Document x1dzYX2GaJwE7YMMYLVNebOD1

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 of 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 09/24/98 09/24/98 10/07/98 10/07/98 01/05/99 01/05/99 04/01/99 04/01/99 05/03/99 05/03/99 06/18/99 06/18/99 07/29/99 07/29/99 08/11/99 08/11/99 09/02/99 10/01/99 09/13/99 10/01/99 11/15/99 11/15/99 01/15/01 01/15/01 02/26/01 02/27/01 12/04/01 12/04/01 Phase Protocol Review Analytical Laboratory Inspection Body Weight Protocol Amendment Review Clinical Laboratory Inspection Data Review Protocol Amendment Review Protocol Amendment Review Data Review Report Review Protocol Amendment Review Protocol Amendment Review Report Review 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 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 Ident ification .............................................................................................................. 16 Just ification ................................................................................................................ 16 Husbandry.................................................................................................................. 16 Acclimat ion................................................................................................................ 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 - Week 40 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 Data ....................................................................................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 Data .......................................................................244 Individual Clinical Chemistry Data ..........................................................................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 1 through 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 of liver 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 1 (Control) 2 (Low) 3 (Mid) 4 (High)d (mg/kg/day) 0a 3 10 30/20 No. of Males 6b 4c 6b 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 1 through 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 of treatment 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 of covariance (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. 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/L). 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 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, I05722, 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 A Pale B Straw C Yellow D Dark yellow URINE APPEARANCE 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 Covance 6329-231 3M T-6889.3 Codes for Clinical Pathology (Continued) 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 X106/L) HGB (G/DL) HCT (%) MCV (FL) MCH (PG) MCHC (%) PLT (E3/UL or X103/L) MPV (FL) RETIC (%) RETIC (E3/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) SP GR U OSMO (MOSM/KG) QUAN PRO (MG/DL) PRO EXC (MG) U PH U PRO (MG/DL) U GLU U KET U BILI U BLOOD UROBILI U RE SUB RBC (PER HPF) WBC (PER HPF) EPITH (PER HPF) BACT (PER HPF) CASTS (PER LPF) CRYSTALS (PER LPF1 or PER LPF2) URINE APP1 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 Covance 6329-231 3M T-6889.3 Summary of Clinical Observations PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ NUMBER OF ANIMALS AFFECTED DAYS 1-184 SEX: -------MALE------- CATEGORY GROUP: 1 2 3 4a DOSE: 0 3 10 20 KEYWORD QUALIFIER NUMBER: 6 4 6 6 ------------------------------------------------------------------------------------------------------------------------------------ *** TOP OF LIST *** APPEARANCE LIMITED USE LIMBS-HIND 0100 PARALYSIS HIND QUARTERS 0100 THIN 0002 BEHAVIOR ATAXIC <UNSPECIFIED> HYPOACTIVE <UNSPECIFIED> 0100 0101 DISCHARGE VOMITUS CONTAINING FOOD 4232 EXCRETION DISCOLORED URINE BROWN IN COLOR FEW FECES LIQUID FECES MUCOID FECES NO FECES NON-FORMED FECES 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 Covance 6329-231 3M T-6889.3 Summary of Clinical Observations PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ NUMBER OF ANIMALS AFFECTED DAYS 1-184 SEX: -------MALE------- CATEGORY GROUP: 1 2 3 4a DOSE: 0 3 10 20 KEYWORD QUALIFIER 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 1000 1000 1000 1000 0001 0010 0010 0001 0010 QUALITATIVE FOOD CONSUMPTION LOW NONE *** END OF LIST *** 5336 0104 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 Table 2 Covance 6329-231 3M T-6889.3 Summary of Clinical Observations Recovery PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ NUMBER OF ANIMALS AFFECTED DAYS 185-277 SEX: --MALE-- GROUP: 1 3 CATEGORY DOSE: 0 10 KEYWORD QUALIFIER NUMBER: 2 2 ------------------------------------------------------------------------------------------------------------------------------------ *** TOP OF LIST *** DISCHARGE VOMITUS CONTAINING FOOD 21 EXCRETION NO FECES 01 QUALITATIVE FOOD CONSUMPTION LOW *** END OF LIST *** 12 58 Table 3 Covance 6329-231 3M T-6889.3 Summary of Ophthalmic Observations PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ NUMBER OF ANIMALS AFFECTED WEEK -1 SEX: -------MALE------- GROUP: 1 2 3 4 CATEGORY DOSE: 0 3 10 20 KEYWORD QUALIFIER NUMBER: 6 4 6 6 ------------------------------------------------------------------------------------------------------------------------------------ *** TOP OF LIST *** NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 6466 *** END OF LIST *** 59 Table 3 Covance 6329-231 3M T-6889.3 Summary of Ophthalmic Observations PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ NUMBER OF ANIMALS AFFECTED WEEK 27 SEX: -------MALE------- CATEGORY GROUP: 1 2 3 4 DOSE: 0 3 10 20a KEYWORD QUALIFIER NUMBER: 6 3 6 5 ------------------------------------------------------------------------------------------------------------------------------------ *** TOP OF LIST *** NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 6365 *** END OF LIST *** 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 Table 4 Covance 6329-231 3M T-6889.3 Summary of Ophthalmic Observations Recovery PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ NUMBER OF ANIMALS AFFECTED WEEK 40 SEX: --MALE-- GROUP: 1 3 CATEGORY DOSE: 0 10 KEYWORD QUALIFIER NUMBER: 2 2 ------------------------------------------------------------------------------------------------------------------------------------ *** TOP OF LIST *** NO VISIBLE LESIONS NO VISIBLE LESIONS EYES 22 *** END OF LIST *** 61 Table 5 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEK UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ -2 N MEAN S.D. -1b N MEAN S.D. -1c N MEAN S.D. 6 3.7 0.45 6 3.8 0.52 6 3.8 0.54 4 4.0 0.24 4 4.0 0.34 4 3.9 0.34 6 3.8 0.34 6 3.8 0.37 6 3.7 0.43 6 3.8 0.26 6 3.8 0.27 6 3.8 0.29 1 N MEAN S.D. 6 3.8 0.56 4 4.0 0.36 6 3.8 0.33 6 3.9 0.32 2 N CAM MEAN S.D. 6 3.8 3.8 0.59 4 3.9 4.0 0.29 6 3.8 3.7 0.42 6 3.7 * 3.7 0.29 3 N CAM MEAN S.D. 6 3.9 3.9 0.56 4 3.8 4.0 0.24 6 3.7 3.7 0.46 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEK UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 4 N CAM MEAN S.D. 6 4.0 4.0 0.57 4 3.9 4.0 0.22 6 3.9 3.8 0.44 6 3.7 * 3.7 0.27 5 N CAM MEAN S.D. 6 4.0 4.0 0.63 4 3.8 3.9 0.24 6 3.8 3.8 0.45 6 3.7 * 3.7 0.30 6 N CAM MEAN S.D. 6 4.0 4.0 0.53 4 4.0 4.1 0.21 6 3.9 3.9 0.53 5 3.7 3.7 0.30 7 N CAM MEAN S.D. 6 4.1 4.1 0.62 4 3.9 4.1 0.13 6 4.0 3.9 0.57 5 3.7 3.7 0.42 8 N CAM MEAN S.D. 6 4.0 4.0 0.51 4 4.0 4.1 0.14 6 4.0 3.9 0.52 4 3.6 3.6 0.42 9 N CAM MEAN S.D. 6 4.0 4.0 0.55 4 4.0 4.2 0.05 6 4.0 4.0 0.60 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEK UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 10 N CAM MEAN S.D. 6 4.0 4.0 0.54 4 4.0 4.1 0.10 6 4.0 4.0 0.58 4 3.5 * 3.4 0.56 11 N CAM MEAN S.D. 6 4.1 4.1 0.58 4 4.0 4.2 0.05 6 4.1 4.0 0.59 3 3.6 3.5 0.60 12 N CAM MEAN S.D. 6 4.1 4.1 0.53 4 4.0 4.2 0.06 6 4.0 4.0 0.60 3 3.5 3.4 0.76 13 N CAM MEAN S.D. 6 4.1 4.1 0.53 4 4.1 4.2 0.10 6 4.2 4.1 0.58 2 3.8 3.9 0.35 14 N CAM MEAN S.D. 6 4.1 4.1 0.55 4 4.1 4.2 0.05 6 4.1 4.0 0.59 2 3.7 3.9 0.35 15 N CAM MEAN S.D. 6 4.2 4.2 0.53 4 4.2 4.3 0.06 6 4.1 4.1 0.59 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEK UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 16 N CAM MEAN S.D. 6 4.2 4.2 0.53 4 4.1 4.2 0.05 6 4.2 4.1 0.56 2 3.7 3.8 0.49 17 N CAM MEAN S.D. 6 4.2 4.2 0.53 4 4.2 4.3 0.08 6 4.2 4.1 0.56 2 3.8 3.9 0.42 18 N CAM MEAN S.D. 6 4.3 4.2 0.57 4 4.3 4.4 0.10 6 4.3 4.2 0.58 2 3.9 4.0 0.42 19 N CAM MEAN S.D. 6 4.3 4.2 0.58 4 4.3 4.4 0.13 6 4.3 4.2 0.60 2 3.8 4.0 0.49 20 N CAM MEAN S.D. 6 4.3 4.3 0.56 4 4.2 4.3 0.32 6 4.3 4.2 0.58 2 3.7 3.9 0.64 21 N CAM MEAN S.D. 6 4.3 4.3 0.59 3 4.3 4.5 0.06 6 4.3 4.2 0.58 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) PAGE: 5 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEK UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 22 N CAM MEAN S.D. 6 4.3 4.3 0.59 3 4.3 4.5 0.06 6 4.3 4.3 0.58 2 3.7 3.9 0.64 23 N CAM MEAN S.D. 6 4.4 4.3 0.60 3 4.4 4.5 0.06 6 4.4 4.3 0.56 2 3.9 4.0 0.57 24 N CAM MEAN S.D. 6 4.4 4.3 0.59 3 4.4 4.6 0.00 6 4.4 4.4 0.58 2 4.0 4.1 0.57 25 N CAM MEAN S.D. 6 4.4 4.4 0.59 3 4.5 4.6 0.06 6 4.4 4.3 0.60 2 3.9 3.9 0.64 26 N CAM MEAN S.D. 6 4.5 4.4 0.60 3 4.6 4.7 0.06 6 4.5 4.4 0.62 2 3.9 4.0 0.71 27 N CAM MEAN S.D. 6 4.5 4.5 0.64 3 4.6 4.8 0.06 6 4.5 4.4 0.60 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) Recovery PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------MALE--------- GROUP: 1 3 DOSE: 0 10 WEEK UNITS: MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 28 N MEAN S.D. 2 5.1 0.28 2 3.8 0.07 29 N MEAN S.D. 2 5.2 0.28 2 3.8 0.00 30 N MEAN S.D. 2 5.2 0.21 2 3.7 0.07 31 N MEAN S.D. 2 5.2 0.21 2 3.7 0.14 32 N MEAN S.D. 2 5.3 0.28 2 3.8 0.07 33 N MEAN S.D. 2 5.3 0.42 2 3.8 0.14 34 N MEAN S.D. 2 5.5 0.28 2 3.8 0.14 67 Table 6 Covance 6329-231 3M T-6889.3 Summary of Body Weight Data (kg) Recovery PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------MALE--------- GROUP: 1 3 DOSE: 0 10 WEEK UNITS: MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 35 N MEAN S.D. 2 5.5 0.28 2 3.8 0.14 36 N MEAN S.D. 2 5.6 0.35 2 3.8 0.14 37 N MEAN S.D. 2 5.6 0.28 2 3.8 0.14 38 N MEAN S.D. 2 5.6 0.28 2 3.8 0.14 39 N MEAN S.D. 2 5.7 0.28 2 3.8 0.21 40 N MEAN S.D. 2 5.7 0.28 2 3.8 0.21 68 Table 7 Covance 6329-231 3M T-6889.3 Summary of Body Weight Change Data (kg) PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEKS UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 1-2 N MEAN S.D. 6 -0.1 0.05 4 0.0 0.08 6 -0.1 0.12 6 -0.2 0.08 2-3 N MEAN S.D. 6 0.1 0.06 4 0.0 0.05 6 0.0 0.05 6 -0.1 * 0.17 3-4 N MEAN S.D. 6 0.1 0.04 4 0.0 0.06 6 0.1 0.05 6 0.2 0.08 4-5 N MEAN S.D. 6 0.0 0.10 4 -0.1 0.08 6 -0.1 0.05 6 -0.1 0.08 5-6 N MEAN S.D. 6 0.0 0.10 4 0.2 0.05 6 0.1 0.10 5 0.0 0.07 6-7 N MEAN S.D. 6 0.1 0.10 4 0.0 0.08 6 0.0 0.10 5 0.0 0.15 7-8 N MEAN S.D. 6 -0.1 0.12 4 0.0 0.10 6 0.0 0.09 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Change Data (kg) PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEKS UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 8-9 N MEAN S.D. 6 0.0 0.13 4 0.1 0.13 6 0.1 0.08 4 0.0 0.08 9-10 N MEAN S.D. 6 0.0 0.05 4 0.0 0.06 6 0.0 0.08 4 -0.1 * 0.13 10-11 N MEAN S.D. 6 0.0 0.05 4 0.0 0.06 6 0.1 0.10 3 0.0 0.00 11-12 N MEAN S.D. 6 0.0 0.06 4 0.0 0.05 6 0.0 0.05 3 -0.1 0.17 12-13 N MEAN S.D. 6 0.0 0.05 4 0.1 0.05 6 0.1 0.06 2 0.1 0.00 13-14 N MEAN S.D. 6 0.0 0.04 4 -0.1 0.10 6 -0.1 0.05 2 -0.1 0.00 14-15 N MEAN S.D. 6 0.1 0.05 4 0.1 0.05 6 0.1 0.08 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Change Data (kg) PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEKS UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 15-16 N MEAN S.D. 6 0.0 0.06 4 0.0 0.05 6 0.0 0.05 2 0.0 0.00 16-17 N MEAN S.D. 6 0.0 0.00 4 0.1 0.05 6 0.0 0.05 2 0.0 0.07 17-18 N MEAN S.D. 6 0.1 0.05 4 0.1 0.13 6 0.0 0.05 2 0.1 0.00 18-19 N MEAN S.D. 6 0.0 0.06 4 0.0 0.10 6 0.0 0.08 2 0.0 0.07 19-20 N MEAN S.D. 6 0.0 0.05 4 -0.1 0.20 6 0.0 0.04 2 -0.1 0.14 20-21 N MEAN S.D. 6 0.0 0.04 3 0.0 0.06 6 0.0 0.00 2 0.0 0.00 21-22 N MEAN S.D. 6 0.0 0.00 3 0.0 0.00 6 0.0 0.04 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Change Data (kg) PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ SEX: ---------------------MALE--------------------- GROUP: 1 DOSE: 0 2 3 4 3 10 20a WEEKS UNITS: MG/KG/DAY MG/KG/DAY MG/KG/DAY MG/KG/DAY ------------------------------------------------------------------------------------------------------------------------------------ 22-23 N MEAN S.D. 6 0.1 0.05 3 0.1 0.06 6 0.0 0.05 2 0.1 0.07 23-24 N MEAN S.D. 6 0.0 0.06 3 0.1 0.06 6 0.1 0.05 2 0.1 0.00 24-25 N MEAN S.D. 6 0.0 0.05 3 0.0 0.06 6 0.0 0.05 2 -0.2 * 0.07 25-26 N MEAN S.D. 6 0.1 0.04 3 0.1 0.00 6 0.1 0.04 2 0.1 0.07 26-27 N MEAN S.D. 6 0.0 0.05 3 0.0 0.06 6 0.0 0.06 2 0.1 0.00 1-27 N MEAN S.D. 6 0.7 0.33 3 0.7 0.35 6 0.6 0.34 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 Covance 6329-231 3M T-6889.3 Summary of Body Weight Change Data (kg) Recovery PAGE: 1 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. 2 -0.1 0.07 2 -0.1 0.07 28-29 N MEAN S.D. 2 0.1 0.00 2 0.1 0.07 29-30 N MEAN S.D. 2 0.0 0.07 2 -0.2 0.07 30-31 N MEAN S.D. 2 0.0 0.00 2 0.1 0.07 31-32 N MEAN S.D. 2 0.2 0.07 2 0.0 0.07 32-33 N MEAN S.D. 2 0.0 0.14 2 0.0 0.07 33-34 N MEAN S.D. 2 0.2 0.14 2 0.0 0.00 73 Table 8 Covance 6329-231 3M T-6889.3 Summary of Body Weight Change Data (kg) Recovery PAGE: 2 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. 2 0.0 0.00 2 0.0 0.00 35-36 N MEAN S.D. 2 0.1 0.07 2 0.0 0.00 36-37 N MEAN S.D. 2 0.0 0.07 2 0.0 0.00 37-38 N MEAN S.D. 2 0.0 0.00 2 0.0 0.00 38-39 N MEAN S.D. 2 0.1 0.00 2 0.0 0.07 39-40 N MEAN S.D. 2 0.0 0.00 2 0.0 0.00 27-40 N MEAN S.D. 2 0.5 0.07 2 0.0 0.21 74 Table 9 Summary of Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.60 12.4 42.1 63.9 18.9 29.5 513 .7 S.D. .405 .26 .85 3.05 1.21 1.03 155.0 .36 N 6 6 6 6 6 6 6 6 45 26.3 6 9.7 .32 6 18.2 1.23 6 286 32.2 6 3 MEAN 6.88 12.9 43.9 63.8 18.8 29.4 562 .7 S.D. .433 1.23 4.51 3.80 .95 .22 109.5 .42 N 4 4 4 4 4 4 4 4 48 29.9 4 9.6 .10 4 20.5 5.03 4 345 52.3 4 10 MEAN 6.70 12.1 40.4 60.4 18.1 30.0 515 .6 S.D. .268 .56 1.92 3.78 1.02 .48 98.3 .38 N 6 6 6 6 6 6 6 6 43 24.7 6 9.6 .18 6 18.3 1.59 6 315 22.2 6 30/20 MEAN 6.84 12.2 41.2 60.2 17.8 29.6 547 .7 S.D. .302 .83 2.68 2.63 .89 .58 90.6 .22 N 6 6 6 6 6 6 6 6 49 16.9 6 9.8 .36 6 20.0 3.76 6 304 44.9 6 75 Table 9 Summary of Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% 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 6 6 6 6 6 6 6 6 6 6 6 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 4 4 4 4 4 4 4 4 4 4 4 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 6 6 6 6 6 6 6 6 6 6 6 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 6 6 6 6 6 6 6 6 6 6 6 76 Table 10 Summary of Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.81 12.9 44.0 64.7 19.0 29.3 428 .3 S.D. .415 .80 1.88 3.01 1.12 1.23 87.8 .11 N 6 6 6 6 6 6 6 6 21 8.4 6 10.0 .26 6 19.8 1.26 6 369 187.4 6 3 MEAN 6.47 12.4 41.3 64.0 19.2 30.0 499 .2 S.D. .378 .57 1.76 3.43 1.06 .45 98.7 .14 N 4 4 4 4 4 4 4 4 13 10.4 4 9.8 .29 4 21.9 4.98 4 334 24.0 4 10 MEAN 6.73 12.3 41.8 62.2 18.4 29.6 446 .2 S.D. .387 .51 2.11 3.73 1.09 .46 107.9 .08 N 6 6 6 6 6 6 6 6 11 5.2 6 10.1 .34 6 20.0 2.02 6 291 38.8 6 30/20 MEAN 6.63 12.1 40.9 61.6 18.2 29.6 516 .3 S.D. .396 .99 3.06 3.23 .54 1.56 159.7 .26 N 5 5 5 5 5 5 5 5 23 19.1 5 10.0 .47 5 24.0 4.22 5 475 250.9 5 77 Table 10 Summary of Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% 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 6 6 6 6 6 6 6 6 6 6 6 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 4 4 4 4 4 4 4 4 4 4 4 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 6 6 6 6 6 6 6 6 6 6 6 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 5 5 5 5 5 5 5 5 5 5 5 78 Table 11 Summary of Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.66 12.5 42.1 63.3 18.8 29.7 458 .3 S.D. .641 1.10 3.75 3.24 1.03 .97 187.7 .05 N 6 6 6 6 6 6 6 6 18 4.4 6 10.1 .41 6 19.2 1.59 6 343 100.1 6 3 MEAN 6.75 13.0 43.0 63.9 19.2 30.0 467 .4 S.D. .485 .90 2.45 4.66 1.27 .83 104.0 .17 N 4 4 4 4 4 4 4 4 28 10.4 4 10.0 .30 4 21.7 3.83 4 318 33.9 4 10 MEAN 6.78 12.4 41.2 60.9 18.3 30.1 436 .2 S.D. .323 .37 1.17 2.86 1.05 .53 87.3 .11 N 6 6 6 6 6 6 6 6 13 6.6 6 10.2 .27 6 20.0 2.47 6 257 46.5 6 30/20 MEAN 6.77 12.0 40.6 60.0 17.8 29.6 433 .2 S.D. .600 1.28 4.58 2.31 .54 .59 131.4 .10 N 4 4 4 4 4 4 4 4 12 5.6 4 10.8 .95 4 24.7 * 2.15 4 194 * 85.7 4 79 Table 11 Summary of Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% 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 6 6 6 6 6 6 6 6 6 6 6 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 4 4 4 4 4 4 4 4 4 4 4 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 6 6 6 6 6 6 6 6 6 6 6 30/20 MEAN 7.7 2.7 4.2 .6 .2 .0 34 54 9 2 0 S.D. 1.96 1.44 .95 .13 .17 .00 11.4 7.0 3.2 2.2 .6 N 4 4 4 4 4 4 4 4 4 4 4 80 Table 12 Summary of Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.87 12.9 44.2 64.4 18.8 29.1 435 .3 S.D. .372 .84 2.83 3.88 1.35 1.18 145.1 .11 N 6 6 6 6 6 6 6 6 21 8.2 6 10.2 .19 6 18.1 1.31 6 278 15.2 6 3 MEAN 6.61 12.6 42.1 63.8 19.1 30.0 504 .3 S.D. .455 .91 3.30 4.08 .98 .81 129.5 .29 N 4 4 4 4 4 4 4 4 22 19.4 4 10.3 .22 4 19.6 2.73 4 311 49.0 4 10 MEAN 6.82 12.5 41.6 61.1 18.4 30.1 421 .3 S.D. .374 .32 1.12 3.41 1.10 .75 42.1 .23 N 6 6 6 6 6 6 6 6 20 14.3 6 10.4 .34 6 19.2 1.64 6 262 36.2 6 30/20 MEAN 6.46 11.1 37.2 * 57.6 17.2 29.8 406 .2 S.D. .559 .57 2.97 .42 .64 .92 70.7 .07 N 2 2 2 2 2 2 2 2 10 3.5 2 10.4 .49 2 22.5 2.05 2 244 57.3 2 81 Table 12 Summary of Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% 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 6 6 6 6 6 6 6 6 6 6 6 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 4 4 4 4 4 4 4 4 4 4 4 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 6 6 6 6 6 6 6 6 6 6 6 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 2 2 2 2 2 2 2 2 2 2 2 82 Table 13 Summary of Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.69 12.6 40.6 60.8 19.0 31.1 408 .6 S.D. .263 .55 .82 3.33 1.17 .98 133.8 .41 N 6 6 6 6 6 6 6 6 42 27.0 6 10.2 .43 6 17.9 1.53 6 272 30.2 6 3 MEAN 6.91 12.7 40.9 59.4 18.5 31.2 516 .9 S.D. .928 1.04 4.41 2.56 1.01 1.21 132.3 .06 N 3 3 3 3 3 3 3 3 60 11.7 3 10.1 .45 3 20.6 4.98 3 294 7.5 3 10 MEAN 6.76 12.3 39.1 58.1 18.3 31.5 416 .5 S.D. .470 .57 2.19 4.19 1.14 .67 103.5 .41 N 6 6 6 6 6 6 6 6 35 25.5 6 10.3 .23 6 19.6 1.74 6 278 66.9 6 30/20 MEAN 6.18 10.6 * 33.9 55.0 17.2 31.4 378 .2 S.D. .841 1.13 4.45 .21 .49 .85 180.3 .21 N 2 2 2 2 2 2 2 2 8 12.0 2 10.3 .07 2 25.5 7.00 2 224 69.3 2 83 Table 13 Summary of Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% 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 6 6 6 6 6 6 6 6 6 6 6 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 3 3 3 3 3 3 3 3 3 3 3 10 MEAN 9.7 4.4 4.1 .8 .3 .1 45 43 9 3 1 S.D. 2.93 1.84 1.53 .23 .19 .04 12.5 11.2 1.8 1.6 .4 N 6 6 6 6 6 6 6 6 6 6 6 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 2 2 2 2 2 2 2 2 2 2 2 84 Table 14 Summary of Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 7.00 13.7 44.8 64.0 19.6 30.6 492 .6 S.D. .191 .14 .00 1.84 .28 .42 247.5 .07 N 2 2 2 2 2 2 2 2 46 6.4 2 9.8 .35 2 17.9 .92 2 305 53.7 2 10 MEAN 7.04 12.3 39.8 56.5 17.5 31.0 390 .3 S.D. .389 .64 .99 1.70 .07 .71 78.5 .28 N 2 2 2 2 2 2 2 2 20 19.1 2 10.2 .21 2 20.2 1.34 2 214 14.8 2 85 Table 14 Summary of Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% BASO% ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 18.7 7.4 8.8 1.7 .5 .2 36 49 10 3 1 S.D. 8.56 5.87 2.62 .00 .00 .07 14.8 8.5 4.9 1.4 .0 N 2 2 2 2 2 2 2 2 2 2 2 10 MEAN 11.1 4.6 4.9 1.1 .4 .1 42 43 10 4 0 S.D. 1.13 1.48 1.56 .57 .42 .14 17.7 9.9 3.5 3.5 .7 N 2 2 2 2 2 2 2 2 2 2 2 86 Table 15 Summary of Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.92 13.6 44.4 64.1 19.6 30.5 529 .4 S.D. .028 .21 .85 1.56 .49 .00 190.9 .07 N 2 2 2 2 2 2 2 2 24 4.9 2 9.8 .35 2 18.0 1.77 2 323 4.2 2 10 MEAN 7.25 12.7 40.8 56.3 17.5 31.2 421 .2 S.D. .410 .85 .85 1.98 .14 1.34 97.6 .21 N 2 2 2 2 2 2 2 2 10 14.8 2 10.2 .07 2 19.2 .21 2 227 14.1 2 87 Table 15 Summary of Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% BASO% ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 15.8 5.7 8.2 1.4 .5 .2 35 52 8 4 1 S.D. 2.90 2.83 .49 .21 .28 .07 11.3 5.7 3.5 2.1 .0 N 2 2 2 2 2 2 2 2 2 2 2 10 MEAN 10.7 4.4 4.9 1.0 .3 .0 44 44 10 2 0 S.D. 5.09 1.34 3.11 .35 .28 .07 8.5 7.8 .7 1.4 .7 N 2 2 2 2 2 2 2 2 2 2 2 88 Table 16 Summary of Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE RBC HGB HCT MCV MCH MCHC PLT RETIC RETIC PT mg/kg/day X106/L G/DL % FL PG % X103/L % X103/L SEC PTT SEC FBR MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 6.96 13.8 43.6 62.5 19.8 31.6 584 .2 S.D. .714 1.20 3.89 .85 .35 .14 244.0 .07 N 2 2 2 2 2 2 2 2 10 4.2 2 9.8 .57 2 17.6 .49 2 530 173.2 2 10 MEAN 7.20 12.8 41.1 57.2 17.7 31.0 446 .4 S.D. .325 .49 .64 1.63 .14 .64 53.7 .49 N 2 2 2 2 2 2 2 2 24 34.6 2 10.2 .21 2 18.3 .71 2 300 26.2 2 89 Table 16 Summary of Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day WBC X103/L N-SEG X103/L LYMPH X103/L MONO X103/L EOSIN BASO X103/L X103/L N-SEG% LYMPH% MONO% EOSIN% BASO% ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 15.0 7.4 5.6 1.6 .2 .1 49 38 12 2 1 S.D. 4.31 2.55 1.77 .07 .00 .00 2.8 .7 2.8 .7 .0 N 2 2 2 2 2 2 2 2 2 2 2 10 MEAN 16.2 9.1 5.6 1.3 .1 .0 54 38 8 0 0 S.D. 4.17 5.94 1.77 .00 .00 .00 23.3 20.5 2.1 .7 .0 N 2 2 2 2 2 2 2 2 2 2 2 90 Table 17 Summary of Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 TRIG MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 92 16 1.2 9.4 4.8 4.6 .0 S.D. 15.3 2.6 .15 .58 .40 .56 .05 N 6 6 6 6 6 6 6 9 147 2.0 44.3 6 6 39 11.3 6 3 MEAN 88 14 1.1 9.4 5.2 4.2 .1 10 174 50 S.D. 11.7 4.6 .15 .87 .29 .63 .15 4.6 53.7 10.2 N 4 4 4 4 4 4 4 4 4 4 10 MEAN 92 16 1.2 9.1 4.8 4.3 .2 S.D. 21.5 1.6 .05 .68 .21 .63 .23 N 6 6 6 6 6 6 6 9 145 1.7 22.0 6 6 61 18.0 6 30/20 MEAN 81 15 1.1 9.1 4.8 4.4 .2 S.D. 4.6 2.0 .21 .77 .20 .70 .15 N 6 6 6 6 6 6 6 8 140 4.7 26.3 6 6 56 13.2 6 91 Table 17 Summary of Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 35 9.6 6 58 28.8 6 455 202.2 6 126 32.4 6 3 145 516 .8 77.2 214.2 6 6 6 25 9.1 6 237 79.8 6 3 MEAN S.D. N 40 3.9 4 42 8.1 4 556 180.3 4 135 24.3 4 5 142 377 2.7 19.1 41.6 4 4 4 38 27.3 4 183 30.4 4 10 MEAN S.D. N 40 7.3 6 77 52.6 6 604 173.8 6 120 38.0 6 5 128 369 2.1 45.0 98.5 6 6 6 14 8.7 6 195 70.6 6 30/20 MEAN S.D. N 39 8.3 6 66 41.8 6 521 231.6 6 117 49.1 6 3 142 380 1.4 56.6 89.3 6 6 6 37 29.6 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 11.4 S.D. .45 N 6 5.8 .69 6 163 2.9 6 5.8 .50 6 114 1.6 6 3 MEAN 11.4 S.D. .70 N 4 6.7 .53 4 162 5.7 4 5.9 .78 4 110 1.7 4 10 MEAN S.D. N 10.9 .45 6 6.3 1.37 6 158 2.4 6 5.4 .48 6 112 1.5 6 30/20 MEAN S.D. N 10.7 .57 6 6.1 .96 6 159 4.2 6 5.6 .56 6 112 2.2 6 Covance 6329-231 3M T-6889.3 93 Table 18 Summary of Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 TRIG MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 78 15 1.3 9.2 4.7 4.6 .2 S.D. 22.9 2.4 .17 .58 .42 .56 .12 N 6 6 6 6 6 6 6 8 146 2.9 19.1 6 6 44 22.9 6 3 MEAN 78 16 1.2 8.6 4.9 3.7 .1 S.D. 9.3 4.4 .17 .37 .24 .45 .14 N 4 4 4 4 4 4 4 7 151 1.4 60.4 4 4 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 6 6 6 6 6 6 6 6 6 6 30/20 MEAN 75 16 1.3 8.8 4.5 4.3 .1 S.D. 9.3 2.4 .13 .49 .38 .37 .09 N 5 5 5 5 5 5 5 8 158 108 * 1.9 20.8 57.3 5 5 5 94 Table 18 Summary of Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 34 6.7 6 48 16.7 6 577 232.0 6 121 29.3 6 4 115 551 1.6 51.3 177.3 6 6 6 39 20.2 6 255 87.1 6 3 MEAN S.D. N 39 10.9 4 29 6.4 4 629 193.9 4 107 24.5 4 3 157 396 2.6 88.3 58.3 4 4 4 46 21.0 4 181 33.5 4 10 MEAN S.D. N 36 7.0 6 55 22.6 6 704 165.2 6 107 29.6 6 2 144 372 1.4 36.4 109.2 6 6 6 19 10.6 6 197 85.8 6 30/20 MEAN S.D. N 33 6.6 5 36 13.5 5 571 313.5 5 98 34.1 5 1 128 434 1.3 66.4 109.7 5 5 5 34 28.5 5 205 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 11.0 S.D. .45 N 6 5.9 1.12 6 158 3.3 6 5.8 .37 6 113 2.8 6 3 MEAN 10.1 S.D. .14 N 4 5.8 .88 4 152 2.5 4 5.3 .22 4 111 1.3 4 10 MEAN S.D. N 10.4 .34 6 5.9 .75 6 153 5.1 6 5.0 .55 6 110 2.1 6 30/20 MEAN S.D. N 10.7 .81 5 4.9 .63 5 157 6.2 5 5.8 .90 5 112 3.7 5 Covance 6329-231 3M T-6889.3 96 Table 19 Summary of Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 TRIG MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 78 17 1.2 9.0 4.6 4.4 .4 S.D. 21.1 3.8 .19 .39 .42 .39 .18 N 6 6 6 6 6 6 6 5 151 3.7 36.9 6 6 43 13.5 6 3 MEAN 68 18 1.1 8.9 5.0 3.8 .3 S.D. 7.0 4.3 .10 .48 .25 .31 .08 N 4 4 4 4 4 4 4 9 161 5.1 61.3 4 4 59 20.4 4 10 MEAN 71 17 1.2 8.6 4.6 4.0 .2 S.D. 10.7 1.5 .16 .67 .35 .54 .10 N 6 6 6 6 6 6 6 9 158 3.2 46.2 6 6 76 27.4 6 30/20 MEAN 76 20 1.2 8.1 3.9 4.2 .3 22 146 66 S.D. 7.0 5.0 .13 1.20 .75 .67 .21 25.8 12.2 39.0 N 4 4 4 4 4 4 4 4 4 4 97 Table 19 Summary of Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 36 8.0 6 62 23.9 6 582 193.3 6 123 31.2 6 4 139 481 2.9 78.9 147.1 6 6 6 28 16.2 6 262 81.8 6 3 MEAN S.D. N 35 10.4 4 45 26.7 4 612 169.9 4 121 15.9 4 2 131 396 1.0 16.2 58.5 4 4 4 86 81.3 4 220 45.4 4 10 MEAN S.D. N 36 6.9 6 53 19.4 6 668 190.3 6 114 29.7 6 3 143 347 1.5 65.6 106.2 6 6 6 13 12.2 6 211 83.4 6 30/20 MEAN S.D. N 141 187.4 4 192 269.7 4 484 159.5 4 110 55.7 4 9 379 352 8.6 496.0 71.3 4 4 4 8 13.6 4 204 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 10.6 S.D. .32 N 6 5.9 .44 6 156 3.4 6 5.1 .31 6 111 2.9 6 3 MEAN 10.6 S.D. .33 N 4 6.2 1.07 4 154 3.9 4 5.0 .13 4 111 2.2 4 10 MEAN S.D. N 10.4 .38 6 5.7 .69 6 150 * 1.8 6 4.6 .45 6 110 2.6 6 30/20 MEAN S.D. N 9.8 .93 4 4.9 .48 4 152 3.9 4 5.8 .94 4 111 2.6 4 Covance 6329-231 3M T-6889.3 99 Table 20 Summary of Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 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 6 6 6 6 6 6 6 6 6 6 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 4 4 4 4 4 4 4 4 4 4 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 6 6 6 6 6 6 6 6 6 6 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 2 2 2 2 2 2 2 2 2 2 100 Table 20 Summary of Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 38 7.8 6 63 22.7 6 529 240.3 6 128 31.4 6 10 3.7 6 143 55.8 6 515 148.7 6 20 17.4 6 270 66.1 6 3 MEAN S.D. N 40 6.7 4 47 25.2 4 585 177.6 4 118 22.5 4 10 1.0 4 126 35.3 4 378 63.6 4 50 32.0 4 207 47.2 4 10 MEAN S.D. N 40 6.8 6 53 15.5 6 656 208.6 6 113 30.8 6 11 2.9 6 133 34.4 6 367 100.7 6 9 12.6 6 219 77.0 6 30/20 MEAN S.D. N 38 7.1 2 48 17.7 2 432 306.2 2 120 88.4 2 10 .0 2 156 31.8 2 318 67.9 2 11 15.6 2 184 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 11.3 S.D. .20 N 6 6.4 .60 6 167 3.0 6 5.3 .38 6 117 2.7 6 3 MEAN 10.8 * 6.3 S.D. .44 1.10 N 4 4 162 2.5 4 5.1 .46 4 118 1.7 4 10 MEAN S.D. N 10.8 * .34 6 6.1 .80 6 160 * 3.7 6 4.8 .37 6 117 1.9 6 30/20 MEAN S.D. N 10.1 * .71 2 5.0 .42 2 158 * 2.8 2 5.4 .85 2 114 3.5 2 Covance 6329-231 3M T-6889.3 102 Table 21 Summary of Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 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 6 6 6 6 6 6 6 6 6 6 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 3 3 3 3 3 3 3 3 3 3 10 MEAN 66 20 1.1 8.4 4.6 3.8 .2 16 154 72 S.D. 19.7 2.4 .19 .71 .26 .62 .23 1.4 30.6 24.5 N 6 6 6 6 6 6 6 6 6 6 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 2 2 2 2 2 2 2 2 2 2 103 Table 21 Summary of Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 37 4.8 6 68 15.7 6 444 190.8 6 124 30.5 6 5 140 500 2.3 28.8 144.3 6 6 6 39 25.0 6 328 91.9 6 3 MEAN S.D. N 46 1.5 3 43 5.8 3 574 290.4 3 130 39.2 3 6 139 457 106 313 2.0 37.6 105.5 63.8 72.0 3 3 3 3 3 10 MEAN S.D. N 44 11.6 6 53 26.7 6 544 181.0 6 110 24.1 6 7 922 2.2 1902.1 6 6 362 114.7 6 11 * 9.1 6 268 107.9 6 30/20 MEAN S.D. N 40 3.5 2 48 7.8 2 384 260.9 2 122 95.5 2 2 169 305 .7 58.0 55.2 2 2 2 8 12.0 2 215 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 10.0 S.D. .23 N 6 5.8 .44 6 152 2.0 6 4.9 .33 6 106 1.3 6 3 MEAN 10.3 S.D. 1.29 N 3 6.0 2.12 3 154 10.4 3 4.9 .96 3 109 1.7 3 10 MEAN S.D. N 9.7 .52 6 5.8 1.16 6 148 3.9 6 4.3 .57 6 106 2.3 6 30/20 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 Covance 6329-231 3M T-6889.3 105 Table 22 Summary of Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 TRIG MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 101 17 1.4 9.2 4.8 4.4 .4 S.D. 36.8 .0 .07 .28 .35 .07 .07 N 2 2 2 2 2 2 2 6 194 .0 48.8 2 2 40 .7 2 10 MEAN 61 21 1.4 8.0 4.6 3.3 .2 S.D. 9.9 1.4 .14 .21 .21 .42 .07 N 2 2 2 2 2 2 2 7 159 .0 39.6 2 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 Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 34 7.8 2 42 17.0 2 247 18.4 2 140 51.6 2 5 92 612 20 415 1.4 14.1 221.3 13.4 192.3 2 2 2 2 2 10 MEAN S.D. N 29 2.8 2 18 8.5 2 548 196.6 2 120 31.1 2 6 140 477 1.4 3.5 94.8 2 2 2 22 7.1 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 10.9 S.D. .00 N 2 6.3 .28 2 156 4.2 2 5.8 .35 2 108 3.5 2 10 MEAN S.D. N 9.9 .00 2 6.2 1.41 2 146 1.4 2 4.6 .14 2 108 .7 2 Covance 6329-231 3M T-6889.3 108 Covance 6329-231 3M T-6889.3 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 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 TRIG MG/DL ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN 95 15 1.3 9.1 4.8 4.2 .2 S.D. 1.4 .0 .14 .00 .35 .35 .07 N 2 2 2 2 2 2 2 4 203 .0 67.9 2 2 49 2.8 2 10 MEAN 80 20 1.3 8.1 4.8 3.2 .2 S.D. 2.1 2.8 .14 .14 .21 .35 .07 N 2 2 2 2 2 2 2 5 164 1.4 30.4 2 2 92 64.3 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 Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 35 7.1 2 44 1.4 2 245 58.0 2 134 65.8 2 4 508 604 .7 559.3 219.2 2 2 2 46 2.1 2 420 186.0 2 10 MEAN S.D. N 28 3.5 2 44 9.2 2 635 206.5 2 120 32.5 2 2 164 490 .7 53.0 70.0 2 2 2 56 13.4 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 10.7 S.D. .00 N 2 6.8 .21 2 158 .0 2 5.6 1.27 2 110 .7 2 10 MEAN S.D. N 10.3 .00 2 6.4 1.06 2 153 2.8 2 5.3 .42 2 114 .7 2 Covance 6329-231 3M T-6889.3 111 Table 24 Summary of Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS Covance 6329-231 3M T-6889.3 DOSE mg/kg/day 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 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 2 2 2 2 2 2 2 2 2 2 10 MEAN 90 21 1.3 8.2 4.9 3.3 .3 S.D. 4.2 .0 .00 .00 .42 .42 .00 N 2 2 2 2 2 2 2 8 150 .7 39.6 2 2 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 Covance 6329-231 3M T-6889.3 DOSE AST/SGOT ALT/SGPT ALK PHOS mg/kg/day IU/L IU/L IU/L GGT IU/L SDH IU/L CK IU/L AMYLASE IU/L LIPASE IU/L P AMYL U/L ------ -------- -------- -------- -------- -------- -------- -------- -------- -------- 0 MEAN S.D. N 60 6.4 2 108 63.6 2 270 75.7 2 112 21.2 2 2 1024 2.1 533.9 2 2 826 224.2 2 164 61.5 2 574 168.3 2 10 MEAN S.D. N 50 4.9 2 76 7.8 2 603 210.7 2 116 31.1 2 2 1524 1074 1.4 563.6 813.2 2 2 2 357 422.8 2 903 787.7 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 10.9 S.D. .42 N 2 4.9 .99 2 154 .7 2 6.0 .78 2 107 4.2 2 10 MEAN S.D. N 10.2 .00 2 5.2 1.91 2 150 2.8 2 4.4 .00 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 136.8 1.016 S.D. 131.02 .0073 N 6 6 8.2 .41 6 3 MEAN 231.0 1.010 S.D. 220.83 .0086 N 4 4 7.9 .25 4 10 MEAN 141.0 1.014 S.D. 157.36 .0060 N 6 6 8.2 .41 6 30/20 MEAN S.D. N 88.3 66.52 6 1.014 .0081 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 mg/kg/day U VOL ML SP GR U PH ------ -------- -------- -------- 0 MEAN 166.5 1.015 S.D. 158.98 .0066 N 6 6 7.9 .38 6 3 MEAN 241.8 1.010 S.D. 141.01 .0092 N 4 4 7.8 .50 4 10 MEAN 155.3 1.014 S.D. 111.19 .0067 N 6 6 8.1 .20 6 30/20 MEAN S.D. N 223.2 99.35 5 1.007 .0056 5 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 189.0 1.013 S.D. 191.82 .0078 N 6 6 8.1 .20 6 3 MEAN 253.0 1.010 S.D. 145.45 .0097 N 4 4 7.5 * .41 4 10 MEAN 190.0 1.012 S.D. 188.04 .0057 N 6 6 8.2 .26 6 30/20 MEAN S.D. N 83.0 22.89 4 1.016 .0048 4 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 186.0 1.017 S.D. 182.11 .0083 N 6 6 8.2 .27 6 3 MEAN 272.0 1.012 S.D. 218.99 .0088 N 4 4 7.8 * .29 4 10 MEAN 222.0 1.012 S.D. 174.10 .0054 N 6 6 7.9 .20 6 30/20 MEAN S.D. N 71.0 9.90 2 1.020 .0000 2 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 mg/kg/day U VOL ML SP GR U PH ------ -------- -------- -------- 0 MEAN 159.5 1.015 S.D. 67.63 .0063 N 6 6 7.7 .41 6 3 MEAN 172.3 1.016 S.D. 71.07 .0060 N 3 3 7.8 .29 3 10 MEAN 208.5 1.013 S.D. 159.04 .0067 N 6 6 7.2 .27 6 30/20 MEAN S.D. N 197.0 154.15 2 1.014 .0113 2 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 2 2 8.0 .00 2 10 MEAN 290.0 1.006 S.D. 233.35 .0035 N 2 2 7.8 .35 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 2 2 8.0 .00 2 10 MEAN 341.5 1.005 S.D. 246.78 .0028 N 2 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 2 2 7.0 .00 2 10 MEAN 135.5 1.012 S.D. 61.52 .0028 N 2 2 8.0 .00 2 Covance 6329-231 3M T-6889.3 122 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 1 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 0.3085 0.0078 0.0048 STANDARD DEV: 591.1 0.0462 0.0003 0.0004 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 0.3720 0.0083 0.0056 STANDARD DEV: 30.6 0.0460 0.0010 0.0009 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 0.3030 0.0069 0.0048 STANDARD DEV: 498.5 0.0940 0.0024 0.0017 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 0.3320 0.0087 0.0045 STANDARD DEV: 583.0 0.0311 0.0006 0.0002 --------------------------------------------------------------- 123 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 2 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 0.2513 0.0063 0.0039 STANDARD DEV: 591.1 0.0503 0.0008 0.0006 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 0.3573 0.0080 0.0054 STANDARD DEV: 30.6 0.0492 0.0010 0.0009 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 0.2328 0.0054 0.0036 STANDARD DEV: 498.5 0.0512 0.0016 0.0009 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 0.2620 0.0067 0.0035 STANDARD DEV: 583.0 0.0891 0.0012 0.0010 --------------------------------------------------------------- 124 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 3 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 64.5708 1.6471 1.0000 STANDARD DEV: 591.1 7.6823 0.1763 0.0000 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 66.5134 1.4827 1.0000 STANDARD DEV: 30.6 2.3695 0.0614 0.0000 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 64.2743 1.4622 1.0000 STANDARD DEV: 498.5 4.2590 0.2194 0.0000 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 74.2460 1.9603 1.0000 STANDARD DEV: 583.0 3.6416 0.2309 0.0000 --------------------------------------------------------------- 125 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 4 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 1.6380 0.0410 0.0256 STANDARD DEV: 591.1 0.5473 0.0112 0.0095 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 2.3627 0.0526 0.0355 STANDARD DEV: 30.6 0.6805 0.0151 0.0100 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 1.7010 0.0382 0.0268 STANDARD DEV: 498.5 0.5692 0.0127 0.0094 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 1.8945 0.0510 0.0257 STANDARD DEV: 583.0 0.3345 0.0172 0.0058 --------------------------------------------------------------- 126 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 5 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 1.7750 0.0449 0.0278 STANDARD DEV: 591.1 0.4542 0.0100 0.0086 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 2.3617 0.0526 0.0356 STANDARD DEV: 30.6 0.5749 0.0127 0.0087 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 1.6640 0.0375 0.0261 STANDARD DEV: 498.5 0.5738 0.0133 0.0091 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 1.7740 0.0476 0.0240 STANDARD DEV: 583.0 0.2489 0.0144 0.0045 --------------------------------------------------------------- 127 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 6 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 6.5898 0.1674 0.1023 STANDARD DEV: 591.1 0.9070 0.0133 0.0110 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 8.0123 0.1785 0.1209 STANDARD DEV: 30.6 1.1567 0.0245 0.0216 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 8.0508 0.1818 0.1260 STANDARD DEV: 498.5 0.6366 0.0136 0.0168 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 9.1090 * 0.2437 0.1232 STANDARD DEV: 583.0 1.0041 0.0668 0.0196 --------------------------------------------------------------- 128 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 7 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 6.5520 0.1660 0.1014 STANDARD DEV: 591.1 1.0155 0.0085 0.0092 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 7.7810 0.1733 0.1175 STANDARD DEV: 30.6 1.2850 0.0274 0.0237 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 7.8853 0.1777 0.1235 STANDARD DEV: 498.5 0.7930 0.0124 0.0191 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 9.1500 0.2447 0.1237 STANDARD DEV: 583.0 0.9772 0.0663 0.0192 --------------------------------------------------------------- 129 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 8 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 60.1698 1.5303 0.9344 STANDARD DEV: 591.1 6.9386 0.0769 0.0736 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 81.7917 * 1.8228 * 1.2317 STANDARD DEV: 30.6 2.8112 0.0502 0.0856 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 83.1743 * 1.8700 * 1.3042 * STANDARD DEV: 498.5 9.6617 0.0616 0.2255 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 90.3925 * 2.4057 * 1.2203 STANDARD DEV: 583.0 4.2208 0.5106 0.1167 --------------------------------------------------------------- 130 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 9 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 5.6195 0.1427 0.0872 STANDARD DEV: 591.1 1.0600 0.0212 0.0136 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 6.1023 0.1359 0.0922 STANDARD DEV: 30.6 1.2194 0.0262 0.0214 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 5.2703 0.1194 0.0828 STANDARD DEV: 498.5 1.0885 0.0281 0.0206 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 6.2610 0.1653 0.0843 STANDARD DEV: 583.0 0.3168 0.0192 0.0001 --------------------------------------------------------------- 131 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 10 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 9.9312 0.2516 0.1580 STANDARD DEV: 591.1 3.9350 0.0984 0.0783 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 15.1513 0.3375 0.2279 STANDARD DEV: 30.6 3.7198 0.0822 0.0552 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 12.1860 0.2728 0.1915 STANDARD DEV: 498.5 4.6403 0.1022 0.0740 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 10.2960 0.2777 0.1396 STANDARD DEV: 583.0 2.1680 0.1029 0.0360 --------------------------------------------------------------- 132 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 11 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 9.6432 0.2453 0.1540 STANDARD DEV: 591.1 3.8907 0.1000 0.0788 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 16.1067 0.3588 0.2425 STANDARD DEV: 30.6 4.2181 0.0930 0.0641 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 11.5203 0.2584 0.1810 STANDARD DEV: 498.5 3.9126 0.0867 0.0633 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 9.8880 0.2667 0.1340 STANDARD DEV: 583.0 2.0633 0.0983 0.0344 --------------------------------------------------------------- 133 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 12 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 0.2205 0.0058 0.0035 STANDARD DEV: 591.1 0.0617 0.0023 0.0011 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 0.1677 0.0037 0.0025 STANDARD DEV: 30.6 0.0422 0.0009 0.0007 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 0.3340 0.0074 0.0053 STANDARD DEV: 498.5 0.1502 0.0028 0.0025 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 0.2435 0.0063 0.0033 STANDARD DEV: 583.0 0.0700 0.0008 0.0008 --------------------------------------------------------------- 134 TABLE 33 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 13 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 3947.5 0.2225 0.0058 0.0035 STANDARD DEV: 591.1 0.0654 0.0023 0.0011 --------------------------------------------------------------- M2 ------------------------------- NUMBER IN GROUP: 3 3 3 3 MEAN: 4486.7 0.1850 0.0041 0.0028 STANDARD DEV: 30.6 0.0305 0.0007 0.0004 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 4 4 4 4 MEAN: 4447.5 0.3135 0.0070 0.0049 STANDARD DEV: 498.5 0.1146 0.0023 0.0019 --------------------------------------------------------------- M4 ------------------------------- NUMBER IN GROUP: 5 2 2 2 MEAN: 3925.0 0.2150 0.0054 0.0029 STANDARD DEV: 583.0 0.1273 0.0024 0.0016 --------------------------------------------------------------- 135 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 1 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 0.3990 0.0074 0.0061 STANDARD DEV: 240.4 0.0438 0.0005 0.0000 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 0.2770 0.0072 0.0041 STANDARD DEV: 618.7 0.0509 0.0024 0.0004 --------------------------------------------------------------- 136 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 2 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 0.2465 0.0045 0.0037 STANDARD DEV: 240.4 0.0389 0.0005 0.0002 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 0.1920 0.0050 0.0029 STANDARD DEV: 618.7 0.0382 0.0018 0.0003 --------------------------------------------------------------- 137 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 3 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 65.7115 1.2128 1.0000 STANDARD DEV: 240.4 7.2811 0.0807 0.0000 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 66.8240 1.7330 1.0000 STANDARD DEV: 618.7 6.1559 0.4292 0.0000 --------------------------------------------------------------- 138 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 4 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 2.6085 0.0481 0.0397 STANDARD DEV: 240.4 0.2963 0.0033 0.0001 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 1.6595 0.0425 0.0250 STANDARD DEV: 618.7 0.0955 0.0043 0.0037 --------------------------------------------------------------- 139 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 5 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 2.7290 0.0505 0.0418 STANDARD DEV: 240.4 0.0382 0.0015 0.0040 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 1.5995 0.0415 0.0239 STANDARD DEV: 618.7 0.1605 0.0106 0.0002 --------------------------------------------------------------- 140 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 6 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 9.0575 0.1680 0.1396 STANDARD DEV: 240.4 1.0232 0.0264 0.0310 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 5.8750 0.1493 0.0890 STANDARD DEV: 618.7 0.9942 0.0018 0.0231 --------------------------------------------------------------- 141 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 7 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 8.8620 0.1644 0.1365 STANDARD DEV: 240.4 0.9730 0.0253 0.0299 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 5.6370 0.1438 0.0852 STANDARD DEV: 618.7 0.6449 0.0062 0.0175 --------------------------------------------------------------- 142 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 8 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 90.1885 1.6697 1.3831 STANDARD DEV: 240.4 2.4816 0.1201 0.1910 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 66.0390 1.6898 0.9961 STANDARD DEV: 618.7 5.2212 0.1331 0.1699 --------------------------------------------------------------- 143 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 9 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 8.4993 0.1570 0.1295 STANDARD DEV: 240.4 0.7025 0.0060 0.0037 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 5.4815 0.1409 0.0824 STANDARD DEV: 618.7 0.0955 0.0197 0.0090 --------------------------------------------------------------- 144 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 10 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 16.0235 0.2975 0.2474 STANDARD DEV: 240.4 2.4600 0.0587 0.0649 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 10.0800 0.2598 0.1514 STANDARD DEV: 618.7 0.1329 0.0443 0.0120 --------------------------------------------------------------- 145 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 11 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 16.3235 0.3030 0.2519 STANDARD DEV: 240.4 2.3553 0.0570 0.0638 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 10.2370 0.2627 0.1542 STANDARD DEV: 618.7 0.4454 0.0300 0.0209 --------------------------------------------------------------- 146 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 12 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 0.2545 0.0047 0.0039 STANDARD DEV: 240.4 0.0134 0.0005 0.0006 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 0.3165 0.0085 0.0046 STANDARD DEV: 618.7 0.1732 0.0057 0.0022 --------------------------------------------------------------- 147 TABLE 34 Summary of Organ Weight Data Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 13 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 -------------------------------- TERMINAL ORGAN ORGAN-TO- ORGAN-TO- SEX DOSE BODY WT WEIGHT BODY WT BRAIN WT GROUP (g) (g) (%) RATIO --------------------------------------------------------------- M1 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 5410.0 0.2570 0.0048 0.0039 STANDARD DEV: 240.4 0.0127 0.0004 0.0006 --------------------------------------------------------------- M3 ------------------------------- NUMBER IN GROUP: 2 2 2 2 MEAN: 3932.5 0.3000 0.0081 0.0044 STANDARD DEV: 618.7 0.1937 0.0062 0.0025 --------------------------------------------------------------- 148 TABLE 35 Incidence of Macroscopic Observations Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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: 2 2 NOT REMARKABLE: 1 2 ADHESION(S) ** END OF LIST 10 151 TABLE 37 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 1 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 --- 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 0102 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 2 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 --- 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 ------------------------------------------------------------------------ -=- -=- -=- -=- TESTIS (TE) .......................................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 4 --ATROPHY/DEGENERATION 0001 BONE, FEMUR (FE) ..................................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 MARROW, FEMUR (FM) ................................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 MARROW, STERNUM (SE) ................................. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 BONE, STERNUM (SB) ................................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 4 5 EYE (EY) ............................................. NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 4 3 3 5 --INFILTRATE, LYMPHOHISTIOCYTIC, CONJUNCTIVAL 0010 153 TABLE 37 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 3 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 --- 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 2032 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 4 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 --- 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 0120 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 5 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 --- 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 0021 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 6 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 --- 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 7 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 --- 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 Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 8 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 --- 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 0020 EPIDIDYMIDES (EP) .................................... NUMBER EXAMINED: 4 3 4 5 NOT REMARKABLE: 3 3 4 4 --INFILTRATE, LYMPHOHISTIOCYTIC 1001 159 TABLE 37 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 27 Sacrifice PAGE: 9 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 --- 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 Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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: 2 2 NOT REMARKABLE: 1 0 --CORTICAL TISSUE, EXTRACAPSULAR 12 ADRENAL, MEDULLA (MA) ................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 LIVER (LI) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 1 --FIBROSIS, CAPSULAR/SUBCAPSULAR --INFILTRATE, LYMPHOHISTIOCYTIC --PIGMENT, HEPATOCELLULAR 10 21 10 SPLEEN (SP) .......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 PANCREAS (PA) ........................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 TESTIS (TE) .......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 161 TABLE 38 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------ -=- -=- BONE, FEMUR (FE) ..................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 MARROW, FEMUR (FM) ................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 MARROW, STERNUM (SE) ................................. NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 BONE, STERNUM (SB) ................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 EYE (EY) ............................................. NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 2 --INFILTRATE, LYMPHOHISTIOCYTIC, CHOROIDAL 20 BRAIN (BR) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 1 --INFILTRATE, LYMPHOHISTIOCYTIC --MINERALIZATION 21 10 162 TABLE 38 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------ -=- -=- KIDNEY (KD) .......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 2 --INFILTRATE, LYMPHOHISTIOCYTIC --INFLAMMATION, VASCULAR --THICKENING, INTIMAL, VASCULAR 10 10 10 LUNG (LU) ............................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 0 --PIGMENT 22 HEART (HT) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 1 --INFILTRATE, LYMPHOHISTIOCYTIC 01 GALLBLADDER (GB) ..................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 THYMUS (TH) .......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 2 --INVOLUTION 20 163 TABLE 38 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------ -=- -=- LN, MESENTERIC (MS) .................................. NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 2 --PIGMENT 20 TRACHEA (TR) ......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 2 --INFLAMMATION, ACUTE 10 ESOPHAGUS (ES) ....................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 THYROID (TY) ......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 1 --CYST, GLANDULAR 01 PARATHYROID (PT) ..................................... NUMBER EXAMINED: 1 2 NOT REMARKABLE: 1 1 --INFILTRATE, LYMPHOHISTIOCYTIC 01 AORTA (AO) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 1 --THICKENING, INTIMAL 01 164 TABLE 38 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 5 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------ -=- -=- PITUITARY (PI) ....................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 SALIV GL, MANDIB (SG) ................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 0 --INFILTRATE, LYMPHOHISTIOCYTIC 22 MUSCLE, SKELETAL (SM) ................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 1 --PARASITISM 01 SPINAL CORD (SC) ..................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 NERVE, SCIATIC (SN) .................................. NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 2 --FIBROSIS --INFILTRATE, LYMPHOHISTIOCYTIC 10 10 STOMACH, GL (ST) ..................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 1 --INFLAMMATION, CHRONIC 01 165 TABLE 38 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 6 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------ -=- -=- ** FROM PREVIOUS PAGE ** STOMACH, GL (ST) ..................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 1 --PARASITISM --THICKENING, INTIMAL, VASCULAR 01 10 DUODENUM (DU) ........................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 2 --PARASITISM 10 JEJUNUM (JE) ......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 ILEUM (IL) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 CECUM (CE) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 COLON (CO) ........................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 1 2 --INFLAMMATION, EOSINOPHILIC 10 166 TABLE 38 Incidence of Microscopic Observations Covance 6329-231 3M T-6889.3 Week 40 Recovery Sacrifice PAGE: 7 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------ -=- -=- RECTUM (RE) .......................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 SKIN (SK) ............................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 MAMMARY, MALE (MM) ................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 URINARY BLADDER (UB) ................................. NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 0 --INFILTRATE, LYMPHOHISTIOCYTIC 22 PROSTATE (PR) ........................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 0 0 --INFILTRATE, LYMPHOHISTIOCYTIC 22 SEMINAL VESICLES (SV) ................................ NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 EPIDIDYMIDES (EP) .................................... NUMBER EXAMINED: 2 2 NOT REMARKABLE: 2 2 ** END OF LIST 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 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 Covance 6329-231 3M T-6889.3 202 Covance 6329-231 3M T-6889.3 203 Covance 6329-231 3M T-6889.3 204 Covance 6329-231 3M T-6889.3 205 Covance 6329-231 3M T-6889.3 206 Covance 6329-231 3M T-6889.3 207 Covance 6329-231 3M T-6889.3 208 Covance 6329-231 3M T-6889.3 209 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 PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL NUMBER -----I05709 I05714 I05715 I05718 I05720 I05725 I05702 I05706 I05717 I05721 I05707 I05708 I05710 I05712 I05716 I05719 I05703 I05704 I05711 I05713 I05722 I05724 DOSE GROUP ----- 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 ----- T T T U U T T T T M T T T U U T T T T T T M TYPE OF DEATH ----------SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED UNSCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED SCHEDULED UNSCHEDULED DESCRIPTION OF DEATH ------------------------TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE FIRST POST-RECOV SAC FIRST POST-RECOV SAC TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE UNSCHEDULED DEATH TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE FIRST POST-RECOV SAC FIRST POST-RECOV SAC TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE TERMINAL SACRIFICE UNSCHEDULED DEATH DATE OF DEATH -------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 DAY OF STUDY ------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 5 212 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M1 DOSE: 0 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05709 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 EXCRETION FEW FECES 31 SKIN & PELAGE ALOPECIA HEAD-CRANIAL LIMB-FRONT-RIGHT 62 9-10, 15-17, 23, 27 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 36 I05714 T 27 DISCHARGE VOMITUS CONTAINING FOOD 142 EXCRETION FEW FECES 56 LIQUID FECES 102 MUCOID FECES 31 NORMAL NO REMARKABLE OBSERVATIONS 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 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M1 DOSE: 0 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ (CONTINUED FROM PREVIOUS PAGE) I05714 T 27 QUALITATIVE FOOD CONSUMPTION LOW 1, 22, 24, 54-56, 58, 123 I05715 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 EXCRETION FEW FECES 31, 36 NORMAL NO REMARKABLE OBSERVATIONS 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 I05718 U 40 DISCHARGE VOMITUS CONTAINING FOOD 275 EXCRETION FEW FECES 31, 50-51 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 50-51 214 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M1 DOSE: 0 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05720 U 40 DISCHARGE VOMITUS CONTAINING FOOD 275 EXCRETION FEW FECES LIQUID FECES NON-FORMED FECES 6 5-6 4, 7-11, 14-15, 17 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 6, 185, 263 I05725 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 SKIN & PELAGE ALOPECIA LIMB-FRONT-LEFT LIMBS-FRONT 107, 113, 116 62, 64 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 1, 122 215 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M2 DOSE: 3 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05702 T 27 NORMAL NO REMARKABLE OBSERVATIONS 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 I05706 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 10-12, 14 I05717 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 14, 16, 34, 45, 53, 55, 57, 67, 73, 86, 88, 110-111, 114 216 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 5 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M2 DOSE: 3 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05721a M 20 APPEARANCE LIMITED USE LIMBS-HIND 137 PARALYSIS HIND QUARTERS 137 BEHAVIOR ATAXIC <UNSPECIFIED> HYPOACTIVE <UNSPECIFIED> 137 136-137 EXCRETION FEW FECES LIQUID FECES MUCOID FECES NON-FORMED FECES 29-30, 125, 127, 129, 133-137 16, 18, 27-28 18, 29 18, 21-24, 27-28, 32, 54 NORMAL NO REMARKABLE OBSERVATIONS 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120 QUALITATIVE FOOD CONSUMPTION LOW NONE 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 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 6 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M3 DOSE: 10 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05707 T 27 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 18 I05708 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 NORMAL NO REMARKABLE OBSERVATIONS 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 I05710 T 27 SKIN & PELAGE SCAB(S) PERI-ORBITAL-LEFT PERI-ORBITAL-RIGHT 9-10 23, 27 NORMAL NO REMARKABLE OBSERVATIONS 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 I05712 U 40 DISCHARGE VOMITUS CONTAINING FOOD 184, 275 EXCRETION NO FECES 275 NON-FORMED FECES 1 218 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 7 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M3 DOSE: 10 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ (CONTINUED FROM PREVIOUS PAGE) I05712 U 40 NORMAL NO REMARKABLE 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 QUALITATIVE FOOD CONSUMPTION LOW 185 I05716 U 40 DISCHARGE VOMITUS CONTAINING FOOD 55, 184 NORMAL NO REMARKABLE OBSERVATIONS 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 QUALITATIVE FOOD CONSUMPTION LOW 13, 21, 185, 187, 276 I05719 T 27 EXCRETION LIQUID FECES NON-FORMED FECES 140-141, 175-176, 178-180 34, 142-143, 147-151, 174 SKIN & PELAGE OTHER 140-143C, 147-151C, 155C, 161-162C, 164-165C, 169C, 174-180C 183-184C NORMAL NO REMARKABLE OBSERVATIONS 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120 127, 134 219 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 8 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M3 DOSE: 10 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ (CONTINUED FROM PREVIOUS PAGE) I05719 T 27 QUALITATIVE FOOD CONSUMPTION LOW 1, 3, 23-24, 29, 33, 55, 177-180 220 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 9 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY STUDY KEYWORD ANIMAL GROUP DAY WK QUALIFIER FREE-TEXT COMMENT ------------------------------------------------------------------------------------------------------------------------------------ I05719 M3 140 20 TO 184 27 SKIN & PELAGE OTHER APPROX 1CM X 1CM MASS ON FACE NEXT TO NOSE 221 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 10 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M4 DOSE: 20 MG/KG/DAYb ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05703c T 27 APPEARANCE THIN 76-83 DISCHARGE VOMITUS CONTAINING FOOD 77, 184 EXCRETION DISCOLORED URINE BROWN IN COLOR FEW FECES LIQUID FECES NO FECES 79 11, 45-46, 50-52, 54-60, 62, 64-66, 68, 70, 72, 75, 77-80, 82-83 76 43, 61, 71 NORMAL NO REMARKABLE OBSERVATIONS 1, 22, 29, 36, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148 155, 162, 169, 176, 183-184 QUALITATIVE FOOD CONSUMPTION LOW NONE 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 I05704 T 27 DISCHARGE VOMITUS CONTAINING FOOD 184 EXCRETION FEW FECES 11-12 NORMAL NO REMARKABLE OBSERVATIONS 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 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M4 DOSE: 20 MG/KG/DAYb ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ (CONTINUED FROM PREVIOUS PAGE) I05704 T 27 NORMAL NO REMARKABLE OBSERVATIONS 120, 127, 134, 141, 148, 155, 162, 169, 176, 183-184 I05711d T QUALITATIVE FOOD CONSUMPTION LOW 27 EXCRETION FEW FECES NO FECES 11-12, 15 11-12, 29-30, 38-46, 121-122, 124-125, 127 31, 35-36 NORMAL NO REMARKABLE OBSERVATIONS 1, 22, 50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120, 134, 141 148, 155, 162, 169, 176, 183-184 QUALITATIVE FOOD CONSUMPTION LOW NONE 7-12, 14-16, 18, 28-30, 32-34, 38-45, 120-122, 124-125, 127-128 158 35-37 I05713 T 27 EXCRETION FEW FECES LIQUID FECES NON-FORMED FECES 45, 49-51, 66, 70, 134, 136, 138 34-36 32-33, 37-38, 46 NORMAL NO REMARKABLE OBSERVATIONS 1, 8, 22, 29, 57, 71, 78, 85, 92, 99, 106, 113, 120, 127, 141 148, 155, 162, 169, 176, 183-184 QUALITATIVE FOOD CONSUMPTION LOW 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 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 12 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M4 DOSE: 20 MG/KG/DAYb ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05722e T 27 APPEARANCE THIN 65-69, 71-76 EXCRETION FEW FECES NO FECES 29, 35-36, 45-46, 49-52, 56-62, 69 43, 53-55, 64-66 SKIN & PELAGE SCAR LIP(S) 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 NORMAL NO REMARKABLE OBSERVATIONS 8, 22, 78, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155 162, 169, 176, 183-184 QUALITATIVE FOOD CONSUMPTION LOW NONE 3, 10-12, 15, 28-30, 32-35, 37-39, 42-43, 45-48, 50-59, 61-62 67-69 60, 64-66 I05724 M 5 BEHAVIOR HYPOACTIVE <UNSPECIFIED> 28-29 EXCRETION FEW FECES NO FECES 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 Covance 6329-231 3M T-6889.3 Individual Clinical Observations PAGE: 13 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M4 DOSE: 20 MG/KG/DAYb ANIMAL DEATH WK OF KEYWORD DAYS 1-277 - OBSERVED DURING THE DAYS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ (CONTINUED FROM PREVIOUS PAGE) I05724 M 5 SKIN & PELAGE COLD TO TOUCH BODY-ENTIRE 29 NORMAL NO REMARKABLE OBSERVATIONS 1, 22 QUALITATIVE FOOD CONSUMPTION LOW NONE 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 Covance 6329-231 3M T-6889.3 Individual Ophthalmic Observations PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M1 DOSE: 0 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05709 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05714 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05715 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05718 U 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27, 40 I05720 U 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27, 40 I05725 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 226 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Ophthalmic Observations PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M2 DOSE: 3 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05702 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05706 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05717 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05721 M 20 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1 227 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Ophthalmic Observations PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M3 DOSE: 10 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05707 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05708 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05710 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05712 U 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27, 40 I05716 U 40 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27, 40 I05719 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 228 Appendix 2 Covance 6329-231 3M T-6889.3 Individual Ophthalmic Observations PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ CATEGORY GROUP: M4 DOSE: 20 MG/KG/DAY ANIMAL DEATH WK OF KEYWORD WEEKS -1, 27, AND 40 - OBSERVED DURING THE WEEKS LISTED BELOW; NUMBER CODE DEATH QUALIFIER 'C' - COMMENTS LISTED AT END OF OBSERVATIONS ------------------------------------------------------------------------------------------------------------------------------------ I05703 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05704 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05711 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05713 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05722 T 27 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -1, 27 I05724 M 5 NO VISIBLE LESIONS NO VISIBLE LESIONS EYES -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 Covance 6329-231 3M T-6889.3 Individual Body Weight Data (kg) PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEKa WEEKb WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER -2 -1 -1 1 2 3 4 5 6 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 I05717 3.8 3.8 3.7 3.8 3.8 3.8 3.9 3.9 4.1 4.1 I05721c 3.9 3.8 3.7 3.7 3.8 3.8 3.8 3.6 3.8 3.9 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 Covance 6329-231 3M T-6889.3 Individual Body Weight Data (kg) PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEKa WEEKb WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER -2 -1 -1 1 2 3 4 5 6 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. Beginning 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). 232 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Data (kg) PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 8 9 10 11 12 13 14 15 16 17 ------------------------------------------------------------------------------------------------------------------------------------ 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 4.5 4.5 3.3 3.1 3.2 3.2 3.3 3.3 3.3 3.4 3.4 3.4 4.0 4.0 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 4.7 4.7 4.3 4.4 4.4 4.4 4.4 4.4 4.4 4.5 4.6 4.6 3.5 3.6 3.6 3.6 3.6 3.7 3.6 3.7 3.7 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 4.2 4.3 4.3 4.2 4.2 4.2 4.2 4.3 4.2 4.2 4.2 4.3 4.1 4.2 4.2 4.2 4.2 4.3 4.2 4.3 4.3 4.4 4.0 4.2 4.1 4.2 4.1 4.1 4.2 4.3 4.2 4.2 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 4.1 4.2 4.2 4.3 4.2 4.3 4.3 4.3 4.3 4.4 4.8 5.0 4.9 5.0 5.0 5.1 5.0 5.1 5.1 5.1 3.4 3.4 3.3 3.5 3.4 3.5 3.4 3.6 3.6 3.6 3.4 3.4 3.5 3.4 3.4 3.6 3.5 3.5 3.6 3.6 3.8 3.8 3.7 3.8 3.8 3.9 3.8 3.8 3.9 4.0 GROUP: MALE 4 - 20 MG/KG/DAY I05703f 3.1 3.1 2.9 2.9 2.6 2.8 2.9 3.2 3.3 3.4 I05704 4.1 4.1 4.1 4.1 4.1 4.2 4.1 4.2 4.2 4.2 I05711g 3.3 3.6 3.7 3.9 3.9 3.9 3.9 3.9 3.9 3.9 I05713 3.6 3.7 3.6 3.6 3.6 3.7 3.6 3.5 3.5 3.6 I05722h 3.4 3.3 3.0 3.1 3.3 3.6 3.6 4.0 4.1 4.3 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). 233 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Data (kg) PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 18 19 20 21 22 23 24 25 26 27 ------------------------------------------------------------------------------------------------------------------------------------ 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 4.8 4.8 3.4 3.4 3.5 3.5 3.5 3.5 3.6 3.6 3.7 3.7 4.0 4.0 4.0 4.0 4.0 4.1 4.0 4.1 4.1 4.1 4.8 4.9 4.9 5.0 5.0 5.1 5.1 5.1 5.2 5.3 4.7 4.7 4.7 4.7 4.7 4.8 4.8 4.8 4.9 5.0 3.8 3.8 3.8 3.8 3.8 3.9 3.9 3.9 4.0 4.0 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 4.8 4.8 4.5 4.5 4.5 4.5 4.5 4.6 4.6 4.6 4.7 4.8 4.3 4.4 4.4 4.5 4.5 4.5 4.6 4.6 4.7 4.7 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 4.3 4.4 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.6 4.6 5.2 5.2 5.2 5.2 5.2 5.2 5.3 5.3 5.4 5.4 3.6 3.6 3.7 3.7 3.7 3.7 3.8 3.7 3.8 3.8 3.7 3.6 3.6 3.6 3.6 3.7 3.7 3.7 3.7 3.8 4.1 4.2 4.2 4.2 4.3 4.4 4.5 4.5 4.6 4.6 GROUP: MALE 4 - 20 MG/KG/DAY I05703f 3.5 3.5 3.5 3.5 3.5 3.6 3.5 3.6 3.6 3.7 I05704 4.3 4.3 4.3 4.3 4.3 4.4 4.5 4.4 4.5 4.6 I05711g 3.9 3.7 3.8 3.9 3.9 4.0 4.0 4.0 4.0 4.1 I05713 3.7 3.6 3.4 3.4 3.4 3.6 3.7 3.5 3.5 3.6 I05722h 4.5 4.5 4.6 4.7 4.7 4.8 4.8 4.8 4.9 4.9 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). 234 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Data (kg) Recovery PAGE: 5 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 28 29 30 31 32 33 34 35 36 37 ------------------------------------------------------------------------------------------------------------------------------------ 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 5.8 5.8 4.9 5.0 5.0 5.0 5.1 5.0 5.3 5.3 5.3 5.4 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 3.9 3.9 3.7 3.8 3.6 3.6 3.7 3.7 3.7 3.7 3.7 3.7 235 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Data (kg) Recovery PAGE: 6 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK NUMBER 38 39 40 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 1 - 0 MG/KG/DAY I05718 I05720 5.8 5.9 5.9 5.4 5.5 5.5 GROUP: MALE 3 - 10 MG/KG/DAY I05712 I05716 3.9 4.0 4.0 3.7 3.7 3.7 236 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Change Data (kg) PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 1 - 0 MG/KG/DAY I05709 0.0 0.1 0.1 0.1 -0.1 0.1 -0.2 -0.1 0.0 0.1 I05714 -0.1 0.1 0.1 -0.1 0.1 -0.1 0.1 -0.2 0.1 0.0 I05715 0.0 0.0 0.1 0.0 0.1 0.0 0.0 0.0 0.0 0.0 I05718 -0.1 0.1 0.1 -0.1 0.0 0.1 -0.2 0.1 0.1 0.1 I05720 -0.1 0.1 0.2 0.1 0.0 0.2 -0.1 0.1 0.0 0.0 I05725 -0.1 0.2 0.1 -0.1 0.2 0.0 0.0 0.1 0.0 0.0 GROUP: MALE 2 - 3 MG/KG/DAY I05702 0.0 0.0 0.1 -0.1 0.2 0.0 -0.1 0.1 -0.1 0.1 I05706 -0.1 -0.1 0.0 -0.1 0.1 -0.1 0.1 -0.1 0.0 0.0 I05717 0.0 0.0 0.1 0.0 0.2 0.0 0.0 0.1 0.0 0.0 I05721a 0.1 0.0 0.0 -0.2 0.2 0.1 0.1 0.2 -0.1 0.1 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 0.0 0.1 0.0 0.2 -0.1 0.1 0.0 0.2 -0.1 0.2 0.0 0.0 0.2 0.0 -0.1 0.2 0.1 0.0 0.0 0.0 0.1 0.1 -0.1 0.1 0.0 0.2 -0.1 0.1 0.0 0.0 0.1 0.0 0.1 0.2 -0.1 0.1 0.0 -0.1 0.2 0.0 0.1 -0.1 0.0 -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 Covance 6329-231 3M T-6889.3 Individual Body Weight Change Data (kg) PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 4 - 20 MG/KG/DAYb I05703 -0.1 0.0 0.2 -0.1 0.1 0.0 -0.2 0.0 -0.2 0.0 I05704 -0.1 0.0 0.2 0.0 0.0 0.2 -0.2 0.0 0.0 0.0 I05711c -0.3 -0.1 0.2 -0.2 -0.1 -0.2 0.0 0.3 0.1 0.2 I05713 -0.2 -0.1 0.1 -0.1 0.0 0.1 -0.2 0.1 -0.1 0.0 I05722d -0.2 0.1 0.0 0.0 0.0 0.0 -0.4 -0.1 -0.3 0.1 I05724 -0.2 -0.4 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. Beginning 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). 238 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Change Data (kg) PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 11-12 12-13 13-14 14-15 15-16 16-17 17-18 18-19 19-20 20-21 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 1 - 0 MG/KG/DAY I05709 -0.1 0.1 0.0 0.0 -0.1 0.0 0.1 -0.1 0.1 0.0 I05714 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.1 0.0 I05715 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 I05718 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.1 0.0 0.1 I05720 0.0 0.0 0.0 0.1 0.1 0.0 0.1 0.0 0.0 0.0 I05725 0.0 0.1 -0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 GROUP: MALE 2 - 3 MG/KG/DAY I05702 0.0 0.1 -0.1 0.1 0.0 0.1 0.0 0.1 0.0 0.0 I05706 0.0 0.1 -0.1 0.0 0.0 0.1 0.2 0.0 0.0 0.0 I05717 0.0 0.1 -0.1 0.1 0.0 0.1 -0.1 0.1 0.0 0.1 I05721 -0.1 0.0 0.1 0.1 -0.1 0.0 0.1 -0.1 -0.4 GROUP: MALE 3 - 10 MG/KG/DAY I05707 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 I05708 -0.1 0.1 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.0 I05710 0.0 0.1 -0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 I05712 -0.1 0.1 -0.1 0.2 0.0 0.0 0.0 0.0 0.1 0.0 I05716 0.0 0.2 -0.1 0.0 0.1 0.0 0.1 -0.1 0.0 0.0 I05719 0.0 0.1 -0.1 0.0 0.1 0.1 0.1 0.1 0.0 0.0 GROUP: MALE 4 - 20 MG/KG/DAY I05703e -0.3 0.2 0.1 0.3 0.1 0.1 0.1 0.0 0.0 0.0 I05704 0.0 0.1 -0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 I05711c 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.2 0.1 0.1 I05713 0.0 0.1 -0.1 -0.1 0.0 0.1 0.1 -0.1 -0.2 0.0 I05722d 0.2 0.3 0.0 0.4 0.1 0.2 0.2 0.0 0.1 0.1 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). 239 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Change Data (kg) PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK TOTAL NUMBER 21-22 22-23 23-24 24-25 25-26 26-27 1-27 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 1 - 0 MG/KG/DAY I05709 I05714 I05715 I05718 I05720 I05725 0.0 0.0 0.0 0.1 0.1 0.0 0.3 0.0 0.0 0.1 0.0 0.1 0.0 0.5 0.0 0.1 -0.1 0.1 0.0 0.0 0.3 0.0 0.1 0.0 0.0 0.1 0.1 0.9 0.0 0.1 0.0 0.0 0.1 0.1 1.1 0.0 0.1 0.0 0.0 0.1 0.0 0.8 GROUP: MALE 2 - 3 MG/KG/DAY I05702 I05706 I05717 0.0 0.1 0.1 0.1 0.1 0.0 0.9 0.0 0.1 0.0 0.0 0.1 0.1 0.3 0.0 0.0 0.1 0.0 0.1 0.0 0.9 GROUP: MALE 3 - 10 MG/KG/DAY I05707 I05708 I05710 I05712 I05716 I05719 0.0 0.1 0.1 -0.1 0.1 -0.1 0.3 0.0 0.0 0.0 0.0 0.1 0.0 0.7 0.0 0.0 0.1 0.0 0.1 0.0 1.1 0.0 0.0 0.1 -0.1 0.1 0.0 0.4 0.0 0.1 0.0 0.0 0.0 0.1 0.3 0.1 0.1 0.1 0.0 0.1 0.0 0.9 GROUP: MALE 4 - 20 MG/KG/DAY I05703e 0.0 0.1 -0.1 0.1 0.0 0.1 0.5 I05704 0.0 0.1 0.1 -0.1 0.1 0.1 0.6 I05711c 0.0 0.1 0.0 0.0 0.0 0.1 0.1 I05713 0.0 0.2 0.1 -0.2 0.0 0.1 -0.4 I05722d 0.0 0.1 0.0 0.0 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 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Change Data (kg) Recovery PAGE: 5 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK WEEK NUMBER 27-28 28-29 29-30 30-31 31-32 32-33 33-34 34-35 35-36 36-37 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 1 - 0 MG/KG/DAY I05718 0.0 0.1 -0.1 0.0 0.2 0.1 0.1 0.0 0.1 0.0 I05720 -0.1 0.1 0.0 0.0 0.1 -0.1 0.3 0.0 0.0 0.1 GROUP: MALE 3 - 10 MG/KG/DAY I05712 0.0 0.0 -0.1 0.1 0.0 0.1 0.0 0.0 0.0 0.0 I05716 -0.1 0.1 -0.2 0.0 0.1 0.0 0.0 0.0 0.0 0.0 241 Appendix 3 Covance 6329-231 3M T-6889.3 Individual Body Weight Change Data (kg) Recovery PAGE: 6 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ ANIMAL WEEK WEEK WEEK TOTAL NUMBER 37-38 38-39 39-40 27-40 ------------------------------------------------------------------------------------------------------------------------------------ GROUP: MALE 1 - 0 MG/KG/DAY I05718 I05720 0.0 0.1 0.0 0.6 0.0 0.1 0.0 0.5 GROUP: MALE 3 - 10 MG/KG/DAY I05712 I05716 0.0 0.1 0.0 0.2 0.0 0.0 0.0 -0.1 242 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 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 7.15 12.7 42.1 59.0 17.8 30.1 576 .7 6.13 12.3 41.6 67.8 20.1 29.6 499 .8 7.04 12.0 43.6 62.0 17.0 27.4 362 1.3 6.46 12.4 41.7 64.5 19.3 29.9 785 .5 6.32 12.4 41.2 65.2 19.6 30.0 475 .3 6.52 12.7 42.5 65.2 19.5 29.9 380 .4 50 9.8 19.2 313 49 10.1 19.2 261 92 10.0 17.4 299 32 9.4 16.1 285 19 9.3 18.8 236 26 9.7 18.6 320 6.60 12.4 42.1 63.9 18.9 29.5 513 .7 .405 .26 .85 3.05 1.21 1.03 155.0 .36 6 6 6 6 6 6 6 6 45 26.3 6 9.7 .32 6 18.2 1.23 6 286 32.2 6 Dose Level: 3 Dosage Unit: mg/kg/day 6.36 12.1 41.2 64.9 19.0 29.3 416 .8 7.17 13.3 45.2 63.1 18.6 29.5 677 1.1 6.70 11.8 39.6 59.0 17.6 29.7 599 .8 7.30 14.5 49.7 68.1 19.9 29.2 555 .1 51 9.7 16.5 317 79 9.5 27.7 331 54 9.6 17.7 309 7 9.5 20.2 422 6.88 12.9 43.9 63.8 18.8 29.4 562 .7 .433 1.23 4.51 3.80 .95 .22 109.5 .42 4 4 4 4 4 4 4 4 48 29.9 4 9.6 .10 4 20.5 5.03 4 345 52.3 4 Dose Level: 10 Dosage Unit: mg/kg/day 6.99 11.9 40.4 57.8 17.0 29.4 489 .6 6.77 12.2 40.6 60.0 18.1 30.1 474 1.2 6.43 12.9 43.5 67.7 20.0 29.6 692 .4 6.32 11.2 37.6 59.4 17.7 29.9 482 1.0 6.91 12.2 39.6 57.2 17.6 30.8 550 .2 6.80 12.3 40.9 60.2 18.0 30.0 404 .5 42 9.7 16.2 309 81 9.5 19.7 309 26 9.4 19.5 346 63 9.6 17.8 280 14 9.9 19.7 315 34 9.7 16.7 329 6.70 12.1 40.4 60.4 18.1 30.0 515 .6 .268 .56 1.92 3.78 1.02 .48 98.3 .38 6 6 6 6 6 6 6 6 43 24.7 6 9.6 .18 6 18.3 1.59 6 315 22.2 6 244 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 7.31 13.3 44.9 61.4 18.2 29.7 635 1.1 6.46 10.8 36.8 57.0 16.7 29.3 437 .7 6.73 12.4 41.4 61.5 18.5 30.0 639 .5 7.07 11.8 40.3 57.0 16.7 29.2 494 .5 6.72 12.3 42.6 63.4 18.3 28.8 468 .7 6.74 12.5 41.1 61.0 18.6 30.4 608 .8 80 9.8 20.0 310 45 9.6 20.6 324 34 9.9 18.8 330 35 10.4 27.0 339 47 9.4 17.1 308 54 9.5 16.6 216 6.84 12.2 41.2 60.2 17.8 29.6 547 .7 .302 .83 2.68 2.63 .89 .58 90.6 .22 6 6 6 6 6 6 6 6 49 16.9 6 9.8 .36 6 20.0 3.76 6 304 44.9 6 245 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 13.1 5.6 6.6 .7 .2 .0 42 50 6 2 0 9.2 4.9 3.4 .7 .1 .0 53 37 8 1 0 15.5 6.6 7.8 .9 .2 .0 42 50 6 1 0 15.0 6.5 6.5 1.6 .3 .1 43 43 11 2 1 17.4 9.5 6.0 1.5 .3 .1 54 35 9 2 0 5.8 2.8 2.5 .5 .0 .0 48 43 8 1 0 12.7 6.0 5.5 1.0 .2 .0 47 43 8 2 0 4.36 2.21 2.06 .46 .12 .05 5.5 6.3 1.9 .5 .4 6 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 10.6 5.2 4.9 .4 .0 .0 50 46 4 0 0 15.5 8.2 5.9 1.2 .2 .1 53 38 7 1 1 10.1 3.2 6.2 .5 .3 .0 32 61 5 2 0 6.7 1.6 4.0 1.0 .0 .0 24 60 16 0 1 10.7 4.6 5.2 .8 .1 .0 40 51 8 1 0 3.62 2.84 1.00 .39 .15 .05 14.0 11.2 5.5 1.0 .6 4 4 4 4 4 4 4 4 4 4 4 Dose Level: 10 Dosage Unit: mg/kg/day 7.7 2.4 4.4 .8 .1 .0 31 58 10 1 0 8.2 2.8 4.0 .9 .4 .0 34 49 11 6 0 15.0 9.4 4.3 .9 .3 .1 63 29 6 2 1 10.7 7.0 3.1 .4 .1 .0 66 30 4 1 0 13.9 6.3 6.0 1.4 .1 .1 45 44 10 1 0 12.9 6.3 5.6 1.0 .1 .0 49 43 7 1 0 11.4 5.7 4.6 .9 .2 .0 48 42 8 2 0 3.03 2.66 1.07 .32 .13 .05 14.4 11.2 2.8 2.0 .4 6 6 6 6 6 6 6 6 6 6 6 246 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 11.3 6.1 4.2 .6 .3 .0 54 38 6 2 0 13.8 6.9 6.1 .5 .3 .0 50 44 4 2 0 14.1 6.8 5.8 1.1 .3 .0 48 41 8 2 0 11.5 6.4 2.9 1.9 .2 .2 55 25 16 2 1 11.9 7.2 4.4 .3 .0 .0 60 37 3 0 0 17.2 10.4 5.1 1.3 .4 .1 60 30 7 2 0 13.3 7.3 4.8 1.0 .2 .0 54 36 7 2 0 2.25 1.57 1.17 .60 .14 .08 5.0 7.1 4.6 .8 .4 6 6 6 6 6 6 6 6 6 6 6 247 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 - - - - - I05714 - - - - - I05715 - - - - - I05718 - - - - - I05720 - - - - - I05725 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 a - - - - - I05706 - - - - - I05717 - - - - - I05721 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 - - - - - I05708 - - - - - I05710 - - - - - I05712 - - - - - I05716 - - - - - I05719 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 - - - - - I05704 - - - - - I05711 - - - - - I05713 - - - - - I05722 - - - - - I05724 - - - - - a Plasmodium was observed. 248 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 7.25 13.3 43.4 59.8 18.4 30.7 521 .5 36 10.0 19.6 339 6.42 12.7 43.7 68.1 19.8 29.1 438 .2 13 10.0 20.3 234 6.87 11.8 43.4 63.2 17.1 27.1 273 .3 21 10.2 17.8 293 7.29 13.8 46.9 64.3 18.9 29.3 502 .3 22 10.2 20.5 745 6.28 12.2 41.4 65.9 19.5 29.5 424 .2 13 9.5 19.3 314 6.76 13.6 45.3 67.1 20.2 30.1 411 .3 20 10.1 21.5 290 6.81 12.9 44.0 64.7 19.0 29.3 428 .3 .415 .80 1.88 3.01 1.12 1.23 87.8 .11 6 6 6 6 6 6 6 6 21 8.4 6 10.0 .26 6 19.8 1.26 6 369 187.4 6 Dose Level: 3 Dosage Unit: mg/kg/day 6.06 11.6 38.9 64.3 19.1 29.7 402 .1 6 9.9 17.9 308 6.60 12.7 41.3 62.6 19.2 30.6 626 .2 13 10.2 29.0 325 6.93 12.4 41.8 60.4 17.9 29.6 525 .4 28 9.5 19.1 338 6.29 12.9 43.1 68.5 20.5 29.9 444 .1 6 9.8 21.6 365 6.47 12.4 41.3 64.0 19.2 30.0 499 .2 .378 .57 1.76 3.43 1.06 .45 98.7 .14 4 4 4 4 4 4 4 4 13 10.4 4 9.8 .29 4 21.9 4.98 4 334 24.0 4 Dose Level: 10 Dosage Unit: mg/kg/day 7.21 12.4 42.7 59.3 17.2 29.0 384 .1 7 10.1 18.0 306 6.58 12.3 41.5 63.0 18.7 29.7 459 .3 20 9.7 20.3 277 6.29 12.8 43.2 68.6 20.3 29.7 644 .2 13 10.0 18.5 311 6.33 11.4 38.1 60.1 18.0 29.9 353 .2 13 9.9 19.0 229 7.03 12.4 41.1 58.5 17.6 30.1 469 .1 7 10.0 20.9 278 6.96 12.8 44.1 63.4 18.4 29.0 370 .1 7 10.7 23.5 343 6.73 12.3 41.8 62.2 18.4 29.6 446 .2 .387 .51 2.11 3.73 1.09 .46 107.9 .08 6 6 6 6 6 6 6 6 11 5.2 6 10.1 .34 6 20.0 2.02 6 291 38.8 6 a Dosing was started on Day 17. 249 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 a MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 7.24 13.3 44.1 60.9 18.4 30.1 750 .7 51 10.1 23.8 325 6.24 10.9 37.1 59.4 17.5 29.5 360 .2 12 10.2 21.5 336 6.80 12.9 41.9 61.6 19.0 30.9 598 .0 0 9.3 21.6 349 6.47 11.7 38.2 59.1 18.1 30.6 474 .4 26 10.5 31.4 451 6.41 11.6 43.0 67.1 18.1 27.0 396 .4 26 9.7 21.9 915 6.21 11.7 39.1 63.0 18.8 29.9 361 .1 6 NO COAG NO COAG UTD 6.63 12.1 40.9 61.6 18.2 29.6 516 .3 .396 .99 3.06 3.23 .54 1.56 159.7 .26 5 5 5 5 5 5 5 5 23 19.1 5 10.0 .47 5 24.0 4.22 5 475 250.9 5 a Unscheduled sacrifice on Day 29. 250 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 19.5 13.6 4.9 .8 .2 .0 70 25 4 1 0 11.0 6.7 3.5 .7 .1 .0 61 32 6 0 0 14.3 7.6 5.8 .6 .1 .0 53 41 4 1 0 15.3 9.6 3.9 1.8 .0 .0 63 25 12 0 0 9.6 3.9 5.0 .4 .2 .0 41 53 4 2 0 7.0 2.3 4.3 .3 .1 .0 33 61 5 1 0 12.8 7.3 4.6 .8 .1 .0 54 40 6 1 0 4.48 4.05 .83 .54 .08 .00 14.1 15.0 3.1 .8 .0 6 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 8.8 3.8 4.5 .4 .0 .0 43 52 5 0 0 9.4 4.8 3.9 .6 .0 .0 51 42 7 0 0 8.6 1.6 5.3 1.1 .6 .1 18 62 13 7 1 4.3 1.1 2.9 .3 .0 .0 25 67 7 1 0 7.8 2.8 4.2 .6 .2 .0 34 56 8 2 0 2.34 1.76 1.01 .36 .30 .05 15.3 11.1 3.5 3.4 .5 4 4 4 4 4 4 4 4 4 4 4 Dose Level: 10 Dosage Unit: mg/kg/day 7.6 3.2 4.0 .4 .1 .0 42 52 5 1 0 8.6 3.3 4.1 .8 .3 .0 38 48 10 4 0 16.7 12.5 3.4 .5 .2 .0 75 20 3 1 0 8.0 5.0 2.4 .5 .0 .0 62 30 6 1 0 12.8 6.8 4.7 1.0 .2 .1 53 36 8 2 0 10.7 5.4 4.7 .6 .1 .0 50 43 6 1 0 10.7 6.0 3.9 .6 .2 .0 53 38 6 2 0 3.51 3.45 .88 .23 .10 .04 13.6 11.9 2.4 1.2 .0 6 6 6 6 6 6 6 6 6 6 6 a Dosing was started on Day 17. 251 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 a MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 7.6 3.3 3.3 .9 .2 .0 43 43 12 2 0 10.0 4.4 4.8 .6 .2 .0 44 48 6 2 0 7.3 2.7 3.6 .9 .1 .0 37 49 12 2 0 9.2 4.7 3.3 1.0 .1 .0 51 36 11 1 1 11.8 5.0 3.9 2.8 .0 .0 43 33 24 0 0 16.4 13.7 2.4 .1 .1 .0 84 15 1 1 0 9.2 4.0 3.8 1.2 .1 .0 44 42 13 1 0 1.84 .98 .62 .88 .08 .00 5.0 7.1 6.6 .9 .4 5 5 5 5 5 5 5 5 5 5 5 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 Dosage Unit: mg/kg/day I05709 - - - - - I05714 - - - - - I05715 - - - - - I05718 - - - - - I05720 - - - - - I05725 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 - - - - - I05706 - - - - - I05717 - - - - - I05721 b - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 - - - - - I05708 - - - - - I05710 - - - - - I05712 - - - - - I05716 - - - - - I05719 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 - - - - - I05704 - - - - - I05711 - - - - - I05713 - - - - - I05722 - - - - - I05724 a - - - - - 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 7.21 13.0 42.1 58.4 18.0 30.9 461 .3 22 10.5 19.7 338 5.54 11.1 36.9 66.6 20.0 30.1 631 .2 11 9.9 21.0 361 6.79 11.6 41.2 60.7 17.2 28.3 230 .3 20 10.4 17.4 253 6.28 11.9 39.7 63.2 19.0 30.1 725 .3 19 9.7 17.5 530 7.10 13.6 47.1 66.3 19.1 28.8 342 .3 21 9.7 18.8 273 7.04 13.7 45.5 64.7 19.5 30.1 361 .2 14 10.6 20.9 301 6.66 12.5 42.1 63.3 18.8 29.7 458 .3 .641 1.10 3.75 3.24 1.03 .97 187.7 .05 6 6 6 6 6 6 6 6 18 4.4 6 10.1 .41 6 19.2 1.59 6 343 100.1 6 Dose Level: 3 Dosage Unit: mg/kg/day 6.19 11.9 40.1 64.8 19.2 29.6 385 .5 31 10.2 19.6 286 7.25 13.8 44.2 60.9 19.0 31.3 599 .2 14 10.2 26.8 338 7.05 12.5 42.1 59.8 17.7 29.6 502 .4 28 9.6 18.1 294 6.52 13.6 45.7 70.1 20.8 29.7 383 .6 39 9.8 22.5 356 6.75 13.0 43.0 63.9 19.2 30.0 467 .4 .485 .90 2.45 4.66 1.27 .83 104.0 .17 4 4 4 4 4 4 4 4 28 10.4 4 10.0 .30 4 21.7 3.83 4 318 33.9 4 Dose Level: 10 Dosage Unit: mg/kg/day 7.03 12.1 40.8 58.0 17.3 29.8 397 .1 7 10.4 17.6 309 6.53 12.1 40.3 61.8 18.5 29.9 403 .2 13 9.8 19.9 248 6.27 12.7 41.2 65.7 20.3 30.9 602 .4 25 10.0 18.1 287 6.75 12.0 40.5 60.0 17.8 29.7 347 .2 14 10.2 19.4 191 7.02 12.5 40.9 58.2 17.8 30.6 434 .1 7 10.4 20.8 216 7.06 12.9 43.5 61.7 18.2 29.6 431 .2 14 10.5 24.5 290 6.78 12.4 41.2 60.9 18.3 30.1 436 .2 .323 .37 1.17 2.86 1.05 .53 87.3 .11 6 6 6 6 6 6 6 6 13 6.6 6 10.2 .27 6 20.0 2.47 6 257 46.5 6 254 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 7.47 13.7 46.1 61.7 18.4 29.8 623 .2 15 10.7 24.6 166 6.01 10.6 35.1 58.4 17.6 30.2 325 .3 18 9.8 21.7 279 6.66 12.8 41.9 62.9 19.2 30.6 558 .1 7 9.8 20.0 309 6.88 11.7 39.6 57.6 17.1 29.6 410 .1 7 10.8 26.4 245 6.73 12.0 41.8 62.2 17.9 28.8 374 .1 7 12.1 26.1 87 6.77 12.0 40.6 60.0 17.8 29.6 433 .2 .600 1.28 4.58 2.31 .54 .59 131.4 .10 4 4 4 4 4 4 4 4 12 5.6 4 10.8 .95 4 24.7 2.15 4 194 85.7 4 a Dosing was stopped on Day 43; not included in the statistical analyses. 255 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 10.8 3.9 6.2 .4 .2 .0 36 58 4 2 0 13.6 8.9 3.9 .6 .1 .0 66 29 5 1 0 10.9 6.5 4.1 .2 .1 .0 59 38 2 1 0 11.7 5.4 5.1 1.0 .1 .1 46 44 8 1 0 11.3 5.7 4.0 1.3 .2 .1 50 36 12 2 1 8.1 4.1 3.3 .5 .1 .0 51 41 6 1 0 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 6 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 13.7 9.0 3.9 .7 .0 .1 66 28 5 0 0 11.2 5.9 4.4 .8 .0 .1 53 40 7 0 0 11.7 5.2 5.0 .7 .7 .0 45 43 6 6 0 5.5 1.9 3.2 .4 .0 .0 34 58 7 1 0 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 4 4 4 4 4 4 4 4 4 4 4 Dose Level: 10 Dosage Unit: mg/kg/day 8.4 4.5 3.1 .7 .1 .0 54 37 8 1 0 8.9 3.9 3.9 .8 .2 .0 44 44 9 3 0 11.7 7.4 3.3 .6 .3 .1 64 28 5 3 1 11.1 8.3 2.4 .4 .1 .0 74 21 4 1 0 11.8 5.8 4.7 1.0 .3 .1 49 40 8 2 0 8.7 3.6 4.4 .5 .1 .0 41 51 6 2 1 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 6 6 6 6 6 6 6 6 6 6 6 256 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- 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 9 2 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 9 2 0 1.96 1.44 .95 .13 .17 .00 11.4 7.0 3.2 2.2 .6 4 4 4 4 4 4 4 4 4 4 4 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 - - - - - I05714 - - - - - I05715 - - - - - I05718 - - - - - I05720 - - - - - I05725 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 - - - - - I05706 - - - - - I05717 - - - - - I05721 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 - - - - - I05708 - - - - - I05710 - - - - - I05712 - - - - - I05716 - - - - - I05719 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 - - - - - I05704 - - - - - I05711 a - - - - - I05713 - - - - - I05722 - - - - - 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 6.82 12.3 40.1 58.8 18.0 30.6 441 .3 20 10.5 18.3 299 6.15 12.6 42.6 69.2 20.4 29.5 477 .1 6 10.3 19.8 256 7.14 11.9 44.1 61.8 16.7 27.0 238 .4 29 10.2 16.6 267 6.95 12.8 43.9 63.2 18.4 29.1 680 .3 21 10.2 16.6 288 7.05 13.5 46.5 65.9 19.2 29.1 378 .3 21 9.9 18.5 281 7.11 14.2 48.1 67.6 19.9 29.5 397 .4 28 10.2 19.1 279 6.87 12.9 44.2 64.4 18.8 29.1 435 .3 .372 .84 2.83 3.88 1.35 1.18 145.1 .11 6 6 6 6 6 6 6 6 21 8.2 6 10.2 .19 6 18.1 1.31 6 278 15.2 6 Dose Level: 3 Dosage Unit: mg/kg/day 6.00 11.5 37.9 63.1 19.1 30.3 381 .4 24 10.4 17.1 287 7.06 13.4 43.4 61.4 19.0 30.9 632 .1 7 10.5 23.4 329 6.82 12.2 41.5 60.8 17.9 29.5 599 .7 48 10.0 18.3 258 6.55 13.3 45.7 69.7 20.3 29.1 405 .1 7 10.3 19.8 370 6.61 12.6 42.1 63.8 19.1 30.0 504 .3 .455 .91 3.30 4.08 .98 .81 129.5 .29 4 4 4 4 4 4 4 4 22 19.4 4 10.3 .22 4 19.6 2.73 4 311 49.0 4 Dose Level: 10 Dosage Unit: mg/kg/day 6.84 12.3 40.1 58.6 18.0 30.7 388 .1 7 10.6 17.1 301 6.59 12.3 40.5 61.4 18.6 30.4 431 .2 13 10.0 19.7 241 6.24 12.8 42.0 67.3 20.5 30.5 487 .7 44 10.1 17.6 263 6.95 12.2 41.9 60.2 17.5 29.1 383 .3 21 10.1 19.2 224 7.33 13.0 42.2 57.6 17.7 30.7 448 .1 7 10.6 20.2 233 7.00 12.6 43.1 61.5 18.0 29.2 387 .4 28 10.8 21.5 310 6.82 12.5 41.6 61.1 18.4 30.1 421 .3 .374 .32 1.12 3.41 1.10 .75 42.1 .23 6 6 6 6 6 6 6 6 20 14.3 6 10.4 .34 6 19.2 1.64 6 262 36.2 6 259 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 6.30 11.8 39.3 62.4 18.7 30.0 587 1.8 113 9.7 22.4 274 6.06 10.7 35.1 57.9 17.6 30.5 356 .2 12 10.1 21.0 285 6.92 13.3 42.9 62.0 19.2 31.0 510 .1 7 10.5 19.5 283 6.85 11.5 39.3 57.3 16.7 29.2 456 .1 7 10.8 23.9 204 6.59 12.6 44.8 68.0 19.0 28.0 436 .3 20 10.2 19.7 221 6.46 11.1 37.2 57.6 17.2 29.8 406 .2 .559 .57 2.97 .42 .64 .92 70.7 .07 2 2 2 2 2 2 2 2 10 3.5 2 10.4 .49 2 22.5 2.05 2 244 57.3 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 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 10.4 4.1 5.8 .4 .1 .0 40 55 4 1 0 13.5 7.9 4.6 .7 .2 .0 59 34 5 2 0 10.2 3.9 5.8 .4 .1 .0 38 57 4 1 0 10.5 3.8 6.1 .4 .2 .0 36 58 4 2 0 11.8 4.2 5.7 1.4 .4 .1 36 48 12 3 1 8.5 2.8 5.0 .7 .0 .0 33 58 8 1 0 10.8 4.4 5.5 .7 .2 .0 40 52 6 2 0 1.68 1.76 .57 .39 .14 .04 9.4 9.4 3.3 .8 .4 6 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 10.0 5.7 3.8 .3 .1 .1 57 38 3 1 1 11.1 6.0 4.2 .8 .1 .0 54 38 7 1 0 13.0 3.7 6.8 .6 1.8 .0 28 52 5 14 0 6.5 1.9 3.8 .5 .3 .0 30 58 7 5 0 10.2 4.3 4.6 .6 .6 .0 42 46 6 5 0 2.73 1.91 1.45 .21 .82 .05 15.4 10.1 1.9 6.1 .5 4 4 4 4 4 4 4 4 4 4 4 Dose Level: 10 Dosage Unit: mg/kg/day 9.2 4.8 3.4 .7 .1 .0 53 38 8 1 0 7.3 2.4 3.8 .8 .3 .0 32 53 10 4 0 15.0 9.5 4.0 .8 .5 .1 64 27 6 3 0 9.5 6.2 2.8 .4 .1 .0 65 29 5 1 0 11.0 3.8 5.3 1.3 .4 .1 35 48 12 4 1 10.5 5.4 4.6 .4 .1 .0 52 44 4 1 0 10.4 5.4 4.0 .7 .2 .0 50 40 8 2 0 2.58 2.42 .88 .33 .18 .05 14.0 10.4 3.1 1.5 .4 6 6 6 6 6 6 6 6 6 6 6 261 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 10.0 4.0 4.2 1.4 .3 .0 40 42 14 4 0 9.8 5.3 3.8 .5 .1 .0 54 39 5 1 0 16.0 9.8 4.3 1.5 .4 .1 61 27 9 2 0 5.6 1.5 3.3 .7 .1 .0 26 59 12 2 1 8.2 1.8 5.3 .7 .4 .0 22 64 8 5 0 7.7 3.4 3.6 .6 .1 .0 40 49 8 2 0 2.97 2.69 .35 .14 .00 .00 19.8 14.1 4.9 .7 .7 2 2 2 2 2 2 2 2 2 2 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. 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 - - - - - I05714 - - - - - I05715 - - - - - I05718 - - - - - I05720 - - - - - I05725 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 - - - - - I05706 - - - - - I05717 - - - - - I05721 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 - - - - - I05708 - - - - - I05710 - - - - - I05712 - - - - - I05716 - - - - - I05719 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a - - - - - I05704 - - - - - I05711 b - - - - - I05713 - - - - - I05722 c - - - - - 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 7.11 12.8 39.7 55.7 18.0 32.2 488 .4 6.33 12.6 40.8 64.5 19.9 30.8 390 .9 6.83 11.7 39.6 58.0 17.2 29.6 245 .6 6.67 12.7 40.9 61.3 19.0 31.1 630 1.2 6.56 12.7 41.1 62.5 19.3 30.9 346 .7 6.63 13.4 41.7 63.0 20.3 32.2 352 .0 28 10.3 19.3 313 57 10.2 19.0 233 41 10.3 16.0 277 80 10.2 16.3 300 46 9.4 17.3 261 0 10.7 19.3 251 6.69 12.6 40.6 60.8 19.0 31.1 408 .6 .263 .55 .82 3.33 1.17 .98 133.8 .41 6 6 6 6 6 6 6 6 42 27.0 6 10.2 .43 6 17.9 1.53 6 272 30.2 6 Dose Level: 3 Dosage Unit: mg/kg/day 5.86 11.5 36.4 62.1 19.6 31.6 366 .8 47 10.1 17.3 302 7.23 13.2 41.2 57.0 18.3 32.1 617 .9 65 10.5 26.3 287 7.63 13.4 45.2 59.2 17.6 29.8 564 .9 69 9.6 18.1 293 5.26 10.7 35.4 67.2 20.3 30.2 399 .3 16 10.2 22.1 702 6.91 12.7 40.9 59.4 18.5 31.2 516 .9 .928 1.04 4.41 2.56 1.01 1.21 132.3 .06 3 3 3 3 3 3 3 3 60 11.7 3 10.1 .45 3 20.6 4.98 3 294 7.5 3 Dose Level: 10 Dosage Unit: mg/kg/day 7.20 12.1 39.2 54.5 16.8 30.9 409 .5 6.24 11.7 36.6 58.6 18.7 32.0 383 .6 6.38 12.9 42.0 65.9 20.2 30.6 609 1.3 6.43 11.7 36.5 56.7 18.2 32.1 322 .2 7.36 13.0 40.3 54.7 17.6 32.1 432 .2 6.93 12.5 40.2 58.0 18.1 31.2 338 .4 36 10.2 17.1 315 37 10.7 21.9 243 83 10.1 18.9 273 13 10.3 18.8 216 15 10.1 20.0 226 28 10.4 21.1 393 6.76 12.3 39.1 58.1 18.3 31.5 416 .5 .470 .57 2.19 4.19 1.14 .67 103.5 .41 6 6 6 6 6 6 6 6 35 25.5 6 10.3 .23 6 19.6 1.74 6 278 66.9 6 a Unscheduled sacrifice on Day 137. 264 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 7.12 13.4 41.7 58.6 18.8 32.2 610 .8 57 10.3 19.4 244 5.58 9.8 30.8 55.2 17.6 32.0 250 .3 17 10.3 20.6 273 7.00 13.1 40.6 58.0 18.6 32.2 428 .3 21 10.1 19.1 338 6.77 11.4 37.1 54.9 16.9 30.8 505 .0 0 10.4 30.5 175 6.81 12.9 42.3 62.1 18.9 30.4 406 .2 14 9.5 17.2 293 6.18 10.6 33.9 55.0 17.2 31.4 378 .2 .841 1.13 4.45 .21 .49 .85 180.3 .21 2 2 2 2 2 2 2 2 8 12.0 2 10.3 .07 2 25.5 7.00 2 224 69.3 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 ------ 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 10.5 4.1 5.8 .4 .3 .0 39 55 4 2 0 11.5 6.5 3.5 1.3 .1 .1 57 30 11 1 1 10.3 4.3 5.6 .3 .1 .0 42 54 2 1 0 15.7 8.0 6.0 1.3 .3 .1 51 38 8 2 0 12.1 5.2 5.3 1.2 .3 .1 43 44 10 2 1 5.1 2.0 2.6 .5 .0 .0 39 51 9 1 0 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 6 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 11.0 5.9 4.4 .5 .1 .0 54 40 5 1 0 12.0 5.1 5.5 1.2 .1 .1 43 46 10 1 1 14.4 2.0 8.9 2.2 1.2 .1 14 62 15 9 1 9.4 6.6 1.7 1.1 .0 .0 70 18 12 0 0 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 3 3 3 3 3 3 3 3 3 3 3 Dose Level: 10 Dosage Unit: mg/kg/day 8.2 4.0 3.0 .9 .1 .1 50 37 11 1 1 8.2 3.4 3.4 .8 .4 .1 42 42 10 5 1 12.9 6.9 4.5 1.0 .4 .1 54 35 8 3 0 9.3 5.6 3.0 .5 .1 .1 60 32 6 1 1 13.5 4.9 7.0 1.1 .5 .1 36 52 8 4 1 6.0 1.6 3.6 .6 .1 .0 26 61 10 2 1 9.7 4.4 4.1 .8 .3 .1 45 43 9 3 1 2.93 1.84 1.53 .23 .19 .04 12.5 11.2 1.8 1.6 .4 6 6 6 6 6 6 6 6 6 6 6 a Unscheduled sacrifice on Day 137. 266 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- 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 2 2 2 2 2 2 2 2 2 2 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. 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 - - - - - I05714 - - - - - I05715 - - - - - 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 I05707 - - - - - I05708 - - - - - I05710 - - - - - I05712 - - - - - I05716 - - - - - I05719 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a - - - - - I05704 - - - - - 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 7.14 13.8 44.8 62.7 19.4 30.9 667 .7 50 10.0 17.3 343 6.87 13.6 44.8 65.3 19.8 30.3 317 .6 41 9.5 18.6 267 7.00 13.7 44.8 64.0 19.6 30.6 492 .6 .191 .14 .00 1.84 .28 .42 247.5 .07 2 2 2 2 2 2 2 2 46 6.4 2 9.8 .35 2 17.9 .92 2 305 53.7 2 Dose Level: 10 Dosage Unit: mg/kg/day 6.77 11.9 39.1 57.7 17.6 30.5 335 .5 34 10.1 19.2 203 7.32 12.8 40.5 55.3 17.5 31.5 446 .1 7 10.4 21.1 224 7.04 12.3 39.8 56.5 17.5 31.0 390 .3 .389 .64 .99 1.70 .07 .71 78.5 .28 2 2 2 2 2 2 2 2 20 19.1 2 10.2 .21 2 20.2 1.34 2 214 14.8 2 269 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Hematology Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 24.7 11.6 10.7 1.7 .5 .2 47 43 7 2 1 12.6 3.3 7.0 1.7 .5 .1 26 55 14 4 1 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 2 2 2 2 2 2 2 2 2 2 2 Dose Level: 10 Dosage Unit: mg/kg/day 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 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 2 2 2 2 2 2 2 2 2 2 2 270 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 - - - - - I05720 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 - - - - - I05716 - - - - - 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 6.94 13.4 43.8 63.0 19.2 30.5 664 .4 28 10.0 16.7 326 6.90 13.7 45.0 65.2 19.9 30.5 394 .3 21 9.5 19.2 320 6.92 13.6 44.4 64.1 19.6 30.5 529 .4 .028 .21 .85 1.56 .49 .00 190.9 .07 2 2 2 2 2 2 2 2 24 4.9 2 9.8 .35 2 18.0 1.77 2 323 4.2 2 Dose Level: 10 Dosage Unit: mg/kg/day 6.96 12.1 40.2 57.7 17.4 30.2 352 .3 21 10.1 19.0 217 7.54 13.3 41.4 54.9 17.6 32.1 490 .0 0 10.2 19.3 237 7.25 12.7 40.8 56.3 17.5 31.2 421 .2 .410 .85 .85 1.98 .14 1.34 97.6 .21 2 2 2 2 2 2 2 2 10 14.8 2 10.2 .07 2 19.2 .21 2 227 14.1 2 272 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Hematology Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 17.9 7.7 8.5 1.2 .3 .2 43 48 6 2 1 13.8 3.7 7.8 1.5 .7 .1 27 56 11 5 1 15.8 5.7 8.2 1.4 .5 .2 35 52 8 4 1 2.90 2.83 .49 .21 .28 .07 11.3 5.7 3.5 2.1 .0 2 2 2 2 2 2 2 2 2 2 2 Dose Level: 10 Dosage Unit: mg/kg/day 7.1 3.5 2.7 .7 .1 .0 50 39 10 1 0 14.3 5.4 7.1 1.2 .5 .1 38 50 9 3 1 10.7 4.4 4.9 1.0 .3 .0 44 44 10 2 0 5.09 1.34 3.11 .35 .28 .07 8.5 7.8 .7 1.4 .7 2 2 2 2 2 2 2 2 2 2 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 - - - - - I05720 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 - - - - - I05716 - - - - - 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC X106/L -------- HGB G/DL -------- HCT % -------- MCV FL -------- MCH PG -------- MCHC % -------- PLT X103/L -------- RETIC % -------- RETIC X103/L PT SEC -------- -------- PTT SEC -------- FBR MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 7.47 14.6 46.3 61.9 19.5 31.5 756 .1 7 10.2 17.3 408 6.46 12.9 40.8 63.1 20.0 31.7 411 .2 13 9.4 18.0 653 6.96 13.8 43.6 62.5 19.8 31.6 584 .2 .714 1.20 3.89 .85 .35 .14 244.0 .07 2 2 2 2 2 2 2 2 10 4.2 2 9.8 .57 2 17.6 .49 2 530 173.2 2 Dose Level: 10 Dosage Unit: mg/kg/day 6.97 12.4 40.7 58.3 17.8 30.5 408 .7 49 10.1 17.8 282 7.43 13.1 41.6 56.0 17.6 31.4 484 .0 0 10.4 18.8 319 7.20 12.8 41.1 57.2 17.7 31.0 446 .4 .325 .49 .64 1.63 .14 .64 53.7 .49 2 2 2 2 2 2 2 2 24 34.6 2 10.2 .21 2 18.3 .71 2 300 26.2 2 275 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Covance 6329-231 3M T-6889.3 Appendix 4 Individual Clinical Hematology Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS WBC X103/L -------- N-SEG X103/L -------- LYMPH X103/L -------- MONO X103/L -------- EOSIN X103/L -------- BASO X103/L -------- N-SEG% -------- LYMPH% -------- MONO% -------- EOSIN% -------- BASO% -------- Dose Level: 0 Dosage Unit: mg/kg/day 18.1 9.2 6.9 1.7 .2 .1 51 38 10 1 1 12.0 5.6 4.4 1.6 .2 .1 47 37 14 2 1 15.0 7.4 5.6 1.6 .2 .1 49 38 12 2 1 4.31 2.55 1.77 .07 .00 .00 2.8 .7 2.8 .7 .0 2 2 2 2 2 2 2 2 2 2 2 Dose Level: 10 Dosage Unit: mg/kg/day 19.1 13.3 4.4 1.3 .1 .0 70 23 7 0 0 13.2 4.9 6.9 1.3 .1 .0 37 52 10 1 0 16.2 9.1 5.6 1.3 .1 .0 54 38 8 0 0 4.17 5.94 1.77 .00 .00 .00 23.3 20.5 2.1 .7 .0 2 2 2 2 2 2 2 2 2 2 2 276 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 - - - - - I05720 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 - - - - - I05716 - - - - - Covance 6329-231 3M T-6889.3 277 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 85 20 1.3 8.9 4.3 4.6 .0 11 132 28 96 15 1.3 8.8 5.0 3.8 .0 7 128 48 83 15 1.2 10.4 5.3 5.1 .1 8 122 30 122 16 1.2 9.4 5.0 4.4 .0 12 237 57 82 12 .9 9.7 4.4 5.3 .0 8 127 33 87 17 1.3 9.3 5.1 4.2 .1 10 138 40 92 16 1.2 9.4 4.8 4.6 .0 15.3 2.6 .15 .58 .40 .56 .05 6 6 6 6 6 6 6 9 147 2.0 44.3 6 6 39 11.3 6 Dose Level: 3 Dosage Unit: mg/kg/day 78 13 1.0 10.0 5.2 4.8 .3 4 154 45 78 19 1.3 9.2 5.2 4.0 .0 11 120 55 96 15 1.0 8.3 4.9 3.4 .0 9 176 61 100 8 1.2 10.2 5.6 4.6 .0 15 247 38 88 14 1.1 9.4 5.2 4.2 .1 10 174 50 11.7 4.6 .15 .87 .29 .63 .15 4.6 53.7 10.2 4 4 4 4 4 4 4 4 4 4 Dose Level: 10 Dosage Unit: mg/kg/day 78 15 1.2 8.9 4.6 4.3 .1 11 127 50 77 16 1.2 8.7 4.8 3.9 .0 7 138 57 134 18 1.3 10.1 4.9 5.2 .1 9 139 65 85 17 1.2 8.6 5.1 3.5 .0 7 183 80 96 14 1.3 8.5 4.6 3.9 .1 10 125 33 84 14 1.3 9.8 5.0 4.8 .6 10 158 79 92 16 1.2 9.1 4.8 4.3 .2 21.5 1.6 .05 .68 .21 .63 .23 6 6 6 6 6 6 6 9 145 1.7 22.0 6 6 61 18.0 6 278 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 88 14 1.4 10.3 4.7 5.6 .1 3 153 61 79 17 1.0 9.9 5.1 4.8 .4 2 123 75 84 14 1.2 8.6 4.7 3.9 .3 9 165 42 75 12 .8 8.8 4.5 4.3 .1 6 106 43 78 17 1.2 8.7 4.8 3.9 .0 14 170 52 80 16 1.2 8.5 4.7 3.8 .1 11 122 66 81 15 1.1 9.1 4.8 4.4 .2 4.6 2.0 .21 .77 .20 .70 .15 6 6 6 6 6 6 6 8 140 4.7 26.3 6 6 56 13.2 6 279 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 37 42 290 109 28 36 699 99 24 35 442 151 52 96 300 107 34 44 288 181 36 93 711 111 4 88 376 3 102 320 2 128 552 4 160 917 3 100 420 4 294 514 26 194 24 175 25 266 21 387 13 191 41 210 35 9.6 6 58 28.8 6 455 202.2 6 126 32.4 6 3 145 516 .8 77.2 214.2 6 6 6 25 9.1 6 237 79.8 6 Dose Level: 3 Dosage Unit: mg/kg/day 44 38 333 101 42 52 514 159 40 33 762 141 35 43 616 138 3 146 391 4 121 358 9 134 428 4 166 332 31 202 69 166 46 214 4 149 40 3.9 4 42 8.1 4 556 180.3 4 135 24.3 4 5 142 377 2.7 19.1 41.6 4 4 4 38 27.3 4 183 30.4 4 Dose Level: 10 Dosage Unit: mg/kg/day 42 144 903 136 42 45 598 158 51 130 468 84 38 91 673 167 30 40 411 85 34 14 572 92 5 139 409 6 129 246 8 205 285 5 80 374 3 126 526 2 86 375 26 196 0 129 10 157 19 184 13 331 13 173 40 7.3 6 77 52.6 6 604 173.8 6 120 38.0 6 5 128 369 2.1 45.0 98.5 6 6 6 14 8.7 6 195 70.6 6 280 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 I05713 I05722 I05724 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 42 38 790 72 43 98 581 57 40 48 266 176 25 24 288 139 49 56 774 162 34 135 427 96 6 136 448 3 200 390 3 117 413 2 122 331 3 213 469 3 61 226 85 249 50 215 41 184 0 155 32 200 15 118 39 8.3 6 66 41.8 6 521 231.6 6 117 49.1 6 3 142 380 1.4 56.6 89.3 6 6 6 37 29.6 6 187 46.0 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 11.3 6.0 164 6.0 114 11.5 4.6 164 5.4 113 12.2 5.6 168 6.0 116 11.5 6.1 162 6.4 111 10.9 6.2 159 5.0 113 11.1 6.6 163 5.8 114 MEAN S.D. N 11.4 .45 6 5.8 .69 6 163 2.9 6 5.8 .50 6 114 1.6 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 11.6 6.9 166 6.3 112 11.5 6.8 164 5.8 112 10.5 5.9 154 4.9 109 12.2 7.1 166 6.7 109 MEAN S.D. N 11.4 .70 4 6.7 .53 4 162 5.7 4 5.9 .78 4 110 1.7 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 10.7 7.0 158 5.1 113 10.7 6.0 159 5.4 112 11.8 8.1 162 6.1 111 10.7 6.7 155 4.9 109 10.6 4.0 156 4.9 111 11.0 5.9 158 5.7 113 MEAN S.D. N 10.9 .45 6 6.3 1.37 6 158 2.4 6 5.4 .48 6 112 1.5 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 I05704 I05711 I05713 I05722 I05724 11.5 7.0 159 6.3 110 11.1 5.8 159 5.4 109 10.2 5.1 157 5.3 113 10.1 6.3 158 5.7 111 10.9 7.3 166 6.3 115 10.3 5.0 153 4.9 113 MEAN S.D. N 10.7 .57 6 6.1 .96 6 159 4.2 6 5.6 .56 6 112 2.2 6 Covance 6329-231 3M T-6889.3 283 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 72 17 1.2 8.6 4.2 4.4 .3 5 123 24 61 14 1.5 8.8 4.9 3.9 .0 10 153 40 63 19 1.4 10.2 5.1 5.1 .1 12 126 36 123 13 1.3 9.6 4.5 5.1 .3 8 174 89 81 13 1.0 9.2 4.2 5.0 .1 5 143 36 71 15 1.3 9.1 5.1 4.0 .1 10 154 36 78 15 1.3 9.2 4.7 4.6 .2 22.9 2.4 .17 .58 .42 .56 .12 6 6 6 6 6 6 6 8 146 2.9 19.1 6 6 44 22.9 6 Dose Level: 3 Dosage Unit: mg/kg/day 80 18 1.1 9.0 4.7 4.3 .3 64 18 1.2 8.8 5.2 3.6 .1 81 17 1.2 8.4 4.7 3.7 .0 85 9 1.5 8.2 5.0 3.2 .0 7 130 38 5 76 37 8 190 87 8 209 42 78 16 1.2 8.6 4.9 3.7 .1 9.3 4.4 .17 .37 .24 .45 .14 4 4 4 4 4 4 4 7 151 1.4 60.4 4 4 51 24.1 4 Dose Level: 10 Dosage Unit: mg/kg/day 70 16 1.4 8.9 4.9 4.0 .0 8 120 64 70 17 1.2 8.5 4.5 4.0 .1 8 148 82 81 16 1.5 9.4 4.7 4.7 .3 11 138 90 84 18 1.1 8.3 4.7 3.6 .3 16 190 116 69 19 1.2 8.1 4.5 3.6 .2 7 120 38 61 15 1.3 10.1 5.2 4.9 .1 9 137 65 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 26.6 6 6 6 6 6 6 6 6 6 6 a Dosing was started on Day 17. 284 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ 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 -------- TRIG MG/DL -------- Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 71 I05704 68 I05711 70 I05713 75 I05722 91 I05724 SH,a 53 19 1.5 9.3 4.9 4.4 .1 18 1.4 9.0 4.9 4.1 .2 17 1.2 8.1 4.1 4.0 .2 13 1.2 8.5 4.4 4.1 .0 15 1.4 9.1 4.2 4.9 .2 29 1.9 5.6 2.9 2.7 1.8 7 179 122 11 146 129 6 181 45 8 137 57 7 145 185 49 14 87 MEAN S.D. N 75 16 1.3 8.8 4.5 4.3 .1 9.3 2.4 .13 .49 .38 .37 .09 5 5 5 5 5 5 5 8 158 108 1.9 20.8 57.3 5 5 5 a Unscheduled sacrifice on Day 29. 285 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 40 34 364 121 33 53 810 96 27 45 632 151 30 40 411 80 32 39 363 154 45 80 882 122 6 78 429 5 112 368 2 124 550 3 70 838 4 93 446 6 211 675 25 213 24 202 43 244 31 426 34 192 78 251 34 6.7 6 48 16.7 6 577 232.0 6 121 29.3 6 4 115 551 1.6 51.3 177.3 6 6 6 39 20.2 6 255 87.1 6 Dose Level: 3 Dosage Unit: mg/kg/day 47 33 362 85 25 22 686 104 48 26 824 142 35 36 645 98 4 114 354 0 77 342 6 157 466 2 280 421 66 179 57 156 42 229 18 160 39 10.9 4 29 6.4 4 629 193.9 4 107 24.5 4 3 157 396 2.6 88.3 58.3 4 4 4 46 21.0 4 181 33.5 4 Dose Level: 10 Dosage Unit: mg/kg/day 41 80 906 113 47 52 682 149 38 74 587 80 28 65 811 134 33 42 452 78 31 19 785 90 2 162 391 5 187 272 3 151 272 2 88 335 2 161 565 1 113 397 30 181 9 145 12 144 27 164 28 369 7 177 36 7.0 6 55 22.6 6 704 165.2 6 107 29.6 6 2 144 372 1.4 36.4 109.2 6 6 6 19 10.6 6 197 85.8 6 a Dosing was started on Day 17. 286 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 36 32 696 67 I05704 41 60 738 60 I05711 31 31 188 130 I05713 23 29 300 133 I05722 33 28 931 98 I05724 SH,a 1974 1463 452 90 3 111 438 0 244 372 0 78 409 2 116 333 2 93 617 59 68850 180 34 241 79 203 27 176 0 142 30 264 64 95 MEAN S.D. N 33 6.6 5 36 13.5 5 571 313.5 5 98 34.1 5 1 128 434 1.3 66.4 109.7 5 5 5 34 28.5 5 205 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 10.5 6.3 157 5.8 117 11.5 6.1 160 6.3 112 11.0 6.1 162 5.2 112 11.5 4.1 158 5.7 109 10.5 5.4 153 5.9 115 10.9 7.5 161 6.0 113 MEAN S.D. N 11.0 .45 6 5.9 1.12 6 158 3.3 6 5.8 .37 6 113 2.8 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 10.0 5.3 150 5.1 111 I05706 10.3 4.9 152 5.6 111 I05717 10.1 6.9 152 5.3 112 I05721 a 10.0 6.0 156 5.2 109 MEAN S.D. N 10.1 .14 4 5.8 .88 4 152 2.5 4 5.3 .22 4 111 1.3 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 10.4 6.1 153 4.6 109 10.5 6.0 156 5.8 114 10.7 6.8 157 5.6 110 10.0 5.8 145 4.7 109 9.9 4.5 149 4.5 111 10.7 6.0 158 5.0 108 MEAN S.D. N 10.4 .34 6 5.9 .75 6 153 5.1 6 5.0 .55 6 110 2.1 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 Dosage Unit: mg/kg/day I05703 11.6 5.6 164 6.8 115 I05704 10.3 5.4 152 4.5 107 I05711 10.1 4.2 154 6.5 116 I05713 9.9 4.8 151 5.6 110 I05722 11.5 4.3 163 5.8 111 I05724 SH,a 8.0 4.9 133 5.6 89 MEAN S.D. N 10.7 .81 5 4.9 .63 5 157 6.2 5 5.8 .90 5 112 3.7 5 a Unscheduled sacrifice on Day 29. Covance 6329-231 3M T-6889.3 289 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 61 20 1.2 8.7 4.4 4.3 .5 4 126 30 67 18 1.0 8.5 4.1 4.4 .3 10 113 61 60 23 1.2 9.5 5.1 4.4 .7 6 139 33 115 14 1.3 9.1 4.1 5.0 .2 1 216 59 74 13 .9 9.3 4.7 4.6 .5 2 168 42 88 16 1.4 8.7 4.9 3.8 .5 9 143 35 78 17 1.2 9.0 4.6 4.4 .4 21.1 3.8 .19 .39 .42 .39 .18 6 6 6 6 6 6 6 5 151 3.7 36.9 6 6 43 13.5 6 Dose Level: 3 Dosage Unit: mg/kg/day 75 20 1.0 9.3 5.1 4.2 .3 2 132 46 62 23 1.2 9.0 5.3 3.7 .2 8 91 39 73 17 1.1 8.2 4.7 3.5 .4 14 191 83 62 13 1.0 9.1 5.1 4.0 .3 11 229 69 68 18 1.1 8.9 5.0 3.8 .3 7.0 4.3 .10 .48 .25 .31 .08 4 4 4 4 4 4 4 9 161 5.1 61.3 4 4 59 20.4 4 Dose Level: 10 Dosage Unit: mg/kg/day 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 71 17 1.2 8.6 4.6 4.0 .2 10.7 1.5 .16 .67 .35 .54 .10 6 6 6 6 6 6 6 9 158 3.2 46.2 6 6 76 27.4 6 290 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 81 19 1.4 8.9 3.8 5.1 .3 15 143 72 69 20 1.2 9.0 4.7 4.3 .3 12 138 116 61 18 1.2 8.5 4.5 4.0 .0 12 166 47 83 15 1.2 8.1 4.1 4.0 .0 2 139 56 71 27 1.1 6.4 2.9 3.5 .5 60 164 22 76 20 1.2 8.1 3.9 4.2 .3 22 146 66 7.0 5.0 .13 1.20 .75 .67 .21 25.8 12.2 39.0 4 4 4 4 4 4 4 4 4 4 a Dosing was stopped on Day 43; not included in the statistical analyses. 291 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 31 36 366 143 46 63 729 80 30 52 534 126 31 70 592 111 30 46 400 170 46 104 870 107 2 85 426 7 118 287 2 113 465 3 113 729 0 105 435 7 298 542 9 245 17 176 17 252 41 418 38 226 49 255 36 8.0 6 62 23.9 6 582 193.3 6 123 31.2 6 4 139 481 2.9 78.9 147.1 6 6 6 28 16.2 6 262 81.8 6 Dose Level: 3 Dosage Unit: mg/kg/day 45 46 386 104 21 21 576 113 34 31 757 140 40 82 727 128 2 114 400 113 237 2 121 415 187 228 0 143 455 36 260 2 147 316 6 155 35 10.4 4 45 26.7 4 612 169.9 4 121 15.9 4 2 131 396 1.0 16.2 58.5 4 4 4 86 81.3 4 220 45.4 4 Dose Level: 10 Dosage Unit: mg/kg/day 33 48 880 115 45 51 603 154 32 52 502 86 44 88 908 147 32 53 452 91 29 28 665 94 2 108 334 5 256 226 2 117 248 4 84 364 1 187 519 2 105 391 25 188 0 138 5 154 24 212 22 371 0 203 36 6.9 6 53 19.4 6 668 190.3 6 114 29.7 6 3 143 347 1.5 65.6 106.2 6 6 6 13 12.2 6 211 83.4 6 292 ANIMAL NUMBER ------ Group: 4 I05703 I05704 I05711 a I05713 I05722 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 85 90 496 70 37 49 591 57 38 42 186 167 22 34 255 175 419 595 595 136 11 114 418 2 167 330 2 137 351 2 113 262 20 1122 400 0 262 28 207 17 185 0 141 3 205 141 187.4 4 192 269.7 4 484 159.5 4 110 55.7 4 9 379 352 8.6 496.0 71.3 4 4 4 8 13.6 4 204 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 10.7 6.2 158 5.5 112 10.5 5.9 150 5.3 106 10.9 5.9 159 5.3 115 10.5 5.1 155 5.2 110 10.8 6.0 158 4.8 111 10.0 6.4 154 4.7 111 MEAN S.D. N 10.6 .32 6 5.9 .44 6 156 3.4 6 5.1 .31 6 111 2.9 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 10.5 5.8 156 4.9 109 10.8 5.2 153 5.2 114 10.1 6.2 150 5.0 110 10.8 7.7 159 5.1 111 MEAN S.D. N 10.6 .33 4 6.2 1.07 4 154 3.9 4 5.0 .13 4 111 2.2 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 10.7 5.7 151 4.3 110 9.9 5.9 150 4.5 111 10.2 5.9 149 5.5 112 10.8 6.1 151 4.5 112 10.1 4.4 147 4.3 111 10.7 6.4 152 4.6 105 MEAN S.D. N 10.4 .38 6 5.7 .69 6 150 1.8 6 4.6 .45 6 110 2.6 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 10.6 5.1 158 7.0 111 I05704 10.4 5.3 151 4.7 107 I05711 a 10.9 5.0 155 6.4 116 I05713 9.4 4.2 152 5.8 113 I05722 8.6 4.9 149 5.8 112 MEAN S.D. N 9.8 .93 4 4.9 .48 4 152 3.9 4 5.8 .94 4 111 2.6 4 a Dosing was stopped on Day 43; not included in the statistical analyses. Covance 6329-231 3M T-6889.3 295 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 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 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 66 19 1.7 9.0 4.5 4.5 .2 11 131 33 71 20 1.3 9.2 4.7 4.5 .1 10 158 55 68 22 1.2 10.5 5.4 5.1 .3 19 144 32 88 18 1.4 9.5 4.9 4.6 .0 5 257 43 86 18 1.0 9.5 4.9 4.6 .5 12 154 40 93 17 1.3 9.5 5.2 4.3 .2 10 158 36 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 8.5 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 74 22 1.0 9.0 4.8 4.2 .3 17 137 40 68 20 1.3 9.0 5.2 3.8 .2 8 97 33 91 17 1.3 8.8 4.9 3.9 .4 14 180 89 79 14 1.2 8.8 4.8 4.0 .2 10 215 62 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 25.2 4 4 4 4 4 4 4 4 4 4 Dose Level: 10 Dosage Unit: mg/kg/day 77 16 1.3 9.3 4.7 4.6 .2 9 124 66 67 21 1.1 8.5 4.3 4.2 .3 6 170 83 84 17 1.4 9.4 4.7 4.7 .0 6 136 112 90 21 1.4 8.6 5.0 3.6 .2 15 205 148 76 24 1.3 8.4 4.5 3.9 .1 11 131 46 68 20 1.2 10.2 5.2 5.0 .3 19 163 70 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 36.8 6 6 6 6 6 6 6 6 6 6 296 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 96 20 1.2 8.9 3.8 5.1 .1 12 186 75 71 18 1.2 9.8 4.9 4.9 .2 9 148 138 63 23 1.4 8.9 4.8 4.1 .4 11 159 58 98 16 .9 8.2 4.0 4.2 .0 17 135 60 74 19 1.1 9.1 4.6 4.5 .2 14 177 41 84 17 1.0 9.0 4.4 4.6 .1 13 142 99 19.1 1.4 .21 1.13 .64 .49 .14 5.7 9.2 55.2 2 2 2 2 2 2 2 2 2 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. 297 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 36 47 328 128 48 69 637 103 26 54 509 126 38 65 322 100 35 40 424 187 45 104 956 121 5 99 413 14 144 319 9 110 520 11 120 694 9 131 463 15 252 679 7 238 12 201 10 278 12 384 26 222 53 297 38 7.8 6 63 22.7 6 529 240.3 6 128 31.4 6 10 3.7 6 143 55.8 6 515 148.7 6 20 17.4 6 270 66.1 6 Dose Level: 3 Dosage Unit: mg/kg/day 48 44 344 96 10 104 340 21 199 32 27 571 107 10 90 378 94 197 41 33 757 148 12 147 468 33 272 38 83 667 121 10 165 327 50 159 40 6.7 4 47 25.2 4 585 177.6 4 118 22.5 4 10 1.0 4 126 35.3 4 378 63.6 4 50 32.0 4 207 47.2 4 Dose Level: 10 Dosage Unit: mg/kg/day 32 49 897 115 8 99 387 3 204 46 48 592 145 16 165 248 0 153 43 62 410 78 12 122 261 0 164 48 78 871 154 13 118 393 33 229 35 50 445 87 10 186 520 12 366 34 32 720 101 9 109 395 5 200 40 6.8 6 53 15.5 6 656 208.6 6 113 30.8 6 11 2.9 6 133 34.4 6 367 100.7 6 9 12.6 6 219 77.0 6 298 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 55 58 347 80 15 130 446 5 279 43 60 648 57 10 178 366 22 229 46 55 277 160 8 151 389 21 209 33 35 215 182 10 133 270 0 140 44 51 390 133 9 188 390 26 184 38 7.1 2 48 17.7 2 432 306.2 2 120 88.4 2 10 .0 2 156 31.8 2 318 67.9 2 11 15.6 2 184 62.9 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 10.9 6.1 164 5.5 119 11.4 6.4 165 5.1 115 11.4 5.8 170 5.2 118 11.2 6.0 163 6.0 112 11.4 6.4 169 4.9 119 11.4 7.5 169 5.3 117 MEAN S.D. N 11.3 .20 6 6.4 .60 6 167 3.0 6 5.3 .38 6 117 2.7 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 10.2 5.5 159 4.6 119 11.1 5.2 163 5.4 120 11.1 7.3 162 5.6 119 10.6 7.2 165 4.9 116 MEAN S.D. N 10.8 .44 4 6.3 1.10 4 162 2.5 4 5.1 .46 4 118 1.7 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 11.2 6.0 162 4.9 119 10.4 6.2 160 5.1 119 10.7 6.3 159 5.2 119 10.9 6.6 158 4.5 116 10.4 4.6 155 4.3 115 11.1 6.9 166 5.1 116 MEAN S.D. N 10.8 .34 6 6.1 .80 6 160 3.7 6 4.8 .37 6 117 1.9 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a 11.2 6.3 164 7.4 121 I05704 10.6 5.3 156 4.8 112 I05711 b 10.8 4.4 159 5.3 121 I05713 9.6 4.7 160 6.0 117 I05722 c 10.9 8.4 169 6.3 119 MEAN S.D. N 10.1 .71 2 5.0 .42 2 158 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 ------ 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 60 21 1.3 8.6 4.3 4.3 .5 14 134 34 71 22 .9 8.3 4.7 3.6 .2 15 149 52 56 23 1.2 9.6 5.2 4.4 .3 15 138 31 95 17 1.2 8.5 4.8 3.7 .2 23 225 48 63 15 .9 8.5 4.4 4.1 .4 20 153 47 79 19 1.2 8.2 4.8 3.4 .4 19 134 49 71 20 1.1 8.6 4.7 3.9 .3 18 156 44 14.5 3.1 .17 .50 .32 .41 .12 3.6 35.0 8.7 6 6 6 6 6 6 6 6 6 6 Dose Level: 3 Dosage Unit: mg/kg/day 68 19 .9 8.3 4.6 3.7 .1 14 120 40 54 29 1.1 8.0 4.9 3.1 .2 17 109 34 68 19 1.4 9.0 5.3 3.7 .4 19 196 79 96 6 .8 8.5 3.3 5.2 .1 6 94 61 63 22 1.1 8.4 4.9 3.5 .2 17 142 51 8.1 5.8 .25 .51 .35 .35 .15 2.5 47.4 24.4 3 3 3 3 3 3 3 3 3 3 Dose Level: 10 Dosage Unit: mg/kg/day 54 18 1.0 8.6 4.5 4.1 .1 17 128 68 71 23 .9 7.7 4.2 3.5 .4 14 174 57 101 21 1.3 9.6 4.9 4.7 .6 18 157 99 67 19 1.1 7.8 4.8 3.0 .1 16 203 102 61 20 1.4 8.0 4.6 3.4 .0 16 134 39 43 16 1.1 8.6 4.4 4.2 .3 17 126 66 66 20 1.1 8.4 4.6 3.8 .2 16 154 72 19.7 2.4 .19 .71 .26 .62 .23 1.4 30.6 24.5 6 6 6 6 6 6 6 6 6 6 a Unscheduled sacrifice on Day 137. 302 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 64 21 1.3 8.8 4.6 4.2 .2 16 151 100 61 17 1.0 8.4 4.5 3.9 .0 17 139 120 44 21 1.3 8.5 4.7 3.8 .5 17 162 53 100 16 .8 8.2 3.8 4.4 .5 18 161 63 82 20 1.2 8.4 4.7 3.7 .4 21 194 56 80 16 .9 8.3 4.2 4.2 .2 18 150 92 27.6 .7 .14 .14 .49 .35 .35 .7 15.6 40.3 2 2 2 2 2 2 2 2 2 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. 303 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 Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 33 55 291 151 45 68 553 110 33 52 401 115 39 88 280 101 38 57 364 173 33 85 778 97 3 110 402 9 128 356 5 122 480 3 137 745 4 153 428 4 191 590 73 282 8 270 30 308 65 510 25 271 31 327 37 4.8 6 68 15.7 6 444 190.8 6 124 30.5 6 5 140 500 2.3 28.8 144.3 6 6 6 39 25.0 6 328 91.9 6 Dose Level: 3 Dosage Unit: mg/kg/day 48 36 251 93 45 46 659 125 46 46 813 171 21 9 611 83 6 119 350 89 249 8 115 460 177 299 4 182 561 53 391 4 201 361 2 185 46 1.5 3 43 5.8 3 574 290.4 3 130 39.2 3 6 139 457 106 313 2.0 37.6 105.5 63.8 72.0 3 3 3 3 3 Dose Level: 10 Dosage Unit: mg/kg/day 41 43 798 115 42 48 512 132 67 104 339 82 39 53 724 142 39 46 397 95 35 25 496 91 8 103 358 10 206 237 8 4804 258 5 105 391 8 194 558 4 122 371 17 241 0 179 0 199 12 273 22 478 15 241 44 11.6 6 53 26.7 6 544 181.0 6 110 24.1 6 7 922 2.2 1902.1 6 6 362 114.7 6 11 9.1 6 268 107.9 6 a Unscheduled sacrifice on Day 137. 304 ANIMAL NUMBER ------ Group: 4 I05703 a I05704 I05711 b I05713 I05722 c MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 30/20 Dosage Unit: mg/kg/day 45 41 1070 104 10 117 452 88 338 42 54 568 54 3 210 344 17 261 47 47 350 156 2 141 415 25 273 37 43 199 189 2 128 266 0 169 63 70 833 174 6 302 531 46 333 40 3.5 2 48 7.8 2 384 260.9 2 122 95.5 2 2 169 305 .7 58.0 55.2 2 2 2 8 12.0 2 215 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 10.1 6.2 153 5.1 107 10.2 6.1 154 4.9 107 10.0 5.6 153 4.7 107 10.3 5.2 153 5.4 104 9.8 5.4 149 4.5 105 9.7 6.2 150 4.7 105 MEAN S.D. N 10.0 .23 6 5.8 .44 6 152 2.0 6 4.9 .33 6 106 1.3 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 9.2 4.4 147 4.0 108 I05706 9.9 5.2 149 4.7 108 I05717 11.7 8.4 166 5.9 111 I05721 a 9.0 4.8 142 3.9 100 MEAN S.D. N 10.3 1.29 3 6.0 2.12 3 154 10.4 3 4.9 .96 3 109 1.7 3 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 9.8 5.0 146 3.8 108 9.3 5.3 146 3.8 108 10.7 7.8 155 5.2 103 9.5 6.2 149 4.2 108 9.5 4.5 145 3.9 105 9.4 5.8 145 4.7 104 MEAN S.D. N 9.7 .52 6 5.8 1.16 6 148 3.9 6 4.3 .57 6 106 2.3 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a 9.8 6.7 151 5.3 107 I05704 9.4 4.8 148 4.2 107 I05711 b 9.8 3.9 148 5.5 111 I05713 9.1 4.8 152 5.9 109 I05722 c 10.3 8.1 155 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 ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 127 17 1.4 9.4 5.0 4.4 .3 75 17 1.5 9.0 4.5 4.5 .4 6 228 40 6 159 39 101 17 1.4 9.2 4.8 4.4 .4 36.8 .0 .07 .28 .35 .07 .07 2 2 2 2 2 2 2 6 194 .0 48.8 2 2 40 .7 2 Dose Level: 10 Dosage Unit: mg/kg/day 68 20 1.3 7.8 4.8 3.0 .2 54 22 1.5 8.1 4.5 3.6 .3 7 187 111 7 131 49 61 21 1.4 8.0 4.6 3.3 .2 9.9 1.4 .14 .21 .21 .42 .07 2 2 2 2 2 2 2 7 159 .0 39.6 2 2 80 43.8 2 308 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 40 54 234 103 29 30 260 176 6 102 769 4 82 456 11 551 30 279 34 7.8 2 42 17.0 2 247 18.4 2 140 51.6 2 5 92 612 20 415 1.4 14.1 221.3 13.4 192.3 2 2 2 2 2 Dose Level: 10 Dosage Unit: mg/kg/day 31 24 687 142 27 12 409 98 7 143 410 5 138 544 27 298 17 487 29 2.8 2 18 8.5 2 548 196.6 2 120 31.1 2 6 140 477 1.4 3.5 94.8 2 2 2 22 7.1 2 392 133.6 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 10.9 6.1 153 6.0 106 10.9 6.5 159 5.5 111 MEAN S.D. N 10.9 .00 2 6.3 .28 2 156 4.2 2 5.8 .35 2 108 3.5 2 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 9.9 7.2 147 4.5 108 9.9 5.2 145 4.7 107 MEAN S.D. N 9.9 .00 2 6.2 1.41 2 146 1.4 2 4.6 .14 2 108 .7 2 Covance 6329-231 3M T-6889.3 310 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 96 15 1.4 9.1 5.1 4.0 .2 94 15 1.2 9.1 4.6 4.5 .3 4 251 51 4 155 47 95 15 1.3 9.1 4.8 4.2 .2 1.4 .0 .14 .00 .35 .35 .07 2 2 2 2 2 2 2 4 203 .0 67.9 2 2 49 2.8 2 Dose Level: 10 Dosage Unit: mg/kg/day 82 18 1.2 8.0 5.0 3.0 .2 79 22 1.4 8.2 4.7 3.5 .3 6 186 138 4 143 47 80 20 1.3 8.1 4.8 3.2 .2 2.1 2.8 .14 .14 .21 .35 .07 2 2 2 2 2 2 2 5 164 1.4 30.4 2 2 92 64.3 2 311 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 30 43 204 87 40 45 286 180 3 113 759 4 904 449 44 551 47 288 35 7.1 2 44 1.4 2 245 58.0 2 134 65.8 2 4 508 604 .7 559.3 219.2 2 2 2 46 2.1 2 420 186.0 2 Dose Level: 10 Dosage Unit: mg/kg/day 25 51 781 143 30 38 489 97 3 127 441 2 202 540 66 315 47 474 28 3.5 2 44 9.2 2 635 206.5 2 120 32.5 2 2 164 490 .7 53.0 70.0 2 2 2 56 13.4 2 394 112.4 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 10.7 6.6 158 6.5 111 10.7 6.9 158 4.7 110 MEAN S.D. N 10.7 .00 2 6.8 .21 2 158 .0 2 5.6 1.27 2 110 .7 2 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 10.3 7.1 155 5.0 113 10.3 5.6 151 5.6 114 MEAN S.D. N 10.3 .00 2 6.4 1.06 2 153 2.8 2 5.3 .42 2 114 .7 2 Covance 6329-231 3M T-6889.3 313 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual 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 -------- TRIG MG/DL -------- Dose Level: 0 Dosage Unit: mg/kg/day 93 20 1.5 9.6 5.3 4.3 .2 10 256 30 76 17 .9 8.8 4.1 4.7 .4 9 131 47 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 2 2 2 2 2 2 2 2 2 2 Dose Level: 10 Dosage Unit: mg/kg/day 93 21 1.3 8.2 5.2 3.0 .3 87 21 1.3 8.2 4.6 3.6 .3 8 178 74 7 122 22 90 21 1.3 8.2 4.9 3.3 .3 4.2 .0 .00 .00 .42 .42 .00 2 2 2 2 2 2 2 8 150 .7 39.6 2 2 48 36.8 2 314 ANIMAL NUMBER ------ Group: 1 I05718 I05720 MEAN S.D. N Group: 3 I05712 I05716 MEAN S.D. N Appendix 4 Covance 6329-231 3M T-6889.3 Individual Clinical Chemistry Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS AST/SGOT IU/L -------- ALT/SGPT IU/L -------- ALK PHOS IU/L -------- GGT IU/L -------- SDH IU/L -------- CK IU/L -------- AMYLASE IU/L -------- LIPASE IU/L -------- P AMYL U/L -------- Dose Level: 0 Dosage Unit: mg/kg/day 64 153 216 97 55 63 323 127 4 647 984 208 693 1 1402 667 121 455 60 6.4 2 108 63.6 2 270 75.7 2 112 21.2 2 2 1024 2.1 533.9 2 2 826 224.2 2 164 61.5 2 574 168.3 2 Dose Level: 10 Dosage Unit: mg/kg/day 47 70 752 138 54 81 454 94 1 1922 499 3 1125 1649 58 346 656 1460 50 4.9 2 76 7.8 2 603 210.7 2 116 31.1 2 2 1524 1074 1.4 563.6 813.2 2 2 2 357 422.8 2 903 787.7 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 11.2 5.6 154 6.6 104 10.6 4.2 153 5.5 110 MEAN S.D. N 10.9 .42 2 4.9 .99 2 154 .7 2 6.0 .78 2 107 4.2 2 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 10.2 6.6 152 4.4 103 10.2 3.9 148 4.4 103 MEAN S.D. N 10.2 .00 2 5.2 1.91 2 150 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 100.0 1.021 8.5 395.0 1.002 7.5 50.0 1.021 8.5 128.0 1.016 8.0 108.0 1.019 8.0 40.0 1.019 8.5 MEAN S.D. N 136.8 131.02 6 1.016 .0073 6 8.2 .41 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 64.0 1.015 8.0 129.0 1.019 8.0 176.0 1.006 8.0 555.0 1.000 7.5 MEAN S.D. N 231.0 220.83 4 1.010 .0086 4 7.9 .25 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 50.0 1.021 8.5 50.0 1.012 8.5 139.0 1.016 8.0 455.0 1.003 7.5 86.0 1.014 8.0 66.0 1.016 8.5 MEAN S.D. N 141.0 157.36 6 1.014 .0060 6 8.2 .41 6 317 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 I05704 I05711 I05713 I05722 I05724 158.0 1.005 8.0 19.0 1.027 8.5 166.0 1.010 7.5 11.0 1.020 8.5 73.0 1.014 8.5 103.0 1.009 8.5 MEAN S.D. N 88.3 66.52 6 1.014 .0081 6 8.2 .42 6 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 10 - - - - - I05714 10 - - - - - I05715 10 - - - - - I05718 10 - - - - - I05720 10 - - - - - I05725 10 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 10 - - - + - I05706 10 - - - - - I05717 0 - - - - - I05721 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 10 - - - - - I05708 0 - - - - - I05710 0 - - - - - I05712 0 - - - - - I05716 0 - - - - - I05719 10 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 0 - - - - - I05704 10 - - - - - I05711 0 - - - - - I05713 0 - - - - - I05722 0 - - - - - I05724 10 - - - - - Covance 6329-231 3M T-6889.3 319 ANIMAL NUMBER ------ 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 Appendix 4 Individual Clinical Urinalysis Data Males Day -11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- CRYSTALS PER LPF2 -------- URINE APP1 -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 2 0 1B4E 0 CK 0 0 0 2 0 0 0 AJ 0 0 0 1 0 3B1D 0 CK 0 0 0 2 0 2B2E 0 CK 0 0 0 2 0 2B1E 0 CK 0 0 0 2 0 2B2D 0 CK Dose Level: 3 Dosage Unit: mg/kg/day 0 0 1 3 0 4B4D 0 CK 0 0 0 3 0 4E4F 0 CK 0 0 0 3 0 2B1E 0 BK 0 0 0 2 0 0 0 AJ Dose Level: 10 Dosage Unit: mg/kg/day 0 0 1 3 0 3B2D 1F CK 0 0 1 3 0 2B1F 0 BK 0 0 0 2 0 3B1E 2F BK 0 0 0 3 0 0 0 AJ 0 1 0 2 0 2B1D 0 BK 0 0 0 1 0 3B1E 0 CK Dose Level: 30/20 Dosage Unit: mg/kg/day 0 0 0 3 0 2B 0 AJ 0 0 0 3 0 3E4F 0 CK 0 0 0 3 0 2B1E 0 BK 0 0 0 3 0 4F 0 GK 0 0 0 3 0 0 0 CJ 0 0 0 3 0 1E 0 BK COMMENTS -------- Q - - Q - Q - Covance 6329-231 3M T-6889.3 320 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 89.0 1.021 8.0 490.0 1.002 7.5 98.0 1.017 8.5 90.0 1.016 7.5 122.0 1.018 8.0 110.0 1.014 8.0 MEAN S.D. N 166.5 158.98 6 1.015 .0066 6 7.9 .38 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 210.0 1.010 8.0 I05706 64.0 1.023 8.0 I05717 397.0 1.004 8.0 I05721 a 296.0 1.003 7.0 MEAN S.D. N 241.8 141.01 4 1.010 .0092 4 7.8 .50 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 84.0 1.020 8.0 94.0 1.018 8.0 228.0 1.008 8.0 350.0 1.003 8.0 107.0 1.014 8.0 69.0 1.018 8.5 MEAN S.D. N 155.3 111.19 6 1.014 .0067 6 8.1 .20 6 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 I05704 I05711 I05713 I05722 215.0 1.005 7.5 282.0 1.005 7.0 180.0 1.006 7.0 350.0 1.003 8.0 89.0 1.017 8.0 MEAN S.D. N 223.2 99.35 5 1.007 .0056 5 7.5 .50 5 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 10 - - - + - I05714 0 - - - - - I05715 10 - - - - - I05718 30 - - - - - I05720 0 - - - - - I05725 0 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 0 - - - ++ - I05706 0 - - - - - I05717 0 - - - - - I05721 a 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 - - - - - I05708 0 - - - - - I05710 0 - - - - - I05712 0 - - - - - I05716 0 - - - - - I05719 0 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 0 - - - - - I05704 0 - - - + - I05711 0 - - - - - I05713 0 - - - - - I05722 0 - - - - - a Dosing was started on Day 17. 323 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER ------ 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 Appendix 4 Individual Clinical Urinalysis Data Males Day 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- CRYSTALS PER LPF2 -------- URINE APP1 -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 3 0 4B3D 0 BK 0 0 0 3 0 0 0 AJ 0 0 1 3 0 4B 0 BK 0 1 1 3 0 0 0 BJ 0 0 0 3 0 4B1E 0 BL 0 0 0 3 0 4B 0 BK Dose Level: 3 Dosage Unit: mg/kg/day 0 0 0 3 0 4B 0 AK 0 0 0 3 0 4B 0 BJ 0 0 1 3 0 0 0 AJ 0 1 0 3 0 1B 0 AJ Dose Level: 10 Dosage Unit: mg/kg/day 0 1 0 3 0 2B2D 0 BJ 0 0 0 3 0 4B2E 3F BL 0 1 1 3 0 1E 0 AJ 0 0 0 2 0 1D 0 AJ 0 0 0 3 0 4B 0 BL 0 0 0 3 0 2B1D 0 CJ Dose Level: 30/20 Dosage Unit: mg/kg/day 0 0 1 3 0 0 0 AJ 0 1 1 2 0 1B 0 AJ 0 0 0 3 1H 2B 0 AJ 0 0 1 3 0 3B 0 AJ 0 0 0 2 0 2B4D 0 BL COMMENTS -------- Q - Q - Q PQ Q - Covance 6329-231 3M T-6889.3 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 48.0 1.024 8.0 570.0 1.002 8.0 124.0 1.014 8.0 170.0 1.009 8.5 78.0 1.019 8.0 144.0 1.010 8.0 MEAN S.D. N 189.0 191.82 6 1.013 .0078 6 8.1 .20 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 240.0 1.006 7.5 52.0 1.024 7.0 360.0 1.004 7.5 360.0 1.004 8.0 MEAN S.D. N 253.0 145.45 4 1.010 .0097 4 7.5 .41 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 88.0 1.019 8.5 162.0 1.011 8.5 96.0 1.015 8.0 570.0 1.002 8.0 122.0 1.011 8.0 102.0 1.014 8.0 MEAN S.D. N 190.0 188.04 6 1.012 .0057 6 8.2 .26 6 325 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 114.0 1.011 8.0 I05704 74.0 1.021 8.0 I05711 a 98.0 1.015 8.0 I05713 60.0 1.020 7.0 I05722 84.0 1.014 7.0 MEAN S.D. N 83.0 22.89 4 1.016 .0048 4 7.5 .58 4 Covance 6329-231 3M T-6889.3 a Dosing was stopped on Day 43; not included in the statistical 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 10 - - - - - I05714 0 - - - - - I05715 10 - - - - - I05718 0 - - - - - I05720 10 - - - - - I05725 0 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 0 - - - + - I05706 10 - - - - - I05717 0 - - - - - I05721 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 - - - - - I05708 10 - - - - - I05710 0 - - - - - I05712 0 - - - - - I05716 0 - - - - - I05719 0 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 0 - - - - - I05704 0 - - - - - I05711 a 0 - - - - - I05713 0 - - - - - I05722 0 - - - - - a Dosing was stopped on Day 43. 327 Covance 6329-231 3M T-6889.3 ANIMAL NUMBER ------ 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 Appendix 4 Individual Clinical Urinalysis Data Males Day 63 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- CRYSTALS PER LPF2 -------- URINE APP1 -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 3 0 4D 0 CK 0 0 1 3 0 0 0 AJ 0 0 0 3 0 2B1D 0 BK 0 0 0 3 0 0 0 BK 0 0 0 3 0 4B2D 1E CK 0 1 0 3 0 0 0 BJ Dose Level: 3 Dosage Unit: mg/kg/day 0 0 1 3 0 0 0 AK 0 1 0 3 0 1E 0 CK 0 0 1 3 0 0 0 AJ 0 0 1 3 0 2B 0 AK Dose Level: 10 Dosage Unit: mg/kg/day 0 0 0 3 0 1B2D 1E CK 0 0 0 3 0 4B4D 0 BK 0 0 0 3 0 2E4F 0 CK 0 0 0 3 0 0 0 AJ 0 0 0 3 0 4B4D 1E BK 0 0 0 3 0 2B 0 CK Dose Level: 30/20 Dosage Unit: mg/kg/day 0 0 0 3 0 4B3D 2E BK 0 0 0 1 0 1B1D 1E CK 0 0 0 3 0 4B1E 0 BK 0 0 1 2 0 1D 0 CK 0 1 1 3 0 1B4D 0 CJ COMMENTS -------- Q Q Q Q Q Q - Q PQ - Covance 6329-231 3M T-6889.3 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 69.0 1.025 8.5 546.0 1.004 8.0 93.0 1.020 8.0 137.0 1.017 8.5 79.0 1.025 8.5 192.0 1.011 8.0 MEAN S.D. N 186.0 182.11 6 1.017 .0083 6 8.2 .27 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 124.0 1.018 8.0 74.0 1.021 7.5 338.0 1.006 8.0 552.0 1.003 7.5 MEAN S.D. N 272.0 218.99 4 1.012 .0088 4 7.8 .29 4 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 88.0 1.019 8.0 163.0 1.015 7.5 234.0 1.010 8.0 564.0 1.003 8.0 146.0 1.012 8.0 137.0 1.014 8.0 MEAN S.D. N 222.0 174.10 6 1.012 .0054 6 7.9 .20 6 329 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a 402.0 1.005 8.0 I05704 78.0 1.020 8.0 I05711 b 106.0 1.018 7.5 I05713 64.0 1.020 8.5 I05722 c 185.0 1.010 8.0 MEAN S.D. N 71.0 9.90 2 1.020 .0000 2 8.2 .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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 10 - - - - - I05714 0 - - - - - I05715 10 - - - - - I05718 0 - - - - - I05720 10 - - - - - I05725 0 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 0 - - - - - I05706 0 - - - - - I05717 0 - - - - - I05721 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 - - - - - I05708 0 - - - - - I05710 0 - - - - - I05712 0 - - - - - I05716 0 - - - - - I05719 0 - - - - - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a 0 - - - - - I05704 0 - - - - - I05711 b 0 - - - - - I05713 0 - - - - - I05722 c 0 - - - - - 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 ------ 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 Appendix 4 Individual Clinical Urinalysis Data Males Day 91 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- CRYSTALS PER LPF2 -------- URINE APP1 -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 3 0 4B4D 0 BJ 0 0 1 2 0 0 0 AJ 0 0 0 3 0 2B 0 BK 0 0 0 3 0 2B2E 0 BJ 0 0 1 2 0 4B4D 4E3F BK 0 0 0 3 0 3B 0 BJ Dose Level: 3 Dosage Unit: mg/kg/day 0 0 0 3 0 4B2D 2E2F BK 0 0 1 3 0 4B4D 3E BJ 0 0 1 3 0 0 0 AJ 0 0 1 3 0 1B1E 0 AJ Dose Level: 10 Dosage Unit: mg/kg/day 0 0 0 3 0 4B4D 0 BK 0 0 0 3 0 3B2E 2F BK 0 0 0 2 0 1B3E 0 AJ 0 0 1 2 0 0 0 AJ 0 0 0 3 0 4B 0 BK 0 0 0 3 0 4B4E 2F BJ Dose Level: 30/20 Dosage Unit: mg/kg/day 0 0 1 2 0 2E 0 AJ 0 0 0 3 0 3B4D 1E BK 0 0 0 3 0 4B1F 0 BK 0 0 0 3 0 4B4D 0 BK 0 0 0 3 0 4B1E 1F BK COMMENTS -------- Q Q PQ - Q - - - Covance 6329-231 3M T-6889.3 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 I05714 I05715 I05718 I05720 I05725 86.0 1.026 8.0 218.0 1.010 7.5 158.0 1.013 8.0 255.0 1.011 8.0 90.0 1.019 7.5 150.0 1.011 7.0 MEAN S.D. N 159.5 67.63 6 1.015 .0063 6 7.7 .41 6 Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 198.0 1.015 8.0 92.0 1.022 7.5 227.0 1.010 8.0 MEAN S.D. N 172.3 71.07 3 1.016 .0060 3 7.8 .29 3 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 I05708 I05710 I05712 I05716 I05719 66.0 1.021 7.0 306.0 1.006 7.5 214.0 1.012 7.5 473.0 1.004 7.5 122.0 1.015 7.0 70.0 1.018 7.0 MEAN S.D. N 208.5 159.04 6 1.013 .0067 6 7.2 .27 6 333 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 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a 290.0 1.005 7.5 I05704 88.0 1.022 8.0 I05711 b 159.0 1.012 7.0 I05713 306.0 1.006 7.5 I05722 c 49.0 1.020 8.0 MEAN S.D. N 197.0 154.15 2 1.014 .0113 2 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 Dose Level: 0 Dosage Unit: mg/kg/day I05709 0 - - - - - I05714 0 - - - - - I05715 0 - - - - - I05718 0 - - - - - I05720 0 - + - - - I05725 0 - - - - - Group: 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 0 - - - + - I05706 0 - + - - - I05717 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05707 0 - + - - - I05708 0 - - - - - I05710 0 - - - - - I05712 0 - - - - - I05716 0 - - - - - I05719 0 - ++++ - + - Group: 4 Dose Level: 30/20 Dosage Unit: mg/kg/day I05703 a 0 - - - - - I05704 0 - - - - - I05711 b 0 - - - - - I05713 0 - - - - - I05722 c 0 - - - - - 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 ------ 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 Appendix 4 Individual Clinical Urinalysis Data Males Day 182 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- CRYSTALS PER LPF2 -------- URINE APP1 -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 2 1H 3B1D 3F BJ 0 0 1 3 0 2B 0 BJ 0 0 1 3 0 4B3D 0 BK 0 0 1 3 0 2B 0 BJ 0 0 0 3 1H 2B4D 3E BJ 0 1 0 3 0 0 0 BJ Dose Level: 3 Dosage Unit: mg/kg/day 0 0 0 2 0 3B1E 0 BK 0 0 1 3 0 3B1F 0 BJ 0 0 1 3 0 0 0 AJ Dose Level: 10 Dosage Unit: mg/kg/day 0 0 1 3 0 1B3D 0 BJ 0 0 1 3 0 2B 0 AJ 0 0 0 3 0 3B2D 0 BJ 0 0 0 3 0 0 0 AJ 0 0 1 3 0 2B 0 BJM 0 0 1 3 0 1D 0 BJ Dose Level: 30/20 Dosage Unit: mg/kg/day 0 0 1 3 0 0 0 AJ 0 0 0 3 0 4B4D 0 BK 0 0 0 3 0 1B 0 BJ 0 0 0 3 0 0 0 AJ 0 0 0 1 0 3B4D 1E BJ COMMENTS -------- Q Q P Q Q Q Q Q Q Q Covance 6329-231 3M T-6889.3 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 240.0 1.013 8.0 545.0 1.003 8.0 MEAN S.D. N 392.5 215.67 2 1.008 .0071 2 8.0 .00 2 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 455.0 1.004 8.0 125.0 1.009 7.5 MEAN S.D. N 290.0 233.35 2 1.006 .0035 2 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 0 - - - - - I05720 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 0 - - - - - I05716 0 - - - - - Covance 6329-231 3M T-6889.3 338 ANIMAL NUMBER ------ Group: 1 I05718 I05720 Group: 3 I05712 I05716 Appendix 4 Individual Clinical Urinalysis Data Males Day 217 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- CRYSTALS PER LPF2 -------- URINE APP1 -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 1 0 3B1D 0 BJ 0 0 0 2 0 3B1D 1E AJ Dose Level: 10 Dosage Unit: mg/kg/day 0 0 0 2 0 1B 0 AJ 0 0 0 3 0 2B1D 0 AJ COMMENTS -------- - - Covance 6329-231 3M T-6889.3 339 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 78.0 1.020 8.0 314.0 1.006 8.0 MEAN S.D. N 196.0 166.88 2 1.013 .0099 2 8.0 .00 2 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 516.0 1.003 7.5 167.0 1.007 7.5 MEAN S.D. N 341.5 246.78 2 1.005 .0028 2 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 0 - - - - - I05720 0 - - - - - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 0 - - - - - I05716 0 - - - - - Covance 6329-231 3M T-6889.3 341 ANIMAL NUMBER ------ Group: 1 I05718 I05720 Group: 3 I05712 I05716 Appendix 4 Individual Clinical Urinalysis Data Males Day 245 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- URINE APP1 -------- COMMENTS -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 0 0 3 0 4B1E BL Q 0 0 0 2 0 1B BK - Dose Level: 10 Dosage Unit: mg/kg/day 0 0 1 3 0 1B AKM Q 0 0 1 3 0 2B BK 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 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 158.0 1.015 7.0 72.0 1.021 7.0 MEAN S.D. N 115.0 60.81 2 1.018 .0042 2 7.0 .00 2 Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 179.0 1.010 8.0 92.0 1.014 8.0 MEAN S.D. N 135.5 61.52 2 1.012 .0028 2 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 -------- UROBILI -------- Group: 1 Dose Level: 0 Dosage Unit: mg/kg/day I05718 10 + - - + - I05720 10 + + - + - Group: 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 0 - - - - - I05716 10 + - - + - Covance 6329-231 3M T-6889.3 344 ANIMAL NUMBER ------ Group: 1 I05718 I05720 Group: 3 I05712 I05716 Appendix 4 Individual Clinical Urinalysis Data Males Day 275 (Recovery) 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS RBC PER HPF -------- WBC PER HPF -------- EPITH PER HPF -------- BACT PER HPF -------- CASTS PER LPF -------- CRYSTALS PER LPF1 -------- URINE APP1 -------- COMMENTS -------- Dose Level: 0 Dosage Unit: mg/kg/day 0 2 1 3 0 3B BK - 0 0 0 3 0 3B1D CK - Dose Level: 10 Dosage Unit: mg/kg/day 0 1 1 1 0 1D BJ Q 0 0 1 3 0 3B1D 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 PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3730 .0078 % .0050 WEIGHT TAKEN RT ADRENAL (AD1) .3040 .0063 % .0041 WEIGHT TAKEN BRAIN (BR) 73.9130 1.5399 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.0600 .0429 % .0279 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.0060 .0418 % .0271 WEIGHT TAKEN LF KIDNEY (KD0) 7.5960 .1582 % .1028 WEIGHT TAKEN RT KIDNEY (KD1) 7.9230 .1651 % .1072 WEIGHT TAKEN LIVER (LI) 69.5030 1.4480 % .9403 WEIGHT TAKEN PANCREAS (PA) 6.9550 .1449 % .0941 WEIGHT TAKEN LF TESTIS (TE0) 10.4110 .2169 % .1409 WEIGHT TAKEN RT TESTIS (TE1) 9.5080 .1981 % .1286 WEIGHT TAKEN LF THYROID/PARA (TT0) .1850 .0039 % .0025 WEIGHT TAKEN RT THYROID/PARA (TT1) .2090 .0044 % .0028 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY 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 (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), 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 PAGE: 3 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .2650 .0077 % .0043 WEIGHT TAKEN RT ADRENAL (AD1) .1840 .0053 % .0030 WEIGHT TAKEN BRAIN (BR) 61.7660 1.7929 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) .9650 .0280 % .0156 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.1580 .0336 % .0187 WEIGHT TAKEN LF KIDNEY (KD0) 5.4390 .1579 % .0881 WEIGHT TAKEN RT KIDNEY (KD1) 5.5320 .1606 % .0896 WEIGHT TAKEN LIVER (LI) 53.0460 1.5398 % .8588 WEIGHT TAKEN PANCREAS (PA) 5.8810 .1707 % .0952 WEIGHT TAKEN LF TESTIS (TE0) 6.0980 .1770 % .0987 WEIGHT TAKEN RT TESTIS (TE1) 6.1630 .1789 % .0998 WEIGHT TAKEN LF THYROID/PARA (TT0) .3120 .0091 % .0051 WEIGHT TAKEN RT THYROID/PARA (TT1) .3150 .0091 % .0051 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL CECUM (CE) : CECUM (CE) : -RED FOCUS(I)/AREA(S); WITHIN WALL: SINGLE DARK RED AND FIRM -INFLAMMATION, GRANULOMATOUS,-MODERATE AREA, 0.4 CM IN DIAMETER; COLLECTED ON ROUTINE SECTION -PARASITISM,-PRESENT COLON (CO) : -INFLAMMATION, CHRONIC,-MINIMAL 349 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- SKIN (SK) : SKIN (SK) : >NOTE:>TRIMMING COMMENT: MISSING FROM WET TISSUE >TISSUE MISSING MAMMARY, MALE (MM) : MAMMARY, MALE (MM) : >NOTE:>TRIMMING COMMENT: MISSING FROM WET TISSUE >TISSUE MISSING GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 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), 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), 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 PAGE: 5 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .2900 .0076 % .0052 WEIGHT TAKEN RT ADRENAL (AD1) .2490 .0065 % .0045 WEIGHT TAKEN BRAIN (BR) 55.8000 1.4550 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.1070 .0549 % .0378 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.2030 .0574 % .0395 WEIGHT TAKEN LF KIDNEY (KD0) 6.4160 .1673 % .1150 WEIGHT TAKEN RT KIDNEY (KD1) 6.1400 .1601 % .1100 WEIGHT TAKEN LIVER (LI) 57.6270 1.5027 % 1.0327 WEIGHT TAKEN PANCREAS (PA) 5.1700 .1348 % .0927 WEIGHT TAKEN LF TESTIS (TE0) 15.2070 .3965 % .2725 WEIGHT TAKEN RT TESTIS (TE1) 15.1080 .3940 % .2708 WEIGHT TAKEN LF THYROID/PARA (TT0) .1820 .0047 % .0033 WEIGHT TAKEN RT THYROID/PARA (TT1) .1610 .0042 % .0029 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 6 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- 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 GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 352 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 7 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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, 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 PAGE: 8 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .4300 .0077 % .0061 WEIGHT TAKEN RT ADRENAL (AD1) .2740 .0049 % .0039 WEIGHT TAKEN BRAIN (BR) 70.8600 1.2699 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.8180 .0505 % .0398 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.7560 .0494 % .0389 WEIGHT TAKEN LF KIDNEY (KD0) 8.3340 .1494 % .1176 WEIGHT TAKEN RT KIDNEY (KD1) 8.1740 .1465 % .1154 WEIGHT TAKEN LIVER (LI) 88.4330 1.5848 % 1.2480 WEIGHT TAKEN PANCREAS (PA) 8.9960 .1612 % .1270 WEIGHT TAKEN LF TESTIS (TE0) 14.2840 .2560 % .2016 WEIGHT TAKEN RT TESTIS (TE1) 14.6580 .2627 % .2069 WEIGHT TAKEN LF THYROID/PARA (TT0) .2450 .0044 % .0035 WEIGHT TAKEN RT THYROID/PARA (TT1) .2480 .0044 % .0035 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 9 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- 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 GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 355 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 10 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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, 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 (TY), 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) ------------------------------------------------------------------------------------------------------------------------------------ 356 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 11 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3680 .0070 % .0061 WEIGHT TAKEN RT ADRENAL (AD1) .2190 .0042 % .0036 WEIGHT TAKEN BRAIN (BR) 60.5630 1.1558 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.3990 .0458 % .0396 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.7020 .0516 % .0446 WEIGHT TAKEN LF KIDNEY (KD0) 9.7810 .1867 % .1615 WEIGHT TAKEN RT KIDNEY (KD1) 9.5500 .1823 % .1577 WEIGHT TAKEN LIVER (LI) 91.9440 1.7547 % 1.5182 WEIGHT TAKEN PANCREAS (PA) 8.0025 .1527 % .1321 WEIGHT TAKEN LF TESTIS (TE0) 17.7630 .3390 % .2933 WEIGHT TAKEN RT TESTIS (TE1) 17.9890 .3433 % .2970 WEIGHT TAKEN LF THYROID/PARA (TT0) .2640 .0050 % .0044 WEIGHT TAKEN RT THYROID/PARA (TT1) .2660 .0051 % .0044 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : LIVER (LI) : -ADHESION(S); LEFT AND RIGHT MEDIAN LOBES TO OMENTUM: -FIBROSIS, CAPSULAR/SUBCAPSULAR,-MODERATE MULTIPLE GRAY FIBROUS ADHESIONS; COLLECTED -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 PAGE: 12 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- 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 GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -ANIMAL OBESE -------------------------------------------- 358 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 13 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 PAGE: 14 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3060 .0082 % .0046 WEIGHT TAKEN RT ADRENAL (AD1) .2680 .0072 % .0040 WEIGHT TAKEN BRAIN (BR) 66.8040 1.8006 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.4200 .0383 % .0213 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.7330 .0467 % .0259 WEIGHT TAKEN LF KIDNEY (KD0) 6.9080 .1862 % .1034 WEIGHT TAKEN RT KIDNEY (KD1) 6.6130 .1782 % .0990 WEIGHT TAKEN LIVER (LI) 60.5030 1.6308 % .9057 WEIGHT TAKEN PANCREAS (PA) 4.4720 .1205 % .0669 WEIGHT TAKEN LF TESTIS (TE0) 8.0090 .2159 % .1199 WEIGHT TAKEN RT TESTIS (TE1) 7.7940 .2101 % .1167 WEIGHT TAKEN LF THYROID/PARA (TT0) .2030 .0055 % .0030 WEIGHT TAKEN RT THYROID/PARA (TT1) .2050 .0055 % .0031 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 15 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- THYROID (TY) : THYROID (TY) : >NOTE:>TRIMMING COMMENT: ONLY ONE THYROID FOUND AT TRIMMING -ONE EXAMINED,-PRESENT PARATHYROID (PT) : PARATHYROID (PT) : >NOTE:>TRIMMING COMMENT: ONLY ONE PARATHYROID FOUND AT >SECTION EXAMINED; TISSUE NOT PRESENT TRIMMING GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 361 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 16 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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), 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 PAGE: 17 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .4180 .0092 % .0065 WEIGHT TAKEN RT ADRENAL (AD1) .4140 .0092 % .0065 WEIGHT TAKEN BRAIN (BR) 63.8380 1.4123 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.4140 .0534 % .0378 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.5390 .0562 % .0398 WEIGHT TAKEN LF KIDNEY (KD0) 9.2760 .2052 % .1453 WEIGHT TAKEN RT KIDNEY (KD1) 9.2350 .2043 % .1447 WEIGHT TAKEN LIVER (LI) 84.9350 1.8791 % 1.3305 WEIGHT TAKEN PANCREAS (PA) 7.3540 .1627 % .1152 WEIGHT TAKEN LF TESTIS (TE0) 15.7540 .3485 % .2468 WEIGHT TAKEN RT TESTIS (TE1) 17.5050 .3873 % .2742 WEIGHT TAKEN LF THYROID/PARA (TT0) .2150 .0048 % .0034 WEIGHT TAKEN RT THYROID/PARA (TT1) .1860 .0041 % .0029 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 18 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- THYMUS (TH) : -INVOLUTION,-SLIGHT LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-SLIGHT CECUM (CE) : CECUM (CE) : -RED FOCUS(I)/AREA(S); DIFFUSE, WITHIN WALL: MULTIPLE DARK >UNREMARKABLE RED AND FIRM AREAS, UP TO 0.4 CM IN DIAMETER; COLLECTED ON ROUTINE SECTION GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 364 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 19 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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), 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, 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 PAGE: 20 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3260 .0073 % .0048 WEIGHT TAKEN RT ADRENAL (AD1) .3330 .0074 % .0049 WEIGHT TAKEN BRAIN (BR) 68.3500 1.5257 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 3.0160 .0673 % .0441 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.8270 .0631 % .0414 WEIGHT TAKEN LF KIDNEY (KD0) 7.7550 .1731 % .1135 WEIGHT TAKEN RT KIDNEY (KD1) 7.3100 .1632 % .1069 WEIGHT TAKEN LIVER (LI) 80.9240 1.8063 % 1.1840 WEIGHT TAKEN PANCREAS (PA) 6.0350 .1347 % .0883 WEIGHT TAKEN LF TESTIS (TE0) 18.5330 .4137 % .2711 WEIGHT TAKEN RT TESTIS (TE1) 19.4480 .4341 % .2845 WEIGHT TAKEN LF THYROID/PARA (TT0) .1540 .0034 % .0023 WEIGHT TAKEN RT THYROID/PARA (TT1) .2150 .0048 % .0031 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LUNG (LU) : LUNG (LU) : -RED FOCUS(I)/AREA(S); ALL LOBES: MULTIPLE LINEAR AREAS, UP -CONGESTION,-MINIMAL TO 2 X LESS THAN 1 MM -PIGMENT,-MINIMAL PARATHYROID (PT) : -CYST, GLANDULAR,-PRESENT GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 366 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 21 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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), 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) ------------------------------------------------------------------------------------------------------------------------------------ 367 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 22 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3720 .0083 % .0055 WEIGHT TAKEN RT ADRENAL (AD1) .3250 .0073 % .0048 WEIGHT TAKEN BRAIN (BR) 67.3520 1.5101 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.6580 .0372 % .0246 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.7190 .0385 % .0255 WEIGHT TAKEN LF KIDNEY (KD0) 7.0060 .1571 % .1040 WEIGHT TAKEN RT KIDNEY (KD1) 6.7980 .1524 % .1009 WEIGHT TAKEN LIVER (LI) 79.5160 1.7829 % 1.1806 WEIGHT TAKEN PANCREAS (PA) 4.9180 .1103 % .0730 WEIGHT TAKEN LF TESTIS (TE0) 11.1670 .2504 % .1658 WEIGHT TAKEN RT TESTIS (TE1) 11.3670 .2549 % .1688 WEIGHT TAKEN LF THYROID/PARA (TT0) .1340 .0030 % .0020 WEIGHT TAKEN RT THYROID/PARA (TT1) .1540 .0035 % .0023 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 23 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY 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 (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, 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 PAGE: 24 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3040 .0076 % .0052 WEIGHT TAKEN RT ADRENAL (AD1) .2430 .0061 % .0042 WEIGHT TAKEN BRAIN (BR) 58.4860 1.4640 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.3310 .0333 % .0228 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.4600 .0365 % .0250 WEIGHT TAKEN LF KIDNEY (KD0) 8.9430 .2239 % .1529 WEIGHT TAKEN RT KIDNEY (KD1) 9.1420 .2288 % .1563 WEIGHT TAKEN LIVER (LI) 97.3000 2.4355 % 1.6636 WEIGHT TAKEN PANCREAS (PA) 6.5560 .1641 % .1121 WEIGHT TAKEN LF TESTIS (TE0) 8.3940 .2101 % .1435 WEIGHT TAKEN RT TESTIS (TE1) 8.3410 .2088 % .1426 WEIGHT TAKEN LF THYROID/PARA (TT0) .1220 .0031 % .0021 WEIGHT TAKEN RT THYROID/PARA (TT1) .1460 .0037 % .0025 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : LIVER (LI) : -LIGHT FOCUS(I)/AREA(S); ALONG MARGIN OF LEFT LATERAL LOBE: -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL SINGLE TAN AREA, 0.3 CM IN DIAMETER; COLLECTED ON ROUTINE -VACUOLATION, HEPATOCELLULAR, FOCAL,-MINIMAL SECTION 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 PAGE: 25 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- COLON (CO) : COLON (CO) : -DIVERTICULUM(A); PROXIMAL TO CECUM: SINGLE DIVERTICULUM, >UNREMARKABLE 1.0 CM IN DIAMETER; COLLECTED >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 GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 371 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 26 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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), 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 PAGE: 27 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .2600 .0064 % .0038 WEIGHT TAKEN RT ADRENAL (AD1) .2490 .0061 % .0036 WEIGHT TAKEN BRAIN (BR) 68.6950 1.6796 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) .8690 .0212 % .0127 WEIGHT TAKEN RT EPIDIDYMIS (EP1) .8850 .0216 % .0129 WEIGHT TAKEN LF KIDNEY (KD0) 7.9840 .1952 % .1162 WEIGHT TAKEN RT KIDNEY (KD1) 7.7280 .1889 % .1125 WEIGHT TAKEN LIVER (LI) 73.6910 1.8017 % 1.0727 WEIGHT TAKEN PANCREAS (PA) 3.8970 .0953 % .0567 WEIGHT TAKEN LF TESTIS (TE0) 5.7840 .1414 % .0842 WEIGHT TAKEN RT TESTIS (TE1) 6.0340 .1475 % .0878 WEIGHT TAKEN LF THYROID/PARA (TT0) .1490 .0036 % .0022 WEIGHT TAKEN RT THYROID/PARA (TT1) .1690 .0041 % .0025 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL LUNG (LU) : LUNG (LU) : -MOTTLED; ALL LOBES: RED AND GRAY -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 PAGE: 28 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 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 PAGE: 29 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .2260 .0053 % .0034 WEIGHT TAKEN RT ADRENAL (AD1) .2200 .0051 % .0033 WEIGHT TAKEN BRAIN (BR) 67.1490 1.5671 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.1590 .0504 % .0322 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 2.2640 .0528 % .0337 WEIGHT TAKEN LF KIDNEY (KD0) 7.2760 .1698 % .1084 WEIGHT TAKEN RT KIDNEY (KD1) 6.9880 .1631 % .1041 WEIGHT TAKEN LIVER (LI) 79.9010 1.8647 % 1.1899 WEIGHT TAKEN PANCREAS (PA) 5.6250 .1313 % .0838 WEIGHT TAKEN LF TESTIS (TE0) 16.7130 .3900 % .2489 WEIGHT TAKEN RT TESTIS (TE1) 15.2510 .3559 % .2271 WEIGHT TAKEN LF THYROID/PARA (TT0) .4190 .0098 % .0062 WEIGHT TAKEN RT THYROID/PARA (TT1) .4110 .0096 % .0061 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 30 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- 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 GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 376 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 31 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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, 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 PAGE: 32 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .2870 .0055 % .0047 WEIGHT TAKEN RT ADRENAL (AD1) .1700 .0033 % .0028 WEIGHT TAKEN BRAIN (BR) 60.6750 1.1702 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.8850 .0364 % .0311 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.7040 .0329 % .0281 WEIGHT TAKEN LF KIDNEY (KD0) 8.8300 .1703 % .1455 WEIGHT TAKEN RT KIDNEY (KD1) 8.9130 .1719 % .1469 WEIGHT TAKEN LIVER (LI) 96.5540 1.8622 % 1.5913 WEIGHT TAKEN PANCREAS (PA) 5.0640 .0977 % .0835 WEIGHT TAKEN LF TESTIS (TE0) 13.9480 .2690 % .2299 WEIGHT TAKEN RT TESTIS (TE1) 12.8270 .2474 % .2114 WEIGHT TAKEN LF THYROID/PARA (TT0) .4870 .0094 % .0080 WEIGHT TAKEN RT THYROID/PARA (TT1) .4000 .0077 % .0066 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : LIVER (LI) : -DIFFUSELY DARK; ALL LOBES: BROWN -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 PAGE: 33 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- PARATHYROID (PT) : PARATHYROID (PT) : -CYST(S); LEFT: SINGLE CLEAR FLUID FILLED CYST, 0.5 CM IN -CYST, GLANDULAR,-PRESENT DIAMETER 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) : LN, TRACHEOBRON (TB) : -DIFFUSELY DARK; BROWN (CAP 32) -PIGMENT,-SLIGHT GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 379 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 34 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (GB), 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) ------------------------------------------------------------------------------------------------------------------------------------ 380 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 35 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .2410 .0055 % .0039 WEIGHT TAKEN RT ADRENAL (AD1) .1650 .0038 % .0026 WEIGHT TAKEN BRAIN (BR) 62.4710 1.4295 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.7270 .0395 % .0276 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.4860 .0340 % .0238 WEIGHT TAKEN LF KIDNEY (KD0) 6.5780 .1505 % .1053 WEIGHT TAKEN RT KIDNEY (KD1) 6.0930 .1394 % .0975 WEIGHT TAKEN LIVER (LI) 69.7310 1.5957 % 1.1162 WEIGHT TAKEN PANCREAS (PA) 5.5490 .1270 % .0888 WEIGHT TAKEN LF TESTIS (TE0) 9.9860 .2285 % .1599 WEIGHT TAKEN RT TESTIS (TE1) 10.5520 .2415 % .1689 WEIGHT TAKEN LF THYROID/PARA (TT0) .1940 .0044 % .0031 WEIGHT TAKEN RT THYROID/PARA (TT1) .1630 .0037 % .0026 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 36 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- STOMACH, GL (ST) : -INFLAMMATION, CHRONIC,-SLIGHT -PARASITISM,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 382 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 37 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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, 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 (CE), COLON (CO), RECTUM (RE), SKIN (SK), MAMMARY, MALE (MM), SEMINAL VESICLES (SV), EPIDIDYMIDES (EP) ------------------------------------------------------------------------------------------------------------------------------------ 383 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 38 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3130 .0090 % .0044 WEIGHT TAKEN RT ADRENAL (AD1) .2190 .0063 % .0031 WEIGHT TAKEN BRAIN (BR) 71.1770 2.0365 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.5920 .0456 % .0224 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.7130 .0490 % .0241 WEIGHT TAKEN LF KIDNEY (KD0) 5.1720 .1480 % .0727 WEIGHT TAKEN RT KIDNEY (KD1) 5.1810 .1482 % .0728 WEIGHT TAKEN LIVER (LI) 62.3470 1.7839 % .8759 WEIGHT TAKEN PANCREAS (PA) 5.4140 .1549 % .0761 WEIGHT TAKEN LF TESTIS (TE0) 10.1740 .2911 % .1429 WEIGHT TAKEN RT TESTIS (TE1) 9.9220 .2839 % .1394 WEIGHT TAKEN LF THYROID/PARA (TT0) .4390 .0126 % .0062 WEIGHT TAKEN RT THYROID/PARA (TT1) .4370 .0125 % .0061 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 39 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- MUSCLE, SKELETAL (SM) : -PARASITISM,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 385 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 40 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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, 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 PAGE: 41 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .4390 .0104 % .0072 WEIGHT TAKEN RT ADRENAL (AD1) .2920 .0069 % .0048 WEIGHT TAKEN BRAIN (BR) 60.5780 1.4321 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.8910 .0447 % .0312 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.8030 .0426 % .0298 WEIGHT TAKEN LF KIDNEY (KD0) 8.1130 .1918 % .1339 WEIGHT TAKEN RT KIDNEY (KD1) 7.9120 .1870 % .1306 WEIGHT TAKEN LIVER (LI) 82.5510 1.9516 % 1.3627 WEIGHT TAKEN PANCREAS (PA) 6.4950 .1535 % .1072 WEIGHT TAKEN LF TESTIS (TE0) 12.2990 .2908 % .2030 WEIGHT TAKEN RT TESTIS (TE1) 11.9690 .2830 % .1976 WEIGHT TAKEN LF THYROID/PARA (TT0) .2810 .0066 % .0046 WEIGHT TAKEN RT THYROID/PARA (TT1) .2740 .0065 % .0045 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 42 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- THYROID (TY) : -ECTOPIC THYMUS,-PRESENT SKIN (SK) : SKIN (SK) : -CRUSTED AREA(S); LEFT SIDE OF MUZZLE: SINGLE DARK BROWN, -ACANTHOSIS,-MODERATE DRY AREA, 0.6 CM IN DIAMETER (CAP 32) -INFLAMMATION, CHRONIC,-SLIGHT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL SEMINAL VESICLES (SV) : -MINERALIZATION,-MINIMAL GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 388 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 43 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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), MAMMARY, MALE (MM), EPIDIDYMIDES (EP) ------------------------------------------------------------------------------------------------------------------------------------ 389 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 44 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3150 .0093 % .0045 EXCLUDE RT ADRENAL (AD1) .2230 .0066 % .0032 EXCLUDE BRAIN (BR) 70.4970 2.0765 % 1.0000 EXCLUDE LF EPIDIDYMIS (EP0) 1.0740 .0316 % .0152 EXCLUDE RT EPIDIDYMIS (EP1) 1.1260 .0332 % .0160 EXCLUDE LF KIDNEY (KD0) 5.2860 .1557 % .0750 EXCLUDE RT KIDNEY (KD1) 5.3070 .1563 % .0753 EXCLUDE LIVER (LI) 63.4060 1.8676 % .8994 EXCLUDE PANCREAS (PA) 5.1560 .1519 % .0731 EXCLUDE LF TESTIS (TE0) 5.4680 .1611 % .0776 EXCLUDE RT TESTIS (TE1) 5.6610 .1667 % .0803 EXCLUDE LF THYROID/PARA (TT0) .1370 .0040 % .0019 EXCLUDE RT THYROID/PARA (TT1) .1310 .0039 % .0019 EXCLUDE ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 45 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- SALIV GL, MANDIB (SG) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 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 (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), 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 PAGE: 46 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3540 .0083 % .0046 WEIGHT TAKEN RT ADRENAL (AD1) .3250 .0076 % .0042 WEIGHT TAKEN BRAIN (BR) 76.8210 1.7970 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.6580 .0388 % .0216 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.5980 .0374 % .0208 WEIGHT TAKEN LF KIDNEY (KD0) 8.3990 .1965 % .1093 WEIGHT TAKEN RT KIDNEY (KD1) 8.4590 .1979 % .1101 WEIGHT TAKEN LIVER (LI) 87.4080 2.0446 % 1.1378 WEIGHT TAKEN PANCREAS (PA) 6.4850 .1517 % .0844 WEIGHT TAKEN LF TESTIS (TE0) 8.7630 .2050 % .1141 WEIGHT TAKEN RT TESTIS (TE1) 8.4290 .1972 % .1097 WEIGHT TAKEN LF THYROID/PARA (TT0) .2930 .0069 % .0038 WEIGHT TAKEN RT THYROID/PARA (TT1) .3050 .0071 % .0040 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : LIVER (LI) : >NOTE:>TRIMMING COMMENT: LIVER GALLBLADDER SECTION NOT FOUND -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL AT TRIMMING 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 PAGE: 47 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL 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 (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), 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 PAGE: 48 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3190 .0083 % .0055 EXCLUDE RT ADRENAL (AD1) .3180 .0083 % .0055 EXCLUDE BRAIN (BR) 57.7460 1.4999 % 1.0000 EXCLUDE LF EPIDIDYMIS (EP0) 1.8990 .0493 % .0329 EXCLUDE RT EPIDIDYMIS (EP1) 1.9690 .0511 % .0341 EXCLUDE LF KIDNEY (KD0) 6.1270 .1591 % .1061 EXCLUDE RT KIDNEY (KD1) 6.7780 .1761 % .1174 EXCLUDE LIVER (LI) 59.5960 1.5479 % 1.0320 EXCLUDE PANCREAS (PA) 4.7660 .1238 % .0825 EXCLUDE LF TESTIS (TE0) 14.5170 .3771 % .2514 EXCLUDE RT TESTIS (TE1) 13.5200 .3512 % .2341 EXCLUDE LF THYROID/PARA (TT0) .1430 .0037 % .0025 EXCLUDE RT THYROID/PARA (TT1) .1270 .0033 % .0022 EXCLUDE ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- 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) : KIDNEY (KD) : -CYST(S); RIGHT CORTICAL SURFACE: SINGLE CLEAR FLUID FILLED -CYST,-MODERATE CYST, 0.4 CM IN DIAMETER -MINERALIZATION, TUBULAR,-MINIMAL 394 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 49 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- 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) : LN, MANDIBULAR (MN) : -LARGE; BILATERAL: EACH IS UP TO 1.4 X 1.0 X 0.8 CM (CAP 32) >UNREMARKABLE GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -------------------------------------------- 395 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 50 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 PAGE: 51 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3100 .0092 % .0043 WEIGHT TAKEN RT ADRENAL (AD1) .1990 .0059 % .0028 WEIGHT TAKEN BRAIN (BR) 71.6710 2.1236 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 2.1310 .0631 % .0297 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.9500 .0578 % .0272 WEIGHT TAKEN LF KIDNEY (KD0) 9.8190 .2909 % .1370 WEIGHT TAKEN RT KIDNEY (KD1) 9.8410 .2916 % .1373 WEIGHT TAKEN LIVER (LI) 93.3770 2.7667 % 1.3029 WEIGHT TAKEN PANCREAS (PA) 6.0370 .1789 % .0842 WEIGHT TAKEN LF TESTIS (TE0) 11.8290 .3505 % .1650 WEIGHT TAKEN RT TESTIS (TE1) 11.3470 .3362 % .1583 WEIGHT TAKEN LF THYROID/PARA (TT0) .1940 .0057 % .0027 WEIGHT TAKEN RT THYROID/PARA (TT1) .1250 .0037 % .0017 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY 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 PAGE: 52 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LN, MESENTERIC (MS) : -PIGMENT,-MINIMAL URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL PROSTATE (PR) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS -NO MACROSCOPIC LESIONS -------------------------------------------- 398 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 53 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 (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, 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 PAGE: 54 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3570 .0075 % .0049 EXCLUDE RT ADRENAL (AD1) .2810 .0059 % .0039 EXCLUDE BRAIN (BR) 72.5150 1.5331 % 1.0000 EXCLUDE LF EPIDIDYMIS (EP0) 1.4080 .0298 % .0194 EXCLUDE RT EPIDIDYMIS (EP1) 1.6810 .0355 % .0232 EXCLUDE LF KIDNEY (KD0) 9.3880 .1985 % .1295 EXCLUDE RT KIDNEY (KD1) 8.4920 .1795 % .1171 EXCLUDE LIVER (LI) 94.6850 2.0018 % 1.3057 EXCLUDE PANCREAS (PA) 5.9610 .1260 % .0822 EXCLUDE LF TESTIS (TE0) 9.1580 .1936 % .1263 EXCLUDE RT TESTIS (TE1) 8.6990 .1839 % .1200 EXCLUDE LF THYROID/PARA (TT0) .3060 .0065 % .0042 EXCLUDE RT THYROID/PARA (TT1) .2680 .0057 % .0037 EXCLUDE ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- LIVER (LI) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL -PIGMENT, KUPFFER CELL,-MINIMAL LUNG (LU) : -PIGMENT,-MINIMAL THYROID (TY) : -ECTOPIC THYMUS,-PRESENT URINARY BLADDER (UB) : -INFILTRATE, LYMPHOHISTIOCYTIC,-MINIMAL GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS 400 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 55 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY 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 (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), 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 PAGE: 56 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ ABSOLUTE ORGAN WEIGHT ORGAN WEIGHT RELATIVE ORGAN TO BRAIN ORGAN ORGAN NAME (GRAMS) TO BODY WEIGHT (%) WEIGHT RATIO STATUS ---------------------- -------- -------- -------- ----------- LF ADRENAL (AD0) .3680 .0105 % .0066 WEIGHT TAKEN RT ADRENAL (AD1) .2850 .0081 % .0051 WEIGHT TAKEN BRAIN (BR) 56.1560 1.6022 % 1.0000 WEIGHT TAKEN LF EPIDIDYMIS (EP0) 1.1670 .0333 % .0208 WEIGHT TAKEN RT EPIDIDYMIS (EP1) 1.3200 .0377 % .0235 WEIGHT TAKEN LF KIDNEY (KD0) 7.9420 .2266 % .1414 WEIGHT TAKEN RT KIDNEY (KD1) 7.6550 .2184 % .1363 WEIGHT TAKEN LIVER (LI) 83.1880 2.3734 % 1.4814 WEIGHT TAKEN PANCREAS (PA) 6.3820 .1821 % .1136 WEIGHT TAKEN LF TESTIS (TE0) 5.0850 .1451 % .0906 WEIGHT TAKEN RT TESTIS (TE1) 5.3130 .1516 % .0946 WEIGHT TAKEN LF THYROID/PARA (TT0) .1970 .0056 % .0035 WEIGHT TAKEN RT THYROID/PARA (TT1) .2210 .0063 % .0039 WEIGHT TAKEN ------------------------------------------------------------------------------------------------------------------------------------ OBSERVATIONS NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- ADRENAL, CORTEX (AC) : -HYPERTROPHY, CORTICAL CELL,-MINIMAL LIVER (LI) : LIVER (LI) : -DIFFUSELY LIGHT; ALL LOBES: TAN -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 PAGE: 57 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY HISTOPATHOLOGY ---------------------------------------------------------------- ---------------------------------------------------------------- KIDNEY (KD) : -MINERALIZATION, TUBULAR,-SLIGHT -VACUOLATION, TUBULAR EPITHELIUM,-SLIGHT HEART (HT) : HEART (HT) : -DIFFUSELY LIGHT; TAN -DEGENERATION/NECROSIS,-SLIGHT THYMUS (TH) : -INVOLUTION,-MODERATELY SEVERE LN, MESENTERIC (MS) : -INFILTRATE, NEUTROPHILIC,-SLIGHT ESOPHAGUS (ES) : ESOPHAGUS (ES) : -THICKENED WALL; AREA THAT LIES ALONG THE LUNGS: FIRM -EDEMA, SUBMUCOSAL,-MODERATELY SEVERE -LARGE; AREA THAT LIES ALONG THE LUNGS: UP TO 1.0 CM IN -EROSION,-MODERATE DIAMETER -INFLAMMATION, ACUTE,-SLIGHT -ULCERATION,-MINIMAL STOMACH, GL (ST) : STOMACH, GL (ST) : -THICKENED WALL; DIFFUSE -EROSION,-SLIGHT -DARK FOCUS(I)/AREA(S); MUCOSA: MULTIPLE, DARK BROWN FOCI, -ULCERATION,-MODERATE UP TO 0.1 CM IN DIAMETER ILEUM (IL) : -INFLAMMATION, ACUTE,-MINIMAL CECUM (CE) : -INFLAMMATION, ACUTE,-MINIMAL CAUSE OF DEATH (CD) : -DOSING INJURY,-PRESENT GENERAL COMMENT (GC) : -BONE MARROW SMEAR TAKEN -EYES - DAVIDSONS 403 APPENDIX 5 Individual Anatomic Pathology Data Covance 6329-231 3M T-6889.3 PAGE: 58 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 ------------------------------------------------------------------------------------------------------------------------------------ O B S E R V A T I O N S (CONTINUED) NECROPSY 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 (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, 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-6889.3 406 Covance 6329-231 3M T-6889.3 407 Covance 6329-231 3M T-6889.3 408 Covance 6329-231 3M T-6889.3 409 Appendix 6 Summary of Hormone Analyses Data Day -18 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 52.49 10.538 6 32.82 11.396 6 0.00 0.000 6 0.60 0.446 6 258.48 66.361 6 5.65 1.130 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 48.22 3.001 4 36.82 4.435 4 0.01 0.025 4 0.53 0.713 4 316.73 54.114 4 4.43 0.746 4 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 49.71 9.152 6 33.94 6.474 6 0.00 0.000 6 0.38 0.437 6 253.91 39.961 6 3.92 1.142 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 50.97 11.508 6 27.54 5.889 6 0.00 0.000 6 0.27 0.192 6 245.32 59.058 6 4.82 0.988 6 FREE TRIIODOTHYRONINE pg/mL ---------------- 9.74 0.983 6 9.65 0.598 4 8.88 1.805 6 8.17 1.006 6 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 2.96 0.483 6 3.13 0.338 4 2.55 0.399 6 2.81 0.334 6 410 Appendix 6 Summary of Hormone Analyses Data Day -8 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 53.67 12.749 6 29.96 12.677 6 0.00 0.000 6 0.61 0.321 6 222.54 60.023 6 3.93 0.554 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 47.64 8.506 4 31.53 3.840 4 0.00 0.000 4 0.68 0.715 4 247.69 32.547 4 3.71 0.345 4 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 54.51 9.283 6 34.54 5.880 6 0.00 0.000 6 0.56 0.556 6 253.54 74.851 6 3.49 0.865 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 49.94 10.167 6 29.81 7.632 6 0.00 0.000 6 0.73 0.605 6 198.91 45.640 6 4.24 1.244 6 FREE TRIIODOTHYRONINE pg/mL ---------------- 9.47 1.516 6 11.11 1.705 4 10.28 1.404 6 10.92 2.387 6 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 2.58 0.682 6 2.28 0.367 4 2.24 0.407 6 2.86 0.638 6 411 Appendix 6 Summary of Hormone Analyses Data Day -4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 38.98 10.162 6 24.88 6.306 6 0.00 0.000 6 0.37 0.363 6 155.11 18.112 6 5.13 0.809 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 40.20 6.930 4 35.09 9.703 4 0.00 0.000 4 0.53 0.583 4 149.69 26.462 4 5.16 1.284 4 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 37.25 4.702 6 30.16 7.409 6 0.00 0.000 6 0.46 0.571 6 169.61 23.153 6 4.17 0.511 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 39.40 10.143 6 27.73 6.663 6 0.00 0.000 6 0.29 0.279 6 147.22 16.027 6 4.51 0.788 6 FREE TRIIODOTHYRONINE pg/mL ---------------- 6.39 0.634 6 6.06 0.628 4 6.16 0.440 6 6.00 0.877 6 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.77 0.288 6 1.72 0.354 4 1.56 0.178 6 1.56 0.257 6 412 Appendix 6 Summary of Hormone Analyses Data Day 35 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 46.54 9.590 6 7.62 6.963 6 0.00 0.000 6 0.23 0.232 6 170.71 15.946 6 4.72 0.946 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 41.44 10.467 4 14.67 12.614 4 0.00 0.000 4 0.36 0.533 4 166.57 29.681 4 4.02 0.756 4 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 37.54 7.589 6 11.23 7.403 6 0.00 0.000 6 0.26 0.440 6 151.51 15.053 6 2.95 0.463 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 36.69 11.745 5 4.63 7.126 5 0.00 0.000 5 0.03 0.044 5 109.80 39.245 5 3.70 0.286 5 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.49 0.699 6 5.58 0.652 4 5.13 0.414 6 3.79 1.178 5 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.60 0.341 6 1.47 0.158 4 1.09 0.171 6 1.23 0.058 5 413 Appendix 6 Summary of Hormone Analyses Data Day 66 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 39.60 7.881 6 15.00 12.534 6 0.00 0.000 6 0.23 0.343 6 163.31 19.398 6 4.65 0.864 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 36.63 7.000 4 18.31 11.446 4 0.00 0.000 4 0.19 0.274 4 169.92 20.976 4 3.52 0.525 4 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 36.04 11.306 6 19.83 10.105 6 0.00 0.000 6 0.56 1.067 6 162.50 9.951 6 3.04 0.455 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 21.78 6.437 4 2.06 4.125 4 0.00 0.000 4 0.22 0.252 4 89.66 51.035 4 3.27 1.023 4 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.71 1.143 6 6.23 0.590 4 5.31 0.537 6 3.01 1.958 4 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.48 0.263 6 1.34 0.300 4 1.08 0.199 6 1.08 0.263 4 414 Appendix 6 Summary of Hormone Analyses Data Day 94 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 41.74 8.263 6 13.46 10.122 6 0.00 0.000 6 0.54 0.463 6 162.04 25.417 6 4.22 0.902 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 37.11 5.322 4 7.74 7.822 4 0.00 0.000 4 0.60 0.552 4 176.93 27.852 4 3.55 0.375 4 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 35.52 8.323 6 6.41 7.867 6 0.00 0.000 6 0.38 0.529 6 156.97 18.134 6 2.93 0.420 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 28.18 8.832 2 0.00 0.000 2 0.00 0.000 2 0.20 0.106 2 120.02 35.171 2 3.76 0.424 2 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.02 0.732 6 5.28 0.343 4 4.98 0.894 6 3.96 1.464 2 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.49 0.504 6 1.32 0.278 4 1.06 0.197 6 1.34 0.269 2 415 Appendix 6 Summary of Hormone Analyses Data Day 183 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 38.69 10.736 6 10.75 17.027 6 0.00 0.000 6 0.40 0.231 6 157.28 15.387 6 3.84 0.769 6 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 46.87 17.528 3 13.56 11.112 3 0.00 0.000 3 0.65 0.171 3 133.47 16.777 3 2.58 0.173 3 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 32.65 7.402 6 7.83 6.225 6 0.00 0.000 6 0.87 1.088 6 134.47 22.554 6 2.71 0.351 6 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 26.90 1.365 2 0.00 0.000 2 0.00 0.000 2 0.39 0.099 2 103.37 32.958 2 2.61 0.247 2 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.62 0.893 6 4.87 0.121 3 4.67 0.637 6 3.39 1.541 2 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.55 0.426 6 1.04 0.035 3 0.96 0.131 6 0.90 0.240 2 416 Appendix 6 Summary of Hormone Analyses Data Day 220 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 51.58 22.847 2 44.19 18.569 2 0.00 0.000 2 0.17 0.212 2 170.61 6.456 2 3.44 1.400 2 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 27.20 8.853 2 27.85 3.974 2 0.00 0.000 2 0.42 0.424 2 175.08 4.660 2 3.39 0.283 2 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.44 0.269 2 5.54 0.445 2 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 0.87 0.474 2 0.93 0.134 2 417 Appendix 6 Summary of Hormone Analyses Data Day 248 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 46.80 7.276 2 40.43 19.537 2 0.00 0.000 2 0.06 0.078 2 162.75 1.853 2 3.46 1.485 2 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 33.81 11.413 2 30.91 7.149 2 0.00 0.000 2 0.34 0.092 2 173.48 17.211 2 3.91 0.163 2 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.36 1.252 2 7.19 0.679 2 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.02 0.629 2 1.13 0.028 2 418 Appendix 6 Summary of Hormone Analyses Data Day 276 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 71.61 18.180 2 46.33 21.362 2 0.00 0.000 2 0.00 0.000 2 167.29 16.023 2 4.81 0.841 2 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 35.81 4.695 2 30.17 10.218 2 0.00 0.000 2 0.01 0.014 2 172.47 35.447 2 4.05 0.396 2 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.02 0.453 2 6.02 0.078 2 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.48 0.728 2 1.47 0.318 2 419 Appendix 6 Covance 6329-231 3M T-6889.3 Summary of Testosterone Analyses Data (ng/mL) PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ DAY DAY DAY DAY DAY DAY DAY DAY DAY DAY -18 -8 -4 35 66 94 183 220 248 276 ------------------------------------------------------------------------------------------------------------------------------------ Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day MEAN S.D. N 2.96 1.917 6 6.53 10.033 6 3.83 3.376 6 2.22 2.629 6 3.67 3.615 6 4.95 4.423 6 6.33 4.070 6 3.90 0.834 2 5.27 0.332 2 9.25 2.362 2 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day MEAN S.D. N 2.87 1.592 4 2.94 2.008 4 6.67 6.550 4 3.03 2.991 4 3.68 2.259 4 7.36 2.656 4 7.81 4.274 3 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day MEAN S.D. N 3.60 2.793 6 3.81 3.896 6 2.47 2.423 6 2.00 2.016 6 5.15 3.918 6 2.89 2.055 6 7.83 3.685 6 5.70 2.213 2 5.58 2.341 2 15.23 17.501 2 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day MEAN S.D. N 1.20 0.505 6 2.13 2.311 6 3.97 3.205 6 0.81 0.484 5 2.76 3.007 4 1.25 0.092 2 1.74 0.438 2 420 Appendix 6 Individual Hormone Analyses Data Day -18 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.46 0.37 1.32 0.00 0.80 0.67 232.97 189.19 180.50 327.72 323.10 297.42 5.94 5.08 4.93 7.57 4.37 6.02 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 52.71 46.90 46.88 46.40 30.68 36.46 39.75 40.37 0.00 0.05 0.00 0.00 0.11 0.46 0.00 1.56 255.67 296.53 331.42 383.31 3.88 3.69 5.07 5.07 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.01 0.49 0.70 1.05 0.00 311.45 269.41 234.48 226.15 202.58 279.41 2.77 2.75 3.64 4.11 4.49 5.76 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.28 0.00 0.22 0.40 0.55 0.15 293.22 257.86 231.62 148.42 224.85 315.97 5.94 5.99 3.90 4.67 3.64 4.79 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 Appendix 6 Individual Hormone Analyses Data Day -8 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.51 0.66 0.95 0.02 0.77 0.73 263.59 295.00 270.09 178.30 159.73 168.55 4.29 3.85 3.93 4.62 2.97 3.93 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 49.71 57.64 46.05 37.14 27.23 34.02 35.42 29.43 0.00 0.00 0.00 0.00 0.09 0.94 0.11 1.57 257.73 254.81 277.04 201.16 3.35 3.69 4.18 3.63 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.36 0.39 0.34 0.68 1.61 0.00 213.19 285.05 249.20 352.02 288.47 133.31 3.26 2.48 4.58 4.50 3.26 2.85 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.38 0.00 0.32 0.95 1.09 1.64 177.15 158.15 246.01 266.86 166.93 178.37 3.42 5.38 2.68 5.89 4.55 3.52 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 Appendix 6 Individual Hormone Analyses Data Day -4 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.06 0.15 0.46 0.00 0.63 0.92 136.58 140.65 150.86 183.59 169.99 149.01 4.58 5.25 4.43 5.66 4.41 6.42 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 35.97 50.27 39.26 35.31 22.63 34.06 46.03 37.63 0.00 0.00 0.00 0.00 0.27 0.02 0.48 1.36 112.59 154.40 175.31 156.45 4.19 4.25 6.94 5.24 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.25 0.00 0.58 0.41 1.53 0.00 172.89 162.30 148.51 214.06 161.96 157.92 3.55 3.93 4.15 5.09 4.25 4.06 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.37 0.00 0.10 0.51 0.06 0.69 168.50 146.82 130.79 149.03 127.68 160.50 3.81 5.63 3.51 4.57 5.10 4.42 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 Appendix 6 Individual Hormone Analyses Data Day 35 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/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 0.29 151.08 172.92 158.25 169.74 174.95 197.30 5.15 5.13 4.28 6.18 3.90 3.66 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717a I05721 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 1.15 147.88 149.50 210.55 158.33 3.04 3.84 4.47 4.74 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 162.71 144.58 144.62 172.47 154.68 130.00 3.08 2.31 3.01 3.20 2.51 3.57 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 0.04 151.98 142.88 74.00 114.82 65.30 3.56 3.62 3.35 3.95 4.04 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 Appendix 6 Individual Hormone Analyses Data Day 66 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.81 0.01 0.01 0.50 0.06 161.17 136.94 152.11 157.79 187.17 184.67 5.42 4.54 4.08 5.72 3.37 4.78 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 44.91 34.58 38.76 28.28 16.02 6.14 33.76 17.31 0.00 0.00 0.00 0.00 0.01 0.06 0.10 0.60 141.93 165.96 188.15 183.65 2.84 3.92 3.95 3.38 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.22 0.26 0.11 2.73 0.00 164.93 159.20 160.10 179.10 163.19 148.48 2.84 2.35 3.15 3.47 2.87 3.58 Group: Male 4 Dose Level: 20 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.01 0.02 0.41 0.47 86.91 146.63 107.53 101.86 23.24 2.79 4.09 2.32 4.15 2.06 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 Appendix 6 Individual Hormone Analyses Data Day 94 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.29 0.64 0.03 0.43 1.39 0.48 149.21 147.60 124.41 179.12 187.51 184.41 4.48 3.49 3.38 5.76 3.68 4.53 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721 43.91 37.28 36.31 30.94 4.65 0.00 18.42 7.90 0.00 0.00 0.00 0.00 0.73 0.32 0.04 1.31 147.42 169.30 214.32 176.69 3.01 3.75 3.85 3.57 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.14 0.20 0.32 0.18 1.44 0.00 159.36 169.28 132.05 180.58 160.71 139.81 3.49 3.03 2.90 2.57 2.35 3.23 Group: Male 4 Dose Level: 20 d I05703 I05704c I05711 I05713e I05722 34.25 34.42 41.78 21.93 28.22 7.04 0.00 4.84 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Dosage Unit: mg/kg/day 0.00 0.12 0.19 0.27 1.27 162.68 144.89 128.34 95.15 121.72 2.91 4.06 2.63 3.46 3.08 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 Appendix 6 Individual Hormone Analyses Data Day 183 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.77 0.21 0.41 0.41 0.47 137.07 151.09 145.02 174.04 162.47 173.98 4.02 3.19 3.88 5.01 2.81 4.10 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 66.27 32.18 42.15 18.72 0.81 21.16 0.00 0.00 0.00 0.83 0.49 0.63 129.99 118.70 151.71 2.43 2.54 2.77 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.51 0.75 0.91 2.97 0.09 132.21 135.82 108.04 175.84 123.73 131.15 3.34 2.47 2.82 2.61 2.34 2.65 Group: Male 4 Dose Level: 20 d I05703 I05704 I05711c I05713e I05722 38.78 25.93 42.26 27.86 34.96 10.05 0.00 22.30 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Dosage Unit: mg/kg/day 0.08 0.32 0.08 0.46 0.47 160.48 126.67 116.73 80.06 123.04 2.75 2.78 2.72 2.43 1.93 FREE TRIIODOTHYRONINE pg/mL ---------------- 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 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 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 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). 427 Appendix 6 Individual Hormone Analyses Data Day 220 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 67.73 35.42 57.32 31.06 0.00 0.00 0.02 0.32 166.04 175.17 4.43 2.45 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 20.94 33.46 30.66 25.04 0.00 0.00 0.12 0.72 178.37 171.78 3.59 3.19 FREE TRIIODOTHYRONINE pg/mL ---------------- 5.25 5.63 5.85 5.22 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.20 0.53 1.02 0.83 428 Appendix 6 Individual Hormone Analyses Data Day 248 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 51.94 41.65 54.24 26.61 0.00 0.00 0.00 0.11 164.06 161.44 4.51 2.41 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 25.74 41.88 25.85 35.96 0.00 0.00 0.40 0.27 185.65 161.31 4.02 3.79 FREE TRIIODOTHYRONINE pg/mL ---------------- 4.47 6.24 7.67 6.71 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.46 0.57 1.15 1.11 429 Appendix 6 Individual Hormone Analyses Data Day 276 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ANIMAL NUMBER ------ ESTRONE pg/mL ------- ESTRADIOL pg/mL --------- ESTRIOL ng/mL ------- THYROID STIMULATING HORMONE IU/mL ------------------- TOTAL TRIIODOTHYRONINE ng/dL ---------------- TOTAL THYROXIN g/DL -------- Group: Male 1 Dose Level: 0 Dosage Unit: mg/kg/day I05718 I05720 58.75 84.46 61.43 31.22 0.00 0.00 0.00 0.00 155.96 178.62 5.40 4.21 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day I05712 I05716 32.49 39.13 37.39 22.94 0.00 0.00 0.02 0.00 197.53 147.40 4.33 3.77 FREE TRIIODOTHYRONINE pg/mL ---------------- 4.70 5.34 6.07 5.96 Covance 6329-231 3M T-6889.3 FREE THYROXIN ng/dL -------- 1.99 0.96 1.69 1.24 430 Appendix 6 Covance 6329-231 3M T-6889.3 Individual Testosterone Analyses Data (ng/mL) PAGE: 1 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 Dosage Unit: mg/kg/day 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 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 0.53 1.23 2.06 11.85 6.94 7.08 12.09 1.91 4.82 10.58 3.44 5.14 3.31 4.49 5.03 5.50 7.58 10.92 Group: Male 2 Dose Level: 3 Dosage Unit: mg/kg/day I05702 I05706 I05717 I05721a 2.39 4.91 3.07 1.09 1.98 5.94 2.11 1.72 1.70 14.34 9.87 0.76 1.45 7.43 2.30 0.92 1.98 4.78 6.32 1.62 6.73 8.20 10.42 4.09 3.88 7.19 12.36 Group: Male 3 Dose Level: 10 Dosage Unit: mg/kg/day 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 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 0.15 3.82 2.21 2.10 6.30 2.73 4.02 10.03 13.09 3.69 9.42 6.74 7.26 4.13 7.23 3.92 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 Covance 6329-231 3M T-6889.3 Individual Testosterone Analyses Data (ng/mL) PAGE: 2 26-WEEK CAPSULE TOXICITY STUDY WITH AMMONIUM PERFLUOROOCTANOATE (APFO) IN CYNOMOLGUS MONKEYS ------------------------------------------------------------------------------------------------------------------------------------ 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 b Dose Level: 20 Dosage Unit: mg/kg/day I05703c I05704 I05711d I05713 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 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. Beginning 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). 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 3M T-6889.3 434 Covance 6329-231 3M T-6889.3 435 Covance 6329-231 3M T-6889.3 436 Covance 6329-231 3M T-6889.3 437 Covance 6329-231 3M T-6889.3 438 Covance 6329-231 3M T-6889.3 439 Covance 6329-231 3M T-6889.3 440 Covance 6329-231 3M T-6889.3 441 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-6889.3 443 Covance 6329-231 3M T-6889.3 444 Covance 6329-231 3M T-6889.3 445 Covance 6329-231 3M T-6889.3 446 Covance 6329-231 3M T-6889.3 447 Covance 6329-231 3M T-6889.3 448 Covance 6329-231 3M T-6889.3 449 Covance 6329-231 3M T-6889.3 450 Covance 6329-231 3M T-6889.3 451 Covance 6329-231 3M T-6889.3 452 Covance 6329-231 3M T-6889.3 453 Covance 6329-231 3M T-6889.3 454 Covance 6329-231 3M T-6889.3 455 Covance 6329-231 3M T-6889.3 456 Covance 6329-231 3M T-6889.3 457 Covance 6329-231 3M T-6889.3 458 Covance 6329-231 3M T-6889.3 459 Covance 6329-231 3M T-6889.3 460 Covance 6329-231 3M T-6889.3 461 Covance 6329-231 3M T-6889.3 462 Covance 6329-231 3M T-6889.3 463