE, MACROPHAGE, ALVEOLAR,-MINIMAL -PIGMENT,-MINIMAL HEART (HT) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL THYROID (TY) : -ECTOPIC THYMUS,-PRESENT -INFILTRATE, LYMPHOHISTIOCYTIC,-SLIGHT 373 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 28 ANIMAL NUMBER: I05707 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4090.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:09 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), GALLBLADDER (GB), THYMUS (TH), TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 374 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 29 ANIMAL NUMBER: I05708 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4285.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:05 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .2260 .2200 67.1490 2.1590 2.2640 7.2760 6.9880 79.9010 5.6250 16.7130 15.2510 .4190 .4110 .0053 % .0051 % 1.5671 % .0504 % .0528 % .1698 % .1631 % 1.8647 % .1313 % .3900 % .3559 % .0098 % .0096 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0034 .0033 1.0000 .0322 .0337 .1084 .1041 1.1899 .0838 .2489 .2271 .0062 .0061 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -HYPERTROPHY, CORTICAL CELL,-MINIMAL LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PANCREAS (PA) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL EYE (EY) : -INFILTRATE, LYMPHOHISTIOCYTIC, CONJUNCTIVAL,-MINIMAL KIDNEY (KD) : -MINERALIZATION, TUBULAR,-MINIMAL LUNG (LU) : -INFILTRATE, MACROPHAGE, ALVEOLAR,-MINIMAL 375 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 30 ANIMAL NUMBER: I05708 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4285.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:05 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS LUNG (LU) : -PIGMENT,-MINIMAL HEART (HT) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL THYROID (TY) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL MUSCLE, SKELETAL (SM) : -DEGENERATION/NECROSIS,-SLIGHT -INFLAMMATION, ACUTE,-SLIGHT ILEUM (IL) : -INFILTRATE, EOSINOPHILIC,-SLIGHT MAMMARY, MALE (MM) : >SECTION EXAMINED; TISSUE NOT PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL SEMINAL VESICLES (SV) : -MINERALIZATION,-MINIMAL 376 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 31 ANIMAL NUMBER: I05708 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4285.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:05 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), BRAIN (BR), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), PROSTATE (PR), EPIDIDYMIDES (EP) 377 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 32 ANIMAL NUMBER: I05710 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 5185.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:12 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .2870 .1700 60.6750 1.8850 1.7040 8.8300 8.9130 96.5540 5.0640 13.9480 12.8270 .4870 .4000 .0055 % .0033 % 1.1702 % .0364 % .0329 % .1703 % .1719 % 1.8622 % .0977 % .2690 % .2474 % .0094 % .0077 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0047 .0028 1.0000 .0311 .0281 .1455 .1469 1.5913 .0835 .2299 .2114 .0080 .0066 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LIVER (LI) : -DIFFUSELY DARK; ALL LOBES: BROWN LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL KIDNEY (KD) : -MINERALIZATION, TUBULAR,-MINIMAL LUNG (LU) : -INFILTRATE, MACROPHAGE, ALVEOLAR,-MINIMAL -PIGMENT,-MINIMAL THYMUS (TH) : -INVOLUTION,-MODERATE THYROID (TY) : -CYST, THYROGLOSSAL,-PRESENT 378 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 33 ANIMAL NUMBER: I05710 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 5185.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:12 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY PARATHYROID (PT) : -CYST(S); LEFT: SINGLE CLEAR FLUID FILLED CYST, 0 5 CM IN DIAMETER LN, TRACHEOBRON (TB) : -DIFFUSELY DARK; BROWN (CAP 32) GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS PARATHYROID (PT) : -CYST, GLANDULAR,-PRESENT DUODENUM (DU) : -PARASITISM,-PRESENT CECUM (CE) : -INFLAMMATION, GRANULOMATOUS,-MODERATE RECTUM (RE) : -INFLAMMATION, GRANULOMATOUS,-SLIGHT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFLAMMATION, SUBACUTE,-MINIMAL LN, TRACHEOBRON (TB) : -PIGMENT,-SLIGHT 379 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 34 ANIMAL NUMBER: I05710 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 5185.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 10:12 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), HEART (HT), GALLBLADDER LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), JEJUNUM (JE), ILEUM (IL), COLON (CO), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) (GB), 380 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 35 ANIMAL NUMBER: I05712 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 4370.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:00 PROSECTOR: STEVE VAN ADESTINE RECORDER: JODI THIEREN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JODI THIEREN ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .2410 .1650 62.4710 1.7270 1.4860 6.5780 6.0930 69.7310 5.5490 9.9860 10.5520 .1940 .1630 .0055 % .0038 % 1.4295 % .0395 % .0340 % .1505 % .1394 % 1.5957 % .1270 % .2285 % .2415 % .0044 % .0037 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0039 .0026 1.0000 .0276 .0238 .1053 .0975 1.1162 .0888 .1599 .1689 .0031 .0026 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -CORTICAL TISSUE, EXTRACAPSULAR,-MINIMAL LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYROID (TY) : -CYST, GLANDULAR,-PRESENT AORTA (AO) : -THICKENING, INTIMAL,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 381 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 36 ANIMAL NUMBER: I05712 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 4370.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:00 PROSECTOR: STEVE VAN ADESTINE RECORDER: JODI THIEREN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JODI THIEREN NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS STOMACH, GL (ST) : -INFLAMMATION, CHRONIC,-SLIGHT -PARASITISM,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 382 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 37 ANIMAL NUMBER: I05712 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 4370.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:00 PROSECTOR: STEVE VAN ADESTINE RECORDER: JODI THIEREN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JODI THIEREN THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) (CE), 383 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 38 ANIMAL NUMBER: I05716 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 3495.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:45 PROSECTOR: STEVE VAN ADESTINE RECORDER: JODI THIEREN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JODI THIEREN ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3130 .2190 71.1770 1.5920 1.7130 5.1720 5.1810 62.3470 5.4140 10.1740 9.9220 .4390 .4370 .0090 % .0063 % 2.0365 % .0456 % .0490 % .1480 % .1482 % 1.7839 % .1549 % .2911 % .2839 % .0126 % .0125 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0044 .0031 1.0000 .0224 .0241 .0727 .0728 .8759 .0761 .1429 .1394 .0062 .0061 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -CORTICAL TISSUE, EXTRACAPSULAR,-MINIMAL BRAIN (BR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL HEART (HT) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PARATHYROID (PT) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 384 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 39 ANIMAL NUMBER: I05716 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 3495.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:45 PROSECTOR: STEVE VAN ADESTINE RECORDER: JODI THIEREN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JODI THIEREN NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS MUSCLE, SKELETAL (SM) : -PARASITISM,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 385 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 40 ANIMAL NUMBER: I05716 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, FIRST POST-RECOV SAC DATE OF DEATH: 07/02/99 STUDY DAY OF DEATH: 277 STUDY WEEK OF DEATH: 40 TERMINAL BODY WEIGHT: 3495.0 GRAMS DATE AND TIME OF NECROPSY: 07/02/99 8:45 PROSECTOR: STEVE VAN ADESTINE RECORDER: JODI THIEREN POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JODI THIEREN THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), KIDNEY (KD), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), AORTA (AO), PITUITARY (PI), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 386 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 41 ANIMAL NUMBER: I05719 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4230.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:36 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .4390 .2920 60.5780 1.8910 1.8030 8.1130 7.9120 82.5510 6.4950 12.2990 11.9690 .2810 .2740 .0104 % .0069 % 1.4321 % .0447 % .0426 % .1918 % .1870 % 1.9516 % .1535 % .2908 % .2830 % .0066 % .0065 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0072 .0048 1.0000 .0312 .0298 .1339 .1306 1.3627 .1072 .2030 .1976 .0046 .0045 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -HYPERTROPHY, CORTICAL CELL,-MINIMAL -MINERALIZATION,-SLIGHT LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL KIDNEY (KD) : -MINERALIZATION, TUBULAR,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYMUS (TH) : -INVOLUTION,-MODERATE 387 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 42 ANIMAL NUMBER: I05719 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4230.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:36 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY SKIN (SK) : -CRUSTED AREA(S); LEFT SIDE OF MUZZLE: SINGLE DARK BROWN, DRY AREA, 0.6 CM IN DIAMETER (CAP 32) GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS THYROID (TY) : -ECTOPIC THYMUS,-PRESENT SKIN (SK) : -ACANTHOSIS,-MODERATE -INFLAMMATION, CHRONIC,-SLIGHT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL SEMINAL VESICLES (SV) : -MINERALIZATION,-MINIMAL 388 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 43 ANIMAL NUMBER: I05719 SEX: MALE DOSE GROUP: 3 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4230.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:36 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), HEART (HT), GALLBLADDER (GB), LN, MESENTERIC TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), MAMMARY, MALE (MM), EPIDIDYMIDES (EP) (MS), 389 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 44 ANIMAL NUMBER: I05703 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3395.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:58 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3150 .2230 70.4970 1.0740 1.1260 5.2860 5.3070 63.4060 5.1560 5.4680 5.6610 .1370 .1310 .0093 % .0066 % 2.0765 % .0316 % .0332 % .1557 % .1563 % 1.8676 % .1519 % .1611 % .1667 % .0040 % .0039 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0045 .0032 1.0000 .0152 .0160 .0750 .0753 .8994 .0731 .0776 .0803 .0019 .0019 ORGAN STATUS EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE HISTOPATHOLOGY LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL BRAIN (BR) : -MINERALIZATION,-MINIMAL KIDNEY (KD) : -MINERALIZATION, TUBULAR,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL LN, MESENTERIC (MS) : -INFILTRATE, EOSINOPHILIC,-MINIMAL THYROID (TY) : -ECTOPIC THYMUS,-PRESENT 390 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 45 ANIMAL NUMBER: I05703 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3395.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:58 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR(FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH),LN, MESENTERIC (MS), TRACHEA (TR),ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR(FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), HEART (HT), GALLBLADDER (GB), THYMUS (TH), TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 391 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 46 ANIMAL NUMBER: I05704 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4275.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:20 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3540 .3250 76.8210 1.6580 1.5980 8.3990 8.4590 87.4080 6.4850 8.7630 8.4290 .2930 .3050 .0083 % .0076 % 1.7970 % .0388 % .0374 % .1965 % .1979 % 2.0446 % .1517 % .2050 % .1972 % .0069 % .0071 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0046 .0042 1.0000 .0216 .0208 .1093 .1101 1.1378 .0844 .1141 .1097 .0038 .0040 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LIVER (LI) : >NOTE:>TRIMMING COMMENT: LIVER GALLBLADDER SECTION NOT FOUND AT TRIMMING LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL KIDNEY (KD) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYROID (TY) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 392 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 47 ANIMAL NUMBER: I05704 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4275.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 11:20 PROSECTOR: NANCY DIEDRICH RECORDER: JERALD W. JOHNSON POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: JERALD W. JOHNSON NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 393 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 48 ANIMAL NUMBER: I05711 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3850.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 12:20 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3190 .3180 57.7460 1.8990 1.9690 6.1270 6.7780 59.5960 4.7660 14.5170 13.5200 .1430 .1270 .0083 % .0083 % 1.4999 % .0493 % .0511 % .1591 % .1761 % 1.5479 % .1238 % .3771 % .3512 % .0037 % .0033 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0055 .0055 1.0000 .0329 .0341 .1061 .1174 1.0320 .0825 .2514 .2341 .0025 .0022 ORGAN STATUS EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE HISTOPATHOLOGY KIDNEY (KD) : -CYST(S); RIGHT CORTICAL SURFACE: SINGLE CLEAR FLUID FILLED CYST, 0.4 CM IN DIAMETER ADRENAL, CORTEX (AC) : -CORTICAL TISSUE, EXTRACAPSULAR,-SLIGHT -ECTOPIC ZONA GLOMERULOSA-LIKE CELLS, ZONA FASCICULATA,PRESENT LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -PIGMENT, KUPFFER CELL,-MINIMAL BRAIN (BR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL KIDNEY (KD) : -CYST,-MODERATE -MINERALIZATION, TUBULAR,-MINIMAL 394 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 49 ANIMAL NUMBER: I05711 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3850.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 12:20 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY LN, MANDIBULAR (MN) : -LARGE; BILATERAL: EACH GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS IS UP TO 1.4 X 1.0 X 0.8 CM (CAP 32) LUNG (LU) : -INFILTRATE, MACROPHAGE, ALVEOLAR,-MINIMAL -PIGMENT,-MINIMAL HEART (HT) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL STOMACH, GL (ST) : -INFLAMMATION, GRANULOMATOUS,-SLIGHT -PARASITISM,-PRESENT PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL EPIDIDYMIDES (EP) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LN, MANDIBULAR (MN) : >UNREMARKABLE 395 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 50 ANIMAL NUMBER: I05711 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3850.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 12:20 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, TRACHEOBRON (TB) THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), SEMINAL VESICLES (SV) 396 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 51 ANIMAL NUMBER: I05713 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3375.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:17 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3100 .1990 71.6710 2.1310 1.9500 9.8190 9.8410 93.3770 6.0370 11.8290 11.3470 .1940 .1250 .0092 % .0059 % 2.1236 % .0631 % .0578 % .2909 % .2916 % 2.7667 % .1789 % .3505 % .3362 % .0057 % .0037 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0043 .0028 1.0000 .0297 .0272 .1370 .1373 1.3029 .0842 .1650 .1583 .0027 .0017 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY ADRENAL, CORTEX (AC) : -HYPERTROPHY, CORTICAL CELL,-MINIMAL LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL TESTIS (TE) : -ATROPHY/DEGENERATION,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL >NOTE:>PIGMENT IS ALSO PRESENT IN THE MEDULLA OF A TRACHEOBRONCHIAL LYMPH NODE AT THE PERIPHERY OF THE SECTION. 397 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 52 ANIMAL NUMBER: I05713 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3375.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:17 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 398 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 53 ANIMAL NUMBER: I05713 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 3375.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:17 PROSECTOR: STEVE VAN ADESTINE RECORDER: TERRI L. WILLIAMS POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: TERRI L. WILLIAMS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 399 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 54 ANIMAL NUMBER: I05722 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4730.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:37 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3570 .2810 72.5150 1.4080 1.6810 9.3880 8.4920 94.6850 5.9610 9.1580 8.6990 .3060 .2680 .0075 % .0059 % 1.5331 % .0298 % .0355 % .1985 % .1795 % 2.0018 % .1260 % .1936 % .1839 % .0065 % .0057 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0049 .0039 1.0000 .0194 .0232 .1295 .1171 1.3057 .0822 .1263 .1200 .0042 .0037 ORGAN STATUS EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE EXCLUDE HISTOPATHOLOGY GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -PIGMENT, KUPFFER CELL,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYROID (TY) : -ECTOPIC THYMUS,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 400 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 55 ANIMAL NUMBER: I05722 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: SCHEDULED, TERMINAL SACRIFICE DATE OF DEATH: 03/31/99 STUDY DAY OF DEATH: 184 STUDY WEEK OF DEATH: 27 TERMINAL BODY WEIGHT: 4730.0 GRAMS DATE AND TIME OF NECROPSY: 03/31/99 8:37 PROSECTOR: TODD ACKER RECORDER: LAURIE J. SCHULLER POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: LAURIE J. SCHULLER NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -NO MACROSCOPIC LESIONS THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), LIVER (LI), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (FE), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), HEART (HT), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), ESOPHAGUS (ES), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), STOMACH, GL (ST), DUODENUM (DU), JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 401 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 56 ANIMAL NUMBER: I05724 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: UNSCHEDULED (M) DATE OF DEATH: 10/27/98 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 3505.0 GRAMS DATE AND TIME OF NECROPSY: 10/27/98 8:40 PROSECTOR: TODD ACKER RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: NANCY DIEDRICH ORGAN NAME ABSOLUTE ORGAN WEIGHT (GRAMS) ORGAN WEIGHT RELATIVE TO BODY WEIGHT (%) LF ADRENAL (AD0) RT ADRENAL (AD1) BRAIN (BR) LF EPIDIDYMIS (EP0) RT EPIDIDYMIS (EP1) LF KIDNEY (KD0) RT KIDNEY (KD1) LIVER (LI) PANCREAS (PA) LF TESTIS (TE0) RT TESTIS (TE1) LF THYROID/PARA (TT0) RT THYROID/PARA (TT1) .3680 .2850 56.1560 1.1670 1.3200 7.9420 7.6550 83.1880 6.3820 5.0850 5.3130 .1970 .2210 .0105 % .0081 % 1.6022 % .0333 % .0377 % .2266 % .2184 % 2.3734 % .1821 % .1451 % .1516 % .0056 % .0063 % NECROPSY OBSERVATIONS ORGAN TO BRAIN WEIGHT RATIO .0066 .0051 1.0000 .0208 .0235 .1414 .1363 1.4814 .1136 .0906 .0946 .0035 .0039 ORGAN S T A rr U S WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN WEIGHT TAKEN HISTOPATHOLOGY LIVER (LI) : -DIFFUSELY LIGHT; ALL LOBES: TAN ADRENAL, CORTEX (AC) : -HYPERTROPHY, CORTICAL CELL,-MINIMAL LIVER (LI) : -BASOPHILIA, HEPATOCELLULAR, CENTRILOBILAR,-MODERATE -DEGENERATION, HEPATOCELLULAR, CENTRILOBULAR AND MIDZONAL,MODERATE -INFILTRATE, LYMPHOHISTIOCYTIC,-SLIGHT -PIGMENT, KUPFFER CELL,-MINIMAL -VACUOLATION, HEPATOCELLULAR, DIFFUSE,-MODERATELY SEVERE >NOTE:>DEGENERATING HEPATOCYTES IN MIDZONAL AREAS HAVE BRIGHTLY EOSINOPHILIC GLOBULAR INTRACYTOPLASMIC MATERIAL. 402 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 57 ANIMAL NUMBER: I05724 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: UNSCHEDULED (M) DATE OF DEATH: 10/27/98 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 3505.0 GRAMS DATE AND TIME OF NECROPSY: 10/27/98 8:40 PROSECTOR: TODD ACKER RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: NANCY DIEDRICH NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY HEART (HT) : -DIFFUSELY LIGHT; TAN ESOPHAGUS (ES) : -THICKENED WALL; AREA THAT LIES ALONG THE LUNGS: FIRM -LARGE; AREA THAT LIES ALONG THE LUNGS: UP TO 1.0 CM IN DIAMETER STOMACH, GL (ST) : -THICKENED WALL; DIFFUSE -DARK FOCUS(I)/AREA(S); MUCOSA: MULTIPLE, DARK BROWN FOCI UP TO 0.1 CM IN DIAMETER GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS KIDNEY (KD) : -MINERALIZATION, TUBULAR,-SLIGHT -VACUOLATION, TUBULAR EPITHELIUM,-SLIGHT HEART (HT) : -DEGENERATION/NECROSIS,-SLIGHT THYMUS (TH) : -INVOLUTION,-MODERATELY SEVERE LN, MESENTERIC (MS) : -INFILTRATE, NEUTROPHILIC,-SLIGHT ESOPHAGUS (ES) : -EDEMA, SUBMUCOSAL,-MODERATELY SEVERE -EROSION,-MODERATE -INFLAMMATION, ACUTE,-SLIGHT -ULCERATION,-MINIMAL STOMACH, GL (ST) : -EROSION,-SLIGHT -ULCERATION,-MODERATE ILEUM (IL) : -INFLAMMATION, ACUTE,-MINIMAL CECUM (CE) : -INFLAMMATION, ACUTE,-MINIMAL CAUSE OF DEATH (CD) : -DOSING INJURY,-PRESENT 403 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS PAGE: 58 ANIMAL NUMBER: I05724 SEX: MALE DOSE GROUP: 4 SACRIFICE STATUS: UNSCHEDULED (M) DATE OF DEATH: 10/27/98 STUDY DAY OF DEATH: 29 STUDY WEEK OF DEATH: 5 TERMINAL BODY WEIGHT: 3505.0 GRAMS DATE AND TIME OF NECROPSY: 10/27/98 8:40 PROSECTOR: TODD ACKER RECORDER: NANCY DIEDRICH POST-FIX WEIGHER: NOT AVAILABLE PATHOLOGIST: JOHN EIGHMY WEIGHER: NANCY DIEDRICH NECROPSY O B S E R V A T I O N S (CONTINUED) HISTOPATHOLOGY GENERAL COMMENT (GC) : -GI TRACT-DARK FLUID CONTENT; STOMACH, DUODENUM, JEJUNUM, AND ILEUM: DARK BROWN, MUCOID SEMIFLUID; GALLBLADDER: DARK GREEN, THICK, MUCOID SEMIFLUID THE FOLLOWING ORGANS WERE UNREMARKABLE AT NECROPSY: ADRENAL, CORTEX (AC), ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), KIDNEY (KD), LUNG (LU), GALLBLADDER (GB), THYMUS (TH), LN, MESENTERIC (MS), TRACHEA (TR), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), DUODENUM JEJUNUM (JE), ILEUM (IL), CECUM (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP), LN, MANDIBULAR (MN), LN, TRACHEOBRON (TB) (DU), (UB), THE FOLLOWING TISSUES WERE UNREMARKABLE AT MICROSCOPIC EXAMINATION: ADRENAL, MEDULLA (MA), SPLEEN (SP), PANCREAS (PA), TESTIS (TE), BONE, FEMUR (FE), MARROW, FEMUR (FM), MARROW, STERNUM (SE), BONE, STERNUM (SB), EYE (EY), BRAIN (BR), LUNG (LU), GALLBLADDER (GB), TRACHEA (TR), THYROID (TY), PARATHYROID (PT), AORTA (AO), PITUITARY (PI), SALIV GL, MANDIB (SG), MUSCLE, SKELETAL (SM), SPINAL CORD (SC), NERVE, SCIATIC (SN), DUODENUM (DU), JEJUNUM (JE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), URINARY BLADDER (UB), PROSTATE (PR), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) 404 APPENDIX 6 Covance 6329-231 3M T-6889.3 Quality Assurance Statements Summary of Hormone Analyses Data Summary of Testosterone Analyses Data (ng/mL) Individual Hormone Analyses Data Individual Testosterone Analyses Data (ng/mL) Note: The data included in this appendix were supplied by Ani Lytics Inc. and have been reviewed by the Quality Assurance Unit of Ani Lytics Inc. 405 Covance 6329-231 3M T-6889.3 jf y f JL J . V _ A j INCORPORATED 200 Girard Street, Suite 200, Gaithersburg, MD 20877 301-921-0168 800-237-2815 The reports listed below was reviewed for compliance with the FDA Good Laboratory Practices and with the EPA Good Laboratory Practices. The final report and all associated raw data were reviewed for accuracy and consistency and the findings were reported to management. The methods used were the methods described and the report accurately reflects the data. Therefore, these studies were done in compliance with the FDA and EPA Good Laboratory - Practices. SPONSOR: REPORT TYPE: 5 ! a ?, ri>}i 77, THf fT3, F t */ Franklin B. Newman QA Auditor A/) 65 / ' ^ STUDY: AUDIT DATE: REPORT TO MGMT: AUDIT #: A 77 MANAGEMENT " 1 ^ / 9 ^ 406 Covance 6329-231 3M T-6889.3 INCORPORATED 200 Girard Street, Suite 200, Gaithersburg, MD 20877 301-921-0168 800-237-2815 The reports listed below was reviewed for compliance with the FDA Good Laboratory Practices and with the EPA Good Laboratory Practices. The final report and all associated raw data were reviewed for accuracy and consistency and the findings were reported to management. . . The methods used were the methods described and the report accurately reflects the data. Therefore, these studies were done in compliance with the FDA and EPA Good Laboratory Practices. Franklin B. Newman QA Auditor SPONSOR: C O V ^ t l&5/ STUDY: REPORT TYPE: [, 3, 3, V iti, ry Fry F ry AUDIT DATE: REPORT TO MGMT: AUDIT #: i rr ,/ MANAGEMENT Lil 407 Covance 6329-231 3M T-6889.3 # _ jf INCORPORATED 200 Girard Street, Suite 200, Gaithersburg, MD 20877 301-921-0168 800-237-2815 The reports listed below was reviewed for compliance with the FDA Good Laboratory Practices and with the EPA Good Laboratory Practices. The final report and all associated raw data were reviewed for accuracy and consistency and the findings were reported to management. The methods used were the methods described and the report accurately reflects the data. Therefore, these studies were done in compliance with the FDA and EPA Good Laboratory Practices. SPONSOR: REPORT TYPE: 7T5 QA Auditor STUDY: C.3^1-23) AUDIT DATE: REPORT TO MGMT: AUDIT #: MANAGEMENT ^ lc^\ 408 Covance 6329-231 3M T-6889.3 200 Girard Street, Suite 200, Gaithersburg, MD 20877 301-921-0168 800-237-2815 The reports listed below was reviewed for compliance with the FDA Good Laboratory Practices and with the EPA Good Laboratory Practices. The final report and all associated raw data were reviewed for accuracy and consistency and the findings were reported to management. The methods used were the methods described and the report accurately reflects the data. Therefore, these studies were done in compliance with the FDA and EPA Good Laboratory Practices. SPONSOR: CO REPORT TYPE: ) ,2 3 TSH-J r 3 H THj f$To5 Franklin B. Newman QA Auditor STUDY: AUDIT #: 409 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day -18 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 52.49 10.538 6 32.82 11.396 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 48.22 3.001 4 36.82 4.435 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 49.71 9.152 6 33.94 6.474 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 50.97 11.508 6 27.54 5.889 6 Dosage Unit: mg/kg/day 0.00 0.000 6 0.60 0.446 6 Dosage Unit: mg/kg/day 0.01 0.025 4 0.53 0.713 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.38 0.437 6 Dosage Unit: mg/kg/day 0.00 0.000 6 0.27 0.192 6 258.48 66.361 6 316.73 54.114 4 253.91 39.961 6 245.32 59.058 6 5.65 1.130 6 4.43 0.746 4 3.92 1.142 6 4.82 0.988 6 9.74 0.983 6 9.65 0.598 4 8.88 1.805 6 8.17 1.006 6 2.96 0.483 6 3.13 0.338 4 2.55 0.399 6 2.81 0.334 6 410 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day -8 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 53.67 12.749 6 29.96 12.677 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 47.64 8.506 4 31.53 3.840 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 54.51 9.283 6 34.54 5.880 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 49.94 10.167 6 29.81 7.632 6 Dosage Unit: mg/kg/day 0.00 0.000 6 0.61 0.321 6 Dosage Unit: mg/kg/day 0.00 0.000 4 0.68 0.715 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.56 0.556 6 Dosage Unit: mg/kg/day 0.00 0.000 6 0.73 0.605 6 222.54 60.023 6 247.69 32.547 4 253.54 74.851 6 198.91 45.640 6 3.93 0.554 6 3.71 0.345 4 3.49 0.865 6 4.24 1.244 6 9.47 1.516 6 11.11 1.705 4 10.28 1.404 6 10.92 2.387 6 2.58 0.682 6 2.28 0.367 4 2.24 0.407 6 2.86 0.638 6 411 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day -4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 38.98 10.162 6 24.88 6.306 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 40.20 6.930 4 35.09 9.703 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 37.25 4.702 6 30.16 7.409 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 39.40 10.143 6 27.73 6.663 6 Dosage Unit: mg/kg/day 0.00 0.000 6 0.37 0.363 6 Dosage Unit: mg/kg/day 0.00 0.000 4 0.53 0.583 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.46 0.571 6 Dosage Unit: mg/kg/day 0.00 0.000 6 0.29 0.279 6 155.11 18.112 6 149.69 26.462 4 169.61 23.153 6 147.22 16.027 6 5.13 0.809 6 5.16 1.284 4 4.17 0.511 6 4.51 0.788 6 6.39 0.634 6 6.06 0.628 4 6.16 0.440 6 6.00 0.877 6 1.77 0.288 6 1.72 0.354 4 1.56 0.178 6 1.56 0.257 6 412 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 35 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 46.54 9.590 6 7.62 6.963 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 41.44 10.467 4 14.67 12.614 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 37.54 7.589 6 11.23 7.403 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 36.69 11.745 5 4.63 7.126 5 Dosage Unit: mg/kg/day 0.00 0.000 6 0.23 0.232 6 Dosage Unit: mg/kg/day 0.00 0.000 4 0.36 0.533 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.26 0.440 6 Dosage Unit: mg/kg/day 0.00 0.000 5 0.03 0.044 5 170.71 15.946 6 166.57 29.681 4 151.51 15.053 6 109.80 39.245 5 4.72 0.946 6 4.02 0.756 4 2.95 0.463 6 3.70 0.286 5 5.49 0.699 6 5.58 0.652 4 5.13 0.414 6 3.79 1.178 5 1.60 0.341 6 1.47 0.158 4 1.09 0.171 6 1.23 0.058 5 413 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 66 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 39.60 7.881 6 15.00 12.534 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 36.63 7.000 4 18.31 11.446 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 36.04 11.306 6 19.83 10.105 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 21.78 6.437 4 2.06 4.125 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.23 0.343 6 Dosage Unit: mg/kg/day 0.00 0.000 4 0.19 0.274 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.56 1.067 6 Dosage Unit: mg/kg/day 0.00 0.000 4 0.22 0.252 4 163.31 19.398 6 169.92 20.976 4 162.50 9.951 6 89.66 51.035 4 4.65 0.864 6 3.52 0.525 4 3.04 0.455 6 3.27 1.023 4 5.71 1.143 6 6.23 0.590 4 5.31 0.537 6 3.01 1.958 4 1.48 0.263 6 1.34 0.300 4 1.08 0.199 6 1.08 0.263 4 414 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 94 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 41.74 8.263 6 13.46 10.122 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 37.11 5.322 4 7.74 7.822 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 35.52 8.323 6 6.41 7.867 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 28.18 8.832 2 0.00 0.000 2 Dosage Unit: mg/kg/day 0.00 0.000 6 0.54 0.463 6 Dosage Unit: mg/kg/day 0.00 0.000 4 0.60 0.552 4 Dosage Unit: mg/kg/day 0.00 0.000 6 0.38 0.529 6 Dosage Unit: mg/kg/day 0.00 0.000 2 0.20 0.106 2 162.04 25.417 6 176.93 27.852 4 156.97 18.134 6 120.02 35.171 2 4.22 0.902 6 3.55 0.375 4 2.93 0.420 6 3.76 0.424 2 5.02 0.732 6 5.28 0.343 4 4.98 0.894 6 3.96 1.464 2 1.49 0.504 6 1.32 0.278 4 1.06 0.197 6 1.34 0.269 2 415 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 183 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 38.69 10.736 6 10.75 17.027 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 46.87 17.528 3 13.56 11.112 3 Group: Male 3 Dose Level: 10 MEAN S.D. N 32.65 7.402 6 7.83 6.225 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 26.90 1.365 2 0.00 0.000 2 Dosage Unit: mg/kg/day 0.00 0.000 6 0.40 0.231 6 Dosage Unit: mg/kg/day 0.00 0.000 3 0.65 0.171 3 Dosage Unit: mg/kg/day 0.00 0.000 6 0.87 1.088 6 Dosage Unit: mg/kg/day 0.00 0.000 2 0.39 0.099 2 157.28 15.387 6 133.47 16.777 3 134.47 22.554 6 103.37 32.958 2 3.84 0.769 6 2.58 0.173 3 2.71 0.351 6 2.61 0.247 2 5.62 0.893 6 4.87 0.121 3 4.67 0.637 6 3.39 1.541 2 1.55 0.426 6 1.04 0.035 3 0.96 0.131 6 0.90 0.240 2 416 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 220 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 51.58 22.847 2 44.19 18.569 2 Group: Male 3 Dose Level: 10 MEAN S.D. N 27.20 8.853 2 27.85 3.974 2 Dosage Unit: mg/kg/day 0.00 0.000 2 0.17 0.212 2 Dosage Unit: mg/kg/day 0.00 0.000 2 0.42 0.424 2 170.61 6.456 2 175.08 4.660 2 3.44 1.400 2 3.39 0.283 2 5.44 0.269 2 5.54 0.445 2 0.87 0.474 2 0.93 0.134 2 417 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 248 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL, THYROID STIMULATING ng/mL HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 46.80 7.276 2 40.43 19.537 2 Group: Male 3 Dose Level: 10 MEAN S.D. N 33.81 11.413 2 30.91 7.149 2 Dosage Unit: mg/kg/day 0.00 0.000 2 0.06 0.078 2 Dosage Unit: mg/kg/day 0.00 0.000 2 0.34 0.092 2 162.75 1.853 2 173.48 17.211 2 3.46 1.485 2 3.91 0.163 2 5.36 1.252 2 7.19 0.679 2 1.02 0.629 2 1.13 0.028 2 418 ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Hormone Analyses Data Day 276 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 MEAN S.D. N 71.61 18.180 2 46.33 21.362 2 Group: Male 3 Dose Level: 10 MEAN S.D. N 35.81 4.695 2 30.17 10.218 2 Dosage Unit: mg/kg/day 0.00 0.000 2 0.00 0.000 2 Dosage Unit: mg/kg/day 0.00 0.000 2 0.01 0.014 2 167.29 16.023 2 172.47 35.447 2 4.81 0.841 2 4.05 0.396 2 5.02 0.453 2 6.02 0.078 2 1.48 0.728 2 1 0 2 419 Appendix 6 Summary of Testosterone Analyses Data (ng/mL) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS DAY DAY DAY DAY DAY DAY DAY DAY -18 -8 -4 35 66 94 183 220 Group: Male 1 Dose Level: 0 MEAN S.D. N 2.96 1.917 6 6.53 10.033 6 Group: Male 2 Dose Level: 3 MEAN S.D. N 2.87 1.592 4 2.94 2.008 4 Group: Male 3 Dose Level: 10 MEAN S.D. N 3.60 2.793 6 3.81 3.896 6 Group: Male 4 Dose Level: 20 MEAN S.D. N 1.20 0.505 6 2.13 2.311 6 Dosage Unit: mg/kg/day 3.83 3.376 6 2.22 2.629 6 3.67 3.615 6 Dosage Unit: mg/kg/day 6.67 6.550 4 3.03 2.991 4 3.68 2.259 4 Dosage Unit: mg/kg/day 2.47 2.423 6 2.00 2.016 6 5.15 3.918 6 Dosage Unit: mg/kg/day 3.97 3.205 6 0.81 0.484 5 2.76 3.007 4 4.95 4.423 6 7.36 2.656 4 2.89 2.055 6 1.25 0.092 2 6.33 4.070 6 7.81 4.274 3 7.83 3.685 6 1.74 0.438 2 3.90 0.834 2 5.70 2.213 2 Covance 6329-231 3M T-6889.3 PAGE: 1 DAY DAY 248 276 5.27 0.332 2 9.25 2.362 2 5.58 2.341 2 15.23 17.501 2 420 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day -18 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 44.14 54.81 70.39 55.35 40.48 49.78 31.72 33.66 33.31 53.44 20.97 23.79 Group: Male 2 Dose Level: 3 I05702 I05706 I05717 I05721 52.71 46.90 46.88 46.40 30.68 36.46 39.75 40.37 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 37.74 47.50 50.43 42.38 59.59 60.61 23.20 36.92 31.77 36.22 32.95 42.57 Group: Male 4 Dose Level: 20 I05703 I05704 I05711 I05713 I05722 I05724 50.41 58.88 68.29 43.24 35.57 49.44 35.60 23.56 32.76 28.23 19.80 25.31 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.46 0.37 1.32 0.00 0.80 0.67 Dosage Unit: mg/kg/day 0.00 0.05 0.00 0.00 0.11 0.46 0.00 1.56 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.01 0.49 0.70 1.05 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.28 0.00 0.22 0.40 0.55 0.15 232.97 189.19 180.50 327.72 323.10 297.42 255.67 296.53 331.42 383.31 311.45 269.41 234.48 226.15 202.58 279.41 293.22 257.86 231.62 148.42 224.85 315.97 5.94 5.08 4.93 7.57 4.37 6.02 3.88 3.69 5.07 5.07 2.77 2.75 3.64 4.11 4.49 5.76 5.94 5.99 3.90 4.67 3.64 4.79 8.31 10.01 9.64 9.80 9.33 11.33 9.24 9.05 10.30 10.00 8.10 8.64 6.87 9.77 12.01 7.88 7.90 8.24 7.11 8.13 7.60 10.05 2.69 3.60 3.03 3.16 2.17 3.08 3.30 3.52 2.90 2.80 2.51 2.08 2.10 2.94 3.00 2.68 2.98 3.32 2.38 2.59 2.93 2.66 421 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day -8 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 49.89 47.97 69.01 69.53 38.17 47.44 29.82 35.78 24.57 51.51 14.70 23.38 Group: Male 2 Dose Level: 3 I05702 I05706 I05717 I05721 49.71 57.64 46.05 37.14 27.23 34.02 35.42 29.43 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 44.28 51.59 67.23 44.66 57.85 61.42 23.99 41.10 35.96 33.74 33.96 38.48 Group: Male 4 Dose Level: 20 I05703 I05704 I05711 I05713 I05722 I05724 50.52 40.33 65.03 44.88 40.21 58.67 32.76 25.33 43.77 26.98 22.41 27.61 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.51 0.66 0.95 0.02 0.77 0.73 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.09 0.94 0.11 1.57 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.36 0.39 0.34 0.68 1.61 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.38 0.00 0.32 0.95 1.09 1.64 263.59 295.00 270.09 178.30 159.73 168.55 257.73 254.81 277.04 201.16 213.19 285.05 249.20 352.02 288.47 133.31 177.15 158.15 246.01 266.86 166.93 178.37 4.29 3.85 3.93 4.62 2.97 3.93 3.35 3.69 4.18 3.63 3.26 2.48 4.58 4.50 3.26 2.85 3.42 5.38 2.68 5.89 4.55 3.52 8.52 10.48 9.84 10.65 10.48 6.82 9.65 13.21 11.77 9.79 12.06 10.86 8.86 11.06 10.47 8.36 10.32 9.64 8.74 10.29 11.01 15.54 1.93 3.03 2.32 3.07 1.74 3.41 2.47 2.10 2.69 1.87 2.90 1.81 2.21 2.54 1.97 2.03 2.23 3.22 2.27 2.77 3.93 2.76 422 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day -4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 38.01 40.66 49.70 50.07 24.50 30.92 22.74 30.15 25.20 33.29 15.40 22.48 Group: Male 2 Dose Level: 3 I05702 I05706 I05717 I05721 35.97 50.27 39.26 35.31 22.63 34.06 46.03 37.63 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 39.08 36.22 40.30 28.25 38.71 40.95 22.41 24.03 33.22 31.56 27.08 42.65 Group: Male 4 Dose Level: 20 I05703 I05704 I05711 I05713 I05722 I05724 52.45 38.96 46.11 39.54 22.27 37.07 31.41 19.52 37.97 27.98 21.72 27.79 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.06 0.15 0.46 0.00 0.63 0.92 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.27 0.02 0.48 1.36 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.58 0.41 1.53 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.37 0.00 0.10 0.51 0.06 0.69 136.58 140.65 150.86 183.59 169.99 149.01 112.59 154.40 175.31 156.45 172.89 162.30 148.51 214.06 161.96 157.92 168.50 146.82 130.79 149.03 127.68 160.50 4.58 5.25 4.43 5.66 4.41 6.42 4.19 4.25 6.94 5.24 3.55 3.93 4.15 5.09 4.25 4.06 3.81 5.63 3.51 4.57 5.10 4.42 5.94 6.75 6.06 6.21 7.52 5.88 5.27 6.70 6.39 5.86 6.72 6.38 5.61 6.20 6.39 5.66 5.82 6.84 5.44 6.35 4.63 6.89 1.42 2.23 1.66 1.98 1.62 1.72 1.38 1.55 2.20 1.75 1.44 1.40 1.57 1.52 1.53 1.90 1.50 2.06 1.36 1.42 1.44 1.60 423 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 35 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 47.59 46.19 53.53 58.70 30.92 42.31 0.00 12.52 3.41 19.11 5.07 5.59 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.31 0.07 0.06 0.62 0.29 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717a I05721a 52.77 47.02 36.62 29.36 2.53 5.13 24.15 26.88 0.00 0.00 0.00 0.00 0.06 0.04 0.17 1.15 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 36.62 34.46 50.13 27.73 41.47 34.81 5.92 2.60 21.41 13.17 6.54 17.71 Group: Male 4 b Dose Level: 20 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.07 0.00 0.41 1.10 0.00 Dosage! Unit: mg/kg/day I05703 I05704 I05711 I05713 I05722 31.99 33.13 33.03 27.95 57.36 17.08 2.80 0.00 3.25 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.04 151.08 172.92 158.25 169.74 174.95 197.30 147.88 149.50 210.55 158.33 162.71 144.58 144.62 172.47 154.68 130.00 151.98 142.88 74.00 114.82 65.30 5.15 5.13 4.28 6.18 3.90 3.66 3.04 3.84 4.47 4.74 3.08 2.31 3.01 3.20 2.51 3.57 3.56 3.62 3.35 3.95 4.04 4.54 6.32 5.42 4.87 5.61 6.16 5.04 5.76 6.43 5.10 4.70 4.74 5.15 5.71 5.52 4.95 4.36 5.35 3.04 3.88 2.30 1.60 1.85 1.71 2.01 1.10 1.30 1.24 1.51 1.57 1.57 1.08 0.81 1.11 1.22 1.01 1.30 1.15 1.24 1.19 1.30 1.25 a Animal No. I05721 :replaced Animal No.. I05723 on Day 15. Dose administration for this animal initiated on Day 17 (Week 3) b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. Beginning on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. 424 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 66 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 32.82 34.56 40.44 51.93 32.39 45.47 5.66 1.75 23.69 35.58 10.87 12.42 Group: Male 2 Dose Level: 3 I05702 I05706 I05717 I05721 44.91 34.58 38.76 28.28 16.02 6.14 33.76 17.31 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 29.88 28.72 57.00 26.14 39.17 35.35 4.46 14.63 31.54 15.34 25.77 27.23 Group: Male 4 Dose Level: 20 I05703 I05704c I05711 I05713 I05722 23.05 28.22 43.55 23.00 12.85 0.00 8.25 20.14 0.00 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.81 0.01 0.01 0.50 0.06 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.01 0.06 0.10 0.60 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.22 0.26 0.11 2.73 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.01 0.02 0.41 0.47 161.17 136.94 152.11 157.79 187.17 184.67 141.93 165.96 188.15 183.65 164.93 159.20 160.10 179.10 163.19 148.48 86.91 146.63 107.53 101.86 23.24 5.42 4.54 4.08 5.72 3.37 4.78 2.84 3.92 3.95 3.38 2.84 2.35 3.15 3.47 2.87 3.58 2.79 4.09 2.32 4.15 2.06 5.84 4.10 5.36 4.97 6.86 7.10 5.71 7.06 6.20 5.94 5.45 4.67 4.68 5.48 6.04 5.54 2.22 5.55 3.50 3.33 0.93 1.48 1.54 1.55 1.82 1.01 1.46 1.20 1.74 1.37 1.04 1.12 0.80 1.10 1.15 0.91 1.37 0.86 1.32 0.72 1.30 0.85 c Dose administration was discontinued on Day 43 (Week 7). 425 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 94 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL, THYROID STIMULATING ng/mL HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 33.68 34.36 47.70 52.75 35.32 46.64 2.52 16.26 19.40 26.08 0.00 16.47 Group: Male 2 Dose Level: 3 I05702 I05706 I05717 I05721 43.91 37.28 36.31 30.94 4.65 0.00 18.42 7.90 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 32.24 27.49 49.47 27.61 38.00 38.32 0.00 2.63 19.42 12.52 0.00 3.88 Group: Male 4 Dose Level: 20 d I05703 I05704c I05711c I05713e I05722e 34.25 34.42 41.78 21.93 28.22 7.04 0.00 4.84 0.00 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.29 0.64 0.03 0.43 1.39 0.48 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.73 0.32 0.04 1.31 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.14 0.20 0.32 0.18 1.44 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.12 0.19 0.27 1.27 149.21 147.60 124.41 179.12 187.51 184.41 147.42 169.30 214.32 176.69 159.36 169.28 132.05 180.58 160.71 139.81 162.68 144.89 128.34 95.15 121.72 4.48 3.49 3.38 5.76 3.68 4.53 3.01 3.75 3.85 3.57 3.49 3.03 2.90 2.57 2.35 3.23 2.91 4.06 2.63 3.46 3.08 4.29 4.67 4.30 5.21 6.10 5.57 5.41 5.70 4.94 5.07 4.54 4.66 3.61 5.34 6.10 5.64 3.99 4.99 4.49 2.92 3.95 1.37 1.05 1.36 2.45 1.15 1.57 1.29 1.63 1.39 0.96 1.12 0.84 1.01 1.13 0.88 1.38 0.76 1.53 1.04 1.15 1.15 c Dose administration was discontinued on Day 43 (Week 7). d Dose administration was discontinued on Day 81 (Week 12). e Dose administration was discontinued on Day 66 (week 10). 426 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 183 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 28.31 33.09 45.72 55.92 29.23 39.86 0.00 6.32 12.20 44.17 0.00 1.81 Group: Male 2 Dose Level: 3 I05702 I05706 I05717 66.27 32.18 42.15 18.72 0.81 21.16 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 36.88 23.41 43.28 25.17 33.64 33.50 0.00 6.72 14.90 12.54 1.17 11.66 Group: Male 4 Dose Level: 20 d I05703 I05704c I05711c I05713e I05722e 38.78 25.93 42.26 27.86 34.96 10.05 0.00 22.30 0.00 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.77 0.21 0.41 0.41 0.47 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.83 0.49 0.63 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.51 0.75 0.91 2.97 0.09 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 0.00 0.08 0.32 0.08 0.46 0.47 137.07 151.09 145.02 174.04 162.47 173.98 129.99 118.70 151.71 132.21 135.82 108.04 175.84 123.73 131.15 160.48 126.67 116.73 80.06 123.04 4.02 3.19 3.88 5.01 2.81 4.10 2.43 2.54 2.77 3.34 2.47 2.82 2.61 2.34 2.65 2.75 2.78 2.72 2.43 1.93 4.65 4.76 5.29 5.81 6.92 6.31 4.98 4.89 4.74 4.33 4.93 3.67 5.58 4.76 4.77 4.81 4.48 3.38 2.30 4.15 1.44 1.26 1.92 2.14 0.98 1.58 1.01 1.04 1.08 1.09 0.76 1.05 0.97 0.84 1.04 0.90 1.07 1.22 0.73 0.83 c Doseadministration was discontinued on Day 43 (Week 7). d Doseadministration was discontinued on Day 81 (Week 12). e Doseadministration was discontinued on Day 66 (Week 10). 427 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 220 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL pg/mL ESTRIOL, THYROID STIMULATING ng/mL HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05718 I05720 67.73 35.42 57.32 31.06 Group: Male 3 Dose Level: 10 I05712 I05716 20.94 33.46 30.66 25.04 Dosage Unit: mg/kg/day 0.00 0.00 0.02 0.32 Dosage Unit: mg/kg/day 0.00 0.00 0.12 0.72 166.04 175.17 178.37 171.78 4.43 2.45 3.59 3.19 5.25 5.63 5.85 5.22 1.20 0.53 1.02 0.83 428 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 248 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL ESTRIOL pg/mL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05718 I05720 51.94 41.65 54.24 26.61 Group: Male 3 Dose Level: 10 I05712 I05716 25.74 41.88 25.85 35.96 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.11 Dosage Unit: mg/kg/day 0.00 0.00 0.40 0.27 164.06 161.44 185.65 161.31 4.51 2.41 4.02 3.79 4.47 6.24 7.67 6.71 1.46 0.57 1.15 1.11 429 ANIMAL NUMBER ESTRONE pg/mL Appendix 6 Covance 6329-231 3M T-6889.3 Individual Hormone Analyses Data Day 276 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRADIOL ESTRIOL pg/mL ng/mL THYROID STIMULATING HORMONE ^IU/mL TOTAL TRIIODOTHYRONINE ng/dL TOTAL THYROXIN ^g/DL FREE TRIIODOTHYRONINE pg/mL FREE THYROXIN ng/dL Group: Male 1 Dose Level: 0 I05718 I05720 58.75 84.46 61.43 31.22 Group: Male 3 Dose Level: 10 I05712 I05716 32.49 39.13 37.39 22.94 Dosage Unit: mg/kg/day 0.00 0.00 0.00 0.00 Dosage Unit: mg/kg/day 0.00 0.00 0.02 0.00 155.96 178.62 197.53 147.40 5.40 4.21 4.33 3.77 4.70 5.34 6.07 5.96 1.99 0.96 1.69 1.24 430 Appendix 6 Individual Testosterone Analyses Data (ng/mL) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 1 ANIMAL DAY DAY DAY DAY DAY DAY DAY DAY DAY DAY NUMBER -18 -8 -4 35 66 94 183 220 248 276 Group: Male 1 Dose Level: 0 I05709 I05714 I05715 I05718 I05720 I05725 3.32 2.32 3.56 6.17 1.88 0.51 3.90 1.64 3.02 26.86 3.25 0.52 Group: Male 2 Dose Level: 3 I05702 I05706 I05717a I05721a 2.39 4.91 3.07 1.09 1.98 5.94 2.11 1.72 Group: Male 3 Dose Level: 10 I05707 I05708 I05710 I05712 I05716 I05719 0.69 7.17 0.98 2.22 6.58 3.97 0.14 10.11 1.02 1.30 6.74 3.57 Dosage Unit: mg/kg/day 3.39 0.79 4.33 10.02 3.59 0.84 0.59 0.61 1.11 7.02 3.55 0.41 0.62 1.89 2.61 7.82 8.59 0.46 Dosage Unit: mg/kg/day 1.70 14.34 9.87 0.76 1.45 7.43 2.30 0.92 1.98 4.78 6.32 1.62 Dosage Unit: mg/kg/day 0.11 1.55 0.60 1.53 5.71 5.31 0.08 1.43 1.12 1.29 2.22 5.87 0.20 10.88 7.12 1.30 5.42 5.95 0.53 1.23 2.06 11.85 6.94 7.08 6.73 8.20 10.42 4.09 0.15 3.82 2.21 2.10 6.30 2.73 12.09 1.91 4.82 10.58 3.44 5.14 3.88 7.19 12.36 3.31 4.49 4.02 10.03 13.09 3.69 9.42 6.74 7.26 4.13 5.03 5.50 7.23 3.92 7.58 10.92 27.60 2.85 a Animal No. I05721 replaced Animal No. I05723 on Day 15. Dose administration for this animal initiated on Day 17 (Week 3). 431 Appendix 6 Individual Testosterone Analyses Data (ng/mL) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 PAGE: 2 ANIMAL DAY DAY DAY DAY DAY DAY DAY DAY DAY DAY NUMBER -18 -8 -4 35 66 94 183 220 248 276 Group: Male 4 Dose Level: 20b I05703c I05704d I05711d I05713e I05722e I05724 0.63 0.94 2.01 1.54 0.87 1.22 0.33 1.74 2.41 1.22 0.52 6.58 Dosage Unit: mg/kg/day 0.50 3.02 8.22 5.25 0.41 6.43 0.66 1.66 0.73 0.48 0.53 0.45 6.47 3.15 3.93 0.18 3.85 1.18 3.30 1.31 4.41 4.84 1.43 4.77 2.05 1.35 b Group 4 males were administered 30 mg/kg/day on Days 1 through 11. Animals were not dosed on Days 12 through 21. on Day 22 and continuing throughout the remainder of the study, Group 4 males were administered 20 mg/kg/day. c Dose administration was discontinued on Day 81 (Week 12). d Dose administration was discontinued on Day 43 (Week 7). e Dose administration was discontinued on Day 66 (Week 10). Beginning 432 APPENDIX 7 Covance 6329-231 3M T-6889.3 Quality Assurance Documentation Hormonal Measurements Report (cholecystokinin analyses data) Note: This appendix of the report contains information supplied by the DuPont and has been reviewed by the Quality Assurance Unit of DuPont. 433 Covance 6329-231 434 Covance 6329-231 3M T-6889.3 435 Covance 6329-231 3M T-6889.3 26-W eek Capsule Toxicity Study W ith Ammonium Perfluorooctanoate (APFO) in Cynomologus M onkeys SUMMARY Ammonium perfluorooctanoate (AFPO) was evaluated for its ability to alter serum cholecystokinin (CCK) concentrations in cynomologous monkeys exposed to either 3, 10, or 30/20 mg/kg/day AFPO. Serum was collected at three time points prior to study initiation, and on test days 35, 66, 94, and 183. CCK concentrations were measured by radioimmunoassay (RIA). No alterations in CCK concentrations were observed at any of the time points. 436 Covance 6329-231 3M T-6889.3 26-W eek Capsule Toxicity Study W ith Ammonium Perfluorooctanoate (APFO) in Cynom oiogus M onkeys INTRODUCTION Ammonium perfluorooctanoate (AFPO) was evaluated for its ability to alter serum cholecystokinin (CCK) concentrations in cynomologous monkeys exposed to either 3, 10 , or 30 mg/kg/day AFPO. Due to excessive toxicity, the animals in the 30 mg/kg/day dose level were removed from compound administration on test day 12 and administered a reduced dose level of 20 mg/kg/day beginning on test day 22. Serum was collected at three time points prior to study initiation, and on test days 35, 66, 94, and 183. CCK concentrations were measured by radioimmunoassay (RIA). METHODS At three time points during the pretest period (Test days --18, -8, and -4) or after exposure to either 3, 10, or 30 mg/kg/day AFPO for either 35, 66, 94, or 183 days, blood was collected from the monkeys from each group designated for CCK evaluation. Due to excessive toxicity, the animals in the 30 mg/kg/day dose level were removed from compound administration on test day 12 and administered a reduced dose level of 20 mg/kg/day beginning on test day 22. Plasma was prepared from the blood and frozen for quantitation of CCK. Frozen plasma samples were sent to Haskell Laboratory for CCK analysis. Plasma samples were extracted over a C-18 Sep Pak column (Supelco Co., Bellefonte, PA) washed with 0.05% trifluoroacetic acid (TFA) and eluted with 50% acetonitrile/50% TFA. Extracted samples were dried under vacuum and reconstituted prior to analysis by radioimmunoassay (RIA). All data were analyzed using Jonckheere's test for trend (p < 0.05). RESULTS and DISCUSSION No statistically significant or biologically significant alterations in plasma CCK concentrations were observed at any of the time points. Under the conditions of the study, AFPO does not alter plasma CCK levels in male cynomologous monkeys when exposed orally to concentrations up to 30/20 mg/kg/day for 183 days. 437 26-W eek Capsule Toxicity Study W ith Ammonium Pertluorooctanoate (APFO) in Cynomologus Monkeys Covance 6329-231 3M T-6889.3 TABLES 438 26-Week Capsule Toxicity Study With Ammonium Perfluorooctanoate (APFO) in Cynomologus Monkeys Table 1 Summary Of Cholecystokinin (CCK) Data In Male Cynomologous Monkeys Covance 6329-231 3M T-6889.3 (jrottp Test Day -18 Test Day -8 Cholecystokinin (fmol/ml) Test Day -4 Test Day 35 Test Day 66 Test Day 94 Test Day 183 1 (0 mg/kg/day)'1 1.0 0.3b,c 1.0 0.4 1.8 0.6 3.1 0.9 3.1 1.5 1.8 0.6 2.4 0.8 2 (3 rng/kg/day)d 1.2 0.2 1.4 0.4 1.8 0.8 3.0 1.3 3.9 2.7 1.4 0.7C 3.0 1.4c 3 (10 mg/kg/day)11 t.l 0.5 1.1 0.4C 1.5 0.6 3.1 1.2 2.7 1.3 1.4 0.2C 2.3 0.9 4 (30 mg/kg/day)11 1.0 0.2 0.9 0.3 1.9 1.1 2.5 0.4C 2.8 1.3C 1.8 0.7d 2.3 0.7C Note: Due toexcessivetoxicity,theanimals inthe30 mg/kg/daydoselevelwereremoved fromcompound administrationontestday 12and administereda reduceddose levelof20 mg/kg/daybeginningon testday22. " The n= 6 unlessotherwisenoted. b Mean standarddeviation. ' " Then = 6. 11 The n= 4 unlessotherwisenoted. c The n= 3. No statisticallysignificantdifferencefromcontrol(p< 0.05)byJonckheere'stest. 439 26-Week Capsule Toxicity Study With Ammonium Perfluorooctanoate (APFO) in Cynomologus Monkeys APPENDIX A INDIVIDUAL ANIMAL DATA Covance 6329-231 3M T-6889.3 440 26-W eek Capsule Toxicity Study With Ammonium Perfluorooctanoate (APFO) in Cynomologus Monkeys Covance 6329-231 3M T-6889.3 individual Animal Data: Plasma Cholecystokinin Concentrations In Male Cynomologous Monkeys G roup Anim al T est Day -18 N um ber T est D ay -8 T est D ay -4 T est Day 35 Test Day 66 Test Day 94 T est Day 183 1 (0mg/kg/day) 105709 105714 105715 105718 105720 105725 1.491 0.863 0.914 0.979 1.002 0.316s 1.526 0.952 1.360 1.039 0.639 0.399 1.970 1.655 2.726 1.717 1.357 1.151 2.179 4.593 2.346 3.236 3.145 3.379 1.450 4.173 5.129 3.783 2.362 1.522 1.771 1.516 2.931 1.222 1.615 1.666 3.056 1.623 3.696 2.586 1.957 1.645 2 (3mg/kg/day) 105702 105706 105717 105721 1.473 1.035 1.237 1.121 1.461 1.926 1.079 1.119 1.147 1.056 2.593 2.451 3.218 1.333 4.455 3.077 7.906 2.214 2.910 2.573 2.193 U 1.160 0.774 3.828 3.866 1.384 b 3 (10 mg/kg/day) 105707 105708 105710 105712 105716 105719 0.968 2.022 0.441 0.8J6 1.088 1.390 0.468 1.546 a 0.970 1.308 1.215 0.579 1.002 2.146 1.758 2.047 1.649 3.114 3.096 2.141 2.484 2,407 5.376 2.462 3.044 1.396 2.535 1.876 5.122 1.056 1.455 -a 1.680 1.557 1.406 1.547 2.200 1.375 2.546 2.371 3.846 4 (30 mg/kg/day) 105703 105704 105711 105713 105722 105724 1.109 0.760 0.952 1.246 1.124 0.899 1.154 0.523 0.995 0.800 0.819 1.345 1.182 1.053 3.841 1.537 2.372 1.305 2.980 2.328 2.197 2.965 2.272 b 3.868 1.233 4.391 2.111 2.538 0.834 1.994 11 1.802 2.376 2.651 2.622 2.437 0.984 2.702 _b Note: Due toexcessivetoxicity,theanimalsinthe30 mg/kg/daydoselevelwereremoved fromcompound administrationon testday 12andadministeredareduced dose levelof20 mg/kg/daybeginningon testday22. "Sample was notincludedingroupmean calculationsduetoatechnicalproblem withtheplasmaextractionprocedure, bNo samplereceivedfromsponsorforanalysis. 441 APPENDIX 8 Cell Proliferation Report Covance 6329-231 3M T-6889.3 Note: This appendix of the report contains information supplied by Pathology Associates, A Charles River Company and has been reviewed by the Quality Assurance Unit of Pathology Associates, A Charles River Company. 442 Covance 6329-231 3M T-6889.3 FINAL CELL PROLIFERATION REPORT 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS COVANCE STUDY NUMBER 6329-231 PREPARED FOR: 3M TOXICOLOGY SERVICES BUILDING 220-2E-02, 3M CENTER ST. PAUL, MN 55144-1000 PREPARED BY: PATHOLOGY ASSOCIATES - A CHARLES RIVER COMPANY 15 WORMAN'S MILL COURT, SUITE I FREDERICK, MD 21701 443 TABLE OF CONTENTS Report Narrative Tables Figures Individuai Animal Histopathology Findings Signature Page Quality Assurance Statement Covance 6329-231 3M T-6889.3 Section I II III IV V VI 444 Covance 6329-231 3M T-6889.3 3M Covance Study No. 6329-231 Final Cell Proliferation Report Page 1-1 CELL PROLIFERATION REPORT FOR: 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS COVANCE STUDY NUMBER 6329-231 INTRODUCTION The purpose of the study was to assess the effect of the test material on critical enzyme levels, hormones, and other selected biochemical parameters when administered daily by capsule to cynomolgus monkeys for at least 26 weeks. . This report, submitted by Pathology Associates - A Charles River Company (PAI) formally Pathology Associates International to the study Sponsor, 3M Toxicology Services, represents the cell proliferation findings and interpretation for Covance Study Number 6329-231 entitled "26Week Capsule Toxicity Study with Ammonium Perfluorooctanoate In Cynomolgus Monkeys". REGULATORY COMPLIANCE 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 Experimental Design Treatment Group 1 (Control) 2 (Low-dose) 3 (Mid-dose) 4 (High-dose) Dose Level (mg/kg/day) 0 3 10 30 Number of Animals Main Study Recovery 42 40 42 42 All animals (main study and recovery) were treated for up to 26 weeks. Two animals in groups 1, 3 and 4 were designated as recovery animals. Treatment in these animals was discontinued and the Sponsor determined the recovery period. 445 Covance 6329-231 3M T-6889.3 3M Covance Study No. 6329-231 Final Cell Proliferation Report Page 1-2 Tissue Collection for Cell Proliferation Representative samples of the left lateral lobe of the liver, left and right testes, and pancreas from each of the 22 animals was fixed and processed to paraffin block by Covance per protocol specifications. Tissue blocks were shipped to PAI for sectioning and staining. From each block, slides were 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 = 5 pm and placed on positively charged slides (Superfrost Plus, Fisher Scientific, Pittsburgh, PA) to ensure adhesion during processing for PCNA. Standard immunohistochemical methods for PCNA (Eldridge, et ah, 1993) were used to stain tissues. Briefly, tissue sections were incubated with a monoclonal antibody to PCNA ( Lot #107 Exp. 11/00 DAKO, Carpintera, CA) and reagents required for the avidin-biotin peroxidase (MslgG Kit Lot# PK6102 Exp. 4/22/00, Vector, Burlingame, CA) method for the detection of the antigen-antibody complex. PCNA expression in cells in all phases of the cell cycle (G l, S, G2 and M) was localized by the chromagen 3,3'-diaminobenzidine (DAB Lot# 108H8210 Exp. 8/20/01; Sigma Chemical Co., St. Louis, MO). Tissue sections were counterstained with hematoxylin. Cell Proliferation Measurements Positive staining for PCNA was categorized based on cellular distribution and intensity of the brown to black reaction product that correlated with the different phases of the cell cycle (Eldridge et al., 1993). Uniform, dark brown to black nuclear staining was judged to be positive for S phase cells. A cell in the G, phase of the cell cycle had diffuse, stippled nuclear staining that was lighter than a cell in S phase. Cells in the G2 phase exhibited distinct, diffuse cytoplasmic stippling with or without nuclear staining. Mitotic figures were conspicuous with diffuse cytoplasmic stippling. A negative control slide was included in the staining run and consisted of study tissue (animal no. 105709) that was not incubated with the primary antibody. For cell proliferation evaluations, slides were first perused at low magnification (100X) to judge quality of staining, processing and sectioning, pattern of cell labeling (e.g., centrilobular or panlobular, extrahepatocellular proliferation, such as Kupffer cells, bile duct epithelium, endothelium), and histomorphologic changes. The later was further assessed by evaluating the serial H&E slide for each animal evaluated for cell proliferation. Cell proliferation was then quantified at higher magnification (200X) as described above. For cell proliferation measurements in the liver, the percentage of dark, nuclear-stained hepatocytes that represent cells in S-phase was determined by scoring at least 3000 hepatocytes in 10 randomly selected fields per animal. Cell proliferation within islet and exocrine cells of the 446 Covance 6329-231 3M T-6889.3 3M Covance Study No. 6329-231 Final Cell Proliferation Report Page 1-3 pancreas was scored subjectively with 3 = exocrine stained greater than islets, and 4 = islets and exocrine stained heavily as determined by positive PCNA staining. The entire tissue section represented on the slide was perused at 100X and 400X. For measuring cell proliferation in the testes, the section farthest from the slide label was scored. The percentage of PCNA-labeled Leydig cells was determined by scoring at least 100 Leydig cells in the entire section that was examined. Statistical Analysis Due to the small samples sizes within main study and recovery groups, and because not all animals within a treatment group were sacrificed on the same day, statistical analysis was not performed on cell proliferation data. RESULTS Cell Proliferation Individual animal cell proliferation data are presented in Section II (Table II-l) and graphically in Figures III-1 - 3. Clearly, cell proliferation was not increased by treatment in the pancreas or testes of monkeys as determined by examining the scatter plots in Section II, Figures III-2 and TTT-3. In the liver, however, there did appear to be an enhancement of cell proliferation in the highest dose tested (30 mg/kg/day) as revealed in Section II, Figure (III -1). Data points 6, 8, 9 and 10 (30 mg/kg/day; animals 105704, 105713, 105711, 105722, and 105703, respectively) were greater than or equal to the highest control value (data point 1; animal 105714). The lowest dose tested (data point 3; 3 mg/kg/day), however, had one animal (animal 105706) with a labeling index that exceeded all animals examined. Thus, an apparent increase in cell proliferation was not necessarily dose-related. Histopathology 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 Section IV. Representative sections of liver, pancreas and testes from 22 monkeys 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 that may alter or confound the specificity of the PCNA staining observed in these animals. The results showed that no significant changes that would alter the interpretation of the PCNA staining in this study were observed in the liver, pancreas or testes from male monkeys. Although chronic inflammation was reported for several animals, it was minimal in severity and occurred across all groups. Furthermore, the PCNA labeling index did not correlate with the 447 Covance 6329-231 3M T-6889.3 3M Covance Study No. 6329-231 Final Cell Proliferation Report Page 1-4 observation of inflammation in the liver. For example, inflammation was not observed in the animal with the highest liver labeling index (animal 105706). Numerous findings were reported for animal 105724 that included hypertrophy, inflammation, fat infiltration and possibly bacterial colonization. Based on the substantial non-specific PCNA staining observed in the liver of this animal, clearly these lesions confounded the ability to measure hepatocellular proliferation; therefore, no attempt was made to evaluate the PCNA labeling index in animal 105724. DISCUSSION In the present study, cell proliferation was measured within the liver, pancreas and testes of male monkeys from control and treated groups after up to 26 weeks on study, as well as a recovery period. An increase in cell proliferation, as determined by the PCNA labeling index, was not observed in the pancreas or testes of male monkeys. Cell proliferation in the liver, however, was equivocal. SUMMARY After up to 26 weeks on study, enhanced cell proliferation was not evident in the pancreas or testes of male monkeys, whereas in the liver the findings were equivocal. LITERATURE CITED Eldridge, S.R., Butterworth, B.E., Goldsworthy, T.L. (1993). Proliferating cell nuclear antigen: a marker for hepatocellular proliferation in rodents. Environ. Health Perspec. 101: 211-218. 448 Covance 6329-231 3M T-6889.3 II. TABLES 449 Covance 6329-231 3M T-6889.3 Dose G roup 0 mg/kg/day (Control) 0 mg/kg/day (Control) 0 mg/kg/day (Control) 0 mg/kg/day (Control) 0 mg/kg/day (Control) 0 mg/kg/day (Control) 3 mg/kg/day (Low dose) 3 mg/kg/day (Low dose) 3 mg/kg/day (Low dose) 3 mg/kg/day (Low dose) 10 mg/kg/day (Mid dose) 10 mg/kg/day (Mid dose) 10 mg/kg/day (Mid dose) 10 mg/kg/day (Mid dose) 10 mg/kg/day (Mid dose) 10 mg/kg/day (Mid dose) 30 mg/kg/day (High dose) 30 mg/kg/day (High dose) 30 mg/kg/day (High dose) 30 mg/kg/day (High dose) 30 mg/kg/day (High dose) 30 mg/kg/day (High dose) TABLE 11-1. CELL PROLIFERATION IN MONKEYS L a b e lin g L a b e lin g Anim al In d e x Index D ay o f Death 26 Weeks N um ber IO5709 L iv e r Pancreas 0.025% 3 26 Weeks 26 Weeks 26 Weeks Recovery animal Recovery animal 26 Weeks 105714 105715 I05725 105718 IO5720 IO5702 0.075% 0.000% 0.074% 0.025% 0.000% 0.000% 3 3 4 3 3 4 26 Weeks 26 Weeks Sacrificed week 20 26 Weeks 26 Weeks 26 Weeks IO5706 105717 105721 IO5707 IO5708 105710 0.170% 0.099% 0.000% 0.075% 0.050% 0.024% 3 3 NP 3 3 3 26 Weeks Recovery animal Recovery animal 26 Weeks 26 Weeks Sacrificed day 29 Stopped dosing week 7; Sacrificed week 27 105719 105712 105716 IO5704 105713 I05724 105711 0.025% 0.073% 0.000% 0.100% 0.075% ND 0.126% 3 3 4 3 4 3 4 Stopped dosing week 10; Sacrificed week 27 Stopped dosing week 12; Sacrificed week 27 I05722 IO5703 0.149% 0.075% 3 3 L a b e lin g In d e x T e s te s 22.86% 11.00% 14.91% 27.00% 41.51% 23.42% 10.58% 21.78% 22.77% 13.00% 15.53% 17.14% 17.92% 35.17% 18.81% 10.89% 10.78% 15.84% 16.35% 21.70% 14.29% 20.19% 3M Covance Study No. 6329-231 Page 11-1 Skip slide=negative control; animal no. IO5709 ND, not determined due to too much non-specific staining NP, tissue not present on slide Liver: Only dark nuclear stained hepatocytes scored as S-phase; 200X Pancreas: Scored subjectively with 4=islets and exocrine stained heavily (>50% labeled); 3=exocrine stained greater than islets; perused at 100X and 400X Testes: Section farthest from slide label scored; Leydig cells scored at 400X 450 Covance 6329-231 3M T-6889.3 III. FIGURES Legend for data points on Figures III-l - 3 Group 1 2 3 4 5 6 7 8 9 10 Treatment 0 mg/kg/day 0 mg/kg/day 3 mg/kg/day 10 mg/kg/day 10 mg/kg/day 30 mg/kg/day 30 mg/kg/day 30 mg/kg/day 30 mg/kg/day 30 mg/kg/day Day of Death 26 weeks Recovery animal 26 weeks 26 weeks Recovery animal 26 weeks Sacrificed day 29 Stopped dosing day 43 Stopped dosing day 66 Stopped dosing day 81 451 0 .200% Covance 6329-231 3M T-6889.3 3M C o va n ce Study No. 6329-231 P age 111-1 Figure 111-1. Labeling Index - Liver 0.150% 0 .100% 0.050% 0 .000% o_ ^ o . _ _ 6* 1 4 5 *6 A 1 2 4 1 - 2 3 5 ........ ...... ..... .......... ...... --9 8 o 1 452 Covance 6329-231 3M T-6889.3 453 Covance 6329-231 3M T-6889.3 454 Covance 6329-231 3M T-6889.3 IV. INDIVIDUAL ANIMAL HISTOPATHOLOGY FINDINGS 455 Covance 6329-231 3M T-6889.3 Individual Animal Findings 3M Covance Study No. 6329-231 Page IV -1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER SEX DOSE GROUP HISTOLOGIC FINDINGS 105709 M 1 Liver - chronic inflammation, minimal Pancreas - autolysis, focal Testes - crush artifact Spleen - NSF 105714 M 1 Liver - chronic inflammation, minimal Pancreas - NSF Testes - NSF Spleen - NSF 105715 M 1 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF 105725 M 1 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF 105718 M 1 L iver-N SF Pancreas - NSF Testes - crush artifacts Spleen - NSF 105720 M 1 L iver-N SF Pancreas - NSF Testes - NSF __________________________________________Spleen - N SF ________________________ 105702 ' M 2 Liver - NSF Pancreas - NSF Testes - NSF Spleen - hem osiderin deposition, mild 105706 M 2 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF 105717 M 2 Liver - NSF Pancreas - NSF Testes - crush artifact Spleen - NSF Legend: NSF = no significant findings 456 Covance 6329-231 3M T-6889.3 Individual Animal Findings 3M Covance Study No. 6329-231 Page IV -1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER SEX DOSE GROUP HISTOLOGIC FINDINGS 105721 105707 105708 105710 105712 105716 105719 105703 105704 M 2 Liver - chronic inflammation, minimal Pancreas - NSF Testes - NSF Spleen - NSF M 3 Liver - NSF Pancreas - NSF Testes - NSF Spleen - hemosiderin deposition, minimal M 3 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF M 3 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF M 3 Liver - chronic inflammation, minimal Pancreas - NSF Testes - NSF Spleen - NSF M 3 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF M . 3 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF M 4 Liver - NSF Pancreas - NSF Testes - NSF Spleen - NSF M 4 Liver - chronic inflammation, minimal Pancreas - NSF Testes - NSF Spleen - hemosiderin, minimal Legend: NSF = no significant findings 457 Covance 6329-231 3M T-6889.3 458 Covance 6329-231 3M T-6889.3 459 Covance 6329-231 3M T-6889.3 VI. QUALITY ASSURANCE STATEMENT 460 Covance 6329-231 3M T-6889.3 461 Covance 6329-231 3M T-6889.3 APPENDIX I 462 Covance 6329-231 3M T-6889.3 PROTOCOL DEVIATION REPORT Date: September 28, 2000 Study Number: Covance Study No. 6329-231 Title: 26-Week Capsule Toxicity Study with Ammonium Perfluorooctanoate In Cynomolgus Monkeys Protocol Deviation #1: Representative samples of liver, testes and pancreas were to be collected for cell proliferation evaluation, which included preparation of an H&E slide for correlative morphologic interpretation of the cell proliferation findings. Samples of spleen were inadvertently submitted to PAI and the H&E slide examined for this tissue. Reason: Spleen was inadvertently submitted. The H&E slide was inadvertently evaluated microscopically and the histologic findings reported. This deviation had no impact on the study. Submitted by: Sandra R. Eldridge, Ph.D. PAI Project Manager Sandra R. Eldridge PAI Project Manager Date 463