Document gay4BB67EZV26r5M7ODnY411J

Aventis Pharma Aventis Pharma Deutschland GmbH Testing Facility Kastengrund ProTox Mainzer Landstr. 500 D - 65795 Hattersheim Germany AR226-1525 Aventis RECEIVED OPPT NCIC 03 SEP 30 PM1:00 TOXICOLOGY STUDY REPORT PT02-0222 T-7758 RAT REPEAT DOSE 28-DAY ORAL TOXICITY + 14-DAYS RECOVERY Author: Date: Original report for the sponsor Total pages: 464 Dr. G. Ehling 18-Aug-2003 3M study number: T-7758.1 Report ID: PT02-0222 Toxicology Study Report - PT02-0222 TABLE OF CONTENTS 1 SUMMARY..............................................................................................................................................7 1.1 OBSERVATIONS AND MEASUREMENTS..................................................................................... 7 1.2 RESULTS..........................................................................................................................................8 1.3 CONCLUSION...................................................................................................................................8 2 STATEMENTS........................................................................................................................................9 2.1 SCHEDULING...................................................................................................................................9 2.2 APPROVALS.....................................................................................................................................9 2.3 STATEMENT OF GOOD LABORATORY PRACTICE....................................................................10 2.4 QUALITY ASSURANCE STATEMENT...........................................................................................11 3 PROFESSIONAL AND SUPERVISORY STAFF................................................................................ 12 4 INTRODUCTION...................................................................................................................................13 4.1 OBJECTIVE.....................................................................................................................................13 4.2 GUIDELINES................................................................................................................................. 13 5 MATERIALS AND METHODS.............................................................................................................14 5.1 TEST COMPOUND.........................................................................................................................14 5.2 TEST SYSTEM................................................................................................................................15 5.3 HOUSING AND CARE OF ANIMALS........................................................................................... 15 5.4 RATIONALE FOR DOSE SELECTION...........................................................................................16 5.5 EXPERIMENTAL DESIGN..............................................................................................................16 5.6 TEST GROUPS............................................................................................................................. 17 5.7 PREPARATION OF THE TEST COMPOUND............................................................................... 18 5.8 IN-LIFE OBSERVATIONS...............................................................................................................18 5.8.1 Mortality....................................................................................................................................18 5.8.2 Clincal observations.................................................................................................................18 5.8.3 Neurological examinations.......................................................................................................19 5.8.4 Body weight..............................................................................................................................19 5.8.5 Food consumption....................................................................................................................19 Page 2 Toxicology Study Report - PT02-0222 5.9 CLINICAL PATHOLOGY................................................................................................................ 20 5.9.1 Hematological investigations................................................................................................... 20 5.9.2 Clinical Chemistry................................................................................................................... 21 5.9.3 Urinalysis................................................................................................................................. 22 5.10 ANATOMIC PATHOLOGY............................................................................................................. 23 5.10.1 Necropsy and macroscopic examination................................................................................ 23 5.10.2 Organ weights......................................................................................................................... 23 5.10.3 Macroscopic and microscopic observations........................................................................... 24 6 RESULTS..............................................................................................................................................25 6.1 DOSE SOLUTION ANALYSIS....................................................................................................... 25 6.2 IN-LIFE OBSERVATIONS.............................................................................................................. 25 6.2.1 Designation of dose groups (pathology designation in brackets*).......................................... 25 6.2.2 Behavior, state of health and mortality.................................................................................... 26 6.2.3 Clinical observation................................................................................................................. 26 6.2.4 Neurobehavioral examinations................................................................................................ 26 6.2.5 Body weight............................................................................................................................. 27 6.2.6 Food consumption................................................................................................................... 27 6.3 CLINICAL PATHOLOGY................................................................................................................ 28 6.3.1 Hematology............................................................................................................................. 28 6.3.2 Clinical chemistry................................................................................................................... 28 6.3.3 Urinalysis................................................................................................................................ 29 6.4 ANATOMIC PATHOLOGY............................................................................................................ 30 6.4.1 Organ weights........................................................................................................................ 30 6.4.2 Relative organ weights........................................................................................................... 30 6.4.3 Macroscopic observations...................................................................................................... 31 6.4.4 Microscopic observations....................................................................................................... 32 7 DISCUSSION........................................................................................................................................33 8 CONCLUSION......................................................................................................................................34 9 REFERENCES......................................................................................................................................35 9.1 HEMATOLOGY EXAMINATIONS.................................................................................................. 35 9.2 CLINICAL CHEMISTRY METHODS............................................................................................. 35 9.3 URINALYSIS...................................................................................................................................35 9.4 STATISTICAL EVALUATION........................................................................................................ 36 Page 3 Toxicology Study Report - PT02-0222 10 TABLES................................................................................................................................................37 10.1 ABBREVIATIONS, UNITS AND METHODOLOGY....................................................................... 37 10.1.1 Hematology............................................................................................................................. 37 10.1.1.1 Red cell count.................................................................................................................. 37 10.1.1.2 White cell count................................................................................................................ 37 10.1.1.3 Blood coagulation............................................................................................................ 37 10.1.2 Clinical chemistry.................................................................................................................... 38 10.1.3 Urinalysis (semiquantitative parameters evaluated)............................................................... 39 10.1.4 Urinalysis (quantitative parameters evaluated).................................................................... 39 10.2 LIST OF ABBREVIATIONS USED IN THE REPORT.................................................................... 40 11 FIGURES..............................................................................................................................................41 11.1 BODY WEIGHT (GROUPS 1 - 5)................................................................................................... 41 11.2 BODY WEIGHT (GROUPS 6 - 7)................................................................................................... 44 11.3 FOOD CONSUMPTION (GROUPS 1 - 5)..................................................................................... 47 11.4 FOOD CONSUMPTION (GROUPS 6 - 7)...................................................................................... 50 11.5 NEUROTOXICOLOGICAL EXAMINATIONS (GROUPS 1 - 5 ) ..................................................... 53 11.6 NEUROTOXICOLOGICAL EXAMINATIONS (GROUPS 6 - 7 ) ..................................................... 58 12 SUMMARY TABLES AND STATISTICS............................................................................................ 63 12.1 CLINICAL OBSERVATIONS - GROUPS 1 - 5 (INDIVIDUAL VALUES, WITHOUT STATS)........ 63 12.2 CLINICAL OBSERVATIONS - GROUPS 6 - 7 (INDIVIDUAL VALUES, WITHOUT STATS)...... 100 12.3 BODY WEIGHT (GROUPS 1 - 5)..................................................................................................105 12.4 BODY WEIGHT (GROUPS 6 - 7)..................................................................................................112 12.5 FOOD CONSUMPTION - GROUPS 1 - 5 (WITHOUT STATS).................................................. 117 12.6 FOOD CONSUMPTION - GROUPS 6 - 7 (WITHOUT STATS).................................................. 122 12.7 CLINICAL PATHOLOGY...............................................................................................................125 12.7.1 Hematology (Groups 1 - 5).....................................................................................................125 12.7.2 Hematology (Groups 6 - 7).....................................................................................................138 12.7.3 Clinical chemistry (Groups 1 - 5)........................................................................................... 145 12.7.4 Clinical chemistry (Groups 6 - 7).......................................................................................... 158 12.7.5 Urinalysis (Groups 1 - 5 )........................................................................................................165 12.7.6 Urinalysis (Groups 6 - 7 )........................................................................................................170 Page 4 Toxicology Study Report - PT02-0222 12.8 ORGAN WEIGHTS (GROUPS 1 - 5 )............................................................................................173 12.9 ORGAN WEIGHTS (GROUPS 6 - 7 )............................................................................................180 12.10 RELATIVE ORGAN WEIGHTS (GROUPS 1 - 5)........................................................................ 184 12.11 RELATIVE ORGAN WEIGHTS (GROUPS 6 - 7)......................................................................... 191 12.12 NEUROTOXICOLOGICAL EXAMINATIONS............................................................................... 195 12.12.1 Griph strength - Groups 1 - 5 .................................................................................................195 12.12.2 Griph strength - Groups 6 - 7 .................................................................................................197 12.12.3 Motor activity (Groups 1 - 5)...................................................................................................199 12.12.4 Motor activity (Groups 6 - 7).................................................................................................. 201 13 APPENDICES.....................................................................................................................................203 13.1 INDIVIDUAL TABLES................................................................................................................... 203 13.1.1 Body weights......................................................................................................................... 203 13.1.2 Food Consumption................................................................................................................ 218 13.1.3 Clinical Pathology.................................................................................................................. 233 13.1.3.1 Hematology.................................................................................................................... 233 13.1.3.2 Clinical chemistry.......................................................................................................... 280 13.1.3.3 Urinalysis (including legend).......................................................................................... 310 13.1.4 Organ weights...................................................................................................................... 336 13.1.5 Neurotoxicological examinations........................................................................................... 351 13.1.5.1 Grip strengh................................................................................................................... 351 13.1.5.2 Motor activity (movements per 60 minutes)................................................................... 366 13.2 ADDITIONAL DATA.................................................................................................................... 370 13.2.1 Composition of d ie t............................................................................................................... 370 13.2.2 Historical control data........................................................................................................... 372 13.3 REPORTS INCLUDING............................................................................................................... 375 13.3.1 Pathology report................................................................................................................... 375 Page 5 Toxicology Study Report - PT02-0222 LIST OF TABLES Table 1: Dose levels and number of animals.............................................................................................. 16 Table 2: Number of animals / Animal numbers........................................................................................... 17 Table 3: Cage numbers / Animal numbers.................................................................................................. 17 Table 4: Formulation of the test compound................................................................................................. 18 Table 5: Red Cell Counts parameters evaluated......................................................................................... 20 Table 6: White Cell Counts parameters evaluated...................................................................................... 20 Table 7: Coagulation parameters evaluated................................................................................................ 20 Table 8: Clinical Chemistry parameters evaluated...................................................................................... 21 Table 9: Urinalysis - Semiquantitative parameters evaluated..................................................................... 22 Table 10: Urinalysis - Quantitative Parameters evaluated.......................................................................... 22 Table 11: List of weighed organs................................................................................................................. 23 Table 12: List of tissues fixed and submitted for histological examinations................................................24 Table 13: Results of dose suspension analysis........................................................................................... 25 Table 14: Designation of the dose groups (1 - 5) for individual data............................................................25 Table 15: Designation of the dose groups (1- 5) for statistical evalutionand figures...................................25 Table 16: Designation of the dose groups (6- 7) for individual data............................................................25 Table 17: Designation of the dose groups (6- 7) for statistical evalutionand figures...................................25 Table 18: Mean body weight gains [g] throughout the study (Groups 1 - 5 ) ................................................ 27 Table 19: Mean body weight gains [g] throughout the study (Groups 6 - 7 ) ................................................ 27 Table 20: Mean food consumption [g/kg bw./day] throughout the study (Group 1- 5 ).................................27 Table 21: Mean food consumption [g/kg bw./day] throughout the study (Group 6- 7 )................................ 27 Page 6 Toxicology Study Report - PT02-0222 1 SUMMARY STUDY NUMBER: TITLE: AUTHOR(S): PT02-0222 T-7758 Rat repeat dose 28-day oral toxicity + 14-days recovery Dr. G. Ehling 1.1 OBSERVATIONS AND MEASUREMENTS Groups of male and female rats received T-7758 by oral gavage at dose levels of 0, 0*, 0.3*, 3, 15, 60 or 240 mg/kg body weight per day for a period of 28 days. On day 29 five males and five females from each group were killed and necropsied. Five males and five females from the control and high dose group were killed and necropsied after a recovery period of 14 days. * Another control- and low dose group was added at the end o f the in-life phase o f the other groups in order to confirm a NOEL. Behavior and state of health were observed daily in all groups. Body weights and food consumption were recorded twice weekly. Once before the first treatment and once a week thereafter, detailed clinical observations were performed in all animals outside the home cage in a standard arena ('open field'). Additionally, the animals were examined for opacity of the refracting media of the eyes and damage to the oral mucosa. Neurotoxicological measurements including assessment of sensory function, motor activity, forelimb and hindlimb grip strength, were conducted at the end of the treatment period. Hematological examinations, clinical chemistry and urine analyses were carried out at the end of the treatment period and after the recovery period. During necropsy the animals were examined for macroscopically visible abnormalities, the main organs were weighed and the organ to body weight ratios calculated. Organs and tissues were processed for histopathological examination and checked for microscopically visible changes. Body weights, hematological and clinical chemistry data, urine data (volume, specific weight), absolute and relative organ weights and neurotoxicological measurements (motor activity, forelimb and hindlimb grip strength) were analyzed with the aid of a statistical program to show differences compared to the controls. Page 7 Toxicology Study Report - PT02-0222 1.2 RESULTS T-7758 induced late-occurring mortality in one male and signs of poor general health condition at 240 mg/kg, as well as clinical findings such as squatting posture, stilted and uncoordinated gait, drawn in flanks and swollen abdomen, from 60 mg/kg onwards. These signs increased in incidence and severity during the treatment and recovery periods. A threshold dose for clinical observations was identified at 3 mg/kg. In addition, the male animal, which was found dead on study day 42, exhibited histopathological signs of severe immune-functional deficiency. Associated with these clinical observations were impairments of neurobehavior (reduced fore- and hindlimb grip strength) and body weight development from 60 mg/kg onwards as compared to the controls (M/F up to -18/-12% at the end of treatment, and -40%/-16% after recovery, at 240 mg/kg). The males were slightly more sensitive than the females. Food consumption remained unaffected except of high dose males during recovery. Major clinical pathology findings at 240 mg/kg comprised lower white blood cell (WBC) counts (in particular for recovery males), decreased triglycerides, increased liver enzyme activity (ALAT, gamma-GT), changes in the albumin/globulin ratio and the mineral household (sodium, potassium, calcium/phosphorus), as well as increased urinary volume. A threshold dose for clinical pathology findings was identified at 60mg/kg body weight. Anatomic pathology findings at 240 mg/kg body weight included increased liver, kidney [females, only] and adrenal [males only] weights, as well as decreased spleen and thymus weight, generally indicating a threshold dose at 60 mg/kg body weight. Histopathological correlates of these findings were hepatocellular hypertrophy (240 mg/kg), tubular changes in the kidneys (from 60 mg/kg onwards), one nephroblastoma (at 240 mg/kg), lymphocyte depletion in spleen and thymus atrophy (at 240 mg/kg), with generally increasing severity during the recovery period. As a secondary result of general toxic stress, functional atrophy of primary and secundary sexual organs was noted for a few males at 240 mg/kg. 1.3 CONCLUSION In conclusion, repeated administration of 240 mg T-7758/kg body weight induced severe clinical signs (and mortality), including changes in neurobehavior, marked impairment of body weight development, as well as clinical pathology findings, which were associated with liver enzyme induction/toxicity, kidney toxicity, and immunological disfunction. A threshold dose of 60 mg/kg body weight was identified for these severe findings. First general clinical signs at 15 and 3.0mg/kg body weight did not show any clinical- and/or anatomic pathology correlates. With regard to the present study the 'No Observed Effect Level' (NOEL) is 0.3mg/kg body weight/day. Based on these results, T-7758 should be classified as `harmful' "Xn", with risk phrase R48/22, "Danger of serious damage to health by prolonged (oral) exposure", according to the EUDirective 2001/59/EC. Page 8 Toxicology Study Report - PT02-0222 2 STATEMENTS T-7758 Rat repeat dose 28-day oral toxicity + 14-days recovery 2.1 SCHEDULING Date of protocol approval 11-Oct-2002 Date of initiation 17-0ct-2002 Date of termination 25-Feb-2003 THIS STUDY WAS CONDUCTED IN ACCORDANCE WITH GOOD LABORATORY PRACTICE REGULATIONS. No unforeseen circumstances were observed which might have affected the quality or integrity of the study. 2.2 APPROVALS STUDY DIRECTOR APPROVED BY Dr. W. Mueller Testing Facility Management Head of ProTox - Germany STUDY MONITOR Dr. A. M. Seacat Date Ay. Bate 2 )Ol> Page 9 Toxicology Study Report - PT02-0222 2.3 STATEMENT OF GOOD LABORATORY PRACTICE STUDY NUMBER: PT02-0222 TITLE: T-7758 Rat repeat dose 28-day oral toxicity + 14-days recovery This study was conducted under my direction and in accordance with the Principles of Good Laboratory Practice (GLP) as described under 19, German Chemical Law (ChemG), Annex 1, in the version of May 8th, 2001, published in Bundesgesetzblatt Jahrgang 2001 Teil I Nr. 21, in Bonn, on May 14th, 2001, aforementioned law is the implementation of the OECD Principles of Good Laboratory Practice as published on March 23rd, 1999 (as revised in Principle 1999/11/EU of March 8th, 1999) Official Journal of the European Union L77/9. No unforeseen circumstances were observed which might have affected the quality or integrity of the study. All raw data, specimens and other study documents pertaining to this study are stored in the respective department archives. The following data are archived: Test-article reference sample, protocol, report, all raw data and specimens of laboratory investigation. THIS STUDY WAS CONDUCTED IN ACCORDANCE WITH THE PROCEDURES HEREIN DESCRIBED AND THIS REPORT FULLY AND ACCURATELY REFLECTS THE RAW DATA GENERATED IN THE STUDY. Study Director Date Page 10 Toxicology Study Report - PT02-0222 2.4 QUALITY ASSURANCE STATEMENT STUDY NUMBER: TITLE: PT02-0222 T-7758 Rat repeat dose 28-day oral toxicity + 14-days recovery This study was periodically inspected and properly signed records of these inspections were submitted to the testing facility management and the study director as shown below. This report has been audited by the quality assurance unit. The reported results accurately reflect the original data of the study. Dates of Inspection Study Phase Dates of Report to Study Director and Management 14-0ct-2002 17- 0ct-2002 18- 0ct-2002 22-Oct-2002 07- NOV-2002 14-NOV-2002 18-NOV-2002 06-Jan-2003 28-Jan-2003 25- Feb-2003 22-May-2003 22-May-2003 22-May-2003 - 03-Jun-2003 26- May-2003 27- May-2003 08- Aug-2003 study plan study conduct study conduct study conduct study conduct study conduct study conduct study conduct study conduct study conduct contributor report contributor report draft report contributor report contributor report final report C ^Ux C. Ehrlich Quality Assurance (GLP) QS-Ou' Date 14-0ct-2002 17- 0ct-2002 18-0ct-2002 22-Oct-2002 07-NOV-2002 H -N ov-2002 18-NOV-2002 06-Jan-2003 28-Jan-2003 25-Feb-2003 22-May-2003 22-May-2003 03-Jun-2003 26- May-2003 27- May-2003 08- Aug-2003 Page 11 Toxicology Study Report - PT02-0222 3 PROFESSIONAL AND SUPERVISORY STAFF Study director Study Investigator Head of ProTox Sponsor Monitor Clinical Pathology Data Management Lab Animal Science & Welfare Analytical toxicology / Test substance administration Quality Assurance (GLP) Histotechnique Histopathology (P.I.) / QAU GLP: H. Kuhn Testing facility and archives Further testing facility Sponsor : Dr. G. Ehling : L. Warzecha : Dr. W. Mueller : 3M Corporate Toxicology 3M Center, Building 220-2E-02 Saint Paul, MN 55133-3220, USA : Dr. Andrew M. Seacat : Dr. A. Bube : DI H. Press : Dr. R. Hack : Dr. H.-M. Kauffmann : M. Michel : Dr. G. Ehling : Dr. B. Hein ProTox Emil v. Behringstrasse 76 Gebude H6 D - 35041 Marburg : Aventis Pharma Deutschland GmbH Testing Facility Kastengrund ProTox Mainzer Landstr. 500 D - 65795 Hatterheim GERMANY : Dave Ehresman C/O Andrew Seacat 3M Center, 236-1B-22 Saint Paul MN, 55144, USA Page 12 Toxicology Study Report - PT02-0222 4 INTRODUCTION 4.1 OBJECTIVE The present 28-day toxicity study was conducted in order to characterize the toxicological profile of T-7758 after repeated oral exposure, including endpoints in neurobehavior, immune function and reproductive target organs. Additionally, the results of this study can be used as a dose-range finding for subchronic and chronic toxicity studies. The study should also provide a no-observedadverse-effect level (NOAEL). Rationale for species selection The rat has proved to be a suitable species for subacute oral toxicity testing with many different substances and is the species of choice according to the international guidelines. Rationale for the route of exposure The oral route is considered to be a potential exposure route in man. 4.2 GUIDELINES The present study was conducted in compliance with the requirements of Commission Directive 96/54/EC Annex IV D Method B.7. "Subacute Oral Toxicity" Adopted July 30 1996 and OECD Guidelines for Testing of Chemicals Section 4 Health Effects 407 Subacute Oral Toxicity Adopted July 27, 1995 and U.S. EPA: OPPTS 870.3050, Health Effects Test Guidelines: Repeated dose 28-day oral toxicity study in rodents, July 2000 Principles of Good Laboratory Practice (GLP) as described under 19, German Chemical Law (ChemG), Annex 1, in the version of May 08th, 2001, published in Bundesgesetzblatt Jahrgang 2001 Teil I Nr. 21, in Bonn, on May 14th, 2001, aforementioned law is the implementation of the OECD Principles of Good Laboratory Practice as published on March 23rd, 1999 (as revised in Principle 1999/11/EU of March 8th, 1999) Official Journal of the European Union L77/9. Page 13 Toxicology Study Report - PT02-0222 5 MATERIALS AND METHODS 5.1 TEST COMPOUND Name of compound Synonym CAS-Number Molecular formula Molecular weight Batch number Certificate of analysis Date of expiry Date of production Date of receiving Appearance Purity Density Storage conditions Dose suspension analysis Stability and homogeneity in the vehicle : T-7758 : MV4S : 88190-28-7 : C6 F12O3 S : 380 g/mol : Lot 1 : NMR dated 09-Apr-2002 and GCMS dated 04-Dec-2001 (3M) : 31-Dec-2003 : 16-Oct-2001 : 16-May-2002 : clear, colourless liquid : 96.5 % : 1.74 g/cm3 : at approximately 5 C in a refrigerator in a stainless steel vessel inerted with nitrogen : Once at start of the study samples were taken by Analytical Toxicology. Three samples were taken per dose group (top, middle and bottom) and analyzed for concentration of test substance by GC (Dr. H-M. Kauffmann, Analytical Toxicology, ProTox). : is guaranteed for 4 hours in sesame oil by GC analysis. (Report Dr. H.-M. Kauffmann, Aventis Pharma Deutschland GmbH, Protox - Analytik, dated 15-Aug-2002 and 21-Jan-2003 archived with the raw data) Page 14 Toxicology Study Report - PT02-0222 5.2 TEST SYSTEM Species of animals Strain of animals Origin (supplier) of animals Animal identification Age at start of study Randomization procedure : Rat : Hsd:Sprague Dawley (SD) : Harlan Winkelmann GmbH Gartenstrasse 27 D-33178 Borchen : Tattoo number on tail, fur marking and cage numbering : approximately 6 weeks : Computer generated algorithm (archived with raw data) 5.3 HOUSING AND CARE OF ANIMALS Animal maintenance : In transparent macrolon cages (type IV) on soft wood granulate* in an air-conditioned rooms, 5 animals per cage, separated according to sex Room temperature : 22 3 C (except short lasting deviations due to disturbances of air condition) Relative humidity : 50 20 % (except short lasting deviations due to disturbances of air condition) Lighting times : 12 hours light / dark cycle Acclimatization : at least five days Food : ssniff R/M-H (V 1534)* ad libitum, exept for the period in which the animals were kept in diuresis cages * (Composition see page 370) Water : Tap water* in plastic bottles ad libitum, exept fot the period in which the animals were kept in diuresis cages * * Results of routine analyzes are available on request (data storage in archive) Page 15 Toxicology Study Report - PT02-0222 5.4 RATIONALE FOR DOSE SELECTION In a dose range finding study 3 male and 3 female rats received T-7758 at doses of 200 and 400 mg/kg body weight per day over a period of 14 days and were necropsied on day 15. There were no deaths throughout the study. From day 1 up to day 10 of the study the animals in both dose groups exhibited stilted and uncoordinated gait, squatting posture, and irregular respiration and discolored feces. Diarrhea was noted in one animal of the 200 mg/kg dose group. Stilted and uncoordinated gait was observed up to the end of the study in the 400 mg/kg dose group. An initial loss of body weight was noted up to study day 4. There were no macroscopically visible changes at final necropsy. Based on these results, dose levels of 0, 15, 60 and 240 mg/kg body weight per day were selected for the present study in the first instance. However, following slightly emerging general clinical signs at 15 mg/kg bw , another low-dose group with 3 mg/kg body weight per day was selected for this study. As this low dose group also exhibited very slight clinical signs at the end of the observation period another low-dose group with 0.3 mg/kg, as well as another corresponding control group, was placed in this study. 5.5 EXPERIMENTAL DESIGN Route of administration Application volume Vehicle Frequency of administrations Duration of the study Duration of recovery period Oral by gavage 5 mL/kg bw. Sesame oil once daily 29 days, 28 applications 14 days Table 1: Dose levels and number of animals Group Dose levels Number cif animals (mg/kg/bw./d) main iroups male female 1 0.0 5 5 2 15.0 5 5 3 60.0 5 5 4 240.0 5 5 5* 3.0 5 5 6** 0.0 7** 0.3 5 5 5 5 * = 1st additional dose group ( group 5) ** = 2nd d additional dose group (group 7) and corresponding 2nd control group (group 6) Nubmer o animals recovery groups male female 55 -- -- 55 -- -- -- Page 16 Toxicology Study Report - PT02-0222 5.6 TEST GROUPS At the beginning of the acclimatization period, the test animals were randomized and assigned to the following groups: Table 2: Number of animals / Animal numbers Group 1 2 3 4 5 6 7 Dose (mg/kg bw.) 0.0 15.0 60.0 240.0 3.0 0.0 0.3 Number cf Animals males females 10 10 55 55 10 10 55 55 55 Animal number males females 1 - 10 31 - 40 11 - 15 41 - 45 16 - 20 46 - 50 21 - 30 51 - 60 61 - 65 66 - 70 71 - 75 81 - 85 76 - 80 86 - 90 Group 1 2 3 4 5 6 7 Table 3: Cage numbers / Animal numbers Cage number 1 2 3 4 5 6 13 15 16 Animal number males 1-5 6 - 10 11 - 15 16 - 20 21 - 25 26 - 30 61 - 65 71 - 75 76 - 80 Cage number 7 8 9 10 11 12 14 17 18 Animal number females 31 - 35 36 - 40 41 - 45 46 - 50 51 - 55 56 - 60 65 - 70 81 - 85 86 - 90 Page 17 Toxicology Study Report - PT02-0222 5.7 PREPARATION OF THE TEST COMPOUND Group 1 2 3 4 5 6 7 Dose (mg / kg bw.) 0.0 15.0 60.0 240.0 3.0 0.0 0.3 Table 4: Formulation of the test compound Concentration in mg / mL 0.00 3.00 12.00 48.00 0.60 0.00 0.06 Volume applied (mL / kg bw.) 5 5 5 5 5 5 5 Vehicle sesame oil sesame oil sesame oil sesame oil sesame oil sesame oil sesame oil T-7758 was dissolved in the stated concentrations in sesame oil daily. After each measurement of the body weight, the calculation of the application volume was repeated. 5.8 IN-LIFE OBSERVATIONS 5.8.1 Mortality Survival control of the animals was examined twice daily (on weekends and public holidays once daily). 5.8.2 Clincal observations Individual clinical observations were observed once daily. Page 18 Toxicology Study Report - PT02-0222 5.8.3 Neurological examinations Once before the first treatment and thereafter once a week detailed clinical observations were performed in all animals outside the home cage in a standard arena ('open field'). Each animal was assessed for changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity such as lacrimation, salivation, nasal discharge, piloerection, pupil size, and unusual respiratory pattern. Changes in gait, posture, and response to handling as well as the presence of clonic or tonic movements, tremor, and any other abnormal motor movements (such as excessive grooming, repetitive circling or other stereotypes) or bizarre behavior (e.g. self-mutilation, walking backwards) were also recorded. In addition, defecation and urination were evaluated. At the termination of the study sensory reactivity to stimuli of different types (auditory, visual, and proprioceptive) was evaluated including startle reflex (click response), response to approach with the finger to the nose of the animal, and righting reflex. The presence and absence of pupillary constriction was assessed using a pen flashlight directed into the eye. Assessments of motor function were performed including measurement of motor activity, and forelimb and hindlimb grip strength. The animals were evaluated for motor activity during a 60-minute period in a 16-station automated motor activity-monitoring device (FMI, Fhr Medical Instruments GmbH). Activity counts were recorded by the interruption of photocells in 3-minute-intervals to give a total of 20 intervals. A strain gauge device (FMI, Fhr Medical Instruments GmbH) measured fore- and hindlimb grip strength. 5.8.4 Body weight The body weights of all animals were determinated before the start of the study and then twice weekly throughout the study. 5.8.5 Food consumption Food consumption was determined continuously (two times per week). Page 19 Toxicology Study Report - PT02-0222 5.9 CLINICAL PATHOLOGY 5.9.1 Hematological investigations At the termination of the study and after the recovery period, hematological examinations were performed on all animals without previous withdrawal of food. Blood samples were taken from the retrobulbar venous plexus in narcosis (intraperitoneal injection of 67 + 6.7 mg/kg body weight Ketamine-Hydrochloride + Xylazine). In order to prevent systematic errors, blood sampling was conducted in a randomized order. The abbreviations, units, instrumentation, and methodologies used for these tests are presented in the tables, page 37. Hematology parameters evaluated consisted of the following: Table 5: Red Cell Counts parameters evaluated Erythrocyte counts (RBC) Heinz Body Counts* Hematocrit (packed cell volume) Hemoglobin Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) Mean corpuscular volume (MCV) Reticulocyte counts * This paramenter was only evaluated in the animals from the control and high dose group, as well as for the amended additional control, 3.0 and 0.3 mg/kg body weight groups. Table 6: White Cell Counts parameters evaluated Differential leukocyte counts Leukocyte counts (WBC) Table 7: Coagulation parameters evaluated Coagulation time (clotting time) Thrombocyte counts (platelets) Page 20 Toxicology Study Report - PT02-0222 5.9.2 Clinical Chemistry After blood sampling for hematological testing, the animals were killed by section of the vena cava cranialis in deep narcosis and exsanguinated. In order to prevent systematic errors, exsanguination was conducted in a randomized order. The abbreviations, units, instrumentation, and methodologies used for these tests are presented in the tables, page 38. Clinical chemistry parameters evaluated consisted of the following: Table 8: Clinical Chemistry parameters evaluated y-Glutamyltranspeptidase Alanine Aminotransferase (ALAT) Albumin Albumin / Globulin ratio (calculated) Alkaline Phosphatase Aspartate Aminotransferase (ASAT) Bilirubin total Calcium Chloride (Cl-) Cholesterol Creatinine Globulin (calculated) Glucose Inorganic Phosphorous Potassium (K+) Sodium (Na+) Total Protein Triglycerides Urea Uric Acid Serum collection (as much as possible) for optional future analysis was amended by the Sponsor for optional further investifgations. Spare serum was kept deep frozen in liquid nitrogen and sent on dry ice to the Sponsor's address, after necropsy. This is not part of the study. Page 21 Toxicology Study Report - PT02-0222 5.9.3 Urinalysis Urine analysis was performed in all animals a few days before termination of the study as well as before the end of the recovery period. For this purpose, the urine was collected by using metabolism cages overnight. This was done from day 22 to day 23 for groups 1-4, from day 25 to day 26 for group 5, from day 23 to day 24 for groups 6 - 7, and from day 40 to day 41 for recovery groups 1 and 4. Food and water was withdrawn during this period. The abbreviations, units, instrumentation, and methodologies used for these tests are presented in the tables, page 39. Urinalysis consisted of the following: Table 9: U rinalysis - S em iq u antitative param eters evaluated Appearence Glucose Protein Bilirubin Ketone bodies Urobilinogen Blood Color Microscopic Examination (Sediment)* pH * This parameter was only evaluated in the animals from the control and high dose group, as well as for the amended additional control and 0.3 mg/kg groups. Table 10: Urinalysis - Quantitative Param eters evaluated Specific Weight Volume Page 22 Toxicology Study Report - PT02-0222 5.10 ANATOMIC PATHOLOGY 5.10.1 Necropsy and macroscopic examination After exsanguination, all animals were necropsied and checked for macroscopically visible abnormalities. The autopsy included macroscopic examination of the skin, orifices, eyes, teeth, oral mucosa and internal organs. Also intercurrend died and moribund killed animals are necropsied and checked for macroscopically visible abnormalities. All abnormal findings were recorded. Endotracheal fixation of the lungs: The lungs, including part of the trachea, were removed. The lungs were then fixed endotracheally with a 4% neutral buffered formalaldehyde (equals 10% formalin) solution using a needle inserted into the trachea. The instillation pressure was between 20 and 30cm water column. Following completion of the endotracheal fixation the lungs were fixed, together with the other organs, in formalin solution. 5.10.2 Organ weights The following organs were weighted: Table 11: List of weighed organs Adrenals Brain Epidymides Heart Kidneys Liver Spleen Testes Thymus Organs from animals found dead are not weighed, these orgens were removed and preserved in a suitable fixative (4% neutral buffered formaldehyde). Page 23 Toxicology Study Report - PT02-0222 5.10.3 Macroscopic and microscopic observations The following tissues or organs (or pieces of them) were preserved in a suitable fixative (4% neutral buffered formaldehyde (equals 10% formalin solution) and processed for histopathological investigations: Table 12: List of tissues fixed and submitted for histological examinations Adrenals Bone marrow / sternum Brain with medulla oblongata Epididymides Heart Small Intestine 2 jejunum Large Intestine 2 colon Kidneys Liver Lungs Lymph nodes 1 mandibular Lymph nodes 2 iliac Nerve sciatic nerve Ovaries with oviducts Prostate Seminal vesicle Spinal cord 1 cervical Spleen Stomach Testes Thymus Thyroid gland with parathyroids Trachea Urinary bladder Uterus All other gross lesions Organs and tissues intended for microscopic examination were embedded by conventional histological technique in Paraplast, and stained with Hematoxylin-Eosin. Histopathological examinations were carried out from all control and high dose group animals, as well as from the 2nd additionally placed dose group 7 (0.3 mg/kg) and its corresponding control group 6. The latter results were reported in a separate addendum to the pathology report. In addition, histopathological evaluation was performed on all macroscopic findings, on all organs of intercurrently died animals, and also on target organs such as kidneys, liver, spleen and thymus of all animals, due to histopathologic findings in the high dose group. Extra liver tissues (> 5 grams, cut into 0.5-1.0g pieces) were requested by the sponsor and were kept deep frozen in liquid nitrogen and send to the Sponsor's address on dry ice for possible future analysis. This was not part of the study. Page 24 Toxicology Study Report - PT02-0222 6 RESULTS 6.1 DOSE SOLUTION ANALYSIS Dose level (mg/kg/day) Concentration (mg/ml) Day 1 n.d. = not detected Table 13: Results of dose suspension analysis 00 00 n.d. n.d. 0.3 3 15 60 0.06 0.6 3 12 Analysed content (mean %) 99 95 107 114 The anticipated concentrations were satisfactorily confirmed. (Analytical report archived with the raw data) 240 48 108 6.2 IN-LIFE OBSERVATIONS 6.2.1 Designation of dose groups (pathology designation in brackets*) The designated groups 1-7 had to be re-allocated for statistical analyses in Provantis/Aventox: Table 14: Designation of the dose groups (1 - 5) for individual data mg / kg bw. / d Group 1 (Co*) 0 Group 2 (D1*) 15 Group 3 (D2*) 60 Group 4 (D3*) 240 Group 5 (D4*) 3 Table 15: Designation of the dose groups (1 - 5) for statistical evalution and figures mg / kg bw. / d Group 1 (Co*) 0 Group 2 (D4*) 3 Group 3 (D1*) 15 Group 4 (D2*) 60 Group 5 (D3*) 240 Table 16: Designation of the dose groups (6 - 7) for individual data mg / kg bw. / d Group 6 (C1 / 06*) 0 Group 7 (D5 / 07*) 0.3 Table 17: Designation of the dose groups (6 - 7) for statistical evalution and figures mg / kg bw. / d Group 1 (C1 / 06*) 0 Group 2 (D5 / 07*) 0.3 Page 25 Toxicology Study Report - PT02-0222 6.2.2 Behavior, state of health and mortality One male (animal No. 30*) at 240 mg/kg was found dead on study day 42 (recovery period). This animal, which was in a bad general health condition, exhibited histopathological signs of severe immune-functional deficiency. This finding was considered the cause of death, and was considered compound-related. * animal no. 30 was excluded from summaries on body weight and food comsumption, as well as from final clinical pathology evalutation (day 43), however, was evaluated for urine analysis and neurobehavior, which were carried out during study week 3. 6.2.3 Clinical observation Behavior and state of health remained uneffected by the administration of the test compound in the at 0.3 mg/kg and generally at 3 mg/kg body weight/day throughout the study. No opacity of the refracting media of the eyes, changes of the oral mucosa, or impairment of dental growth was observed in these groups. Main clinical signs, considered compound-related, comprised the following: At 0.3 mg/kg: No abnormalities At 3,0 mg/kg: generally no abnormalities, apart from squatting posture and stilted gait from day 22 up to the end of study (day 29). At 15 mg/kg: squatting postures, stilted and uncoordinated gait from day 15 up to the end of study (day 29) At 60 mg/kg: Squatting postures, stilted and uncoordinated gait, drawn in flanks, swollen abdomen, within the 1st 10 days; feces and tray bedding discolored yellowish from day 4 up to the end of study. At 240 mg/kg: Squatting postures, stilted and uncoordinated gait, drawn in flanks, swollen abdomen, within the 1st 10 days. Feces and tray bedding discolored yellowish from day 4 up to the end of study. Additionally: swollen snout (No. 27, 30), blood-colored encrusted snout (No. 27, 30) and lower or upper incisors brocken-off (No. 28, 30, 59), stupor and coat bristling (No. 30). Group incidence tables see page 63 6.2.4 Neurobehavioral examinations Motoractivity was not influenced by administration of the test compound in all groups. However, forelimb and hindlimb grip strength was statistically significantly decreased for males at 60 and 240 mg/kg and for females at 240 mg/kg body weight/day. (Figures page 53, Summary tables and Statistics page 195, Individual data page 351) Page 26 Toxicology Study Report - PT02-0222 6.2.5 Body weight Mean body weights were statisitcally significantly decreased from 60 mg/kg onwards from study day 5 until onwards, reaching minus 18/12% for males/females, respectively, at 240 mg/kg body weight/day as compared to the control at study day 29. This finding got worse in particular for the males during the recovery period (M/F: -40/-16%), i.e., there was no evidence of recovery. Accordingly, overall mean body weight gains were markedly lower in these groups as compared to the control. Table 18: Mean body weight gains [g] throughout the study (Groups 1 - 5) Treatment group [mg/kg bw.] day 1 to day 29 day 29 to day 43 Control males females 141.2 82.6 34.8 12.6 3 mg/kg males females 145.8 74.4 -- 15 mg/kg males females 125.6 74.8 -- 60 mg/kg males females 117.8 66.6 -- 240 mg/kg males females 84.4 59.4 -36.0 2.0 Table 19: Mean body weight gains [g] throughout the study (Groups 6 - 7) Treatment group [mg/kg bw.] day 1 to day 29 males 156.4 Control females 66.0 males 165.6 0.3 mg/kg females 73.8 (Figures page 41, Summary tables and Statistics page 105, Individual data page 203) 6.2.6 Food consumption Food consumption remained unaffected by the administration of the test compound throughout the study in all dose groups, except for recovery males (240 mg/kg), which exhibited moderately lower food intake during the recovery period as compared to the controls. Table 20: Mean food consumption [g/kg bw./day] throughout the study (Group 1 - 5) Treatment group [mg/kg bw.] day 1 to day 29 day 29 to day 43 Control males females 82.02 78.14 65.81 68.39 3 mg/kg males females 82.14 74.62 -- 15 mg/kg males females 76.22 76.37 -- 60 mg/kg males females 78.38 74.31 -- 240 mg/kg males females 74.61 78.91 50.98 72.40 Table 21: Mean food consumption [g/kg bw./day] throughout the study (Group 6 - 7) Treatment group [mg/kg bw.] day 1 to day 29 males 86.78 Control females 76.42 males 84.06 0.3 mg/kg females 75.86 (Figures page 47, Summary tables page 117, Individual data page 218) Page 27 Toxicology Study Report - PT02-0222 6.3 CLINICAL PATHOLOGY 6.3.1 Hematology Final hematology revealed the following changes of statistical and/or possible toxicological significance: - reduced blood coagulation time (for females from 15 mg/kg onwards; finding was slightly outside the range of the historical control data, however, was not dose-related, was not observed in males, and hence, considered equivocal. - slightly lower white blood cell (WBC) counts (for males at 240 mg/kg, not statistically significant) Hematology at the end of the recovery period revealed the following changes of statistical and/or possible toxicological significance: - increased red blood cell (RBC) counts (for recovery males, tendency also for females, both at 240 mg/kg) - decreased reticulocytes (for recovery males, tendency also for females, both at 240 mg/kg) - markedly lower WBC counts (for recovery males, at 240 mg/kg) (Summary tables and Statistics page 125, Individual data page 233, Historical control data page 372). 6.3.2 Clinical chemistry Final clinical chemistry revealed the following changes of statistical and/or possible toxicological significance: - decreased triglycerides (males, 240 mg/kg; outside the range of historical control (HC) data) - increased alanine aminotransferase (ALAT) activity (for males from 60 mg/kg, and for both genders at 240 mg/kg) - increased gamma-glutamyltransferase (gGT) activity (for females, tendency also for males, both at 240 mg/kg) - increased sodium (for females from 60 mg/kg onwards, outside the range of historical control data) - increased albumin/globulin ratio (for females from 60 mg/kg onwards, tendency also for males at 240 mg/kg) Page 28 Toxicology Study Report - PT02-0222 Clinical chemistry at the end of the recovery period revealed the following changes of statistical and/or possible toxicological significance: - increased sodium and chloride (recovery males at 240 mg/kg) - decreased potassium at 240 mg/kg for recovery males, increased for recovery females, hence, considered equivocal - increased protein, albumin and globulin at 240 mg/kg for recovery males, decreased/or no finding for females, hence considered equivocal - decreased alkaline phosphatase at 240 mg/kg for recovery males - decreased calcium, increased phosphorus at 240 mg/kg for recovery females, not seen in males, considered equivocal - distinctly decreased triglycerides at 240 mg/kg for recovery females, outside the range of HC- data, also decreased for recovery males (statistical evaluation not possible) - distinctly decreased glucose at 240 mg/kg for recovery males, outside the range of HC-data In addition, sporadic statistically significant changes were noted at 0.3 mg/kg body weight/day as compared to the respective control group, regarding sodium, potassium, phosphorus, total protein, albumin, alkaline phosphatase activity. All these changes were marginal and all within the range of the in-house historical control data. Moreover, no corresponding changes were seen at 3.0 or 15 mg/kg body weight/day. Hence, they were considered incidental. (Summary tables and Statistics page 145, Individual data page 280, Historical control data page 372). 6.3.3 Urinalysis Urinalyses revealed statistically signifanctly increased urine volume for males at 240 mg/kg. This finding was also observed for the females of this group, however, without being statistically significant due to high standard deviation. Apart from this finding urinalysis remained unaffected by administration of the test compound in all groups. The urine sediment was generally unobstrusive in control- and 240 mg/kg-dosed animals. As an exception, the male No. 25 and female Nos. 51 and 59 (at 240 mg/kg) exhibited slightly higher leucocyte counts (degree 6-10), which in the absence of other clinical correlates was considered not toxicologicaly relevant. (Summary tables and Statistics page 165, Individual data (including legende) page 310, Historical control data page 372). Page 29 Toxicology Study Report - PT02-0222 6.4 ANATOMIC PATHOLOGY 6.4.1 Organ weights Evaluation of mean absolute organ weights revealed the following changes of statistical and/or possible toxicological significance: - increased liver weight (from 60 mg/kg body weight/day onwards, both genders) - decreased spleen weight (at 15 mg/kg [males], and from 60 mg/kg onwards [both genders], also recovery males) - decreased thymus weight (at 240 mg/kg, both genders), also recovery males - increased kidney weight (for females from 60 mg/kg onwards) - increased adrenal weight (for males at 240 mg/kg, outside the HC range, not observed for females, relevance considered equivocal) Further mean absolute organ weight changes of statistical significance, i.e. for heart, brain, liver [recovery males], epididymis and kidneys [recovery], were considered due to the markedly decreased terminal body weight at 60 and 240 mg/kg body weight/day, and hence considered not toxicologically significant. 6.4.2 Relative organ weights Evaluation of mean organ weights relative to terminal body weight revealed the following changes of statistical and/or possible toxicological significance: - increased liver weight (from 60 mg/kg onwards, both genders, (M/F up to 49/87%) - increased testes and brain weight (males at 240 mg/kg, testes also at 60 mg/kg, both findings possibly due to reduced terminal body weight as these organ weight changes do not go with body weight, of minor relevance) - decreased thymus weight at 240 mg/kg for males, tendency also in females - increased kidney weight (for females from 60 mg/kg onwards) - decreased spleen weight (dose-related, for females from 60 mg/kg onwards) - increased adrenal weight (males at 240 mg/kg, outside the HC-data range, also for recovery males, not observed in females) Further mean relative organ weight changes of statistical significance at recovery, i.e. for testes and epididymis and brain were considered due to terminal body weight changes at recovery necropsy, and hence considered not toxicologically significant. (Summary tables and Statistics page 173, Individual data page 336, Historical control data page 372). Page 30 Toxicology Study Report - PT02-0222 6.4.3 Macroscopic observations Relevant macroscopic changes were recorded for male or female animals of the following groups: Group 4 (D3, 240 mg/kg): K0/K0 animals: Discoloured kidneys in three females (no. 52, 54, 55) and all 5 males, one enlarged stomach (male no. 24), two enlarged livers (females no. 51, 54), and one opaque eye in female no. 55. R1/R1 animals: Small accessory genital glands (prostate and/ or seminal vesicle) in no. 26, 27 and 28. Additionally, male no. 28 exhibited a small thymus and enlarged adrenal glands. An irregular surface could be observed on the kidney of male no. 28 as well as female no. 59. R1/+1 animal (was found dead): Small accessory genital glands (prostate and seminal vesicle) in combination with small testes and epididymides. Group 3 (D2, 60 mg/kg): K0/K0 animals: Discoloured kidneys in four males (no. 17-20), and four females (no. 46, 47, 49, 50), and a discoloured duodenum in female no. 46. Group 2 (D1,15 mg/kg): K0/K0 animals: Discoloured kidneys in three males (no. 11, 14 and 15), and female no. 45. Group 5 (D4, 3 mg/kg): K0/K0 animals: Transparent margins in the liver of female animal no. 68. Group 7 (D5, 0.3 mg/kg) as compared to control group 6 (C1): There were no gross pathology findings, which could be related to administration of the test compound in the low dose group. Page 31 Toxicology Study Report - PT02-0222 6.4.4 Microscopic observations Animal no. 30 (group 4; 240 mg/kg, recovery) was found dead one day before termination of the recovery period (study day 42). Although autolysis was evident, microscopic examination indicated severe lymphocyte depletion in spleen, thymus and lymph nodes as cause of death. This finding was considered test-article related. Relevant histopathological findings at scheduled necropsy (terminal and/or recovery) were seen in the following organs: Liver: Hypertrophy o f hepatocytes in nearly all animals at 240 mg/kg body weight/day (D3) at terminal necropsy. Spleen: Lymphocyte depletion in the animals at 240 mg/kg (D3): one male at terminal necropsy, and two male at recovery necropsy. Thymus: Atrophy in three males at 240 mg/kg (D3) at recovery necropsy. Iliac lymph node: Lymphoid cell depletion in one animal at 240 mg/kg (D3), which died during the recovery. Testes/ Epididymides: Atrophy in animal no. 30 (unscheduled death). Prostate/ Seminal Vesicles: Atrophy in three animals (240 mg/kg, D3, recovery necropsy). Findings in the kidneys were also noted and included tubular changes. These findings were sporadically seen in males and females with special focus at 240 mg/kg (D3) and at 60 mg/kg (D2) at the terminal sacrifice. A nephroblastoma could be detected in one female at 240 mg/kg (D3). One male and one female at 240 mg/kg (D3) exhibited a chronic nephropathy at recovery necropsy. The other findings should be discussed as spontaneous, they occurred in the control group, too, or could relatively often be observed in historical controls. Sporadic changes in form of cellular infiltrates / inflammatory foci were observed in the lungs and liver of single animals of different groups. At 240 mg/kg (D3) (terminal sacrifice) a submucosal edema in the forestomach, a dilatation of the uterus, and an enlarged epithelium of the cornea, could be observed in different animals. There were no histopathological findings at 0.3 mg/kg body weight/day (D5 /07), which could be related to administration of the test compound as compared to the respective control (C1 /06). Sporadic changes in form of dilatation and cellular infiltration could be observed in the uterus of animal no. 89 (group D5/07). Single control animals (group C1/06) exhibited tubular dilatation in the kidney (no. 71), or cellular infiltrations in the lungs (no. 83) or glandular stomach (no. 75) (Pathology report, page 375) Page 32 Toxicology Study Report - PT02-0222 7 DISCUSSION T-7758 induced late-occurring mortality in one male (240 mg/kg) and signs of poor general health condition at 240 mg/kg, and clinical findings such as squatting posture, stilted and uncoordinated gait, drawn in flanks and swollen abdomen, from 60 mg/kg body weight/day onwards. These signs increased in incidence and severity during both, the treatment and recovery periods. A threshold dose for clinical observations was identified at 3 mg/kg. In addition, the male, which was found dead on study day 42, exhibited histopathological signs of severe immune-functional deficiency. Associated with these clinical observations were impairments of neurobehavior (reduced fore- and hindlimb grip strength) and body weight development from 60 mg/kg onwards as compared to the controls (M/F up to -18/-12% at the end of treatment, and -40%/-16% after recovery, at 240 mg/kg). The males were slightly more affected than the females. Food consumption remained unaffected, except of the high dose males, during recovery. Major clinical pathology findings at 240 mg/kg comprised lower white blood cell (WBC) counts (in particular for recovery males), decreased triglycerides, increased liver enzyme activity (ALAT, gamma-GT), changes in the albumin/globulin ratio and the mineral household (sodium, potassium, calcium/phosphorus), as well as increased urinary volume. A threshold dose for clinical pathology findings was identified at 60mg/kg body weight. Anatomic pathology: The 4-week oral gavage administration of T-7758 caused severe alterations in the target organs and unscheduled death at 240 mg/kg body weight/day one day before the end of the experiment. One of the central organ systems involved in the toxicity of the test article were the "manufacturing plants" of white blood cells, particularly the thymus, but also spleen and lymph nodes, which exhibited a loss of white blood cells in the animals at 240 mg/kg. This effect could only be observed in some males at 240 mg/kg. A comparable effect (tubular atrophy) could be observed in the testes of one recovery group animal (240 mg/kg), which was found dead on study day 42. Both kinds of tissue demonstrate this reaction during the recovery period, following loss of their mature cells. At terminal sacrifice hepatocellular hypertrophy was observed at 240 mg/kg, which had reversed after the 14-day recovery period. The kidney was identified as another target organ of the test compound. Although it showed a more or less diffuse picture regarding incidence and evidence of its tubular alterations - which is not uncommon in particular for the male Sprague Dawley rat - the severity grades of these findings were distinctly higher at 60 and 240 mg/kg body weight/day (D2 and D3). Page 33 Toxicology Study Report - PT02-0222 8 CONCLUSION In conclusion, repeated administration of 240 mg T-7758/kg body weight induced severe clinical signs (and mortality) incl. changes in neurobehavior, marked impairment of body weight development, as well as clinical pathology findings, which were associated with liver enzyme induction/toxicity, kidney toxicity, and immunological disfunction. A threshold dose of 60 mg/kg body weight was identified for these severe findings. First general clinical signs at 15 and 3.0 mg/kg body weight did not show any clinical- and/or anatomic pathology correlates. With regard to the present study the 'No Observed Effect Level' (NOEL) is 0.3mg/kg body weight per day. Based on the results of this study, T-7758 should be classified as `harmful' "Xn", with risk phrase R48/22, "Danger of serious damage to health by prolonged (oral) exposure", according to the EUDirective 2001/59/EC. Page 34 Toxicology Study Report - PT02-0222 9 REFERENCES 9.1 HEMATOLOGY EXAMINATIONS Advia 120 analyzer Online documentation of Advia 120 Coagulation time Watch glass method of BRKER, Hirschfeld, Handbuch der allgemeinen Hmatologie, Vienna (1933) Heinz Bodies Microscopic, brilliant cresyl blue staining, Merck, Klin. Labor, p. 28 (1974) 9.2 CLINICAL CHEMISTRY METHODS Bilirubin total JENDRASSIK L., Grof P., Biochem J 297, 81-89 (1938) PRELLWITZ W., Klinisch-chemische Diagnostik, 2. Aufl., Thieme, 18 (1976) RICHTERLICH R., COLOMBO J.P., Klinische Chemie, 4. Aufl., karger, Basel, 485-486 (1978) Examinations using Vitros 950 Analyzer SONNTAG O., analytical element, coated on a support, Trockenchemie, Thieme Verlag, Stuttgart (1988) 9.3 URINALYSIS Clinitek Atlas: Reagenzienpackung, Bayer Diagnostics GmbH, Mnchen Sediment Microscopic examination (without staining) HALLMANN, Klinische Chemie u. Mikroskopie, 189-202, Stuttgart (1980) Page 35 Toxicology Study Report - PT02-0222 9.4 STATISTICAL EVALUATION All Parameters The assumption of a monotonic dose-response relationship for all parameters justifies the restriction of the significance level to 5 percent (per parameter and sex), using the method of: HOTHORN L, LEHMACHER W.: A Simple Testing Procedure "Control versus k Treatments" for One-sided Ordered Alternatives, with Application in Toxicology, Biom. J. 33, 179-189, Akademie Verlag Bodyweights: The changes of parameter values compared to the treatment-free baseline values are analyzed. The baseline values themselves are not statistically evaluated, since by definition no treatment effect can be present at this stage. Method used: t-Test: HARTUNG J., ELPERT B., KLSENER K. H., Lehr- und Handbuch der angewandten Statistik (1989), R. Oldenbourg Verlag, Mnchen Clinical Pathology Data: In dog studies, the changes of parameter values compared to the treatment-free preliminary values are analyzed. The preliminary values themselves are not statistically evaluated, since by definition no treatment effect can be present at this stage. In rat studies, the absolute values are analyzed. Wilcoxon's Test: HOLLANDER M., WOLFE, D. A:, Nonparametric statistical methods; Wiley Series in Probability and Mathematical Statistics (1973), John Wiley & Sons Inc., New York, with the exact distribution after STEITBERG B, RHMEL J.: Exakte Verteilung fr Rang- und Randomisierungstests im allgemeinen Stichprobenproblem, EDV in Medizin und Biologie 18, 12-19 (1987), Verlag Eugen Ulmer GmbH & Co., Stuttgart; Gustav Fisher Verlag KG, Stuttgart Organ weights (absolute): t-Test (HARTUNG J., ELPERT B., KLSENER K.H.,Lehr- und Handbuch der angewandten Statistik (1989), R. Oldenbourg Verlag, Mnchen Organ weights (relative to bodyweight): Wilcoxon's Test HOLLANDER M., WOLFE, D.A:, Nonparametric statistical methods; Wiley Series in Probabiltiy and Mathematical Statistics (1973), John Wiley & Sons Inc., New York, with the exact distribution after STEITBERG B, RHMEL J.,Exakte Verteilung fr Rang- und Randomisierungstests im allgemeinen Stichprobenproblem, EDV in Medizin und Biologie 18, 12-19 (1987), Verlag Eugen Ulmer gmbH & Co., Stuttgart; Gustav Fisher Verlag KG, Stuttgart Page 36 Toxicology Study Report - PT02-0222 10 TABLES 10.1 ABBREVIATIONS, UNITS AND METHODOLOGY 10.1.1 Hematology 10.1.1.1 Red cell count Abbreviation Parameter Hemato crit Hematocrit Hemo globin Hemoglobin MCH Mean Corpuscular Hemoglobin MCHC Mean Corpuscular Hemoglobin Concentration MCV Mean Corpuscular Volume Red cell count Red blood cell count (Erythrocyte count) Reticulo cytes Reticulocyte count Heinz Bodies Heinz body count Units Unity g/l 10-12 g (pg) g/l 10-15 l (fl) x1012/l Unity Unity Methodology/Instrumentation Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH Microscopic 10.1.1.2 White cell count Abbreviation Parameter Relative Differential Leukocyte Count White cell count White blood cell count (Leucocyte count) Units Unity 109/l Methodology/Instrumentation Advia 120 Bayer Diagnostics GmbH Advia 120 Bayer Diagnostics GmbH 10.1.1.3 Blood coagulation Abbreviation Parameter Plate lets Platelet Count (Thrombocytes count) Coagul. time Coagulation time (Clotting time) Units 109/l s Methodology/Instrumentation Advia 120 Bayer Diagnostics GmbH Watch glass method Ref. see page 35 35 35 35 35 35 35 35 Ref. see page 35 35 Ref. see page 35 35 Page 37 Toxicology Study Report - PT02-0222 10.1.2 Clinical chemistry Abbreviation G-Gluta. Transf. (y-GT) ALAT Albumin Alb/Glob Ratio AP ASAT Total Biliru. Calcium (Ca) Chloride (Cl) Chole sterol Creati nine Globulin Glucose Phos phorus Potas sium (K) Sodium (Na) Total Protein Triglycerides Urea Nitrogen Uric Acid Parameter y-Glutamyltranspeptidase Units U/l Alanine Aminotransferase U/l Albumin Albumin Globulin Ratio g/| Alkaline Phosphatase U/l Aspartate Aminotransferase Bilirubin, total U/l ^mol/l Calcium mmol/l Chloride mmol/l Cholesterol mmol/l Creatinine ^mol/l Globulin Glucose g/l mmol/l Inorganic Phosphorus Potassium mmol/l mmol/l Sodium mmol/l Total Protein g/l Triglycerides mmo/l Urea Nitrogen mmol/l Uric Acic ^mol/l Methodology/Instrumentation Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Calculated: (Albumin / Globulin) Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Cobas Mira Centrifugal Analyzer ABX Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Calculated: (Total Protein - Albumin) Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Vitros 950 Ortho Clinical Diagnostics Ref. see page 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 Page 38 Toxicology Study Report - PT02-0222 10.1.3 Urinalysis (semiquantitative parameters evaluated) Abbreviation Urine Color Appearence pH Value Protein Glucose Ketone Bodies Bili rubin Blood (RBCs) Urobili nogen Microscopy of Sediment Parameter Urine Color Units Appearence of Urine pH Value (sq) Protein (Albumine) (sq) Glucose (sq) Ketone Bodies (sq) Bilirubin (sq) Blood (RBCs) (sq) Urobilinogen (sq) Methodology/Instrumentation Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Clinitek Atlas Bayer Diagnostics GmbH Microscope, without staining Ref. see page 35 35 35 35 35 35 35 35 35 35 10.1.4 Urinalysis (quantivtative parameters evaluated) Abbreviation Volume Specific Weight Parameter Volume Specific Weight Units ml g/l Methodology/Instrumentation Graduated Tube Clinitek Atlas Bayer Diagnostics GmbH Ref. see page 35 Page 39 Toxicology Study Report - PT02-0222 10.2 LIST OF ABBREVIATIONS USED IN THE REPORT approx. bw.; bdwt d M (m) F (f) GLP GC ID incl. LASW max. : Approximately : Body weight : Day : Male : Female : Good Laboratory Practice : Gas Chromatograph : Identification : Includes : Life Animal Safety Welfare : Maximum min. N (n) Rpm S.D. STATS K0/K0 animals R1/R1 animals R1/+1 animal : Minimum : Number of animals : Rotation per minute : Standard deviation : Statistical evaluations : Terminal sacrifice group : Recovery / post-treatment group : Recovery / post-treatment group / Found death Page 40 Toxicology Study Report - PT02-0222 11 FIGURES 11.1 BODY WEIGHT (GROUPS 1 - 5) Page 41 Toxicology Study Report - PT02-0222 Page 42 Toxicology Study Report - PT02-0222 Page 43 Toxicology Study Report - PT02-0222 11.2 BODY WEIGHT (GROUPS 6- 7) Page 44 Toxicology Study Report - PT02-0222 Page 45 Toxicology Study Report - PT02-0222 (1C) ID .2 "i UD PEC VA* 1 i i u y j j ' ccn jiA i I ; i I ;;i [ v jin .il ! N D i - D i i ? - l-r?!:E - 1 i : ( k . o i t I l A I I C J N i t 1j : B G D Y A f E I i H i [ F t. U i i . F r>K I UiJt I - , > E-IJN D a l : : ic L v !_l ? a0 J I B -e -o V Page 46 Toxicology Study Report - PT02-0222 11.3 FOOD CONSUMPTION (GROUPS 1 - 5) Page 47 Toxicology Study Report - PT02-0222 PROVANTIS SUMMARY AND S T A T I S T I C A L EVALUATION STUDY : PTD2-0222 - T-7758 - 4 weeks oral FOOD CONSUMPTION (MALE ANIMALS) 50 30 B- GROUP Page 48 Toxicology Study Report - PT02-0222 Page 49 Toxicology Study Report - PT02-0222 11.4 FOOD CONSUMPTION (GROUPS 6 - 7) Page 50 Toxicology Study Report - PT02-0222 Page 51 Toxicology Study Report - PT02-0222 5T U D V P T 5 - 022? - r - T T - t v{ >[ k [ i r c i I n . i c i l i i r, r n l F ODD C O N S U M P T I O N [ F E M A L E nM I M A L S ] 110 ma nO RUF Page 52 j a y i f s l. u i1. u-iihij Toxicology Study Report - PT02-0222 11.5 NEUROTOXICOLOGICAL EXAMINATIONS (GROUPS 1 - 5) Page 53 Toxicology Study Report - PT02-0222 Page 54 Toxicology Study Report - PT02-0222 Page 55 Toxicology Study Report - PT02-0222 Page 56 Toxicology Study Report - PT02-0222 Page 57 Toxicology Study Report - PT02-0222 11.6 NEUROTOXICOLOGICAL EXAMINATIONS (GROUPS 6 - 7) Page 58 Toxicology Study Report - PT02-0222 Page 59 Toxicology Study Report - PT02-0222 I-c-un MJ ' U'M1f Jh ; St If 1,1 EtALUATIIJN W r nm r UijlCIR A C V 1 1 r/CQUhlTS PER 5-IH IN U rL- INTERVAL! U[ A'lUnCN N =1 L J = RUv DATI n - U A t - i i D J 1 1 1 e r ito I $ Page 60 Toxicology Study Report - PT02-0222 Page 61 Toxicology Study Report - PT02-0222 Page 62 Toxicology Study Report - PT02-0222 12 SUMMARY TABLES AND STATISTICS All tables in this section are with statitics. The statistical markers are placed on the right site of the mean values of each parameter. 12.1 CLINICAL OBSERVATIONS - GROUPS 1 - 5 (INDIVIDUAL VALUES, WITHOUT STATS) Page 63 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 1 Group Animal Sex Number Clinical Sign 1m 1 No Abnormalities Detected Ki lled: end of study 2 No Abnormalities Detected Killed: end of study 3 No Abnormalities Detected Killed: end of study 4 No Abnormalities Detected Killed: end of study 5 No Abnormalities Detected Respiratory sounds Killed: end of study 6 No Abnormalities Detected Killed: end of recovery 7 No Abnormalities Detected Respiratory sounds Killed: end of recovery 8 No Abnormalities Detected Killed: end of recovery 9 No Abnormalities Detected Killed: end of recovery 10 No Abnormalities Detected Killed: end of recovery Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXX XXXXXXXXXXXXXX XXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXX XXXXXXXXXX XX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 64 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 2 (continued) Group Animal Sex Number Clinical Sign 1m 1 No Abnormalities Detected Ki lled: end of study 2 No Abnormalities Detected Killed: end of study 3 No Abnormalities Detected Killed: end of study 4 No Abnormalities Detected Killed: end of study 5 No Abnormalities Detected Respiratory sounds Killed: end of study 6 No Abnormalities Detected Killed: end of recovery 7 No Abnormalities Detected Respiratory sounds Killed: end of recovery 8 No Abnormalities Detected Killed: end of recovery 9 No Abnormalities Detected Killed: end of recovery 10 No Abnormalities Detected Ki lled: end of recovery Day numbers relative to Start Date 222222233333333334444 34567890 1234567890 123 XXXXXXX X XXXXXXX X XXXXXXX X XXXXXXX X XXXXXXX .X XXXXXXXXXXXXXXXXXXXXX . .X XXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX .X .X .X .X .X .X .X .X .X .X .X .X .X .X .X .X .X .X .X .X xxxxxxx * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 65 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 3 Group Animal Sex Number Cl inical Sign 1f 31 No Abnormalities Detected Ki lled: end of study 32 No Abnormalities Detected Ki lled: end of study 33 No Abnormalities Detected Ki lled: end of study 34 No Abnormalities Detected Ki lled: end of study 35 No Abnormalities Detected Ki lled: end of study 36 No Abnormalities Detected Ki lled: end of recovery 37 No Abnormalities Detected Ki lled: end of recovery 38 No Abnormalities Detected Ki lled: end of recovery 39 No Abnormalities Detected Ki lled: end of recovery 40 No Abnormalities Detected Ki lled: end of recovery Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 66 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 4 (continued) Group Animal Sex Number Cl inical Sign 1f 31 No Abnormalities Detected Ki lled: end of study 32 No Abnormalities Detected Ki lled: end of study 33 No Abnormalities Detected Ki lled: end of study 34 No Abnormalities Detected Ki lled: end of study 35 No Abnormalities Detected Ki lled: end of study 36 No Abnormalities Detected Ki lled: end of recovery 37 No Abnormalities Detected Ki lled: end of recovery 38 No Abnormalities Detected Ki lled: end of recovery 39 No Abnormalities Detected Ki lled: end of recovery 40 No Abnormalities Detected Ki lled: end of recovery Day numbers relative to Start Date 22222223333333333444 34567890 1234567890 12 XXXXXXX X XXXXXXX X XXXXXXX X XXXXXXX X XXXXXXX X XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXX xxxxxxxxxx * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 67 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* Date: 16-Dec-2002 Page: 5 Group Animal Sex Number Clinical Sign 2m 11 No Abnormalities Detected Gait stilted Respiratory sounds Ki lled: end of study 12 No Abnormalities Detected Gait uncoordinated Killed: end of study 13 No Abnormalities Detected Gait stilted Gait uncoordinated Killed: end of study 14 No Abnormalities Detected Gait uncoordinated Killed: end of study 15 No Abnormalities Detected Gait uncoordinated Ki lled: end of study Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXXXXXX XXXX XXXXXXX XXXX XXXXXXXXXXXXXX XXXXXXXX XXXXXXXXXXXXXXXX XXX XXX XXXXXXXXXXXXXX XXXXXXXX XXXXXXXXXXXXXX XXXXXXXX * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 68 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 6 (continued) Group Animal Sex Number Clinical Sign 2m 11 No Abnormalities Detected Gait stilted Respiratory sounds Ki lled: end of study 12 No Abnormalities Detected Gait uncoordinated Killed: end of study 13 No Abnormalities Detected Gait stilted Gait uncoordinated Killed: end of study 14 No Abnormalities Detected Gait uncoordinated Killed: end of study 15 No Abnormalities Detected Gait uncoordinated Killed: end of study Day numbers relative to Start Date 222222233333333334444 34567890 1234567890 123 XXXXXXX .. . . . . X XXX XX XX ....................... X XXXXXXX X XXXXXXX X XXXXXXX X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 69 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 7 Group Animal Sex Number Clinical Sign 2f 41 No Abnormalities Detected Gait stilted Gait uncoordinated Ki lled: end of study 42 No Abnormalities Detected Gait stilted Gait uncoordinated Killed: end of study 43 No Abnormalities Detected Gait uncoordinated Squatting posture Killed: end of study 44 No Abnormalities Detected Gait uncoordinated Squatting posture Killed: end of study 45 No Abnormalities Detected Gait uncoordinated Squatting posture Ki lled: end of study Day numbers relative to Start Date 1 1 1 1 1 1 1 1 1 1 22 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 01 2 XXXXXXXXXXXXXX XXXXXXXX XXXXXXXXXXXXXX XXXXXXX XXXXXXXXXXXXXXX X X X X XX X .X X XXXXXXXXXXXXXXXX XXXXXX .X .X .X .X X X X X X X X X X X X X X X X XX X . X X* XX- * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 70 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study PT02 -0222 T-7758 4 weeks oral tox icity in rats Date: 16-Dec-2002 Page: 8 (continued) Group Animal Sex Number Clinical Sign 2f 41 No Abnormalities Detected Gait stilted Gait uncoordinated Ki lled: end of study 42 No Abnormalities Detected Gait stilted Gait uncoordinated Killed: end of study 43 No Abnormalities Detected Gait uncoordinated Squatting posture Killed: end of study 44 No Abnormalities Detected Gait uncoordinated Squatting posture Killed: end of study 45 No Abnormalities Detected Gait uncoordinated Squatting posture Killed: end of study Day numbers relative to Start Date 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 334 44 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 890 12 3 XXXXXXX XXXX X XXXXXXX XXXXXXX X XXXXXXX XXXXXXX X XXXXXXX X X XXXXXXX XXXXXXX X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 71 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* Date: 16-Dec-2002 Page: 9 Group Animal Sex Number Clinical Sign 3m 16 No Abnormalities Detected Gait uncoordinated Squatting posture Tray / bedding discolored Ki lled: end of study 17 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Tray / bedding discolored Killed: end of study 18 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 19 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX XXXXXXXXXXXXXXXXX XXX YYYYYYYYYYY XXX XXXXXXXXXXXXXXX XXXXXXXXXX X YYYYYYYYYYY XXX XXXXXXXX XXXXXXXXXX XXXXXXXXX XXX YY YYYYYYYYYYY XXX XXXXXXXXXXX XXXXXXXX X Y YYYYYYYYYYY * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 72 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study PT02 -0222 T-7758 4 weeks oral tox icity (continued) Group Animal Sex Number Clinical Sign 3m 16 No Abnormalities Detected Gait uncoordinated Squatting posture Tray / bedding discolored Ki lled: end of study 17 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Tray / bedding discolored Killed: end of study 18 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 19 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 22222223333 34567890 123 XXXXXXX .. XXXXXXX .. X .. XXXXXXX .. XXXXXXX .. XXXXXXX .. X .. X X X X X X .X . . XXXXXXX .. XXXXXXX .. X .. XXXXXXX .. XXXXXXX .. XXXXXXX .. X .. Date: 16-Dec-2002 Page: 10 * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 73 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 11 Group Animal Sex Number Clinical Sign 3m 20 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study* Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX XXXXXXX XXXXXXXXXXX XXXXXXXXXXX YY YYYYYYYYYYY * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 74 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study PT02 -0222 T- 7758 4 weeks oral tox icity in rats Date: 16-Dec-2002 Page: 12 (continued) Group Animal Sex Number Clinical Sign 3m 20 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study Day numbers relative to Start Date 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 334 44 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 890 12 3 XXXXXXX XXXXXXX XXXX X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 75 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 13 Group Animal Sex Number Clinical Sign 3f 46 No Abnormalities Detected Gait stilted Gait uncoordinated Squatting posture Tray / bedding discolored Ki lled: end of study 47 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Tray / bedding discolored Killed: end of study 48 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Tray / bedding discolored Killed: end of study 49 No Abnormalities Detected Flanks drawn in Gait stilted Gait uncoordinated Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date i111111111222 12345678901234567890 12 XXX . XX XXXXXXXXXXXXXXX XXX YYYYYYYYYYY XXX . XXXXXXXXXXXXXXX XXX XXXX YYYYYYYYYYY XXX . XX XXXXXXXXXXXXXXXXX X XXXXXXXXX YYYYYYYYYYY XXX . XX X X X X X X X X X .X .X .X XXXXXXXXXX XXXXXXXXXXXXXXXXXX YY YYYYYYYYYYY * = result to left has an associ ated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg / k g Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 76 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 14 (continued) Group Animal Sex Number Clinical Sign 3f 46 No Abnormalities Detected Gait stilted Gait uncoordinated Squatting posture Tray / bedding discolored Ki lled: end of study 47 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Tray / bedding discolored Killed: end of study 48 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Tray / bedding discolored Killed: end of study 49 No Abnormalities Detected Flanks drawn in Gait stilted Gait uncoordinated Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 2 2 2 2 22 2 3 3 4 5 6 78 9 0 333 123 33 45 33 67 334 890 44 12 4 3 XXXX XXXXXXX XXXXXXX X XXXXXXX XXXXXXX XXXXXXX X XXXXXXX XXXXXXX XXXXXXX X XXXXXXX XXXXXXX XXXXXXX X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 77 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* Date: 16-Dec-2002 Page: 15 Group Animal Sex Number Clinical Sign 3f 50 No Abnormalities Detected Gait stilted Gait uncoordinated Squatting posture Tray / bedding discolored Ki lled: end of study Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX XXXXXXXXXXXXXXXX XX YYYYYYYYYYY * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 78 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study PT02 -0222 T- 7758 4 weeks oral tox icity in rats (cont nued) Group Animal Sex Number Clinical Sign 3f 50 No Abnormalities Detected Gait stilted Gait uncoordinated Squatting posture Tray / bedding discolored Ki lled: end of study Day numbers relative to Start Date 2222222333333 34567890 12345 XXXXX .. XXXXXXX .. XXXXXXX .. X .. Date: 16-Dec-2002 Page: 16 334 890 44 12 4 3* * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 79 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 17 Group Animal Sex Number Clinical Sign 4m 21 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Feces discolored Tray / bedding discolored Ki lled: end of study 22 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 23 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX . .. XXXXX . .. .X X X X X X X X X X X X X X X X X . .. XXXXXXXXXXXXXXX . .. YYYYYYY . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. XXX . .. XXXXX . .. XXXXXXXXXXXXXXXXXX . .. XXXXXXXXXXX . .. X . .. YYY . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. XXX . .. XXXXX . .. XXXXXXXXXXXXXXXXXX . .. XXXXXXXXXXXXXXX . .. XXXX . ..Y Y Y Y Y . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 80 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 18 (continued) Group Animal Sex Number Clinical Sign 4m 21 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Feces discolored Tray / bedding discolored Ki lled: end of study 22 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 23 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 2 2 2 2 22 2 3 3 4 5 6 78 9 0 333 123 33 45 33 67 334 890 44 12 4 3 XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXX XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXX XXXXXXX XXXXXXX XXXXXXX YYYYYYY X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 81 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 19 Group Animal Sex Number Clinical Sign 4m 24 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study 25 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 26 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of recovery Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX . .. XXXXXXXXXXXXXXXXXX . .. XXXXXXXXXXXXXX . .. XXXX XXXX . ..Y Y Y Y Y Y . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. XXX . .. XXX . .. XXXXXXXXXXXXXXXXXX . .. XXXXXXXXXXXXXXX . .. XXXXXXX XXXXXXXX . .. YYY . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. XXX . .. . .. XXXXXXXXXXXXXXXXXX . .. XXXXXXXXXXX . .. XXXXXXX . ..Y Y Y Y Y Y . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . .* * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 82 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 20 (continued) Group Animal Sex Number Clinical Sign 4m 24 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study 25 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 26 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of recovery* Day numbers relative to Start Date 222222233333333334444 34567890 1234567890 123 XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXX XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXXX XXXXXXXXXXXX XXXXXXXXXX XXXXXXXXXXXXXXXXXXXXX YYYYYYYYYYYYYYYYY X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 83 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 21 Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1111111111222 12345678901234567890 12 4m 27 No Abnormalities Detected X X X Flanks drawn in . . .. Gait stilted . . .X X X X X Gait uncoordinated . . .. X X X X X X X X X X X X X X X X X X Abdomen swollen . . .. XXXXXXXXXXXXXX Squatting posture . . .. X X X X X X X X X XXXXXXXX Feces discolored . . .Y Y Y Y Y Y Tray / bedding discolored . . .Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Snout encrusted blood-colored . . . . Snout swollen . . .. Ki lled: end of recovery . . .. 28 No Abnormalities Detected XXX . Flanks drawn in . . .. Gait stilted . . .. Gait uncoordinated . . .. X X X X X X X X X X X X X X X X X X Abdomen swollen . . .. XXXXXXXXXXXXXXX Squatting posture . . .. XX Feces discolored . . .Y Y Y Y Y Y Y Tray / bedding discolored . . .Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Lower incisor(s) broken off . . .. Upper incisor(s) broken off . . .. Killed: end of recovery . . .. * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 84 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* Date: 16-Dec-2002 Page: 22 Day numbers relative to Start Date (cont inued) Group Animal Sex Number Clinical Sign 222222233333333334 34567890 1234567890 4m 27 No Abnormalities Detected Flanks drawn in Gait stilted XXXXX Gait uncoordinated XXXXXXXXXXXXXXXXXX Abdomen swollen XXXXXXXXXX Squatting posture XXXXXXXXXXXXXXXXXX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Snout encrusted blood-colored X Snout swollen X Ki lled: end of recovery 28 No Abnormalities Detected Flanks drawn in X Gait stilted XXXXX XXXXXXXX Gait uncoordinated XXXXXXXXXXXXXXXXXX Abdomen swollen XXXXXXXXXX Squatting posture XXXXXXXXXXXXXXXXXX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Lower incisor(s) broken off XXX Upper incisor(s) broken off Killed: end of recovery XX- * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 85 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 23 Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1111111111222 12345678901234567890 12 4m 29 No Abnormalities Detected X X X Gait stilted XX XX Gait uncoordinated XXXXXXXXXXXXXXXXXX Abdomen swollen XXXXXXXXXXXXXXX Squatting posture XXX XXXX Feces discolored YYYYYYY Tray / bedding discolored YYYYYYYYYYYYYYYYYYY Ki lled: end of recovery 30 No Abnormalities Detected XXX Flanks drawn in Gait stilted XXXXXXXXX XX Gait uncoordinated XXXXXXX XXXXXXXXXX Abdomen swollen XXXXXXXXXXXX Squatting posture XXXXXXXX XXXXXXXX Stupor Coat bristling Feces discolored YYYY Tray / bedding discolored YYYYYYYYYYYYYYYYYYY Snout encrusted blood-colored Snout swollen Lower incisor(s) broken off Found dead * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 86 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 24 Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 222222233333333334444 34567890 1234567890 123 4m* 29 No Abnormalities Detected Gait stilted XXXXXXX Gait uncoordinated XXXXXXXXXXXXXXXXXXXXX Abdomen swollen XXXXXXXXXXXX Squatting posture XXXXXXXXXXXXXXXXXXXXX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Ki lled: end of recovery X 30 No Abnormalities Detected Flanks drawn in XXXXXXXXXXXXXXXX Gait stilted XXXXXXXXXXXXXXXXXXX Gait uncoordinated XXXXXXXXX XX Abdomen swollen XXXXXXXXXX Squatting posture XXXXXXXXXXXXXXXXXXX Stupor XX Coat bristling XX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Snout encrusted blood-colored XXX Snout swollen XXX Lower incisor(s) broken off XXXX * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 87 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 25 Group Animal Sex Number Clinical Sign 4f 51 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study 52 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 53 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX . ..X X X X XXX . .. XXXXXXXXXXXXXXXX . .. XXXXXXXXXXXXXX . .. XXXXXXXX . ..Y Y Y Y . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. XXX . .. XXXXXXXXXXXXXXXXXX . .. XXXX . .. XXX XXXX . ..Y Y Y Y Y . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . .. XXX . .. . .. XXXXXXXXXXXXXXXXXX . .. XXXXXXXXXXXXXXX . .. X XXXXXXX . ..Y Y Y Y . ..Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . .* * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 88 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observati ons Clinical Signs by Animal Study : PT02-0222 - T-7758 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 26 (continued) Group Animal Sex Number Clinical Sign 4f 51 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study 52 No Abnormalities Detected Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 53 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study Day numbers relative to Start Date 2 2 2 2 22 2 3 3 4 5 6 78 9 0 333 123 33 45 33 67 334 890 44 12 4 3 XXXXXXX XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXX XXXXXXX XXXXXXX XXXXXXX YYYYYYY X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 89 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* Date: 16-Dec-2002 Page: 27 Group Animal Sex Number Clinical Sign 4f 54 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study 55 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 56 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of recovery Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX XXXXX XXXX XXXXXXXXXXXXXXXXXX XX XXXXXXXX XXXXXXX XXXXXXXX YYYY YYYYYYYYYYYYYYYYYYY XXX XXXXX XXXXXXXX XXXXXXXXXXXXXXXX XXXXX XXXXXXXX YYYY YYYYYYYYYYYYYYYYYYY XXX XXXX XXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXX XXXXXXX YYYY YYYYYYYYYYYYYYYYYYY * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 90 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 28 (continued) Group Animal Sex Number Clinical Sign 4f 54 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of study 55 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of study 56 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Killed: end of recovery* Day numbers relative to Start Date 222222233333333334444 34567890 1234567890 123 XXXXXXX XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXX XXXXXXX XXXXXXX YYYYYYY X XXXXXXX XXXXXXXXX XXXXXXXXXXXX XXXXXXXXXX XXXXXXXXXXXXXXXXXXXXX YYYYYYYYYYYYYYYYY X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 91 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 29 Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1111i111ii222 12345678901234567890 12 4f 57 No Abnormalities Detected X X X Gait stilted XXXXX X Gait uncoordinated XXXXXXXXXXXXXX Abdomen swollen XXX Squatting posture XXXXXXXXXXXXXXXXXX Feces discolored YYYY Tray / bedding discolored YYYYYYYYYYYYYYYYYYY Ki lled: end of recovery 58 No Abnormalities Detected XXX Flanks drawn in Gait stilted XXX X Gait uncoordinated XXXXXXXXXXXXXXX Abdomen swollen XXXXXXX Squatting posture XXXXXXXXXXXXXXXXXX Feces discolored YYYY Tray / bedding discolored YYYYYYYYYYYYYYYYYYY Killed: end of recovery 59 No Abnormalities Detected XXX Flanks drawn in XX Gait stilted XXXXXXXXXXXXXXXXXXX Gait uncoordinated XXXXXXXXXXXXXXXXX Abdomen swollen XXXX Squatting posture XXXXXXXXXXXXXXXXXX Feces discolored YYYY Tray / bedding discolored YYYYYYYYYYYYYYYYYYY Lower incisor(s) broken off Upper incisor(s) trimmed Killed: end of recovery * = result to left has an associ ated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 92 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 30 Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 222222233333333334444 34567890 1234567890 123 4f 57 No Abnormalities Detected Gait stilted XXXXXXXXXXXXXXXXXXXXX Gait uncoordinated XXXXXXXXXXXX Abdomen swollen XX Squatting posture XXXXXXXXXXXXXXXXXXXXX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Ki lled: end of recovery X 58 No Abnormalities Detected Flanks drawn in XX Gait stilted XXXXXXXXXXXXXXXXXXXXX Gait uncoordinated XXXXXXXXXXXX Abdomen swollen XXXXXXXXXX Squatting posture XXXXXXXXXXXXXXXXXXXXX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Killed: end of recovery X 59 No Abnormalities Detected Flanks drawn in Gait stilted XXXXXXXXXXXXXXXXXXXXX Gait uncoordinated XXXXXXXXXXXXXXXXXXXXX Abdomen swollen XX Squatting posture XXXXXXXXXXXXXXXXXXXXX Feces discolored Tray / bedding discolored YYYYYYYYYYYYYYYYY Lower incisor(s) broken off XXXXXXXXXX Upper incisor(s) trimmed X Killed: end of recovery X * = result to left has an associ ated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 93 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 31 Group Animal Sex Number Clinical Sign 4f 60 No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of recovery* Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXX XXX XXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXX XXX XXXXXXXX YYYYY YYYYYYYYYYYYYYYYYYY * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 94 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 32 (continued) Group Animal Sex Number Clinical Sign 4f 60* No Abnormalities Detected Gait stilted Gait uncoordinated Abdomen swollen Squatting posture Feces discolored Tray / bedding discolored Ki lled: end of recovery Day numbers relative to Start Date 222222233333333334444 34567890 1234567890 123 XXXXX XXXXXXXXXXXXXXXXXXXXX XX XXXXXXX XXXXXXXXXXXXXXXXXXXXX YYYYYYYYYYYYYYYYY * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 95 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 33 Group Animal Sex Number Clinical Sign 5m 61 No Abnormalities Detected Squatting posture Ki lled: end of study 62 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 63 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 64 No Abnormalities Detected Squatting posture Killed: end of study 65 No Abnormalities Detected Squatting posture Killed: end of study* Day numbers relative to Start Date 1111111111222 12345678901234567890 12 XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXX * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 96 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 34 (continued) Group Animal Sex Number Clinical Sign 5m 61 No Abnormalities Detected Squatting posture Ki lled: end of study 62 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 63 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 64 No Abnormalities Detected Squatting posture Killed: end of study 65 No Abnormalities Detected Squatting posture Killed: end of study Day numbers relative to Start Date 222222233333333334444 34567890 1234567890 123 X XXXXXX X XXXX XXXXXXX X XXXXX XXXXXXX X XXX XXXX X XXX XXXX X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 97 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 35 X X - X X X - X- X- X X X Group Animal Sex Number Clinical Sign 5f 66 No Abnormalities Detected Gait stilted Squatting posture Ki lled: end of study 67 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 68 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 69 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 70 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study* Day numbers relative to Start Date 111111111122 12345678901234567890 1 XXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXX * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 98 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: 36 (continued) Group Animal Sex Number Clinical Sign 5f 66 No Abnormalities Detected Gait stilted Squatting posture Ki lled: end of study 67 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 68 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 69 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study 70 No Abnormalities Detected Gait stilted Squatting posture Killed: end of study Day numbers relative to Start Date 2 2 2 2 2 2 2 3 333 33 33 3 4 5 6 7 8 9 0 123 45 67 334 890 44 12 4 3 XXXXXXX XXXXXXX X XXXXXXX XXXXX X XXXXXXX XXXXXXX X XXXXXXX XXXXXXX X XXXXXXX XXXXXXX X * = result to left has an associated comment or marker X = Present Y = yellowish Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 99 Toxicology Study Report - PT02-0222 12.2 CLINICAL OBSERVATIONS - GROUPS 6 - 7 (INDIVIDUAL VALUES, WITHOUT STATS) Page 100 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observati ons Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 4 weeks oral toxicity in rats Date: 28-May-2003 Page: 1 xxxxxxxxxx Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 11111111112222222222 12345678901234567890123456 789 6m 71 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 72 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 73 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 74 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 75 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study . .* * = result to left has an associated comment or marker X = Present Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 101 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observati ons Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 4 weeks oral toxicity in rats Date: 28-May-2003 Page: 2 xxxxxxxxxx Day numbers relative to Start Date Group Animal Sex Number Clinical Sign iiiiiiiiii2222222222 1234567890i234567890i23456 789 6f 81 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 82 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 83 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 84 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 85 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study . .* * = result to left has an associated comment or marker X = Present Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 102 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observati ons Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 4 weeks oral toxicity in rats Date: 28-May-2003 Page: 3 xxxxxxxxxx Day numbers relative to Start Date Group Animal Sex Number Clinical Sign iiiiiiiiii2222222222 1234567890i234567890i23456 789 7m 76 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 77 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 78 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 79 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 80 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study . .* * = result to left has an associated comment or marker X = Present Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 103 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Clinical Observati ons Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 4 weeks oral toxicity in rats Date: 28-May-2003 Page: 4 xxxxxxxxxx Day numbers relative to Start Date Group Animal Sex Number Clinical Sign iiiiiiiiii2222222222 1234567890i234567890i23456 789 7f 86 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 87 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 88 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 89 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study .. 90 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X X X X X X X X Killed: end of study . .* * = result to left has an associated comment or marker X = Present Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 104 Toxicology Study Report - PT02-0222 12.3 BODY WEIGHT (GROUPS 1 - 5) Page 105 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 17-DEC-2002 BODY WEIGHT -- MALE ANIMALS (g) STUDY DAY -0003 +0001 +0004 +0005 +0008 +0011 +0012 NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg GROUP 5 240 mg/kg 116.7 5.4 10 138.4 7.3 10 158.4 14.8 10 177.2 17.9 10 204.3 20.2 10 112.2 2.9 5 134.0 3.5 5 152.8 M 4.1 5 183.2 5.4 5 205.0 M 9.1 5 122.2 3.7 5 144.2 5.1 5 162.2 11.5 5 180.4 12.7 5 208.4 13.8 5 121.8 7.9 5 143.4 8.6 5 121.9 4.9 9 146.2 + 5.2 9 143.6 5.7 5 164.6 9.1 5 139.8 10.3 9 156.4 8.0 9 190.2 11.2 5 178.3 8.6 9 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 106 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 17-DEC-2002 BODY WEIGHT -- MALE ANIMALS (g) STUDY DAY +0015 +0018 +0019 +0022 +0025 +0026 +0029 MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg GROUP 5 240 mg/kg 224.9 19.5 10 245.2 23.5 10 257.0 26.5 10 266.0 30.4 10 279.6 31.3 10 228.0 11.6 5 244.4 M 14.6 5 263.0 16.8 5 275.8 M 18.5 5 279.8 18.4 5 223.0 12.7 5 242.4 13.7 5 251.0 12.4 5 258.2 15.3 5 269.8 13.8 5 209.0 13.0 5 194.9 12.1 9 232.0 15.4 5 240.6 17.4 5 215.6 12.5 9 219.3 12.5 9 249.0 19.9 5 261.2 21.6 5 227.0 17.5 9 230.7 17.9 9 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 107 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s BODY WEIGHT - MALE ANIMALS (g) STUDY DAY +0033 +0036 +0040 +0043 MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg 295.8 43.7 5 304.2 44.4 5 319.6 48.4 5 320.0 50.8 5 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 222.3 18.8 4 208.8 24.6 4 203.0 30.7 4 194.0 35.9 4 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 108 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 17-DEC-2002 BODY WEIGHT -- FEMALE ANIMALS (g) STUDY DAY -0003 +0001 +0004 +0005 +0008 +0011 +0012 NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg GROUP 5 240 mg/kg 113.1 4.6 10 129.2 4.5 10 147.1 5.9 10 158.2 8.1 10 169.5 9.9 10 106.6 3.9 5 120.6 2.6 5 134.4 M 3.4 5 148.8 2.6 5 157.8 M 4.1 5 114.6 3.0 5 131.0 3.4 5 145.6 3.9 5 156.8 5.4 5 166.2 4.3 5 115.2 4.2 5 133.2 2.6 5 112.2 4.8 10 126.6 5.4 10 131.0 13.9 5 148.2 12.1 5 126.1 8.0 10 139.2 12.3 10 163.2 10.5 5 154.4 11.0 10 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 109 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 17-DEC-2002 BODY WEIGHT -- FEMALE ANIMALS (g) STUDY DAY +0015 +0018 +0019 +0022 +0025 +0026 +0029 MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg GROUP 5 240 mg/kg 178.0 8.4 10 186.7 8.6 10 193.3 9.6 10 204.3 11.9 10 211.8 12.0 10 168.4 5.1 5 176.2 M 6.4 5 184.8 4.3 5 190.8 M 4.0 5 195.0 4.9 5 176.8 5.1 5 189.2 4.1 5 193.0 4.6 5 202.0 6.0 5 205.8 5.0 5 172.4 9.2 5 162.8 11.8 10 184.2 9.4 5 188.4 11.0 5 175.0 12.6 10 178.4 12.2 10 198.2 10.4 5 199.8 8.7 5 183.9 14.1 10 186.0 20.1 10 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 110 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s BODY WEIGHT - FEMALE ANIMALS (g) STUDY DAY +0033 +0036 +0040 +0043 MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg 220.4 14.9 5 221.6 14.2 5 226.4 18.9 5 225.6 17.5 5 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 193.6 26.2 5 197.2 29.6 5 198.4 27.8 5 189.4 29.9 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 111 Toxicology Study Report - PT02-0222 12.4 BODY WEIGHT (GROUPS 6- 7) Page 112 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 05-MAR-2003 BODY WEIGHT -- MALE ANIMALS (g) STUDY DAY -0004 +0001 +0004 +0008 +0011 +0015 +0018 NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 106.2 4.0 5 139.2 3.8 5 160.0 3.3 5 188.0 4.0 5 212.4 4.6 5 236.6 8.4 5 253.4 13.5 5 GROUP 2 0.3 mg/kg/d 108.8 3.6 5 142.2 4.1 5 163.6 5.7 5 191.2 6.4 5 215.6 10.5 5 242.4 11.3 5 264.0 16.0 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 113 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s BODY WEIGHT -- MALE ANIMALS (g) STUDY DAY +0022 +0025 +0029 MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 270.4 16.5 5 283.4 17.1 5 295.6 17.5 5 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 282.8 22.4 5 292.0 20.4 5 307.8 25.4 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 114 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 05-MAR-2003 BODY WEIGHT -- FEMALE ANIMALS (g) STUDY DAY -0004 +0001 +0004 +0008 +0011 +0015 +0018 NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 104.8 4.1 5 124.6 4.7 5 134.4 5.9 5 145.0 8.3 5 156.8 7.6 5 166.0 8.6 5 174.0 8.9 5 GROUP 2 0.3 mg/kg/d 102.6 3.4 5 125.2 4.2 5 139.2 + 5.6 5 150.4 8.7 5 161.4 8.5 5 172.6 9.2 5 178.4 10.2 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 115 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s BODY WEIGHT -- FEMALE ANIMALS (g) STUDY DAY +0022 +0025 +0029 MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 181.0 8.2 5 184.0 9.3 5 190.6 9.8 5 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 187.8 10.3 5 188.6 9.9 5 199.0 11.7 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL (STATISTICAL ANALYSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 116 Toxicology Study Report - PT02-0222 12.5 FOOD CONSUMPTION - GROUPS 1 - 5 (WITHOUT STATS) Page 117 Toxicology Study Report - PT02-0222 RTA075-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Intergroup Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats Page: 1 Day numbers relative to Start Date Group From: -3 1 5 Sex To: 1 5 8 1m Mean S.D. N 119.69 5.84 10 103.52 6.90 10 97.74 9.41 10 2m Mean S.D. N 3m Mean S.D. N 119.22 3.87 5 117.50 7.31 5 99.73 4.77 5 82.07 3.93 5 91.04 6.52 5 --8 -9 -.-2 -9 4.36 5 4m Mean S.D. N 185.28 72.41 9 60.97 11.40 9 83.31 4.33 9 8 12 90.97 9.05 10 84.42 5.78 5 88.73 5.19 5 87.61 4.51 9 12 15 87.17 7.98 10 76.57 4.65 5 85.-5.31 5 82.27 4.55 9 15 19 81.33 7.56 10 72.81 4.07 5 80.10 5.40 5 81.71 4.85 9 19 22 22 26 72.03 7.96 10 60.49 8.00 10 68.25 3.60 5 74.-2 5.41 5 55.71 3.07 5 --5 -7-.-0 -6 4.54 5 76.29 4.57 9 63.09 4.22 9 26 29 62.89 6.90 10 61.26 3.44 5 70.16 5.95 5 61.68 6.43 9 29 33 72.48 10.73 5 73.77 5.97 4 33 36 69.67 10.52 5 45.85 4.91 4 36 40 67.74 10.29 5 38.68 5.52 4 40 43 53.36 8.38 5 45.62 7.97 4 Mean -3 43 82.98 7.74 10 81.00 4.09 5 -8-2-.-7-2 4.97 5 81.04 3.97 9 Food consumption units are g/kg bodywei ght/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 m g/kg Page 118 Toxicology Study Report - PT02-0222 RTA075-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Intergroup Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats Page: 2 Group From: -3 1 5 Sex To: 1 5 8 1f Mean S.D. N 106.88 3.83 10 105.09 3.86 10 91.44 4.45 10 2f Mean S.D. N 3f Mean S.D. N 109.17 2.66 5 114.39 2.98 5 100.20 2.57 5 70.54 4.08 5 90.01 2.65 5 --9 -1 -.-4 -4 9.55 5 4f Mean S.D. N 106.26 4.58 10 72.17 3.96 10 88.67 7.08 10 Day numbers relative to Start Date 8 12 80.62 4.77 10 79.31 2.36 5 80.43 6.35 5 87.40 7.80 10 12 15 15 19 74.24 3.94 10 73.49 3.59 10 74.29 1.97 5 76.-0 4.81 5 71 .89 1 .76 5 --7 -2 -.-5 -0 3.89 5 84.68 7.50 10 81.33 6.47 10 19 22 72.05 4.99 10 70.84 1.55 5 75.-8 4.25 5 78.45 5.71 10 22 26 26 29 65.54 3.84 10 62.67 3.54 10 60.29 1.64 5 61.98 3.62 5 64.12 1.76 5 --6 -5 -.-4 -5 3.25 5 71.88 7.94 10 66.72 8.25 10 29 33 78.52 5.51 5 92.02 15.44 5 33 36 66.90 4.47 5 77.93 13.29 5 36 40 67.94 5.23 5 75.08 13.17 5 40 43 60.21 5.09 5 44.55 7.60 5 Mean -3 43 79.24 3.97 10 80.01 1.84 5 -7-8-.-7-6 4.41 5 80.39 6.60 10 Food consumption units are g/kg bodywei ght/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 m g/kg Page 119 Toxicology Study Report - PT02-0222 RTA075-01/00 PROVANTIS Date: 16-Dec-2002 Food Consumpt ion By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Page: 1 Group Sex 5m From : To: Mean S.D. N -3 1 123.54 3.04 5 1 4 106.52 2.88 5 Day numbers relative to Start Date 4 8 102.44 2.77 5 8 11 95.24 3.54 5 11 15 86.99 4.16 5 15 18 76.39 4.18 5 18 22 74.72 4.58 5 22 25 63.32 4.17 5 25 29 51.47 3.41 5 Mean -3 29 86.74 3.31 5 Food consumption units are g/kg bodyweight/day Nominal Dose: Group 5 - 3 mg/kg Page 120 Toxicology Study Report - PT02-0222 RTA075-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Intergroup Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats Page: 2 Group Sex 5f From : To: Mean S.D. N -3 1 108.64 3.10 5 1 4 96.77 2.26 5 Day numbers relati ve to Start Date 4 8 90.07 1.81 5 8 11 78.73 1.48 5 11 15 76.38 2.16 5 15 18 68.93 2.21 5 18 22 69.01 1.85 5 22 25 60.02 1.30 5 25 29 57.05 1.30 5 Mean -3 29 78.40 1.75 5 Food consumption units are g/kg bodyweight/day Nominal Dose: Group 5 - 3 mg/kg Page 121 Toxicology Study Report - PT02-0222 12.6 FOOD CONSUMPTION - GROUPS 6 - 7 (WITHOUT STATS) Page 122 Toxicology Study Report - PT02-0222 RTA075-01/00 PROVANTIS Date: 03-Mar-2003 Page: Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m 7m From : To: Mean S.D. N Mean S.D. N -4 1 118.26 3.67 5 118.79 3.21 5 1 4 112.34 2.56 5 110.40 3.43 5 Day numbers relative to Start Date 4 8 109.23 2.15 5 105.51 3.60 5 8 11 102.60 2.18 5 101.75 4.22 5 11 15 89.81 2.51 5 86.17 4.00 5 15 18 79.86 3.72 5 78.12 4.27 5 18 22 69.87 4.15 5 70.33 5.15 5 22 25 58.44 3.68 5 54.06 4.22 5 25 29 72.06 4.52 5 66.18 5.32 5 Mean -4 29 90.28 2.14 5 87.92 3.60 5 Food consumption units are g/kg bodyweight/day Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 123 Toxicology Study Report - PT02-0222 RTA075-01/00 PROVANTIS Date: 03-Mar-2003 Page: Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f 7f From : To: Mean S.D. N Mean S.D. N -4 1 114.35 4.42 5 115.11 3.85 5 1 4 92.26 3.69 5 101.47 3.76 5 Day numbers relative to Start Date 4 8 88.23 4.60 5 92.73 4.74 5 8 11 88.12 4.76 5 84.45 4.79 5 11 15 82.58 4.26 5 77.42 4.25 5 15 18 66.02 3.38 5 65.88 3.67 5 18 22 67.73 3.26 5 60.49 3.30 5 22 25 56.36 2.68 5 53.61 2.86 5 25 29 70.08 3.53 5 70.86 3.89 5 Mean -4 29 80.64 3.67 5 80.22 3.73 5 Food consumption units are g/kg bodyweight/day Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 124 Toxicology Study Report - PT02-0222 12.7 CLINICAL PATHOLOGY 12.7.1 Hematology (Groups 1 - 5) Page 125 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - RED CELL COUNT (MALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg Red b lo o d c e l l c o u n t (1 0 E 1 2 /L ) Hem oglobin (g/L ) Hematocr i t (un ity ) MCV (10E-15 L) MCH (10E-12 g) MCHC (g /L ) Ret ic u lo c y te s (u n ity ) Hei nz Bodies (un ity ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N NE MEAN S.D. N NE MEAN S.D. N MEAN S.D. N NE MEAN S.D. N 7.76 0 .2 6 5 150 4 5 0 .4 5 0.01 5 57 1 5 20 1 5 339 8 5 0 .0 2 9 0.001 5 0 .0 0 0 0 .0 0 0 5 7.91 0 .1 5 5 156 4 5 0 .4 6 0.01 5 58 1 5 20 1 5 342 3 5 0.029 0.003 5 0 .0 0 0 0 .0 0 0 5 7 .8 3 0 .3 5 5 150 3 5 0 .4 5 0 .0 2 5 58 1 5 19 1 5 334 9 5 0 .0 2 6 0 .0 0 2 5 7 .8 0 0 .3 7 5 148 5 5 0 .4 5 0 .0 2 5 58 1 5 19 0 5 326 4 5 0 .0 2 9 0 .0 0 2 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 7 .5 6 0 .4 3 5 149 8 5 0 .4 4 0 .0 2 5 58 1 5 20 0 5 338 4 5 0 .0 2 6 0 .0 0 5 5 0 .0 0 0 0 .0 0 0 5 Page 126 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - RED CELL COUNT (FEMALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg Red b lo o d c e l l c o u n t (1 0 E 1 2 /L ) Hem oglobin (g /L ) Hematocr i t (un ity ) MCV (10E-15 L) MCH (10E-12 g) MCHC (g /L ) Ret ic u lo c y te s (u n ity ) Hei nz Bodies (un ity ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N NE MEAN S.D. N NE MEAN S.D. N MEAN S.D. N NE MEAN S.D. N 7.19 0.31 5 138 6 5 0.41 0 .0 2 5 56 1 5 19 0 5 340 5 5 0 .0 2 9 0 .0 0 4 5 0 .0 0 0 0 .0 0 0 5 7.51 0 .3 0 5 149 4 5 0 .4 3 0 .0 2 5 57 1 5 20 0 5 349 6 5 0.033 0.005 5 0 .0 0 0 0 .0 0 0 5 7 .4 5 0 .6 3 4 141 10 4 0 .4 2 0 .0 3 4 56 1 4 19 0 4 341 3 4 0 .0 2 6 0 .0 0 5 4 7 .4 0 0 .4 0 5 143 5 5 0 .4 2 0 .0 2 5 57 1 5 20 1 5 340 10 5 0 .0 2 9 0 .0 0 6 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 127 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 6 .9 8 0 .2 5 4 130 4 4 0 .3 9 0 .0 2 4 56 2 4 19 1 4 333 5 4 0 .0 2 9 0 .0 0 5 4 0 .0 0 0 0 .0 0 0 4 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE HEMATOLOGY - RED CELL COUNT (MALE) GROUP 1 0 m g/kg Red b lo o d c e l l c o u n t (1 0 E 1 2 /L ) Hem oglobin (g/L ) H e m ato crit (u n ity ) MCV (10E-15 L) MCH (10E-12 g) MCHC (g /L ) R e tic u lo c y te s (u n ity ) Hei nz Bodies (u n ity ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N NE MEAN S.D. N NE MEAN S.D. N MEAN S.D. N NE MEAN S.D. N 8 .6 8 0.27 5 160 7 5 0 .4 8 0 .0 2 5 55 2 5 18 1 5 334 4 5 0 .0 2 4 0 .0 1 0 5 0 .0 0 0 0 .0 0 0 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 128 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 9.22 + 0.31 4 167 3 4 0 .5 0 0.01 4 54 2 4 18 1 4 335 5 4 0.008 0 .0 0 5 4 0 .0 0 0 0 .0 0 0 4 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE HEMATOLOGY - RED CELL COUNT (FEMALE) GROUP 1 0 m g/kg Red b lo o d c e l l c o u n t (1 0 E 1 2 /L ) Hem oglobin (g/L ) H e m ato crit (u n ity ) MCV (10E-15 L) MCH (10E-12 g) MCHC (g /L ) R e tic u lo c y te s (u n ity ) Hei nz Bodies (u n ity ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N NE MEAN S.D. N NE MEAN S.D. N MEAN S.D. N NE MEAN S.D. N 8.07 0 .0 9 5 149 4 5 0 .4 4 0.01 5 54 1 5 19 1 5 344 5 5 0 .0 2 0 0 .0 0 3 5 0 .0 0 0 0 .0 0 0 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 129 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 8 .4 5 0 .4 3 5 156 7 5 0 .4 6 0 .0 2 5 54 1 5 18 1 5 341 3 5 0 .0 1 5 0 .0 0 4 5 0 .0 0 0 0 .0 0 0 5 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - WHITE CELL COUNT (MALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg W hite b lood c e ll co u n t (10E 9/L) N eutroph ils (u n ity ) E o s in o p h ils (u n ity ) B a so p h ils (u n ity ) L ym p h o cyte s (u n ity ) M onocytes (u n ity ) MEAN MEDIAN S.D. XMAX XMIN N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N 10.8 11.4 1 .6 12.6 8 .2 5 0 .1 0 0 .0 8 0 .1 2 5 0 .0 0 0 .0 0 0 .0 2 5 0.01 0.01 0 .0 2 5 0 .8 7 0 .8 5 0 .8 8 5 0 .0 2 0.01 0 .0 2 5 13.5 13.8 1.8 16.2 11.3 5 0 .1 0 0 .0 8 0.11 5 0.01 0 .0 0 0 .0 2 5 0.01 0.01 0.01 5 0 .8 5 0 .8 4 0 .8 8 5 0 .0 2 0.01 0 .0 3 5 13.1 1 2 .9 2 .0 1 5 .3 1 1 .0 5 0 .0 8 0 .0 6 0 .0 8 5 0 .0 0 0 .0 0 0.01 5 0 .0 0 0 .0 0 0.01 5 0 .8 9 0 .8 9 0 .9 2 5 0.01 0.01 0 .0 2 5 11.4 11.1 1 .9 13.4 9 .0 5 0.11 0 .0 8 0 .1 2 5 0 .0 0 0 .0 0 0.01 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 7 0 .8 4 0 .8 9 5 0.01 0.01 0 .0 3 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 9 .4 9.1 1 .8 1 2 .4 7 .8 5 0 .1 2 0 .0 9 0 .1 5 5 0 .0 0 0 .0 0 0.01 5 0 .0 0 0 .0 0 0.01 5 0 .8 5 0.81 0 .8 7 5 0 .0 2 0 .0 2 0 .0 2 5 Page 130 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - WHITE CELL COUNT (FEMALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg W hite b lood c e ll co u n t (10E 9/L) MEAN MEDIAN S.D. XMAX XMIN N N eutroph ils (un ity ) NE MEDIAN XMIN XMAX N E o s in o p h ils (u n ity ) NE MEDIAN XMIN XMAX N B a so p h ils (u n ity ) NE MEDIAN XMIN XMAX N L ym p h o cyte s (u n ity ) NE MEDIAN XMIN XMAX N M onocytes (u n ity ) NE MEDIAN XMIN XMAX N 7 .9 7 .6 1 .3 1 0 .0 6 .4 5 0 .0 8 0 .0 6 0 .1 0 5 0 .0 0 0 .0 0 0.01 5 0 .0 0 0 .0 0 0.01 5 0 .9 0 0 .8 7 0 .9 2 5 0.01 0.01 0.01 5 11.1 11.2 0 .8 12.2 10.1 5 0 .0 9 0 .0 7 0 .1 4 5 0.01 0.01 0 .0 2 5 0 .0 0 0 .0 0 0.01 5 0 .8 8 0 .8 2 0 .8 9 5 0 .0 2 0.01 0 .0 4 5 9 .8 10.1 0 .8 1 0 .4 8 .6 4 0 .0 7 0 .0 5 0 .0 7 4 0.01 0 .0 0 0.01 4 0 .0 0 0 .0 0 0 .0 0 4 0 .9 2 0 .9 0 0 .9 4 4 0.01 0.01 0.01 4 8 .5 8 .0 1 .6 11.3 7 .4 5 0 .0 9 0 .0 7 0.11 5 0 .0 0 0 .0 0 0.01 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 9 0 .8 7 0.91 5 0.01 0.01 0 .0 2 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 131 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 7 .9 7 .9 1 .3 9 .4 6 .5 4 0 .0 8 0 .0 6 0 .0 9 4 0.01 0.01 0.01 4 0 .0 0 0 .0 0 0 .0 0 4 0 .9 0 0 .8 9 0.91 4 0.01 0.01 0 .0 2 4 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE HEMATOLOGY - WHITE CELL COUNT (MALE) GROUP 1 0 m g/kg W hite b lood c e ll co u n t (10E 9/L) MEAN MEDIAN S.D. XMAX XMIN N N eutroph ils (un ity ) NE MEDIAN XMIN XMAX N E o s in o p h ils (u n ity ) NE MEDIAN XMIN XMAX N B a so p h ils (u n ity ) NE MEDIAN XMIN XMAX N L ym p h o cyte s (u n ity ) NE MEDIAN XMIN XMAX N M onocytes (u n ity ) NE MEDIAN XMIN XMAX N 9.1 9 .7 1 .9 11 .1 7 .0 5 0.11 0 .0 9 0 .1 4 5 0.01 0 .0 0 0.01 5 0 .0 0 0 .0 0 0.01 5 0 .8 6 0 .8 4 0.87 5 0 .0 2 0 .0 2 0 .0 3 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 132 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 5 .4 5 .4 1 .2 6 .4 4 .2 4 0.11 0 .0 8 0 .3 8 4 0.01 0.01 0.01 4 0 .0 0 0 .0 0 0 .0 0 4 0 .8 7 0 .5 9 0.91 4 0.01 0.01 0 .0 2 4 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE HEMATOLOGY - WHITE CELL COUNT (FEMALE) GROUP 1 0 m g/kg W hite b lood c e ll co u n t (10E 9/L) MEAN MEDIAN S.D. XMAX XMIN N N eutroph ils (un ity ) NE MEDIAN XMIN XMAX N E o s in o p h ils (u n ity ) NE MEDIAN XMIN XMAX N B a so p h ils (u n ity ) NE MEDIAN XMIN XMAX N L ym p h o cyte s (u n ity ) NE MEDIAN XMIN XMAX N M onocytes (u n ity ) NE MEDIAN XMIN XMAX N 7 .5 7 .4 0 .9 8 .9 6 .6 5 0.07 0 .0 6 0 .1 0 5 0.01 0.01 0.01 5 0 .0 0 0 .0 0 0 .0 0 5 0 .9 0 0.87 0 .9 2 5 0.01 0.01 0 .0 2 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 133 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 7.7 8 .0 1.7 9 .3 5 .3 5 0 .0 8 0 .0 6 0 .1 3 5 0.01 0.01 0.01 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 9 0 .8 3 0 .9 2 5 0 .0 2 0.01 0 .0 2 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - BLOOD COAGULATION (MALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m q/kq GROUP 4 60 m g/kg P la te le ts (10E 9/L) C o a q u la tio n Time (Seconds) MEAN S.D. N MEAN S.D. N 1030 134 5 101 4 5 1070 127 5 158 13 5 1111 42 5 111 9 5 1085 57 5 111 8 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 998 77 5 104 13 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 134 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02 -0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - BLOOD COAGULATION (FEMALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m q/kq GROUP 4 60 m g/kg P la te le ts (10E 9/L) C o a q u la tio n Time (Seconds) MEAN S.D. N MEAN S.D. N 1060 167 5 131 10 5 1128 274 5 160 11 5 1085 59 4 99 7 5 1120 124 5 105 21 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 1100 138 4 104 6 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 135 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE HEMATOLOGY - BLOOD COAGULATION (MALE) GROUP 1 0 m g/kg P la te le ts (10E 9/L) C o a g u la tio n Time (Seconds) MEAN S.D. N MEAN S.D. N 1051 125 5 139 13 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 935 238 4 127 19 4 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 136 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE HEMATOLOGY - BLOOD COAGULATION (FEMALE) GROUP 1 0 m g/kg P la te le ts (10E 9/L) C o a g u la tio n Time (Seconds) MEAN S.D. N MEAN S.D. N 1050 42 5 151 15 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 1280 205 5 135 17 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 137 Toxicology Study Report - PT02-0222 12.7.2 Hematology (Groups 6 - 7) Page 138 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - RED CELL COUNT (MALE) GROUP 1 0 m g/kg/d Red b lo o d c e l l c o u n t (1 0 E 1 2 /L ) Hem oglobin (g/L ) H e m ato crit (u n ity ) MCV (10E-15 L) MCH (10E-12 g) MCHC (g /L ) R e tic u lo c y te s (u n ity ) Hei nz Bodies (u n ity ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N NE MEAN S.D. N NE MEAN S.D. N MEAN S.D. N NE MEAN S.D. N 7.99 0 .2 9 5 156 8 5 0 .4 6 0 .0 2 5 58 1 5 19 1 5 337 4 5 0 .0 3 2 0 .0 0 3 5 0 .0 0 0 0 .0 0 0 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 139 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 7.93 0 .2 7 5 154 2 5 0 .4 5 0 .0 0 5 57 2 5 19 1 5 338 3 5 0 .0 3 3 0 .0 0 5 5 0 .0 0 0 0 .0 0 0 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - RED CELL COUNT (FEMALE) GROUP 1 0 m g/kg/d Red b lo o d c e l l c o u n t (1 0 E 1 2 /L ) Hem oglobin (g/L ) H e m ato crit (u n ity ) MCV (10E-15 L) MCH (10E-12 g) MCHC (g /L ) R e tic u lo c y te s (u n ity ) Hei nz Bodies (u n ity ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N NE MEAN S.D. N NE MEAN S.D. N MEAN S.D. N NE MEAN S.D. N 7.82 0 .2 6 5 149 3 5 0 .4 4 0.01 5 56 1 5 19 0 5 342 3 5 0 .0 2 6 0 .0 0 3 5 0 .0 0 0 0 .0 0 0 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 140 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 7.65 0 .1 7 5 147 3 5 0 .4 3 0.01 5 56 1 5 19 0 5 344 7 5 0 .0 3 3 0 .0 0 8 5 0 .0 0 0 0 .0 0 0 5 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - WHITE CELL COUNT (MALE) GROUP 1 0 m g/kg/d W hite b lood c e ll co u n t (10E 9/L) N eutroph ils (u n ity ) E o s in o p h ils (u n ity ) B a so p h ils (u n ity ) L ym p h o cyte s (u n ity ) M onocytes (u n ity ) MEAN MEDIAN S.D. XMAX XMIN N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N NE MEDIAN XMIN XMAX N 1 3 .0 12.5 2 .8 17.5 10.1 5 0 .1 2 0 .1 0 0 .1 5 5 0.01 0.01 0.01 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 4 0 .8 2 0 .8 6 5 0 .0 2 0.01 0 .0 3 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 141 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 11.2 11.9 2.1 13.3 7 .8 5 0 .1 0 0 .0 9 0.11 5 0.01 0.01 0.01 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 6 0 .8 4 0 .8 8 5 0 .0 2 0 .0 2 0 .0 3 5 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - WHITE CELL COUNT (FEMALE) GROUP 1 0 m g/kg/d W hite b lood c e ll co u n t (10E 9/L) MEAN MEDIAN S.D. XMAX XMIN N N eutroph ils (un ity ) NE MEDIAN XMIN XMAX N E o s in o p h ils (u n ity ) NE MEDIAN XMIN XMAX N B a so p h ils (u n ity ) NE MEDIAN XMIN XMAX N L ym p h o cyte s (u n ity ) NE MEDIAN XMIN XMAX N M onocytes (u n ity ) NE MEDIAN XMIN XMAX N 10.8 11.5 1 .9 12.6 7.7 5 0 .0 8 0 .0 6 0 .1 0 5 0 .0 2 0.01 0 .0 2 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 8 0.87 0 .9 0 5 0 .0 2 0.01 0 .0 2 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 142 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 7 .9 8 .2 1 .2 8 .8 6 .0 5 0 .0 9 0 .0 8 0 .1 2 5 0.01 0.01 0 .0 2 5 0 .0 0 0 .0 0 0 .0 0 5 0 .8 8 0 .8 4 0 .8 9 5 0.01 0.01 0 .0 2 5 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - BLOOD COAGULATION (MALE) GROUP 1 0 m g/kg/d P la te le ts (10E 9/L) C o a q u la tio n Time (Seconds) MEAN S.D. N MEAN S.D. N 1151 132 5 142 11 5 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 1147 44 5 157 21 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 143 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE HEMATOLOGY - BLOOD COAGULATION (FEMALE) GROUP 1 0 m g/kg/d P la te le ts (10E 9/L) C o a q u la tio n Time (Seconds) MEAN S.D. N MEAN S.D. N 1134 109 5 126 6 5 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 1079 78 5 131 11 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 144 Toxicology Study Report - PT02-0222 12.7.3 Clinical chemistry (Groups 1 - 5) Page 145 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE C LINICAL CHEMISTRY (MALE) Sod ium (m m ol/L) P o ta s s iu m (m m ol/L) C alcium (m m ol/L) C h lo rid e (m m ol/L) Phosphorus (m m ol/L) T otal B iliru b in (um ol/L) G lucose (m m ol/L) U ric A cid (um ol/L) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg 141 2 5 6.07 0 .3 3 5 2 .4 2 0 .0 3 5 103 1 5 3 .0 5 0 .1 7 5 5.1 0 .3 5 19.48 2 .8 5 5 33 7 5 GROUP 2 3 m g/kg 138 2 5 5.92 0 .4 0 5 2.43 0 .0 4 5 102 2 5 3.11 0.21 5 4 .5 0 .3 5 17.18 0.71 5 27 3 5 GROUP 3 15 m g/kg 140 1 5 6 .1 2 0 .2 4 5 2.31 0 .0 7 5 101 1 5 3.21 0 .1 3 5 5 .8 0 .5 5 19.86 1 .5 5 5 52 10 5 GROUP 4 60 m g/kg 141 1 5 5 .5 8 0 .2 5 5 2 .3 3 0 .0 6 5 101 2 5 2.87 0 .2 3 5 6 .2 1 .2 5 16.64 1 .7 0 5 63 20 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 142 1 5 5.91 0.51 5 2 .3 4 0 .0 8 5 102 1 5 2 .9 8 0 .1 4 5 5 .5 0 .5 5 1 6 .1 0 2 .9 2 5 51 18 5 Page 146 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 FINAL VALUE C LINICAL CHEMISTRY (MALE) C reat in in e (um ol/L) Urea N itro g e n (m m ol/L) C h o le ste ro l (m m ol/L) T rig ly c e rid e s (m m ol/L) T ota l P ro te in (g /L ) Album in (g /L ) ASAT (IU /L ) ALAT (IU /L ) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y i n r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg 47 2 5 6 .1 0 0 .8 7 5 2 .0 0 0 .0 7 5 0.51 0 .0 9 5 52 2 5 2 6 .0 1 .0 5 81 19 5 42 4 5 GROUP 2 3 m g/kg 46 3 5 6.36 0 .6 8 5 2 .0 0 0 .1 2 5 0 .4 6 0 .0 4 5 50 2 5 2 4 .0 1.4 5 81 11 5 44 10 5 GROUP 3 15 m g/kg 52 5 5 5 .7 8 0 .5 2 5 1 .9 6 0.21 5 0 .4 0 0 .1 7 5 53 2 5 2 6 .2 0 .8 5 103 12 5 45 3 5 GROUP 4 60 m g/kg 47 4 5 5 .5 6 0 .4 4 5 1.98 0 .1 9 5 0 .4 7 0 .0 8 5 54 1 5 2 6 .4 0 .5 5 108 17 5 59 + 4 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 2 7 -JA N -2 0 0 3 GROUP 5 240 m g/kg 43 5 5 7 .0 8 0 .9 6 5 1 .8 6 0 .1 9 5 0.37 0 .1 2 5 52 1 5 2 6 .6 1 .1 5 102 16 5 64 + 10 5 Page 147 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (MALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg G -G lu ta .T ra n sf. (IU /L ) A lk a l ine Phosphatase (IU /L ) Album in /G lo b u lin R a tio G lo b u lin (g /L ) NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 3 0 5 496 75 5 0 .9 9 0 .0 3 5 26 1 5 3 0 5 368 54 5 0.91 0 .0 7 5 26 2 5 3 0 5 474 74 5 0 .9 8 0 .0 4 5 27 2 5 3 0 5 580 67 5 0 .9 6 0 .0 5 5 27 1 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 4 1 5 424 123 5 1 .0 5 0 .0 5 5 25 1 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 148 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg Sod ium (m m ol/L) P o ta s s iu m (m m ol/L) C alcium (m m ol/L) C h lo rid e (m m ol/L) Phosphorus (m m ol/L) T otal B iliru b in (um ol/L) G lucose (m m ol/L) U ric A cid (um ol/L) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 141 2 5 5 .1 9 0 .3 9 5 2.31 0 .0 2 5 104 2 5 2 .7 4 0 .2 2 5 6 .0 0 .4 5 13.36 2.01 5 49 10 5 140 2 5 5.76 0 .2 7 5 2.43 0 .0 7 5 105 1 5 2.85 0 .3 8 5 5 .0 0 .3 5 13.36 1.62 5 69 26 5 140 2 5 6 .0 8 0 .3 7 5 2 .3 6 0 .0 5 5 104 1 5 3 .1 8 0 .1 3 5 6 .3 0 .4 5 16.38 1.67 5 62 15 5 147 + 2 5 5 .4 0 0 .1 7 5 2 .2 3 0 .0 2 5 109 2 5 2 .8 2 0 .0 7 5 6 .9 1 .4 5 13.94 1.83 5 83 16 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 145 + 2 5 5 .8 6 0 .7 7 5 2 .2 5 0 .1 3 5 105 1 5 3 .1 3 0.31 5 5 .9 0 .7 5 1 4 .5 4 1.42 5 128 110 5 Page 149 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg C re a tn in e (um ol/L) Urea N itro g e n (m m ol/L) C h o le ste ro l (m m ol/L) T rig ly c e rid e s (m m ol/L) T ota l P ro te in (g /L ) Album in (g /L ) ASAT (IU /L ) ALAT (IU /L ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 48 2 5 5 .8 4 0 .2 7 5 1 .9 0 0 .2 6 5 0 .4 9 0 .0 8 5 54 2 5 2 7 .0 1 .6 5 101 13 5 41 4 5 53 5 5 5.82 0 .6 9 5 2.18 0 .2 7 5 0 .3 5 0 .0 4 5 55 3 5 27.4 1.1 5 105 18 5 41 4 5 51 5 5 6 .0 2 0.61 5 2 .2 8 0 .0 4 5 0 .3 6 0 .0 5 5 52 2 5 2 5 .4 1 .5 5 110 22 5 48 7 5 47 4 5 5 .7 2 1.33 5 2 .7 4 0 .2 5 5 0 .3 9 0 .0 6 5 61 2 5 3 2 .0 1 .2 5 103 8 5 46 5 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . + / - : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 150 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 46 6 5 5 .8 2 0 .8 4 5 2 .3 8 0 .4 6 5 0 .4 2 0 .1 3 5 56 3 5 3 0 .0 3 .5 5 96 15 5 53 + 6 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o ra l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg GROUP 2 3 m g/kg GROUP 3 15 m g/kg GROUP 4 60 m g/kg G -G lu ta .T ra n sf. (IU /L ) A lk a l ine Phosphatase (IU /L ) Album in /G lo b u lin R a tio G lo b u lin (g /L ) NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 3 0 5 403 29 5 0 .9 9 0 .0 5 5 27 1 5 3 0 5 393 53 5 1.01 0 .0 4 5 27 2 5 3 0 5 320 68 5 0 .9 7 0 .0 5 5 26 1 5 3 0 5 377 44 5 1.11 + 0 .0 4 5 29 1 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 6+ 1 5 458 89 5 1.16 + 0 .1 6 5 26 1 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 151 Toxicology Study Report - PT02-0222 ATOX 10.2 RECOVERY VALUE C LINICAL CHEMISTRY (MALE) Sod ium (m m ol/L) P o ta s s iu m (m m ol/L) C alcium (m m ol/L) C h lo rid e (m m ol/L) Phosphorus (m m ol/L) T otal B iliru b in (um ol/L) G lucose (m m ol/L) U ric A cid (um ol/L) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg 139 1 5 6.01 0 .2 8 5 2 .2 9 0.11 5 102 1 5 2 .9 4 0 .2 4 5 5 .4 0 .7 5 2 0 .1 8 3 .6 8 5 41 14 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 152 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 144 + 1 4 4.90 0 .2 2 4 2.31 0 .0 9 4 107 + 2 4 2.77 0 .1 4 4 6 .4 1 .0 4 6.23 1.04 4 55 14 4 Toxicology Study Report - PT02-0222 ATOX 10.2 RECOVERY VALUE C LINICAL CHEMISTRY (MALE) C re a tn in e (um ol/L) Urea N itro g e n (m m ol/L) C h o le ste ro l (m m ol/L) T rig ly c e rid e s (m m ol/L) T ota l P ro te in (g /L ) Album in (g /L ) ASAT (IU /L ) ALAT (IU /L ) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg 47 5 5 6 .9 8 0 .9 0 5 1.84 0.11 5 0 .4 8 0 .1 0 5 50 3 5 2 3 .4 1.1 5 104 16 5 49 9 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 153 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 55 4 4 11.53 5 .1 5 4 1.95 0 .1 0 4 0.26 M 0 .1 0 3 58 + 4 4 27.8 + 1 .9 4 108 19 4 38 6 4 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE C LINICAL CHEMISTRY (MALE) GROUP 1 0 m g/kg G -G lu ta .T ra n sf. (IU /L ) A lk a l ine Phosphatase (IU /L ) Album in /G lo b u lin R a tio G lo b u lin (g /L ) NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 3 0 5 323 32 5 0.87 0 .0 5 5 27 2 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 3 0 4 214 61 4 0.91 0 .0 5 4 31 + 2 4 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 154 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg Sod ium (m m ol/L) P o ta s s iu m (m m ol/L) C alcium (m m ol/L) C h lo rid e (m m ol/L) Phosphorus (m m ol/L) T otal B iliru b in (um ol/L) G lucose (m m ol/L) U ric A cid (um ol/L) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 143 0 5 4 .7 6 0 .2 6 5 2 .3 8 0 .0 3 5 105 1 5 2 .4 4 0 .1 9 5 5 .2 0 .6 5 1 2 .7 0 1.62 5 61 21 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 155 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 142 2 5 5.69 + 0 .3 5 5 2.30 0 .0 5 5 107 1 5 3.06 + 0 .2 2 5 5 .5 0 .5 5 12.66 4 .2 0 5 67 20 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg C re a tn in e (um ol/L) Urea N itro g e n (m m ol/L) C h o le ste ro l (m m ol/L) T rig ly c e rid e s (m m ol/L) T ota l P ro te in (g /L ) Album in (g /L ) ASAT (IU /L ) ALAT (IU /L ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 55 4 5 5 .7 2 0 .4 0 5 1.84 0 .3 4 5 0 .4 5 0.11 5 58 2 5 2 8 .4 1.1 5 96 20 5 35 4 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 156 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 56 8 5 8 .5 4 4 .1 6 5 1.88 0 .2 2 5 0.29 0 .1 0 5 52 2 5 24.2 0 .8 5 100 34 5 43 21 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg G -G lu ta .T ra n sf. (IU /L ) A lk a l ine Phosphatase (IU /L ) Album in /G lo b u lin R a tio G lo b u lin (g /L ) NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 3 0 5 226 50 5 0 .9 8 0 .0 5 5 29 2 5 RUN DATE: 27-JAN-2003 GROUP 5 240 m g/kg 3 0 5 185 72 5 0.86 0 .0 3 5 28 1 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 157 Toxicology Study Report - PT02-0222 12.7.4 Clinical chemistry (Groups 6 - 7) Page 158 Toxicology Study Report - PT02-0222 ATOX 1 0 .2 FINAL VALUE C LINICAL CHEMISTRY (MALE) Sod ium (m m ol/L) P o ta s s iu m (m m ol/L) C alcium (m m ol/L) C h lo rid e (m m ol/L) Phosphorus (m m ol/L) T otal B iliru b in (um ol/L) G lucose (m m ol/L) U ric A cid (um ol/L) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg/d 138 1 5 5.67 0.11 5 2 .4 9 0 .0 5 5 102 1 5 3 .1 0 0 .1 0 5 4 .8 0 .3 5 19.32 1.12 5 24 7 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 159 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 140 + 1 5 5.09 0.21 5 2 .4 5 0 .0 6 5 102 1 5 2.78 0 .1 3 5 5 .0 0 .2 5 15.72 2.21 5 33 15 5 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE C LINICAL CHEMISTRY (MALE) C re a tn in e (um ol/L) Urea N itro g e n (m m ol/L) C h o le ste ro l (m m ol/L) T rig ly c e rid e s (m m ol/L) T ota l P ro te in (g /L ) Album in (g /L ) ASAT (IU /L ) ALAT (IU /L ) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg/d 47 3 5 5 .9 8 0 .9 2 5 2 .0 0 0 .1 2 5 0 .5 5 0.07 5 52 1 5 2 4 .8 0 .8 5 90 8 5 44 8 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 160 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 47 3 5 5 .5 4 0 .7 9 5 2 .1 8 0 .1 3 5 0 .6 0 0 .1 5 5 55 + 2 5 27.6 + 0 .5 5 78 14 5 40 6 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (MALE) GROUP 1 0 m g/kg/d G -G lu ta .T ra n sf. (IU /L ) A lk a l ine Phosphatase (IU /L ) Album in /G lo b u lin R a tio G lo b u lin (g /L ) NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 4 0 5 365 30 5 0 .9 3 0 .0 5 5 27 1 5 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 4 0 5 448 + 28 5 1 .0 0 0 .0 7 5 28 2 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 161 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg/d Sod ium (m m ol/L) P o ta s s iu m (m m ol/L) C alcium (m m ol/L) C h lo rid e (m m ol/L) Phosphorus (m m ol/L) T otal B iliru b in (um ol/L) G lucose (m m ol/L) U ric A cid (um ol/L) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 141 2 5 5 .6 2 0 .4 3 5 2.41 0.11 5 106 2 5 3 .0 2 0 .1 6 5 5 .3 0 .5 5 15.12 2 .5 6 5 60 6 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 162 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 141 1 5 5 .1 9 0 .1 3 5 2 .4 2 0 .0 5 5 106 2 5 2.68 0 .0 5 5 5 .2 0 .8 5 14.12 2 .0 6 5 62 22 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg/d C re a tn in e (um ol/L) Urea N itro g e n (m m ol/L) C h o le ste ro l (m m ol/L) T rig ly c e rid e s (m m ol/L) T ota l P ro te in (g /L ) Album in (g /L ) ASAT (IU /L ) ALAT (IU /L ) MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 49 4 5 5 .0 2 0 .6 5 5 2 .3 6 0.21 5 0 .4 0 0 .0 8 5 55 3 5 2 7 .0 1 .4 5 118 24 5 43 3 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 163 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 52 5 5 5 .1 6 0 .7 4 5 2 .2 8 0 .2 2 5 0 .3 7 0 .0 7 5 59 1 5 2 8 .8 1.1 5 113 18 5 43 4 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE C LINICAL CHEMISTRY (FEMALE) GROUP 1 0 m g/kg/d G -G lu ta .T ra n sf. (IU /L ) A lk a l ine Phosphatase (IU /L ) Album in /G lo b u lin R a tio G lo b u lin (g /L ) NE MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 4 0 5 307 67 5 0 .9 5 0 .0 4 5 28 2 5 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 4 0 5 328 106 5 0 .9 7 0 .0 5 5 30 1 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 164 Toxicology Study Report - PT02-0222 12.7.5 Urinalysis (Groups 1 - 5) Page 165 Toxicology Study Report - PT02-0222 FINAL VALUE URINALYSIS (MALE) V o lu m e (mL) pH Va lu e (s q ) S p e c ific W eight (g /L ) SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N NE MEDIAN XMIN XMAX MEAN S.D. N GROUP 1 0 m g/kg 2 .9 1.1 5 7 7 7 1059 14 5 GROUP 2 3 m g/kg 2 .9 1 .0 5 7 6 7 1062 10 5 GROUP 3 15 m g/kg 2 .5 0 .8 5 7 6 7 1061 11 5 GROUP 4 60 m g/kg 4 .0 1 .4 5 6 6 7 1050 7 5 GROUP 5 240 m g/kg 5 .3 1 .2 5 7 6 7 1038 9 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 166 Toxicology Study Report - PT02-0222 FINAL VALUE URINALYSIS (FEMALE) V o lu m e (mL) pH Va lu e (s q ) S p e c ific W eight (g /L ) SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N NE MEDIAN XMIN XMAX MEAN S.D. N GROUP 1 0 m g/kg 3.1 1 .5 5 7 6 8 1039 10 4 GROUP 2 3 m g/kg 3.1 0 .8 5 7 7 7 1047 10 5 GROUP 3 15 m g/kg 4 .8 0 .3 5 7 7 7 1032 7 5 GROUP 4 60 m g/kg 3 .7 1 .2 5 7 6 8 1036 2 5 GROUP 5 240 m g/kg 6 .2 3 .6 5 6 6 6 1034 13 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 167 Toxicology Study Report - PT02-0222 RECOVERY VALUE URINALYSIS (MALE) V o lu m e (mL) pH Va lu e (s q ) S p e c ific W eight (g /L ) SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N NE MEDIAN XMIN XMAX MEAN S.D. N GROUP 1 0 m g/kg 4 .9 3 .7 5 7 7 8 1049 20 5 GROUP 5 240 m g/kg 4 .2 2 .9 4 8 8 8 1041 1 18 3 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 168 Toxicology Study Report - PT02-0222 RECOVERY VALUE URINALYSIS (FEMALE) V o lu m e (mL) pH Va lu e (s q ) S p e c ific W eight (g /L ) SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N NE MEDIAN XMIN XMAX MEAN S.D. N GROUP 1 0 m g/kg 5 .9 2 .2 5 7 7 8 1033 9 5 GROUP 5 240 m g/kg 4 .7 2 .3 5 7 6 7 1041 10 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 169 Toxicology Study Report - PT02-0222 12.7.6 Urinalysis (Groups 6 - 7) Page 170 Toxicology Study Report - PT02-0222 FINAL VALUE URINALYSIS (MALE) V o lu m e (mL) pH Va lu e (s q ) S p e c ific W eight (g /L ) SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N NE MEDIAN XMIN XMAX MEAN S.D. N GROUP 1 0 m g/kg/d 3 .7 0 .8 5 7 6 7 1044 7 5 GROUP 2 0 .3 m g/kg/d 5 .9 2 .3 5 7 6 7 1035 12 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 171 Toxicology Study Report - PT02-0222 FINAL VALUE URINALYSIS (FEMALE) V o lu m e (mL) pH Va lu e (s q ) S p e c ific W eight (g /L ) SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N NE MEDIAN XMIN XMAX MEAN S.D. N GROUP 1 0 m g/kg/d 4 .0 1.7 5 6 6 7 1038 10 5 GROUP 2 0 .3 m g/kg/d 3 .9 0 .5 5 6 6 7 1037 6 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 172 Toxicology Study Report - PT02-0222 12.8 ORGAN WEIGHTS (GROUPS 1 - 5) Page 173 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE ORGAN WEIGHTS (MALE) BODY WEIGHT (g ) NE H e a rt W eight (g) a L iv e r W eight (g) a K id n e y s Wei g h t (g) Spleen W eight (g) a T este s W eight (g) a E p id id y m is W eight (g) A d re n a ls W eight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg 2 7 4 .0 2 3 .2 5 1.005 0 .1 2 0 5 11.238 1.106 5 2.097 0 .2 7 9 5 0 .8 1 7 0 .1 4 5 5 3 .2 1 6 0 .2 7 7 5 0 .8 2 4 0 .0 7 6 5 0 .0 4 5 6 0 .0 0 2 2 5 GROUP 2 3 m g/kg 2 7 9 .8 18.4 5 1.129 0.124 5 10.792 0 .9 2 0 5 2 .0 4 9 0.185 5 0.753 0.108 5 3 .5 4 3 0.335 5 0.861 0.062 5 0 .0 4 5 2 0 .0 0 5 4 5 GROUP 3 15 m g/kg 2 6 9 .8 1 3 .8 5 0.871 0 .0 9 4 5 11.084 1.019 5 2 .1 0 5 0 .0 9 2 5 0.676 0 .0 7 0 5 3.297 0 .2 5 6 5 0 .8 2 6 0 .0 6 7 5 0 .0 4 2 6 0 .0 0 4 4 5 GROUP 4 60 m g/kg 2 6 1 .2 2 1 .6 5 0 .9 3 9 0 .0 9 8 5 12.904 + 1.465 5 2 .2 2 9 0.251 5 0.641 0.091 5 3.481 0 .3 3 3 5 0 .8 1 3 0 .0 5 0 5 0.0470 0.0040 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 17-DEC-2002 GROUP 5 240 m g/kg 2 3 1 .2 1 9 .9 5 0.809 0 .0 8 9 5 14.118 + 1 .3 7 2 5 1 .9 6 4 0 .0 9 8 5 0.583 0 .0 9 0 5 3 .4 6 3 0 .0 7 6 5 0 .7 8 0 0 .0 9 0 5 0.0558 + 0.0057 5 Page 174 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE ORGAN WEIGHTS (MALE) B ra in W eight (g) Thymus W e ig h t (g) PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RUN DATE: 17-DEC-2002 MEAN S.D. N MEAN S.D. N GROUP 1 0 m g/kg 1.836 0 .0 9 3 5 0 .4 7 9 0 .0 4 4 5 GROUP 2 3 m g/kg 1 .8 5 0 0.068 5 0.511 0.036 5 GROUP 3 15 m g/kg 1.746 0 .0 7 6 5 0 .4 0 9 0 .0 6 7 5 GROUP 4 60 m g/kg 1 .774 0 .0 8 9 5 0 .4 4 5 0 .0 7 9 5 GROUP 5 240 m g/kg 1.767 0 .0 6 0 5 0.346 0 .0 5 3 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 175 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE ORGAN WEIGHTS (FEMALE) BODY WEIGHT (g) NE Heart Weight (g) a L iv e r Weight (g) K id n e y s Wei g h t (g) J a Spleen Weight (g) a Adrenals Weight (g) Brain Weight (g) y Thymus W eight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg 210.6 9.4 5 0.776 0.060 5 8.408 0.576 5 1.461 0.103 5 0.649 0.040 5 0.0604 0.0095 5 1.781 0.054 5 0.407 0.076 5 GROUP 2 3 mg/kg 195.0 4.9 5 0.828 0.079 5 7.294 0.436 5 1.304 0.059 5 0.641 0.073 5 0.0548 0.0033 5 1.709 0.093 5 0.399 0.054 5 GROUP 3 15 mg/kg 205.8 5.0 5 0.754 0.070 5 8.346 0.507 5 1.513 0.111 5 0.713 0.056 5 0.0590 0.0070 5 1.726 0.093 5 0.430 0.070 5 GROUP 4 60 mg/kg 199.8 8.7 5 0.710 0.032 5 9.804 + 0.666 5 1.929 + 0.142 5 0.581 0.051 5 0.0590 0.0038 5 1.684 0.053 5 0.354 0.022 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 184.6 11.7 5 0.667 0.048 5 13.792 + 1.814 5 1.642 + 0.146 5 0.456 0.038 5 0.0596 0.0086 5 1.659 0.105 5 0.309 0.067 5 Page 176 Toxicology Study Report - PT02-0222 ATOX 10.2 RECOVERY VALUE ORGAN WEIGHTS (MALE) BODY WEIGHT (g) NE Heart Weight (g) a L iv e r Weight (g) K id n e y s Wei g h t (g) Spleen Weight (g) a Testes Weight (g) Epididym is Weight (g) Adrenals Weight (g) y PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg 320.0 50.8 5 1.188 0.252 5 10.446 2.238 5 2.303 0.401 5 0.772 0.125 5 3.510 0.464 5 1.143 0.120 5 0.0486 0.0066 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 177 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 194.0 35.9 4 0.758 0.121 4 5.748 1.373 4 1.496 0.348 4 0.428 0.125 4 3.332 0.294 4 0.910 0.130 4 0.0450 0.0042 4 Toxicology Study Report - PT02-0222 ATOX 10.2 RECOVERY VALUE ORGAN WEIGHTS (MALE) Brain Weight (g) a Thymus W eight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg 1.939 0.140 5 0.385 0.072 5 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 1.730 0.127 4 0.202 0.117 4 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 178 Toxicology Study Report - PT02-0222 ATOX 10.2 RECOVERY VALUE ORGAN WEIGHTS (FEMALE) BODY WEIGHT (g) NE Heart Weight (g) a L iv e r Weight (g) K id n e y s Wei g h t (g) Spleen Weight (g) a Adrenals Weight (g) Brain Weight (g) y Thymus W eight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg 225.6 17.5 5 0.816 0.064 5 7.556 0.864 5 1.572 0.072 5 0.674 0.123 5 0.0636 0.0075 5 1.837 0.072 5 0.350 0.050 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 179 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 189.4 29.9 5 0.710 0.101 5 6.502 1.373 5 1.412 0.187 5 0.537 0.111 5 0.0514 0.0099 5 1 .774 0.066 5 0.311 0.064 5 Toxicology Study Report - PT02-0222 12.9 ORGAN WEIGHTS (GROUPS 6 - 7) Page 180 Toxicology Study Report - PT02-0222 ATOX 1 0 . 2 FINAL VALUE ORGAN WEIGHTS (MALE) BODY WEIGHT (g) NE Heart Weight (g) a L iv e r Weight (g) a K id n e y s Wei g h t (g) Spleen Weight (g) a Testes Weight (g) y Epididym is Weight (g) Adrenals Weight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 295.6 17.5 5 1.171 0.199 5 12.222 1.301 5 2.411 0.208 5 0.801 0.094 5 3.598 0.194 5 0.888 0.056 5 0.0512 0.0070 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 181 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 307.8 25.4 5 1.188 0.115 5 12.174 1.883 5 2.430 0.324 5 0.802 0.052 5 3.579 0.283 5 0.848 0.045 5 0.0466 0.0061 5 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE ORGAN WEIGHTS (MALE) Brain Weight (g) a Thymus W eight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 1.883 0.075 5 0.570 0.116 5 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 1.900 0.076 5 0.584 0.110 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 182 Toxicology Study Report - PT02-0222 ATOX 10.2 FINAL VALUE ORGAN WEIGHTS (FEMALE) BODY WEIGHT (g) NE Heart Weight (g) a L iv e r Weight (g) K id n e y s Wei g h t (g) Spleen Weight (g) a Adrenals Weight (g) Brain Weight (g) y Thymus W eight (g) a PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N GROUP 1 0 mg/kg/d 190.6 9.8 5 0.778 0.074 5 6.948 0.637 5 1.332 0.075 5 0.613 0.060 5 0.0580 0.0087 5 1.720 0.113 5 0.322 0.083 5 T-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 183 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 199.0 11.7 5 0.793 0.068 5 7.480 0.961 5 1.417 0.121 5 0.679 0.072 5 0.0554 0.0072 5 1.757 0.093 5 0.381 0.079 5 Toxicology Study Report - PT02-0222 12.10RELATIVE ORGAN WEIGHTS (GROUPS 1 - 5) Page 184 Toxicology Study Report - PT02-0222 ATOX 1 0 . 2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE RELATIVE ORGAN WEIGHTS MALES ( g / k g b dwt) GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg BODY WEIGHT (g) NE Heart Weight L iv e r Weight K id n e y s Wei g h t Spleen Weight Testes Weight Epididym is Weight Adrenals Weight MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 274.0 23.2 5 3.663 0.189 5 40.983 0.975 5 7.639 0.594 5 2.973 0.390 5 11.767 1.028 5 3.023 0.355 5 0.1676 0.0184 5 279.8 18.4 5 4.027 0.244 5 38.536 0.993 5 7.318 0.284 5 2.696 0.375 5 12.660 0.741 5 3.085 0.264 5 0.1623 0.0245 5 269.8 13.8 5 3.230 0.337 5 41.020 1.985 5 7.819 0.526 5 2.507 0.241 5 12.211 0.536 5 3.067 0.271 5 0.1583 0.0192 5 261.2 21.6 5 3.589 0.114 5 49.301 + 1.620 5 8.532 0.670 5 2.451 0.249 5 13.347 + 0.948 5 3.117 0.105 5 0.1811 0.0244 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 231.2 19.9 5 3 .495 0 .186 5 61 .061 2 .650 5 8 .523 0 .451 5 2 .520 0 .283 5 15 .072 1 .395 5 3 .394 0 .487 5 0. 2413 0. 0128 5 Page 185 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE RELATIVE ORGAN WEIGHTS MALES ( g / k g b dwt) GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg Brain Weight Thymus W eight MEAN S.D. N MEAN S.D. N 6.727 0.477 5 1.750 0.071 5 6.625 0.258 5 1.834 0.176 5 6.485 0.461 5 1.523 0.295 5 6.814 0.443 5 1 .712 0.336 5 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 7.688 0.715 5 1.496 0.171 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 186 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE RELATIVE ORGAN WEIGHTS FEMALES ( g / k g b d w t) GROUP 1 0 mg/kg GROUP 2 3 mg/kg GROUP 3 15 mg/kg GROUP 4 60 mg/kg BODY WEIGHT (g) NE Heart Weight L iv e r Weight K id n e y s Wei g h t Spleen Weight Adrenals Weight Brain Weight Thymus W eight MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 210.6 9.4 5 3.685 0.261 5 39.929 2.145 5 6.952 0.645 5 3.081 0.109 5 0.2882 0.0558 5 8.471 0.521 5 1.931 0.366 5 195.0 4.9 5 4.254 0.502 5 37.383 1.466 5 6.688 0.330 5 3.291 0.402 5 0.2813 0.0203 5 8.778 0.685 5 2.042 0.252 5 205.8 5.0 5 3.668 0.360 5 40.539 1.889 5 7.344 0.381 5 3.463 0.266 5 0.2872 0.0375 5 8.386 0.364 5 2.089 0.313 5 199.8 8.7 5 3.560 0.260 5 49.078 + 2.797 5 9.659 + 0.671 5 2.906 0.183 5 0.2961 0.0280 5 8.438 0.319 5 1 .773 0.074 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 184.6 11.7 5 3.616 0.141 5 74.510 5.710 5 8.902 0.717 5 2.467 0.096 5 0.3221 0.0326 5 8.995 0.366 5 1.677 0.347 5 Page 187 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE RELATIVE ORGAN WEIGHTS MALES ( g / k g b dwt) GROUP 1 0 mg/kg BODY WEIGHT (g) NE Heart Weight L iv e r Weight K id n e y s Wei g h t Spleen Weight Testes Weight Epididym is Weight Adrenals Weight MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 320.0 50.8 5 3.693 0.248 5 32.441 2.019 5 7.194 0.344 5 2.423 0.244 5 11.024 0.784 5 3.605 0.332 5 0.1531 0.0191 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 188 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 194.0 35.9 4 3.934 0.362 4 29.388 1.924 4 7.658 0.579 4 2.172 0.267 4 17.675 + 4.005 4 4.731 + 0.426 4 0.2355 + 0.0272 4 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE RELATIVE ORGAN WEIGHTS MALES ( g / k g b dwt) GROUP 1 0 mg/kg Brain Weight Thymus W eight MEAN S.D. N MEAN S.D. N 6.163 0.954 5 1.207 0.143 5 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 9.088 + 1.276 4 0.978 0.452 4 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 189 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s RECOVERY VALUE RELATIVE ORGAN WEIGHTS FEMALES ( g / k g b d w t) GROUP 1 0 mg/kg BODY WEIGHT (g) NE Heart Weight L iv e r Weight K id n e y s Wei g h t Spleen Weight Adrenals Weight Brain Weight Thymus W eight MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 225.6 17.5 5 3.620 0.170 5 33.510 3.125 5 6.994 0.493 5 2.979 0.411 5 0.2854 0.0570 5 8.178 0.637 5 1.549 0.157 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 190 RUN DATE: 17-DEC-2002 GROUP 5 240 mg/kg 189.4 29.9 5 3 .761 0 .192 5 34 .229 3 .310 5 7 .506 0 .632 5 2 .833 0 .285 5 0. 2715 0. 0360 5 9 .533 + 1 .339 5 1 .643 0 .213 5 Toxicology Study Report - PT02-0222 12.11 RELATIVE ORGAN WEIGHTS (GROUPS 6 - 7) Page 191 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : P T02e0 2 2 2 - T e 7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE RELATIVE ORGAN WEIGHTS MALES ( g / k g b dwt) GROUP 1 0 mg/kg/d BODY WEIGHT (g) NE Heart Weight L iv e r Weight K id n e y s Wei g h t Spleen Weight Testes Weight Epididym is Weight Adrenals Weight MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 295.6 17.5 5 3.940 0.493 5 41.264 2.444 5 8.150 0.330 5 2.705 0.239 5 12.185 0.490 5 3.007 0.158 5 0.1728 0.0176 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 192 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 307.8 25.4 5 3.863 0.259 5 39.383 3.539 5 7.895 0.814 5 2.613 0.139 5 11.656 0.834 5 2.766 0.230 5 0.1522 0.0231 5 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE RELATIVE ORGAN WEIGHTS MALES ( g / k g b dwt) GROUP 1 0 mg/kg/d Brain Weight Thymus W eight MEAN S.D. N MEAN S.D. N 6.385 0.377 5 1.924 0.339 5 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 6.199 0.470 5 1.891 0.277 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 193 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE RELATIVE ORGAN WEIGHTS FEMALES ( g / k g b d w t) GROUP 1 0 mg/kg/d BODY WEIGHT (g) NE Heart Weight L iv e r Weight K id n e y s Wei g h t Spleen Weight Adrenals Weight Brain Weight Thymus W eight MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N MEAN S.D. N 190.6 9.8 5 4.077 0.257 5 36.394 1.542 5 6.987 0.225 5 3.222 0.318 5 0.3037 0.0382 5 9.022 0.297 5 1.683 0.366 5 WILCOXON-TEST. TWO-TAILED TEST FOR THE HIGHEST DOSE AND ONE-TAILED TESTS FOR LOWER DOSES, IF ALL HIGHER DOSES ARE SIGNIFICANTLY DIFFERENT FROM CONTROL (P < 0 . 0 5 ) . +/- : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 194 RUN DATE: 05-MAR-2003 GROUP 2 0.3 mg/kg/d 199.0 11.7 5 3.981 0.207 5 37.491 3.015 5 7.114 0.366 5 3.405 0.229 5 0.2783 0.0327 5 8.850 0.656 5 1.916 0.392 5 Toxicology Study Report - PT02-0222 12.12 NEUROTOXICOLOGICAL EXAMINATIONS 12.12.1 Griph strength - Groups 1 - 5 Page 195 Toxicology Study Report - PT02-0222 Page 196 Toxicology Study Report - PT02-0222 12.12.2 Griph strength - Groups 6 - 7 Page 197 Toxicology Study Report - PT02-0222 vXkQgQHP T iB T i T hILT T H T I TOU U -L C W W I S D K L n K L U H E I A R I C H I -T T R I T I T I i f k l.-. H 1 0 I F 3 c g i E U E ZEST'j u e e i K ? e b i. m . r v h h i j j -lm : f : .j ' - k u n : i c n : i IG tl] T1CXTTL-TT 't r T E P I V T n!O H V T M L IP T 0 O I . i:h f e x i . t h z h u y x a A H r h -t i t -h A : EED KnC U IELT DIFPEFPI PF?: CMTIMC. > m U lK r T C ll MOT H H H U TE l FTJ I H T t n i E U . I VALIATE S? Page 198 Toxicology Study Report - PT02-0222 12.12.3 Motor activity (Groups 1 - 5) Page 199 Toxicology Study Report - PT02-0222 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY t PT02-0222 - T-7758 - 4 weeks oral toxicity in rats PINAL VALUE NEUROTOXICOLOGICAL EVALUATION GROUP 1 0 wg/kg GROUP 2 3 i&g/kg GROUP 3 15 *g/kg GROUP 4 60 iag/kg NUMBER OF MOVEMENTS (MALES) NUMBER OF MOVEMENTS (FEMALES) KEAN S-D. N MEAN S-D. N 547.8 131.8 10 532.2 182.8 10 587.6 131.1 5 653.4 78-0 5 538.4 82 .7 5 579.2 84.6 5 587.0 99.3 5 548.4 69.9 5 RON D A T E t 2 8 -M A Y -2 D 03 GROUP 5 240 g/kg 533.7 134.0 10 508.8 103-4 10 WILCOXON-TEST. SEQUENTIALLY REJECT I'VE MULTIPLE COMPARISONS (P < 0.05). +/- s SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 200 Toxicology Study Report - PT02-0222 12.12.4 Motor activity (Groups 6 - 7) Page 201 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T -7 7 5 8 - 4 weeks o r a l t o x i c i t y in r a t s FINAL VALUE NEUROTOXICOLOGICAL EVALUATION GROUP 1 0 m g/kg/d NUMBER OF MOVEMENTS (MALES) NUMBER OF MOVEMENTS (FEMALES) MEAN S.D. N MEAN S.D. N 5 3 4 .4 78.6 5 5 7 8 .6 8 9 .0 5 RUN DATE: 11-MAR-2003 GROUP 2 0 .3 m g/kg/d 6 1 5 .6 4 5 .4 5 6 4 2 .6 1 2 9 .0 5 WILCOXON-TEST. SEQUENTIALLY REJECTIVE MULTIPLE COMPARISONS (P < 0 . 0 5 ) . + / - : SIGNIFICANTLY DIFFERENT FROM CONTROL M : EVALUATION NOT POSSIBLE NE : NO STATISTICAL EVALUATION Page 202 Toxicology Study Report - PT02-0222 13 APPENDICES 13.1 INDIVIDUAL TABLES 13.1.1 Body weights Page 203 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 1m 1 118 138 166 184 210 224 244 248 254 271 2 111 128 149 165 191 210 229 236 239 255 3 112 134 158 176 202 219 235 242 249 262 4 118 143 171 191 221 246 270 286 299 314 5 120 144 136 157 190 215 238 250 258 268 6 119 142 173 192 219 241 265 279 293 304 324 333 3 5 .6 . 3 5 .3 7 113 132 145 157 173 195 205 214 222 231 240 248 259 . 259 8 109 130 142 158 184 209 228 245 251 266 266 273 289 . 284 9 127 151 180 210 240 259 285 303 321 337 349 358 378 . 385 10 120 142 164 182 213 231 253 267 274 288 300 309 316 . 319 Mean S.D. N 116.5.4 10 136.4 7.3 10 156.6 6616776 .662 6626046 .636 6626246 .669 66264656.62 66265676.60 662666.60 66267696.6 66269656.68 66360646.62 66361696.66 66666.6 66362606.60 14.8 17.9 20.2 19.5 23.5 26.5 30.4 31.3 43.7 44.4 48.4 . 50.8 10 10 10 10 10 10 10 10 5 5 5 0 5 1 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 204 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 1 f 31 1 1 0 126 143 147 152 168 175 178 188 199 32 119 133 149 158 173 177 183 188 201 2 1 0 33 109 127 148 159 172 182 194 198 2 1 0 221 34 117 135 155 170 180 188 197 202 214 219 35 111 125 141 154 165 173 184 189 196 204 36 111 127 141 155 167 174 186 194 2 0 2 204 2 1 2 214 2 1 8 . 213 37 118 132 152 162 176 187 199 206 224 233 239 235 237 . 238 38 1 1 0 123 139 146 155 163 173 179 187 193 2 0 0 201 197 . 201 39 119 136 155 169 182 184 186 201 214 217 225 233 242 . 237 40 107 128 148 162 173 184 190 198 207 218 226 225 238 . 239 Mean S.D. N 1-3.1 4.6 10 123.2 4.5 10 133.1 3 31 3538 3. 32 331 6393 3. 35 331 3783 3.30 5.9 8 .1 9.9 8.4 10 10 10 10 186.7 8 .6 10 193.3 3 3230 34 3. 3 9.6 11.9 10 10 2 1 1 . 8 3 323230 3. 34 1 2 . 0 14.9 10 5 2 2 1 . 6 3 3232363.34 3 3 3 3 3.3 3 3232353.36 14.2 18.9 . 17.5 5 50 5 2 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 205 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 2m 11 122 143 146 162 190 210 233 243 251 264 . 12 116 137 160 178 201 210 226 235 236 250 . 13 125 151 176 197 227 239 261 267 276 287 . 14 125 144 170 185 212 228 243 253 262 273 . 15 123 146 159 180 212 228 249 257 266 275 . Mean 122.2 144.2 162.2 180.4 208.4 223.0 242.4 251.0 258.2 269.8 . S.D. N 3.7 5.1 11.5 12.7 13.8 12.7 13.7 12.4 15.3 13.8 . 55555555550 0. 0. 0. 3 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 206 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 2f 41 118 131 146 160 166 175 191 194 202 207 . 42 115 132 145 152 163 178 192 193 205 206 . 43 117 136 151 161 171 182 191 193 203 206 . 44 111 129 146 161 170 180 190 199 208 212 . 45 112 127 140 150 161 169 182 186 192 198 . Mean 114.6 131.0 145.6 156.8 166.2 176.8 189.2 193.0 202.0 205.8 . S.D. N 3.0 3.4 3.9 5.4 4.3 5.1 4.1 4.6 6.0 5.0 . 55555555550 0. 0. 0. 4 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 207 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 3m 16 112 132 135 151 173 190 207 214 220 230 . 17 122 141 144 163 187 201 227 233 238 249 . 18 130 152 143 165 195 216 242 250 264 276 . 19 116 140 145 168 193 218 241 258 268 283 . 20 129 152 151 176 203 220 243 248 255 268 . Mean 121.8 143.4 143.6 164.6 190.2 209.0 232.0 240.6 249.0 261.2 . S.D. N 7.9 8.6 5.7 9.1 11.2 13.0 15.4 17.4 19.9 21.6 . 55555555550 0. 0. 0. 5 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 208 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 3f 46 111 129 137 156 172 176 187 195 209 210 . 47 113 134 133 150 166 178 183 195 202 200 . 48 122 136 143 155 166 175 194 191 201 202 . 49 114 133 107 127 145 156 169 169 181 186 . 50 116 134 135 153 167 177 188 192 198 201 . Mean 115.2 133.2 131.0 148.2 163.2 172.4 184.2 188.4 198.2 199.8 . S.D. N 4.2 2.6 13.9 12.1 10.5 9.2 9.4 11.0 10.4 8.7 . 55555555550 0. 0. 0. 6 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 209 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 43 4m 21 126 150 156 174 191 211 228 226 237 235 22 118 143 141 155 176 196 214 210 218 228 23 131 157 145 155 177 194 217 220 232 239 24 116 142 145 158 186 208 234 240 251 254 25 120 144 136 152 168 178 197 199 206 200 26 125 148 144 156 181 199 220 226 241 243 235 22 222 216 27 117 141 118 146 164 176 199 207 214 216 219 206 192 176 28 120 142 135 150 177 190 208 218 202 213 197 175 165 153 29 124 149 138 162 185 202 223 228 242 248 238 228 233 231 30 111 134 124 131 156 162 188 185 168 173 184 174 144 133 Mean S.D. N 120.8 5.8 10 140.0 0010380 .0 20 0010530 .009 00170 600.01 0010910 .006 6.3 10.9 11.0 10.8 15.4 10 10 10 10 10 212.8 14.7 10 215.9 16.0 10 221.1 00202040.09 24.9 24.8 10 10 214.6 23.6 5 201.8 00109010.02 26.4 37.5 55 133.0 00109040.00 35.9 14 7 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 210 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date Group Animal Sex Number -3 1 5 8 12 15 19 22 26 29 33 36 40 42 4f 51 119 135 133 149 164 173 186 191 195 198 52 116 129 127 139 158 168 184 183 191 195 53 106 121 122 135 151 152 164 164 166 170 54 107 1 2 0 112 130 150 153 164 169 178 182 55 114 128 127 142 150 159 167 174 174 178 56 111 127 138 154 171 179 192 198 204 209 217 221 221 57 116 130 126 145 156 167 181 181 190 197 198 201 204 58 115 131 130 146 158 172 185 189 198 203 207 2 1 2 207 59 105 118 115 1 1 0 129 140 153 160 161 140 149 146 150 60 113 127 131 142 157 165 174 175 182 188 197 206 2 1 0 Mean S.D. N 112.2 126.6 126.1 139.2 154.4 4.8 5.4 8.0 12.3 11.0 10 10 10 10 10 162.8 11.8 10 175.0 178.4 12.6 12.2 10 10 183.9 14.1 10 186.0 193.6 197.2 198.4 20.1 26.2 29.6 27.8 10 5 5 5 . . 0 43 218 186 184 144 215 189.4 29.9 5 8 * = result to left has an associated comment or marker Nominal Dose: Group 1 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Page 211 Toxicology Study Report - PT02-0222 RTA051-02/00 Group Sex 5m Animal Number 61 62 63 64 65 Mean S.D. N PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date -3 112 108 116 113 112 112.2 2.9 5 1 137 128 135 134 136 134.0 3.5 5 4 157 146 153 155 153 152.8 4.1 5 8 190 177 179 183 187 183.2 5.4 5 11 215 195 197 205 213 205.0 9.1 5 15 238 213 219 231 239 228.0 11.6 5 18 260 232 229 242 259 244.4 14.6 5 22 274 250 243 264 284 263.0 16.8 5 25 290 262 253 277 297 275.8 18.5 5 29 298 272 256 274 299 279.8 18.4 5 1 * = result to left has an associated comment or marker Nominal Dose: Group 5 - 3 mg/kg Page 212 Toxicology Study Report - PT02-0222 RTA051-02/00 Group Sex 5f Animal Number 66 67 68 69 70 Mean S.D. N PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats Date: 16-Dec-2002 Page: Bodyweights (g) Day numbers relative to Start Date -3 112 107 101 107 106 106.6 3.9 5 1 124 122 117 120 120 120.6 2.6 5 4 137 137 129 133 136 134.4 3.4 5 8 148 151 146 147 152 148.8 2.6 5 11 159 163 152 159 156 157.8 4.1 5 15 170 175 161 169 167 168.4 5.1 5 18 174 181 166 179 181 176.2 6.4 5 22 185 189 180 189 181 184.8 4.3 5 25 191 196 186 193 188 190.8 4.0 5 29 198 200 188 197 192 195.0 4.9 5 2 * = result to left has an associated comment or marker Nominal Dose: Group 5 - 3 mg/kg Page 213 Toxicology Study Report - PT02-0222 RTA051-02/00 Group Sex 6m Animal Number 71 72 73 74 75 Mean S.D. N PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats Date: 03-Mar-2003 Page: Bodyweights (g) Day numbers relative to Start Date -4 107 100 111 106 107 106.2 4.0 5 1 139 133 141 140 143 139.2 3.8 5 4 161 156 159 159 165 160.0 3.3 5 8 189 185 183 190 193 188.0 4.0 5 11 214 211 205 216 216 212.4 4.6 5 15 245 241 223 239 235 236.6 8.4 5 18 267 259 231 257 253 253.4 13.5 5 22 286 284 245 270 267 270.4 16.5 5 25 296 297 256 290 278 283.4 17.1 5 29 307 311 268 303 289 295.6 17.5 5 1 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 214 Toxicology Study Report - PT02-0222 RTA051-02/00 Group Sex 6f Animal Number 81 82 83 84 85 Mean S.D. N PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats Date: 03-Mar-2003 Page: Bodyweights (g) Day numbers relative to Start Date -4 106 110 99 103 106 104.8 4.1 5 1 127 128 117 123 128 124.6 4.7 5 4 138 132 125 138 139 134.4 5.9 5 8 151 141 133 146 154 145.0 8.3 5 11 161 155 145 158 165 156.8 7.6 5 15 171 164 153 166 176 166.0 8.6 5 18 173 173 162 175 187 174.0 8.9 5 22 182 181 169 181 192 181.0 8.2 5 25 184 184 172 182 198 184.0 9.3 5 29 191 189 176 194 203 190.6 9.8 5 2 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 215 Toxicology Study Report - PT02-0222 RTA051-02/00 Group Sex 7m Animal Number 76 77 78 79 80 Mean S.D. N PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats Date: 03-Mar-2003 Page: Bodyweights (g) Day numbers relative to Start Date -4 105 105 113 110 111 108.8 3.6 5 1 141 137 141 148 144 142.2 4.1 5 4 164 155 162 167 170 163.6 5.7 5 8 191 183 187 197 198 191.2 6.4 5 11 215 204 207 223 229 215.6 10.5 5 15 242 237 227 250 256 242.4 11.3 5 18 265 260 240 272 283 264.0 16.0 5 22 282 288 246 292 306 282.8 22.4 5 25 294 288 261 300 317 292.0 20.4 5 29 308 312 266 319 334 307.8 25.4 5 3 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 216 Toxicology Study Report - PT02-0222 RTA051-02/00 Group Sex 7f Animal Number 86 87 88 89 90 Mean S.D. N PROVANTIS Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats Date: 03-Mar-2003 Page: Bodyweights (g) Day numbers relative to Start Date -4 97 105 105 104 102 102.6 3.4 5 1 118 125 128 128 127 125.2 4.2 5 4 130 142 138 142 144 139.2 5.6 5 8 137 156 147 153 159 150.4 8.7 5 11 148 163 159 168 169 161.4 8.5 5 15 157 179 172 176 179 172.6 9.2 5 18 165 186 172 179 190 178.4 10.2 5 22 175 191 186 184 203 187.8 10.3 5 25 174 193 188 187 201 188.6 9.9 5 29 185 201 195 197 217 199.0 11.7 5 4 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 217 Toxicology Study Report - PT02-0222 13.1.2 Food Consumption Page 218 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 1 Day numbers relative to Start Date Mean Group Animal From: -3 1 5 8 12) 15 191 22 26 29 33 36 40 -3 Sex Number To: 1 5 8 12) 15 191 22 26 29 33 36 40 43 43 1m 1 2 3 4 5 6 7 8 9 10 118. 75 127. 20 123. 58 116. 48 115. 15 116. 99 124. 63 127. 75 109. 83 116. 54 100. 33 110. 11 104. 45 97. 13 108. 93 97. 46 110. 83 112. 87 92. 75 100. 33 91 .43 101 .91 95. 81 88. 40 109. 22 90. 59 109. 49 110. 22 84. 79 95. 57 88. 58 98. 03 92. 33 84. 71 100. 58 82. 48 102. 73 99. 12 75. 33 85. 82 85. 10 92. 10 87. 73 79. 09 91. 19 81. 16 101. 45 95. 00 74. 82 84. 08 79. 70 84. 97 82. 16 72. 29 82. 34 76. 28 96. 50 88. 33 70. 96 79. 75 69. 38 73. 41 71. 56 61. 39 69. 95 69. 12 89. 74 79. 49 63. 95 72. 31 57. 17 60. 42 58. 45 49. 06 56. 50 59. 44 77. 98 68. 55 54. 49 62. 85 64. 25 68. 29 66. 01 55. 03 64. 13 57. 17 75. 35 66. 02 51. 87 60. 74 65..92 87.90 77.82 60.35 70.41 62..51 84.15 76.19 58.09 67.43 60..23 81.85 73.84 56.39 66.40 47.20 64.61 58.41 43.86 52.70 83.85 90.72 86.90 78.18 88.67 74.35 92.86 87.20 69.04 78.07 Mean S. D. N 119. 69 5. 84 10 103. 52 6. 90 10 97. 74 9. 41 10 90. 97 9. 05 10 87. 17 7. 98 10 81 .33 7. 56 10 72. 03 7. 96 10 60. 49 8. 00 10 62. 89 6. 90 10 - -7 -2 -.-4 -8 10.73 5 - -6 -9 -.-6 -7 10.52 5 - -6 -7-.-7-4 10.29 5 - -5-3-.-3-6 8.38 5 - -8-2-.-9-8 7.74 10 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 219 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 2 Group Animal From: Sex Number To: -3 1 1 5 1f 31 32 33 34 35 36 37 38 39 40 110. 17 103. 17 110. 17 103. 17 110. 17 108. 12 102. 93 110. 44 100. 92 109. 50 108. 18 103. 19 105. 82 100. 34 109. 40 107. 84 101. 76 110. 31 99. 31 104. 71 Mean S. D. N 106. 88 3. 83 10 105. 09 3. 86 10 5 8 94. 25 89. 03 89. 03 84. 10 92. 66 95. 95 90. 45 99. 65 87. 65 91 .61 91 .44 4. 45 10 Day numbers relative to Start Date 8 12) 15 191 22 26 29 33 36 Mean 40 -3 12) 15 191 22 26 29 33 36 40 43 43 85. 95 77. 64 77. 64 73. 43 80. 56 83. 85 79. 88 89. 70 76. 92 80. 60 80. 62 4. 77 10 80. 00 73. 14 72. 32 69. 57 75. 74 75. 86 71. 26 81. 34 70. 67 72. 46 74. 24 3. 94 10 79. 01 75. 28 72. 07 70. 39 75. 91 73. 33 68. 39 78. 57 71. 35 70. 59 73. 49 3. 59 10 73. 28 69. 72 65. 99 64. 83 69. 35 75. 79 71. 11 81. 82 74. 42 74. 23 72. 05 4. 99 10 68. 58 64. 52 61. 52 60. 34 65. 19 67. 93 62. 56 73. 50 64. 82 66. 42 65. 54 3. 84 10 66. 84 62. 94 60. 02 59. 74 64. 67 64. 37 57. 18 68. 77 60. 63 61. 49 62. 67 3. 54 10 81..49 71.82 86.26 76.70 76.35 - -7 -8 -.-5 -2 5.51 5 69.17 62.17 73.48 64.34 65.34 - -6 -6 -.-9 -0 4.47 5 70.14 64.19 76.13 63.79 65.44 - -6 -7-.-9 -4 5.23 5 62..80 56.98 68.01 56.51 56.74 - -6-0 -.-2-1 5.09 5 85.14 79.85 79.40 76.21 82.63 79.74 73.90 84.46 74.46 76.58 - -7-9-.-2-4 3.97 10 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 220 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 3 Day numbers relative to Start Date Mean Group Animal From: -3 1 5 8 12 15 19 22 26 29 33 36 40 -3 Sex Number To: 1 5 8 12 15 19 22 26 29 33 36 40 43 43 2m 11 12 13 14 15 119.75 125.43 114.98 117.97 117.97 105.54 102.69 93.27 97.13 100.00 100.87 91.91 83.29 87.51 91.64 92.90 86.28 77.12 82.37 83.42 82.33 80.13 70.67 74.85 74.85 76.30 77.52 67.60 71.76 70.86 70.59 72.89 63.64 67.74 66.40 57.29 60.08 52.12 54.95 54.11 62.65 66.39 57.31 60.31 59.64 85.36 84.81 75.56 79.40 79.88 Mean S.D. N 119.22 3.87 5 99.73 4.77 5 91.04 6.52 5 84.42 5.78 5 76.57 4.65 5 72.81 4.07 5 68.25 3.60 5 55.71 3.07 5 61.26 3.44 5 81.00 4.09 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 221 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 4 Day numbers relative to Start Date Mean Group Animal From: -3 1 5 8 12 15 19 22 26 29 33 36 40 -3 Sex Number To: 1 5 8 12 15 19 22 26 29 33 36 40 43 43 2f 41 42 43 44 45 107.63 108.50 105.93 111.67 112.13 100.00 100.00 96.52 100.73 103.75 88.89 91.58 87.18 88.60 93.79 78.53 81.27 77.11 77.34 82.32 74.68 74.68 72.14 72.76 77.17 71.86 71.08 70.51 71.08 74.93 70.30 70.30 70.49 69.58 73.55 60.10 59.80 60.10 58.48 62.96 63.90 63.58 63.90 62.22 67.01 79.54 80.09 78.21 79.16 83.07 Mean S.D. N 109.17 2.66 5 100.20 2.57 5 90.01 2.65 5 79.31 2.36 5 74.29 1.97 5 71.89 1.76 5 70.84 1.55 5 60.29 1.64 5 64.12 1.76 5 80.01 1.84 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 222 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 5 Day numbers relative to Start Date Mean Group Animal From: -3 1 5 8 12 15 19 22 26 29 33 36 40 -3 Sex Number To: 1 5 8 12 15 19 22 26 29 33 36 40 43 43 3m 16 17 18 19 20 127.32 118.12 110.17 121.35 110.56 88.01 82.46 79.66 82.46 77.56 96.04 89.47 89.18 87.75 84.00 96.91 89.71 87.22 86.98 82.85 93.66 87.63 82.73 82.73 80.38 88.66 82.24 76.86 76.69 76.03 82.98 75.94 71.00 70.01 71.15 64.06 59.02 54.09 52.85 55.27 79.11 73.10 65.93 64.61 68.07 90.75 84.19 79.65 80.60 78.43 Mean S.D. N 117.50 7.31 5 82.03 3.93 5 89.29 4.36 5 88.73 5.19 5 85.43 5.31 5 80.10 5.40 5 74.22 5.41 5 57.06 4.54 5 70.16 5.95 5 82.72 4.97 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 223 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 6 Day numbers relative to Start Date Mean Group Animal From: -3 1 5 8 12 15 19 22 26 29 33 36 40 -3 Sex Number To: 1 5 8 12 15 19 22 26 29 33 36 40 43 43 3f 46 47 48 49 50 118.33 114.98 110.08 114.98 113.60 69.92 69.66 66.67 77.50 69.14 86.46 89.52 85.01 108.26 87.96 75.91 78.80 77.57 91.54 77.81 73.56 74.42 75.07 85.05 74.42 71.07 71.47 69.92 79.38 70.68 73.65 74.43 73.07 83.23 74.04 59.16 60.20 60.97 68.29 61.28 62.05 64.68 64.52 70.84 65.16 76.68 77.57 75.88 86.56 77.12 Mean S.D. N 114.39 2.98 5 70.58 4.08 5 91.44 9.55 5 80.33 6.35 5 76.50 4.81 5 72.50 3.89 5 75.68 4.25 5 61.98 3.62 5 65.45 3.25 5 78.76 4.41 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 224 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 7 Group Animal From: Sex Number To: -3 1 4m 21 22 23 24 25 26 27 28 29 30 121. 26 128. 22 116. 20 129. 72 126. 77 254. 95 269. 77 265. 65 254. 95 284. 08 Mean S. D. N 195. 16 75. 08 10 1 5 66. 99 72. 18 67. 88 71. 43 73. 21 46. 92 52. 90 49. 46 47. 74 53. 10 60. 18 11. 03 10 Day numbers relative to Start Date Mean 5 8 12) 15 191 22 26 29 33 36 40 -3 8 12) 15 191 22 26 29 33 36 40 43 43 76. 77 85. 59 84. 44 83. 61 87. 96 79. 11 89. 90 83. 27 79. 11 93. 07 79. 45 87. 61 87. 35 84. 30 90. 63 87. 83 95. 48 90. 52 85. 30 103. 14 84. 28 5. 11 10 89. 16 6. 49 10 76. 62 82. 80 83. 02 78. 17 89. 02 80. 00 89. 41 82. 83 78. 55 95. 60 83. 60 6. 01 10 76. 77 82. 20 82. 00 76. 24 89. 87 79. 00 88. 27 83. 17 77. 88 94. 57 83. 00 6. 12 10 71. 95 77. 04 74. 75 68. 92 82. 49 75. 34 82. 76 78. 87 74. 50 90. 08 77. 67 6. 13 10 61. 56 66. 59 63. 05 58. 04 70. 37 58. 89 65. 32 65. 48 58. 51 77. 90 64. 57 6. 14 10 63. 28 66. 97 63. 41 59. 14 73. 56 53. 44 60. 16 62. 33 52. 79 75. 86 63. 09 7. 54 10 69..46 76.32 80.98 68.31 93.00 - -7 -7 -.-6 -1 10.03 5 42.52 46.12 52.69 42.06 54.75 - -4 -7 -.-6 -3 5.82 5 35..04 39.45 46.18 34.06 49.37 - -4 -0 -.-8 -2 6.76 5 40..44 48.14 55.71 38.18 63.95 - -4-9-.-2-8 10.71 5 77.18 83.24 80.23 78.84 87.10 77.15 84.92 84.40 76.30 94.50 - -8-2-.-3-9 5.66 10 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 225 Toxicology Study Report - PT02-0222 RTA072-01/00 Food Consumption By Animal Study : PT02-0222 PROVANTIS Date: 16-Dec-2002 Individual Food Consumption Relative To Bodyweight - T-7758 - 4 weeks oral toxicity in rats* Page: 8 Group Animal From: Sex Number To: 1 4f 51 52 53 54 55 56 57 58 59 60 100. 26 103. 95 112. 19 112. 19 105. 23 105. 88 102. 44 102. 44 113. 00 105. 00 Mean S. D. N 106. 26 4. 58 10 Day numbers relative to Start Date Mean 1 5 8 12) 15 19) 22 26 29 33 36 40 -3 5 8 12) 15 191 22 26 29 33 36 40 43 43 66. 04 69. 14 72. 84 76. 29 69. 41 70. 57 73. 05 71. 65 80. 26 72. 48 83. 69 88. 72 91 .83 97. 52 87. 73 79. 45 85. 61 84. 06 103. 11 84. CO G> 80. 83 85. 19 88. 46 90. 36 86. 64 79. 08 85. 38 84. 54 107. 53 85. 95 75. 96 78. 53 84. 49 84. 49 82. 85 79. 62 86. 27 84. 44 103. 59 86. 54 72. 17 3. 96 10 88. 67 7. 08 10 87. 40 7. 80 10 84. 68 7. 50 10 73. 54 75. 00 83. 54 83. 28 80. 98 76. 28 81. 32 79. 27 96. 59 83. 48 81 .33 6. 47 10 73. 92 75. 93 84. 96 83. 68 81. 72 70. 09 75. 51 73. 08 87. 33 78. 32 78. 45 5. 71 10 61. 14 63. 10 71. 52 68. 01 67. 82 70. 40 76. 28 73. 13 88. 16 79. 27 71 .88 7. 94 10 66. 50 67. 70 77. 78 72. 59 74. 24 55. 21 58. 91 56. 86 75. 75 61. 62 66. 72 8. 25 10 80.75 87.09 83.90 119.03 89.35 --9-2-.-0 -2 15.44 5 6 8 .19 74. 85 71 .28 101 .24 74. 11 77. 93 13. 29 5 65..84 71.85 69.45 98.31 69.95 - -7-5 -.-0 -8 13.17 5 38..57 43.42 43.31 57.60 39.84 - -4-4-.-5-5 7.60 5 75.76 78.58 85.29 85.38 81.85 72.30 77.08 75.19 94.73 77.76 - -8-0 -.-3-9 6.60 10 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Page 226 Toxicology Study Report - PT02-0222 RTA072-01/00 PROVANTIS Date: 16-Dec-2002 Page: Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* 1 Group Sex 5m Animal Number 61 62 63 64 65 From : To: Mean S.D. N -3 1 122.09 128.81 121.12 123.08 122.58 123.54 3.04 5 Day numbers relati ve to Start Date 1 4 103.85 111.44 106.02 105.65 105.65 106.52 2.88 5 4 8 99.14 106.50 103.61 101.78 101.18 102.44 2.77 5 8 11 91.19 99.28 98.23 95.19 92.33 95.24 3.54 5 11 15 83.00 92.16 90.38 86.24 83.19 86.99 4.16 5 15 18 72.29 80.90 80.36 76.11 72.29 76.39 4.18 5 18 22 70.79 78.42 80.08 74.70 69.61 74.72 4.58 5 22 25 60.28 66.41 68.55 62.85 58.52 63.32 4.17 5 25 29 48.47 53.37 55.99 51.72 47.82 51.47 3.41 5 Mean -3 29 83.46 90.81 89.37 86.37 83.69 86.74 3.31 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 5 - 3 mg/kg Page 227 Toxicology Study Report - PT02-0222 RTA072-01/00 PROVANTIS Date: 16-Dec-2002 Page: Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* 2 Group Sex 5f Animal Number 66 67 68 69 70 From : To: Mean S.D. N -3 1 104.52 107.71 113.15 108.66 109.14 108.64 3.10 5 Day numbers relative to Start Date 1 4 94.51 95.24 100.27 97.50 96.35 96.77 2.26 5 4 8 89.47 88.54 92.73 91.07 88.54 90.07 1.81 5 8 11 78.61 76.86 80.98 78.87 78.35 78.73 1.48 5 11 15 75.68 73.67 79.55 75.91 77.09 76.38 2.16 5 15 18 68.99 66.67 72.58 68.20 68.20 68.93 2.21 5 18 22 69.36 67.30 71.97 67.66 68.78 69.01 1.85 5 22 25 59.93 58.53 61.57 58.99 61.07 60.02 1.30 5 25 29 56.56 55.56 58.82 56.41 57.89 57.05 1.30 5 Mean -3 29 77.51 76.68 81.29 78.14 78.38 78.40 1.75 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 5 - 3 mg/kg Page 228 Toxicology Study Report - PT02-0222 RTA072-01/00 PROVANTIS Date: 03-Mar-2003 Page: Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 75 From : To: Mean S.D. N -4 1 117.89 124.46 115.08 117.89 116.00 118.26 3.67 5 Day numbers relative to Start Date 1 4 112.00 116.26 112.00 112.37 109.09 112.34 2.56 5 4 8 108.57 111.44 111 .11 108.88 106.15 109.23 2.15 5 8 11 101.90 103.70 105.84 101.15 100.41 102.60 2.18 5 11 15 87.80 89.16 94.16 88.57 89.36 89.81 2.51 5 15 18 76.30 78.13 86.05 78.76 80.05 79.86 3.72 5 18 22 66.00 67.22 76.68 69.26 70.19 69.87 4.15 5 22 25 55.44 55.54 64.40 57.62 59.20 58.44 3.68 5 25 29 68.99 68.42 79.39 70.15 73.37 72.06 4.52 5 Mean -4 29 88.32 90.48 93.86 89.41 89.31 90.28 2.14 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 229 Toxicology Study Report - PT02-0222 RTA072-01/00 PROVANTIS Date: 03-Mar-2003 Page: Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f Animal Number 81 82 83 84 85 From : To : Mean S.D. N -4 1 112.45 110.08 121.30 115.93 111.97 114.35 4.42 5 Day numbers relati ve to Start Date 1 4 90.06 91.79 98.62 91.44 89.39 92.26 3.69 5 4 8 85.12 90.11 95.35 86.62 83.96 88.23 4.60 5 8 11 85.04 89.64 95.44 87.28 83.18 88.12 4.76 5 11 15 80.12 83.39 89.26 82.10 78.01 82.58 4.26 5 15 18 65.12 66.47 71.11 65.69 61.71 66.02 3.38 5 18 22 67.61 67.80 72.51 67.42 63.32 67.73 3.26 5 22 25 56.10 56.26 60.22 56.57 52.65 56.36 2.68 5 25 29 69.87 70.24 75.29 69.68 65.34 70.08 3.53 5 Mean -4 29 79.05 80.64 86.57 80.30 76.61 80.64 3.67 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 230 Toxicology Study Report - PT02-0222 RTA072-01/00 PROVANTIS Date: 03-Mar-2003 Page: Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 7m Animal Number 76 77 78 79 80 From : To: Mean S.D. N -4 1 121.14 123.14 117.32 115.50 116.86 118.79 3.21 5 Day numbers relative to Start Date 1 4 110.60 115.53 111.33 107.09 107.43 110.40 3.43 5 4 8 105.35 110.65 107.16 102.75 101.63 105.51 3.60 5 8 11 101.81 106.80 104.91 98.41 96.80 101.75 4.22 5 11 15 86.21 89.34 90.78 83.30 81.24 86.17 4.00 5 15 18 77.84 79.41 84.51 75.61 73.22 78.12 4.27 5 18 22 70.02 69.89 78.81 67.91 65.03 70.33 5.15 5 22 25 53.70 53.70 61.01 52.25 49.65 54.06 4.22 5 25 29 65.61 65.83 74.95 63.81 60.68 66.18 5.32 5 Mean -4 29 88.03 90.48 92.31 85.18 83.62 87.92 3.60 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 231 Toxicology Study Report - PT02-0222 RTA072-01/00 PROVANTIS Date: 03-Mar-2003 Page: Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 7f Animal Number 86 87 88 89 90 From : To : Mean S.D. N -4 1 121.86 113.91 112.45 112.93 114.41 115.11 3.85 5 Day numbers relati ve to Start Date 1 4 108.06 100.37 100.75 99.26 98.89 101.47 3.76 5 4 8 100.37 89.93 94.04 90.85 88.45 92.73 4.74 5 8 11 92.16 82.34 85.84 81.83 80.08 84.45 4.79 5 11 15 84.59 75.44 77.95 75.00 74.14 77.42 4.25 5 15 18 71.64 63.20 67.05 64.98 62.51 65.88 3.67 5 18 22 65.00 58.62 61.73 60.88 56.23 60.49 3.30 5 22 25 57.69 52.43 53.83 54.27 49.83 53.61 2.86 5 25 29 76.32 69.54 71.54 71.35 65.55 70.86 3.89 5 Mean -4 29 86.41 78.42 80.58 79.04 76.68 80.22 3.73 5 * = result to left has an associated comment or marker Food consumption units are g/kg bodyweight/day Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 232 Toxicology Study Report - PT02-0222 13.1.3 Clinical Pathology 13.1.3.1 Hematology Page 233 Toxicology Study Report - PT02-0222 L eg en d o f th e p lu s signs in th e re d blood co u n t (ra t) Anisocvtosis: ThevariationinRBC Volume (RedCellDistributionWidth = RDW) isequaltoorgreaterthan 16,1%. + : RDW > 16,1 % -18 ,2 9% ++: RDW > 18.29 % - 20,4 % +++: RDW >20,4% H y p e rc h ro m ia : T h e p e rc e n ta g e of cells with high cellular h em o g lo b in co n cen tratio n [m ore th a n 41 g/dl] (% H yper) is e q u al to o r g re a te r th a n 4 % . + : % H yper > 4 ,0 % - 7,9 % ++ : % H yper > 8,0 % -1 2 ,0 % +++: % Hyper > 1 2 ,0 % H y p o c h ro m ia : T h e p e rc e n ta g e of cells w ith low cellu lar hem o g lo b in c o n c e n tra tio n [less th a n 2 8 g/dl] (% H ypo) is e q u a l to or g reater than 4 %. + : % H ypo > 4,0 % - 7 , 9 % ++ : % H ypo > 8,0 % - 1 2 , 0 % +++: % Hypo > 1 2 ,0 % M acro cv to sis: T h e p e rc e n ta g e of red blood cells with h ig h er th an n o r m a l cell v o l u m e s [> 1 2 0 fl] (% M a c ro ) is e q u a l to or g reater th an 2,5 %. + : % M acro > 2,5 % - 6 ,4 % ++ : % M acro > 6,5 % -1 0 ,5 % +++: % M acro > 1 0 ,5 % M icrocytosis: T h e p e rc e n ta g e of red blood cells with low er th a n n o r m a l cell v o l u m e s [< 6 0 fl] (% M icro ) is e q u a l to or g reater th an 2 ,5 %. + : % M icro > 2,5 % - 6,4 % + + : % M ic ro > 6,5 % - 10,5 % + + + : % M ic ro > 10,5 % P o ly c h ro m a s ie : T h e hem oglobin distribution w idth (HDW ) is eq u al to or g reater th an 3,4 %. + : HDW > 3 ,4 % - 3 ,9 % ++ : HDW > 3 ,9 % - 4,6 % +++: HDW > 4,6 % Page 234 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 29 29 29 29 29 43 43 43 43 43 Red c e ll count 10E12/L 7.53 8.16 7.57 7.85 7.68 8.63 8.35 8.85 9.04 8.54 Hemo globin g/L 154 153 147 146 151 155 158 167 167 152 Hemato crit unity 0.44 0.47 0.44 0.44 0.44 0.47 0.48 0.49 0.50 0.45 MCV 10E-15 L 59 57 58 55 57 54 58 56 55 53 MCH 10E-12 g 20 19 20 19 20 18 19 19 18 18 MCHC g/L 348 330 338 335 346 332 328 337 336 336 Reticulo cytes unity 0.030 0.029 0.028 0.029 0.030 0.023 0.041 0.019 0.019 0.016 Heinz Bodies unity 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Hyper chromas. + Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 235 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 29 29 29 29 29 43 43 43 43 43 Red c e ll count 10E12/L 7.32 7.56 7.28 7.07 6.74 8.05 8.10 8.16 7.93 8.11 Hemo globin g/L 140 146 136 137 130 143 149 153 150 151 Hemato crit unity 0.42 0.43 0.41 0.40 0.39 0.42 0.44 0.45 0.43 0.44 MCV 10E-15 L 57 56 56 56 57 52 54 55 54 54 MCH 10E-12 g 19 19 19 19 19 18 18 19 19 19 MCHC g/L 337 343 335 346 338 338 341 344 351 345 Reticulo cytes unity 0.033 0.030 0.028 0.022 0.030 0.022 0.019 0.022 0.021 0.016 Heinz Bodies unity 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Hyper chromas. Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 236 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 2m Animal Number 11 12 13 14 -5 Day Number 29 29 29 29 55 Red cell count 10E12/L 7.33 7.84 8.11 7.66 8.19 Hemo globin g/L 148 150 148 150 155 Hemato crit unity 0.43 0.45 0.46 0.44 --0 -.4-7-- MCV 10E-15 L 59 58 56 57 58 MCH 10E-12 g 20 19 18 20 19 MCHC g/L 344 331 323 343 328 Reticulo cytes unity 0.029 0.027 0.023 0.025 0.024 Heinz Bodies unity Hyper chromas. Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 237 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 29 29 29 29 44 Red cell count 10E12/L * 8.12 7.76 6.67 44447 4.42 43 4 Hemo globin g/L * 153 143 128 140 Hemato crit unity * 0.45 0.43 0.37 440 4.44 144 MCV 10E-15 L * 56 55 56 57 MCH 10E-12 g * 19 19 19 19 MCHC g/L * 339 338 344 343 Reticulo cytes unity * 0.028 0.018 0.028 0.029 Heinz Bodies unity Hyper chromas. Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 238 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 29 29 29 29 22 Red cell count 10E12/L 8.26 8.12 7.53 7.63 7.44 Hemo globin g/L 151 154 143 146 144 Hemato crit unity 0.47 0.48 0.44 0.44 0.20 MCV 10E-15 L 57 59 59 58 59 MCH 10E-12 g 18 19 19 19 19 MCHC g/L 323 323 324 332 329 Reticulo cytes unity 0.027 0.030 0.030 0.031 0.027 Heinz Bodies unity Hyper chromas. Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 239 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 29 29 29 29 55 Red cell count 10E12/L 7.15 7.60 8.00 7.21 555575.50 535 Hemo globin g/L 140 142 149 145 137 Hemato crit unity 0.40 0.44 0.44 0.42 550 5.35955 MCV 10E-15 L 56 57 56 58 56 MCH 10E-12 g 20 19 19 20 20 MCHC g/L 347 326 335 345 349 Reticulo cytes unity 0.035 0.030 0.019 0.028 0.031 Heinz Bodies unity Hyper chromas. Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 240 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 Day Number 29 29 29 29 29 43 43 43 43 Red ce il count 10E12/L 8.25 7.16 7.61 7.28 7.48 9.04 9.16 9.68 9.00 Hemo globin g/L 160 140 151 144 148 165 164 171 167 Hemato crit unity 0.47 0.41 0.45 0.43 0.44 0.50 0.49 0.50 0.50 MCV 10E-15 L 58 57 59 59 58 56 53 52 55 MCH 10E-12 g 19 20 20 20 20 18 18 18 19 MCHC g/L 337 343 338 333 340 328 337 339 337 Reticulo cytes unity 0.025 0.031 0.031 0.026 0.019 0.010 0.003 0.005 0.013 Heinz Bodies unity 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Hyper chromas. + * = result to left has an associated comment or marker Nom inai Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 241 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* 8 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 29 29 29 29 29 43 43 43 43 43 Red c e ll count 10E12/L * 7.02 7.32 6.73 6.86 8.16 8.30 9.07 8.71 8.02 Hemo globin g/L * 135 131 125 127 153 155 167 157 147 Hemato crit unity * 0.41 0.40 0.37 0.38 0.45 0.45 0.48 0.46 0.44 MCV 10E-15 L * 59 54 55 56 55 55 53 53 54 MCH 10E-12 g * 19 18 19 19 19 19 18 18 18 MCHC g/L * 326 332 338 334 339 342 346 342 338 Reticulo cytes unity * 0.032 0.023 0.034 0.025 0.014 0.019 0.010 0.011 0.019 Heinz Bodies unity 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 Hyper chromas. + + * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 242 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 9 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 29 29 29 29 66 Red c e ll count 10E12/L 8.03 7.88 7.87 8.07 7.69 Hemo globin g/L 155 152 156 162 156 Hemato crit unity 0.45 0.45 0.46 0.47 0.55 MCV 10E-15 L 57 57 58 58 59 MCH 10E-12 g 19 19 20 20 20 MCHC g/L 341 339 340 346 346 Reticulo cytes unity 0.028 0.030 0.031 0.025 0.032 Heinz Bodies unity 0.000 0.000 0.000 0.000 0- .-0-0-0-- Hyper chromas. Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 243 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 10 Group Sex 5f Animal Number 66 67 68 69 -0 Day Number 29 29 29 29 00 Red c e ll count 10E12/L 7.14 7.75 7.28 7.84 7.54 Hemo globin g/L 144 153 145 152 150 Hemato crit unity 0.40 0.45 0.42 0.44 --0 -.4-3-- MCV 10E-15 L 57 58 58 56 57 MCH 10E-12 g 20 20 20 19 20 MCHC g/L 358 343 346 349 351 Reticulo cytes unity 0.030 0.032 0.034 0.029 0.041 Heinz Bodies unity 0.000 0.000 0.000 0.000 0- .-0-0-0-- Hyper chromas. Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 244 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 11 Comments and Markers Group Animal Day Sex Number Number Measurement Marker Comment 2f 41 4f 51 29 Red blood cell count Hemoglobin Hematocrit MCV MCH MCHC Reticulocytes 29 Red blood cell count Hemoglobin Hematocrit MCV MCH MCHC Reticulocytes Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Marker E implies value excluded from means Page 245 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 75 Day Number 29 29 29 29 77 Red c e ll count 10E12/L 8.30 7.58 7.82 8.16 8.08 Hemo globin g/L 166 146 151 161 156 Hemato crit unity 0.49 0.44 0.44 0.48 --0 -.4-7-- MCV 10E-15 L 59 58 56 59 58 MCH 10E-12 g 20 19 19 20 19 MCHC g/L 337 334 344 335 335 Reticulo cytes unity 0.030 0.028 0.030 0.036 0.035 Heinz Bodies unity 0.000 0.000 0.000 0.000 0- .-0-0-0-- Hyper chromas. * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 246 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 29 29 29 29 88 Red c e ll count 10E12/L 7.52 7.68 8.21 7.92 7.75 Hemo globin g/L 150 148 153 149 144 Hemato crit unity 0.44 0.44 0.45 0.43 --0 -.4-2-- MCV 10E-15 L 58 57 55 55 55 MCH 10E-12 g 20 19 19 19 19 MCHC g/L 344 338 342 344 340 Reticulo cytes unity 0.023 0.030 0.022 0.027 0.026 Heinz Bodies unity 0.000 0.000 0.000 0.000 0- .-0-0-0-- Hyper chromas. * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 247 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 29 29 29 29 88 Red c e ll count 10E12/L 8.20 7.73 8.22 7.84 7.65 Hemo globin g/L 155 152 154 152 156 Hemato crit unity 0.46 0.45 0.45 0.45 --0 -.4-5-- MCV 10E-15 L 56 59 55 57 59 MCH 10E-12 g 19 20 19 19 20 MCHC g/L 336 335 340 338 --- Reticulo cytes unity 0.036 0.038 0.026 0.033 0.032 Heinz Bodies unity 0.000 0.000 0.000 0.000 0- .-0-0-0-- Hyper chromas. * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 248 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 29 29 29 29 99 Red c e ll count 10E12/L 7.67 7.80 7.50 7.46 7.84 Hemo globin g/L 144 149 148 143 151 Hemato crit unity 0.43 0.43 0.42 0.41 --0 -.4-5-- MCV 10E-15 L 55 55 56 56 57 MCH 10E-12 g 19 19 20 19 19 MCHC g/L 339 349 353 345 336 Reticulo cytes unity 0.028 0.029 0.025 0.045 0.038 Heinz Bodies unity 0.000 0.000 0.000 0.000 0- .-0-0-0-- Hyper chromas. + * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 249 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex Animal Number 1m* 1 2 3 4 5 6 7 8 9 10 Day Number 29 29 29 29 29 43 43 43 43 43 White cell cnt 10E9/L 12. 55 8. 24 11 .41 10. 40 11 .48 9. 70 6. 99 11 .14 10. 37 7. 25 Neutro phils unity 0.08 0.12 0.10 0.11 0.08 0.09 0.14 0.09 0.11 0.11 1 CO 1 CO 1 CO 1 1 1 4^ 1 1 1 CO 1 CO 1 CD 1 CO 1 CD CO 1 CO 1 CO 1 CO CO 1 Lympho cytes uni ty 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 84 1 1 Ol Mono cytes unity 0.02 0.01 0.02 0.02 0.01 0.02 0.02 0.02 0.02 0.03 Eos ino phils unity 0.00 0.00 0.00 0.00 0.02 0.00 0.00 0.01 0.01 0.01 Baso phils unity 0.02 0.01 0.01 0.01 0.01 0.01 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 250 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 29 29 29 29 29 43 43 43 43 43 White cell cnt 10E9/L 6 41 7 95 7 41 9 99 7 55 6 95 7 74 7 37 6 58 8 85 Neutro phils unity 0.08 0.06 0.10 0.08 0.09 0.08 0.10 0.07 0.07 0.06 1 CO 1 11 1 CO 1 11 CO 1 CO 1 1 aC\>l 1 Lympho cytes uni ty 0. 90 0. 0. 0. 90 0. 0. 89 0. 0. 91 0. 90 0. 92 Mono cytes unity 0.01 0.01 0.01 0.01 0.01 0.01 0.02 0.01 0.02 0.01 Eos ino phils unity 0.00 0.00 0.01 0.00 0.01 0.01 0.01 0.01 0.01 0.01 Baso phils unity 0.00 0.01 0.00 0.01 0.00 0.00 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 251 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 2m Animal Number 11 12 13 14 -5 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 15.31 11.50 14.99 10.99 12.87 Neutro phils unity 0.08 0.06 0.06 0.08 --0 -.0-8-- Lympho cytes unity 0.89 0.92 0.92 0.89 0.89 Mono cytes unity 0.01 0.01 0.01 0.02 0.02 Eos ino phils unity 0.01 0.00 0.00 0.00 --0 -.0-0-- Baso phil unit 0.01 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 252 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L * 10.35 8.55 9.97 10.23 Neutro phils unity * 0.06 0.07 0.05 --0 -.0-7-- Lympho cytes unity * 0.92 0.91 0.94 0.90 Mono cytes unity * 0.01 0.01 0.01 0.01 Eos ino phils unity * 0.01 0.01 0.00 --0 -.0-1-- Baso phil unit 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 253 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 10.49 11.05 8.98 13.41 13.20 Neutro phils unity 0.11 0.12 0.09 0.08 --0 -.1-1-- Lympho cytes unity 0.86 0.84 0.88 0.89 0.87 Mono cytes unity 0.02 0.03 0.01 0.01 0.01 Eos ino phils unity 0.00 0.00 0.01 0.01 --0 -.0-0-- Baso phil unit 0.00 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 254 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 8.24 11.30 8.04 7.76 7.36 Neutro phils unity 0.07 0.08 0.09 0.09 --0 -.1-1-- Lympho cytes unity 0.91 0.90 0.88 0.89 0.87 Mono cytes unity 0.01 0.01 0.02 0.02 0.01 Eos ino phils unity 0.00 0.01 0.00 0.00 --0 -.0-1-- Baso phils unity 0.00 0.00 0.00 0.00 0.00 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 255 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex Animal Number 4m* 21 22 23 24 25 26 27 28 29 Day Number 29 29 29 29 29 43 43 43 --4--3 White cell cnt 10E9/L 7. 99 9. 83 9. 05 7. 82 12. 36 4. 42 6. 44 4. 24 ---- 6 44 Neutro phils unity 0.13 0.09 0.12 0.11 0.15 0.14 0.08 0.38 --0 -.0-8-- 1 CO 1 4^ 1 CO Ol 11 C^JO 11 CO On CD 1 CO 1 Lympho cytes uni ty 0. 0. 0. 0. 0. 81 0. 0. 91 0. 59 --0 - 89 Mono cytes unity 0.02 0.02 0.02 0.02 0.02 0.01 0.01 0.02 0.01 Eos ino phils unity 0.00 0.01 0.00 0.00 0.01 0.01 0.01 0.01 --0 -.0-1-- Baso phils unity 0.01 0.00 0.01 0.00 0.00 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 256 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 8 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 29 29 29 29 29 43 43 43 43 43 White cell cnt 10E9/L * 7. 27 6. 48 8. 58 9. 40 8. 98 5. 29 9. 31 6. 76 7. 99 Neutro phils unity * 0.09 0.07 0.08 0.06 0.06 0.09 0.13 0.07 0.08 1 00 1 CO CO 1 CO 1 C0\5l Lympho cytes uni ty * 0. 89 0. 91 0. 89 0. 91 0. 0. 0. 0. 91 0. 89 Mono cytes unity * 0.01 0.01 0.02 0.01 0.01 0.02 0.02 0.01 0.02 Eos ino phils unity * 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Baso phils unity * 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 257 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 9 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 13.80 11.31 13.77 12.51 16.22 Neutro phils unity 0.11 0.08 0.10 0.11 --0 -.1-0-- Lympho cytes unity 0.84 0.88 0.86 0.84 0.85 Mono cytes unity 0.03 0.02 0.01 0.02 0.03 Eos ino phils unity 0.01 0.00 0.01 0.02 --0 -.0-1-- Baso phil unit 0.01 0.01 0.01 0.01 6.01 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 258 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 10 Group Sex 5f Animal Number 66 67 68 69 -0 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 11.22 10.56 12.18 11.30 10.12 Neutro phils unity 0.09 0.11 0.08 0.14 --0 -.0-7-- Lympho cytes unity 0.89 0.82 0.88 0.82 0.89 Mono cytes unity 0.01 0.04 0.02 0.02 0.02 Eos ino phils unity 0.01 0.01 0.01 0.02 --0 -.0-1-- Baso phil unit 0.00 0.01 0.00 0.01 0.00 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 259 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 11 Comments and Markers Group Animal Day Sex Number Number Measurement Marker Comment 2f 41 4f 51 29 White blood cell count Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils (%) 29 White blood cell count Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils (%) Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Sampl e coagu lated Marker = E implies value excluded from means Page 260 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Mu tiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 -5 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 12.54 10.07 17.52 13.10 11.84 Neutro phils unity 0.13 0.12 0.15 0.11 --0 -.1-0-- Lympho cytes unity 0.82 0.84 0.82 0.86 0.86 Mono cytes unity 0.03 0.03 0.01 0.02 0.02 Eos ino phils unity 0.01 0.01 0.01 0.01 --0 -.0-1-- Baso phil unit 0.00 0.00 0.00 0.00 0.00 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 261 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 12.63 11.49 10.34 7.73 11.85 Neutro phils unity 0.10 0.09 0.08 0.08 --0 -.0-6-- Lympho cytes unity 0.87 0.87 0.88 0.88 0.90 Mono cytes unity 0.02 0.02 0.01 0.02 0.02 Eos ino phils unity 0.01 0.02 0.02 0.02 --0 -.0-1-- Baso phil unit 0.00 0.00 0.00 0.00 0.00 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 262 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Mu tiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 12.31 11.00 7.75 13.26 11.88 Neutro phils unity 0.11 0.11 0.09 0.09 --0 -.1-0-- Lympho cytes unity 0.86 0.84 0.88 0.86 0.86 Mono cytes unity 0.02 0.03 0.02 0.03 0.02 Eos ino phils unity 0.01 0.01 0.01 0.01 --0 -.0-1-- Baso phil unit 0.00 0.00 0.00 0.00 0.00 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 263 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Whit e Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 29 29 29 29 - - 2--9 White cell cnt 10E9/L 5.96 8.80 8.19 8.81 7.68 Neutro phils unity 0.09 0.08 0.09 0.08 --0 -.1-2-- Lympho cytes unity 0.88 0.89 0.88 0.88 0.84 Mono cytes unity 0.01 0.01 0.01 0.01 0.02 Eos ino phils unity 0.01 0.01 0.01 0.02 --0 -.0-1-- Baso phils unity 0.00 0.00 0.00 0.00 0.00 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 264 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 29 29 29 29 29 43 43 43 43 43 Coagul. Ti me sec 100 96 99 102 106 129 126 137 144 159 Plate lets 10E9/L 1119 1049 1021 1153 810 1179 844 1077 1101 1056 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 265 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 29 29 29 29 29 43 43 43 43 43 Coagul. Ti me sec 135 115 133 142 132 151 145 176 138 147 Plate lets 10E9/L 849 1006 1184 992 1270 1065 1076 978 1051 1081 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 266 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 2m Animal Number 11 12 13 14 -5 Day Number 29 29 29 29 55 Coagul. Ti me sec 102 106 111 126 112 Plate lets 10E9/L 1132 1098 1066 1087 1-55 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 267 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 29 29 29 29 44 Coagul. Time sec 105 96 88 105 102 Plate lets 10E9/L * 1095 1087 1007 1155 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 268 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 29 29 29 29 20 Coagul. Ti me sec 124 105 108 115 104 Plate lets 10E9/L 1103 1177 1042 1060 1042 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 269 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 29 29 29 29 55 Coagul. Ti me sec 68 106 112 120 119 Plate lets 10E9/L 1093 1029 1324 1016 1136 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 270 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 Day Number 29 29 29 29 29 43 43 43 99 Coagul. Ti me sec 124 101 97 90 106 148 132 125 102 Plate lets 10E9/L 960 942 1050 930 1108 904 1012 627 12 99 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 271 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 8 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 29 29 29 29 29 43 43 43 43 43 Coagul. Ti me sec 96 108 98 111 105 153 122 153 125 121 Plate lets 10E9/L * 1258 1173 988 982 1206 1316 1443 967 1470 Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 272 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 9 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 29 29 29 29 66 Coagul. Ti me sec 179 157 157 150 145 Plate lets 10E9/L 1141 1229 1088 980 615 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 273 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 10 Group Sex 5f Animal Number 66 67 68 69 70 Day Number 29 29 29 29 70 Coagul. Ti me sec 173 153 164 146 164 Plate lets 10E9/L 1299 1503 815 957 1070 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 274 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 11 Comments and Markers oup Animal Day Sex Number Number Measurement Marker 2f 41 4f 51 29 Platelets 29 Platelets Sample coagul ated Sample coagul ated Marker = E implies value excluded from means Page 275 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 75 Day Number 29 29 29 29 75 Coagul. Time sec 133 132 159 147 139 Plate lets 10E9/L 966 1170 1322 1093 1755 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 276 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 29 29 29 29 88 Coagul. Time sec 126 129 118 134 122 Pl ate lets 10E9/L 1122 1104 996 1147 1555 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 277 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 29 29 29 29 88 Coagul. Time sec 167 168 181 132 137 Plate lets 10E9/L 1088 1158 1143 1211 1180 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 278 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 29 29 29 29 99 Coagul. Time sec 135 123 148 119 131 Plate lets 10E9/L 1143 1088 1166 1001 990 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 279 Toxicology Study Report - PT02-0222 13.1.3.2 Clinical chemistry Page 280 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 29 29 29 29 29 43 43 43 43 43 Sod ium mmol/L 142 142 139 139 141 139 137 139 141 139 Potas sium mmol/L 5.74 5.89 5.85 6.39 6.46 5.80 6.20 6.40 5.90 5.75 Calcium mmol/L 2.39 2.46 2.42 2.45 2.40 2.21 2.18 2.27 2.42 2.39 Chloride mmol/L 105 104 102 102 104 102 102 103 103 101 Phos phorus mmol/L 2.90 2.86 3.05 3.18 3.25 2.53 3.01 3.12 3.08 2.96 Glucose mmol/L 18.5 18.8 18.1 24.5 17.5 17.0 19.8 21.6 25.7 16.8 Uric Acid umol/L 37 21 36 34 38 38 60 49 24 35 Creati nine umol/L 44 47 50 47 45 54 46 51 42 42 Urea Nitrogen mmol/L 5.5 5.4 5.5 6.9 7.2 6.9 5.9 8.3 6.5 7.3 ALAT IU/L 38 46 45 38 45 42 49 60 56 39 ASAT IU/L 67 69 105 66 98 111 116 116 80 95 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 m g/kg Page 281 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 29 29 29 29 29 43 43 43 43 43 Alk.Phos phatase IU/L 515 450 396 532 588 364 307 327 337 279 G-Gluta. Transf. IU/L 3 3 3 3 3 3 3 3 3 4 (continued) Total Protein g/L 51 Cho le sterol mmol/L 1.9 54 2.1 50 2.0 53 2.0 53 2.0 49 1 .7 48 1.8 51 1.9 55 2.0 49 1.8 Triglyce rides mmol/L 0.53 0.35 0.53 0.56 0.59 0.57 0.38 0.55 0.54 0.38 Albumin g/L 25 27 25 26 27 22 23 24 25 23 Globulin g/L 26 27 25 27 26 27 25 27 30 26 Alb/Glob Ratio 0.96 1.00 1.00 0.96 1.04 0.81 0.92 0.89 0.83 0.88 Total Biliru. umol/L 4.7 5.4 5.3 4.9 5.0 6.0 6.1 5.6 4.4 5.0 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 282 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 29 29 29 29 29 43 43 43 43 43 Sod ium mmol/L 142 142 138 140 141 144 143 143 143 143 Potas sium mmol/L 4.65 5.05 5.35 5.18 5.71 4.84 4.41 4.66 4.75 5.12 Calcium mmol/L 2.30 2.29 2.31 2.30 2.34 2.37 2.39 2.41 2.40 2.34 Chloride mmol/L 104 105 101 106 103 106 106 106 104 105 Phos phorus mmol/L 2.54 2.76 3.05 2.51 2.83 2.42 2.44 2.26 2.35 2.75 Glucose mmol/L 12.2 15.5 14.7 10.5 13.9 10.5 12.2 12.2 14.3 14.3 Uric Acid umol/L 47 59 33 54 51 90 33 52 58 72 Creati nine umol/L 51 49 46 45 48 58 48 54 58 58 Urea Nitrogen mmol/L 5.6 5.5 6.0 6.1 6.0 5.7 5.3 5.4 5.9 6.3 ALAT IU/L 43 35 39 42 46 38 29 36 33 38 ASAT IU/L 114 97 87 91 115 124 71 98 85 102 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 m g/kg Page 283 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 29 29 29 29 29 43 43 43 43 43 Alk.Phos phatase IU/L 419 380 442 404 372 201 306 241 209 175 G-Gluta. Transf. IU/L 3 3 3 3 3 3 3 3 3 4 (continued) Total Protein g/L 56 Cho le sterol mmol/L 2.0 53 2.0 51 1.5 55 1.8 56 2.2 61 2.4 59 1.5 55 1.8 56 1 .7 57 1.8 Triglyce rides mmol/L 0.49 0.49 0.44 0.63 0.42 0.27 0.49 0.41 0.55 0.52 Albumin g/L 28 26 25 27 29 30 29 28 28 27 Globulin g/L 28 27 26 28 27 31 30 27 28 30 Alb/Glob Ratio 1.00 0.96 0.96 0.96 1.07 0.97 0.97 1.04 1.00 0.90 Total Biliru. umol/L 6.5 5.8 5.5 6.4 5.9 5.3 6.3 4.9 5.0 4.7 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 284 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 2m Animal Number 11 12 13 14 15 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 140 140 139 141 139 Potas sium mmol/L 6.20 6.35 5.88 6.32 5.85 Calcium mmol/L 2.40 2.23 2.26 2.32 2.32 Chloride mmol/L 101 102 102 101 101 Phos phorus mmol/L 3.27 3.35 3.06 3.29 3.88 Glucose mmol/L 17.4 19.5 21.1 21.2 20.1 Uric Acid umol/L 58 51 46 64 39 Creati nine umol/L 50 55 47 59 48 Urea Nitrogen mmol/L 6.6 5.8 5.5 5.8 5.2 ALAT IU/L 47 40 48 46 43 ASAT IU/L 110 98 97 119 90 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 285 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex 2m Animal Number 11 12 13 14 15 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 516 380 553 412 507 G-Gluta. Transf. IU/L 3 3 3 3 3 (continued) Total Protein g/L Cho le sterol mmol/L 51 1 .7 54 1.8 50 2.1 55 2.0 55 2.2 Triglyce rides mmol/L 0.48 0.18 0.62 0.37 0.33 Albumin g/L 26 26 25 27 27 Globulin g/L 25 28 25 28 28 Alb/Glob Ratio 1.04 0.93 1.00 0.96 0.96 Total Biliru. umol/L 5.9 5.2 6.3 6.4 - --5- -.4-- Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 286 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 142 141 141 140 138 Potas sium mmol/L 5.67 6.15 6.64 5.84 6.09 Calcium mmol/L 2.41 2.30 2.40 2.31 2.38 Chloride mmol/L 106 104 104 104 103 Phos phorus mmol/L 3.33 3.12 3.30 3.04 3.01 Glucose mmol/L 15.7 15.3 14.6 18.4 17.9 Uric Acid umol/L 57 67 82 40 66 Creati nine umol/L 47 53 57 46 50 Urea Nitrogen mmol/L 6.3 6.7 6.3 5.2 5.6 ALAT IU/L 47 44 60 45 43 ASAT IU/L 98 112 148 91 102 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 287 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 8 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 307 296 243 428 325 G-Gluta. Transf. IU/L 3 3 3 3 3 (continued) Total Protein g/L Cho le sterol mmol/L 53 2.3 54 2.2 52 2.3 50 2.3 49 2.3 Triglyce rides mmol/L 0.34 0.35 0.30 0.42 0.41 Albumin g/L 26 27 26 25 23 Globulin g/L 27 27 26 25 26 Alb/Glob Ratio 0.96 1.00 1.00 1.00 0.88 Total Biliru. umol/L 6.5 6.8 6.1 5.7 - --6- -.3-- Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 288 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 9 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 29 29 29 29 - - 2--9 Sodium mmol/L 140 142 141 141 142 Potas sium mmol/L 5.75 5.76 5.25 5.36 --5 -.7--8 - Calcium mmol/L 2.31 2.25 2.41 2.34 2.35 Chloride mmol/L 102 102 103 99 101 Phos phorus mmol/L 3.05 2.82 2.48 3.00 3.00 Glucose mmol/L 14.9 16.9 16.2 15.8 19.4 Uric Acid umol/L 87 76 36 58 56 Creati nine umol/L 49 41 46 50 ---48--- Urea Nitrogen mmol/L 5.7 6.2 5.1 5.2 5.6 ALAT IU/L 58 64 58 53 60 ASAT IU/L 127 102 83 111 119 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 289 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 10 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 608 533 606 661 491 G-Gluta. Transf. IU/L 3 3 3 3 3 (continued) Total Protein g/L Cho le sterol mmol/L 54 2.0 53 1.9 53 2.1 54 2.2 ---1.-7-- 55 Triglyce rides mmol/L 0.44 0.36 0.49 0.51 0.56 Albumin g/L 26 27 26 26 27 Globulin g/L 28 26 27 28 28 Alb/Glob Ratio 0.93 1.04 0.96 0.93 0.96 Total Biliru. umol/L 6.0 7.6 4.9 7.3 - --5- -.4-- Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 290 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 11 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 145 146 147 149 146 Potas sium mmol/L 5.11 5.56 5.46 5.43 5.42 Calcium mmol/L 2.20 2.25 2.25 2.24 2.23 Chloride mmol/L 109 108 106 109 111 Phos phorus mmol/L 2.77 2.81 2.81 2.79 2.44 Glucose mmol/L 12.3 13.5 15.5 12.2 16.2 Uric Acid umol/L 107 66 74 89 78 Creati nine umol/L 45 46 53 49 44 Urea Nitrogen mmol/L 4.3 6.9 7.1 5.9 4.4 ALAT IU/L 43 49 45 53 42 ASAT IU/L 95 99 104 115 100 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 291 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 12 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 377 409 382 412 304 G-Gluta. Transf. IU/L 3 3 3 3 3 (continued) Total Protein g/L Cho le sterol mmol/L 62 2.9 62 3.1 62 2.5 60 2.6 58 2.6 Triglyce rides mmol/L 0.30 0.46 0.40 0.37 0.40 Albumin g/L 32 33 33 32 30 Globulin g/L 30 29 29 28 28 Alb/Glob Ratio 1.07 1.14 1.14 1.14 1.07 Total Biliru. umol/L 6.4 8.6 5.5 8.0 - --5- -.9-- Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 292 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 13 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 Day Number 29 29 29 29 29 43 43 43 43 Sod ium mmol/L 143 144 141 141 141 144 145 144 144 Potas sium mmol/L 5.50 5.71 6.66 5.46 6.20 5.18 4.80 4.94 4.67 Calcium mmol/L 2.24 2.37 2.45 2.35 2.27 2.34 2.31 2.18 2.40 Chloride mmol/L 101 102 102 100 104 106 107 109 105 Phos phorus mmol/L 2.86 2.86 3.20 2.99 2.97 2.88 2.65 2.64 2.90 Glucose mmol/L 15.2 18.5 12.4 14.8 19.6 7.3 5.6 5.1 6.9 Uric Acid umol/L 59 36 50 33 77 52 73 55 38 Creati nine umol/L 40 38 50 42 47 54 59 55 50 Urea Nitrogen mmol/L 7.3 5.8 7.8 6.4 8.1 8.1 11.8 18.7 7.5 ALAT IU/L 66 77 68 59 51 42 44 32 32 ASAT IU/L 87 107 127 88 100 111 108 130 84 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 m g/kg Page 293 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 14 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 Day Number 29 29 29 29 29 43 43 43 43 Alk.Phos phatase IU/L 382 469 303 615 351 266 243 127 219 G-Gluta. Transf. IU/L 4 4 3 3 4 3 3 3 3 (continued) Total Protein g/L 51 Cho le sterol mmol/L 1.6 54 2.0 52 1.8 52 1.8 51 2.1 59 2.0 61 2.0 53 1.8 60 2.0 Triglyce rides mmol/L 0.20 0.50 0.33 0.48 0.36 0.31 0.15 * 0.33 Albumin g/L 26 28 27 27 25 29 28 25 29 Globulin g/L 25 26 25 25 26 30 33 28 31 Alb/Glob Ratio 1.04 1.08 1.08 1.08 0.96 0.97 0.85 0.89 0.94 Total Biliru. umol/L 5.5 5.0 5.2 5.5 6.4 7.4 6.5 6.6 5.1 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 294 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 15 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 29 29 29 29 29 43 43 43 43 43 Sod ium mmol/L 148 144 145 143 143 141 143 142 144 140 Potas sium mmol/L 6.10 5.55 7.07 5.51 5.07 5.23 6.11 5.55 5.96 5.62 Calcium mmol/L 2.45 2.22 2.32 2.15 2.12 2.37 2.27 2.24 2.28 2.34 Chloride mmol/L 105 107 105 105 103 106 109 106 106 106 Phos phorus mmol/L 3.38 2.86 3.55 2.95 2.91 2.83 3.07 2.88 3.13 3.38 Glucose mmol/L 16.0 12.2 14.5 14.8 15.2 16.1 11.2 12.3 6.6 17.1 Uric Acid umol/L 322 80 100 49 89 39 85 86 69 57 Creati nine umol/L 54 50 38 42 45 45 64 61 61 50 Urea Nitrogen mmol/L 6.8 4.9 6.0 5.0 6.4 6.4 7.3 8.8 15.5 4.7 ALAT IU/L 53 49 60 47 58 31 29 80 43 32 ASAT IU/L 82 119 101 82 94 68 97 152 111 71 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 m g/kg Page 295 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 16 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 29 29 29 29 29 43 43 43 43 43 Alk.Phos phatase IU/L 437 328 556 443 524 229 111 112 199 274 G-Gluta. Transf. IU/L 5 5 8 7 6 3 3 3 3 3 (continued) Total Protein g/L 61 Cho le sterol mmol/L 3.1 56 2.3 56 2.1 55 2.5 52 1.9 53 2.1 51 2.1 50 1.8 54 1.6 53 1.8 Triglyce rides mmol/L 0.60 0.48 0.36 0.39 0.25 0.39 0.19 0.24 0.25 0.40 Albumin g/L 36 29 29 29 27 25 24 23 25 24 Globulin g/L 25 27 27 26 25 28 27 27 29 29 Alb/Glob Ratio 1.44 1.07 1.07 1.12 1.08 0.89 0.89 0.85 0.86 0.83 Total Biliru. umol/L 7.2 5.5 5.8 5.4 5.8 4.9 5.4 5.3 6.3 5.4 * = result to left has an associated comment or marker Nominal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 296 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 17 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 29 29 29 29 - - 2--9 Sodium mmol/L 136 137 138 139 140 Potas sium mmol/L 6.33 6.08 6.20 5.52 --5 -.4--7 - Calcium mmol/L 2.39 2.39 2.42 2.45 2.48 Chloride mmol/L 99 101 103 104 104 Phos phorus mmol/L 3.43 2.91 3.17 2.95 3.-- Glucose mmol/L 17.8 16.4 16.6 18.0 17.1 Uric Acid umol/L 25 31 25 30 26 Creati nine umol/L 48 46 50 44 ---44--- Urea Nitrogen mmol/L 7.3 6.4 6.7 5.7 5.7 ALAT IU/L 33 42 41 45 61 ASAT IU/L 67 81 98 79 82 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 297 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 18 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 347 390 371 292 438 G-Gluta. Transf. IU/L 3 3 3 3 3 (continued) Total Protein g/L Cho le sterol mmol/L 53 1.9 47 1.9 50 2.0 51 2.0 51 2.2 Triglyce rides mmol/L 0.54 0.44 0.44 0.43 0.46 Albumin g/L 25 22 25 25 23 Globulin g/L 28 25 25 26 28 Alb/Glob Ratio 0.89 0.88 1.00 0.96 0.82 Total Biliru. umol/L 4.3 4.5 5.0 4.4 - --4- -.5-- Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 298 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 19 Group Sex 5f Animal Number 66 67 68 69 70 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 139 142 138 141 140 Potas sium mmol/L 5.36 5.67 5.77 5.97 6.05 Calcium mmol/L 2.39 2.42 2.55 2.44 2.37 Chloride mmol/L 104 106 104 107 105 Phos phorus mmol/L 2.39 2.53 3.28 2.98 3.09 Glucose mmol/L 11.2 12.5 13.4 14.3 15.4 Uric Acid umol/L 78 90 91 58 29 Creati nine umol/L 48 61 54 54 40 Urea Nitrogen mmol/L 6.2 5.0 5.6 5.5 6.8 ALAT IU/L 46 42 42 43 34 ASAT IU/L 104 100 129 113 81 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 299 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 20 Group Sex 5f Animal Number 66 67 68 69 70 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 411 387 435 304 427 G-Gluta. Transf. IU/L 3 3 3 3 3 (continued) Total Protein g/L Cho le sterol mmol/L 54 2.2 54 2.2 54 2.0 59 2.6 ---1.-9-- 52 Triglyce rides mmol/L 0.30 0.30 0.39 0.38 0.37 Albumin g/L 27 28 27 29 26 Globulin g/L 27 26 27 30 26 Alb/Glob Ratio 1.00 1.08 1.00 0.97 1.00 Total Biliru. umol/L 4.7 4.9 5.6 5.0 - --5- -.0-- Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 300 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 21 Comments and Markers Group Animal Day Sex Number Number Measurement Marker Comment 4m 28 43 Triglycerides Result lies below the detection limit Marker = E implies value excluded from means Page 301 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 75 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 138 139 137 139 137 Potas sium mmol/L 5.51 5.80 5.67 5.62 5.75 Calcium mmol/L 2.44 2.51 2.43 2.56 2.50 Chloride mmol/L 102 101 101 102 102 Phos phorus mmol/L 3.14 3.09 2.95 3.12 3.71 Glucose mmol/L 18.4 18.5 20.1 18.7 20.9 Uric Acid umol/L 21 23 30 15 32 Creati nine umol/L 48 46 51 47 47 Urea Nitrogen mmol/L 7.5 5.1 5.6 6.1 5.6 ALAT IU/L 46 40 38 57 41 ASAT IU/L 97 93 95 82 81 * = result to left has an associated comment or marker Nom ina Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 302 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6m Animal Number 71 72 73 74 75 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 338 412 341 366 369 G-Gluta. Transf. IU/L 4 4 4 4 4 (continued) Total Protein g/L Cho le sterol mmol/L 52 1.9 53 1.9 51 2.0 51 2.2 51 2.0 Triglyce rides mmol/L 0.52 0.57 0.47 0.52 0.65 Albumin g/L 24 26 25 24 25 Globulin g/L 28 27 26 27 26 Alb/Glob Ratio 0.86 0.96 0.96 0.89 0.96 Total Biliru. umol/L 4.3 5.1 5.0 4.6 - --4- -.9-- * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 303 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 138 141 140 143 141 Potas sium mmol/L 5.69 5.63 6.12 5.73 4.93 Calcium mmol/L 2.29 2.42 2.31 2.48 2.56 Chloride mmol/L 104 106 108 108 105 Phos phorus mmol/L 3.15 2.96 2.96 2.82 3.91 Glucose mmol/L 16.1 18.0 16.2 11.3 14.0 Uric Acid umol/L 57 60 65 51 65 Creati nine umol/L 54 50 49 46 49 Urea Nitrogen mmol/L 5.7 5.3 4.8 4.0 5.3 ALAT IU/L 45 41 46 38 44 ASAT IU/L 134 128 141 101 85 * = result to left has an associated comment or marker Nom ina Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 304 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 312 275 370 209 367 G-Gluta. Transf. IU/L 4 4 4 4 4 (continued) Total Protein g/L Cho le sterol mmol/L 54 2.4 55 2.1 52 2.2 57 2.5 59 2.6 Triglyce rides mmol/L 0.34 0.37 0.34 0.39 0.54 Albumin g/L 26 26 26 28 29 Globulin g/L 28 29 26 29 30 Alb/Glob Ratio 0.93 0.90 1.00 0.97 0.97 Total Biliru. umol/L 5.3 4.6 5.8 5.6 - --5- -.1-- * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 305 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 140 141 139 139 142 Potas sium mmol/L 5.45 4.97 5.03 4.95 5.05 Calcium mmol/L 2.47 2.48 2.34 2.47 2.50 Chloride mmol/L 103 102 103 102 102 Phos phorus mmol/L 2.80 2.97 2.82 2.65 2.07 Glucose mmol/L 13.9 14.5 14.2 17.0 19.0 Uric Acid umol/L 57 34 31 27 16 Creati nine umol/L 46 46 48 52 40 Urea Nitrogen mmol/L 6.2 5.7 4.2 5.6 6.0 ALAT IU/L 34 45 41 47 35 ASAT IU/L 79 78 90 88 55 * = result to left has an associated comment or marker Nom ina Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 306 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 428 442 484 416 468 G-Gluta. Transf. IU/L 4 4 4 4 4 (continued) Total Protein g/L Cho le sterol mmol/L 54 2.2 57 2.1 53 2.1 57 2.4 56 2.1 Triglyce rides mmol/L 0.60 0.60 0.50 0.47 0.84 Albumin g/L 28 27 27 28 28 Globulin g/L 26 30 26 29 28 Alb/Glob Ratio 1.08 0.90 1.04 0.97 1.00 Total Biliru. umol/L 5.1 5.2 4.7 5.0 - --5- -.1-- * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 307 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 29 29 29 29 - - 2--9 Sod ium mmol/L 141 140 142 140 143 Potas sium mmol/L 5.35 5.25 5.13 5.22 5.00 Calcium mmol/L 2.36 2.45 2.48 2.40 2.39 Chloride mmol/L 107 104 105 107 108 Phos phorus mmol/L 2.64 2.64 2.68 2.77 2.07 Glucose mmol/L 13.9 11.8 12.7 17.0 15.2 Uric Acid umol/L 67 91 72 40 40 Creati nine umol/L 52 58 50 45 50 Urea Nitrogen mmol/L 5.3 5.6 6.0 4.1 4.8 ALAT IU/L 40 45 46 36 46 ASAT IU/L 114 127 123 83 119 * = result to left has an associated comment or marker Nom ina Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 308 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02 0222 /1 - T-7758 - 4 weeks oral toxicity in rats 8 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 29 29 29 29 - - 2--9 Alk.Phos phatase IU/L 227 486 283 260 382 G-Gluta. Transf. IU/L 4 4 4 4 4 (continued) Total Protein g/L Cho le sterol mmol/L 57 2.1 60 2.4 59 2.1 58 2.6 59 2.2 Triglyce rides mmol/L 0.30 0.36 0.33 0.40 0.48 Albumin g/L 28 30 30 28 28 Globulin g/L 29 30 29 30 31 Alb/Glob Ratio 0.97 1.00 1.03 0.93 0.90 Total Biliru. umol/L 6.5 5.6 5.0 4.5 - --4- -.6-- * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 309 Toxicology Study Report - PT02-0222 13.1.3.3 Urinalysis (including legend) Page 310 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex Animal Number Day Number Appear ence 1m 1 23 CLEAR 2 23 CLEAR 3 23 CLEAR 4 23 CLEAR 5 23 CLOUDY 6 41 CLEAR 7 41 CLEAR 8 41 CLOUDY 9 41 CLEAR 10 41 CLEAR Urine Color DK YELL DK YELL YELLOW YELLOW DK YELL YELLOW DK YELL DK YELL YELLOW YELLOW pH Volume Value mL 3.0 6.5 1.8 6.5 3.2 6.5 4.5 7.0 1.9 6.5 7.6 7.5 1.7 6.5 1.3 6.5 9.8 7.5 3.9 7.0 Specific Weight g/L 1061 1068 1056 1036 1072 1031 1069 1071 1029 1047 Protein (Album.) 3+ 2+ 2+ 1+ 2+ 1+ 3+ 4+ 2+ 1+ Bill rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobll i nogen Ketone Bodies TRACE TRACE TRACE NEGATIV TRACE NEGATIV TRACE TRACE NEGATIV NEGATIV 1+ 1+ 1+ TRACE 1+ TRACE 1+ 2+ 1+ 1+ Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 311 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex Animal Number Day Number Appear ence 1f 31 23 CLEAR Uri ne Col or DK YELL pH Volume Value mL 2.1 6.0 Specific Weight g/L 1054 Prote in (Album.) 1+ Bill rub ln NEGATIV Urobll i nogen Ketone Bodles TRACE TRACE Glucose NEGATIV Blood (RBCs) NEGATIV 32 23 CLEAR YELLOW 3.5 7.5 1034 1+ NEGATIV TRACE TRACE NEGATIV NEGATIV 33 23 * * 1.2 * * * * * * * 34 23 CLEAR YELLOW 3.9 6.5 1034 1+ NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 35 23 CLEAR YELLOW 5.0 6.5 1034 TRACE NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 36 41 CLEAR YELLOW 5.0 7.0 1031 NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 37 41 CLEAR YELLOW 5.2 7.0 1036 1+ NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 38 41 CLEAR YELLOW 2.9 6.5 1048 NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 39 41 CLEAR YELLOW 8.0 7.0 1027 1+ NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 40 41 CLEAR YELLOW 8.2 7.5 1024 TRACE NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 312 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex Animal Number Day Number Appear ence 2m 11 23 CLEAR 12 23 CLOUDY 13 23 CLEAR 14 23 CLOUDY - - 2--3 15 CLEAR Urine Col or DK YELL DK YELL DK YELL DK YELL DK YELL pH Volume Value mL 1.8 6.0 2.2 6.5 3.5 6.5 1.9 6.5 3.3 6.5 Specific Weight 1079 1065 1053 1053 1054 Protein (Album.) 2+ 2+ 3+ 2+ -1 -+ ------ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies TRACE TRACE TRACE TRACE TRACE TRACE 1+ 1+ 1+ TRACE Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 313 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex Animal Number Day Number Appear ence 2f 41 23 CLEAR 42 23 CLEAR 43 23 CLEAR 44 23 CLEAR - - 2--3 45 CLEAR Urine Col or YELLOW YELLOW YELLOW YELLOW YELLOW pH Volume Value mL 5.0 7.0 4.8 6.5 4.3 7.0 4.7 6.5 5.0 --7.-0-- Specific Weight g/L 1027 1041 1024 1038 1055 Protein (Album.) 1+ 1+ TRACE 1+ -1 -+ ------ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobili nogen NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Ketone Bodies TRACE TRACE TRACE TRACE TRACE Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 314 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex Animal Number Day Number Appear ence 3m 16 23 CLEAR 17 23 CLOUDY 18 23 CLEAR 19 23 CLEAR - - 2--3 20 CLOUDY Urine Col or YELLOW YELLOW DK YELL YELLOW DK YELL pH Volume Value mL 2.9 6.0 4.5 6.0 3.4 6.5 6.2 6.0 3.0 6.0 Specific Weight g/L 1051 1044 1058 1042 1007 Protein (Album.) 2+ 1+ 2+ 1+ 2+ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies TRACE TRACE TRACE NEGATIV TRACE TRACE 1+ 1+ 1+ TRACE Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 315 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex Animal Number Day Number Appear ence 3f 46 23 CLEAR 47 23 CLEAR 48 23 CLOUDY 49 23 CLEAR - - 2--3 50 CLOUDY Urine Col or YELLOW YELLOW DK YELL DK YELL DK YELL pH Volume Value mL 4.6 7.0 5.3 6.5 2.8 6.5 3.0 8.0 2.6 6.0 Specific Weight g/L 1035 1036 1039 1036 1000 Protein (Album.) 2+ 1+ 1+ 1+ 2+ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 1+ 1+ 1+ 1+ 1+ Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 316 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex Animal Number Day Number Appear ence 4m 21 23 CLEAR Uri ne Col or YELLOW pH Volume Value mL 5.7 7.0 Specific Weight g/L 1029 Protein (Album.) 1+ Bili rubin NEGATIV Urobil i nogen Ketone Bodies NEGATIV 1+ Glucose NEGATIV Blood (RBCs) NEGATIV 22 23 CLOUDY YELLOW 5.1 6.0 1039 1+ NEGATIV TRACE 1+ NEGATIV NEGATIV 23 23 CLOUDY YELLOW 7.1 6.5 1028 1+ NEGATIV NEGATIV 1+ NEGATIV NEGATIV 24 23 CLEAR DK YELL 4.9 6.5 1044 1+ NEGATIV TRACE 1+ NEGATIV NEGATIV 25 23 CLEAR YELLOW 3.8 6.5 1048 1+ NEGATIV TRACE 1+ NEGATIV NEGATIV 26 41 CLEAR YELLOW 7.8 7.5 1022 1+ NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 27 41 CLEAR DK YELL 3.0 7.5 1058 1+ NEGATIV TRACE TRACE NEGATIV NEGATIV 28 41 * * 1.1 * * * * * * * 29 41 CLEAR YELLOW 4.8 7.5 1044 TRACE NEGATIV NEGATIV TRACE NEGATIV NEGATIV 30 41 CLEAR YELLOW 2.4 6.0 1066 NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 317 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 8 Group Sex Animal Number Day Number Appear ence 4f 51 23 CLEAR 52 23 TURBID 53 23 CLOUDY 54 23 CLEAR 55 23 CLEAR 56 41 CLEAR 57 41 CLEAR 58 41 CLEAR 59 41 CLEAR 60 41 CLEAR Uri ne Col or DK YELL DK YELL YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW YELLOW pH Volume Value mL 4.4 6.0 3.7 6.0 4.9 6.0 12.5 6.0 5.4 6.0 8.4 6.5 4.5 6.5 3.7 7.0 2.3 6.0 4.8 7.0 Specific Weight g/L 1044 1045 1035 1013 1034 1028 1039 1035 1053 1048 Protein (Album.) 1+ 1+ TRACE NEGATIV TRACE 1+ TRACE 1+ 2+ 1+ Bill rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobll i nogen Ketone Bodles TRACE NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV 1+ 1+ 2+ 1+ 1+ NEGATIV NEGATIV NEGATIV NEGATIV TRACE Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV 2+ NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 318 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 9 Group Sex Animal Number Day Number Appear ence 5m 61 26 CLEAR 62 26 CLEAR 63 26 CLEAR 64 26 CLEAR - - 2--6 65 CLOUDY Urine Col or DK YELL DK YELL DK YELL DK YELL DK YELL pH Volume Value mL 3.1 6.5 1.5 6.0 2.6 6.5 3.2 6.0 4.1 6.5 Specific Weight g/L 1064 1075 1055 1069 1055 Protein (Album.) 2+ 2+ 2+ 2+ 1+ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies TRACE TRACE TRACE TRACE TRACE TRACE TRACE 1+ TRACE 1+ Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 319 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 10 Group Sex Animal Number Day Number Appear ence 5f 66 26 CLEAR 67 26 CLEAR 68 26 CLEAR 69 26 CLEAR - - 2--6 70 CLEAR Urine Col or YELLOW YELLOW YELLOW YELLOW YELLOW pH Volume Value mL 2.7 6.5 3.0 6.5 3.4 6.5 4.2 6.5 2.0 --7.-0-- Specific Weight g/L 1057 1042 1043 1035 1057 Protein (Album.) 2+ 1+ 1+ 1+ -1 -+ ------ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies TRACE NEGATIV NEGATIV NEGATIV TRACE TRACE NEGATIV TRACE TRACE TRACE Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 320 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Genera ised Results By Anima - Animals Against Parameters Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 11 Comments and Markers Group Animal Day Sex Number Number Measurement Marker Comment 1f 33 4m 28 23 Appearence of Urine Urine Color pH Value (sq) Specific Weight Protein (Albumine)(sq) Bilirubin (sq) Urobilinogen (sq) Ketone Bodies (sq) Glucose (sq) Blood (RBCs)(sq) 41 Appearence of Urine Urine Color pH Value (sq) Specific Weight Protein (Albumine)(sq) Bilirubin (sq) Urobilinogen (sq) Ketone Bodies (sq) Glucose (sq) Blood (RBCs)(sq) Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal Sampl e too smal - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined - not examined Marker E implies value excluded from means Page 321 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex Animal Number Day Number Appear ence 6m 71 24 CLOUDY 72 24 CLEAR 73 24 CLEAR 74 24 CLEAR - - 2--4 75 CLEAR Urine Col or YELLOW YELLOW YELLOW YELLOW YELLOW pH Volume Value mL 3.0 6.0 4.7 6.5 3.3 6.5 3.0 6.5 4.5 6.5 Specific Weight g/L 1052 1039 1040 1051 1055 Protein (Album.) 4+ 1+ 3+ 4+ 1+ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies TRACE NEGATIV NEGATIV TRACE NEGATIV TRACE TRACE TRACE TRACE 1+ Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) TRACE NEGATIV NEGATIV NEGATIV NEGATIV * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 322 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex Animal Number Day Number Appear ence 6f 81 24 CLEAR 82 24 CLEAR 83 24 CLEAR 84 24 CLEAR - - 2--4 85 CLEAR Urine Col or YELLOW YELLOW YELLOW YELLOW YELLOW pH Volume Value mL 3.8 6.0 3.1 6.0 1.9 6.0 4.9 7.0 6.4 6.5 Specific Weight g/L 1037 1046 1049 1029 1055 Prote in (Album.) 1+ 1+ 1+ TRACE NEGATIV Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV TRACE NEGATIV NEGATIV Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 323 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats* 3 Group Sex Animal Number Day Number Appear ence 7m 76 24 CLEAR 77 24 CLEAR 78 24 CLOUDY 79 24 CLEAR - - 2--4 80 CLEAR Uri ne Color YELLOW YELLOW DK YELL YELLOW YELLOW pH Volume Value mL 7.1 6.5 4.8 6.0 2.4 6.5 7.2 6.5 8.0 6.0 Specific Weight g/L 1028 1038 1055 1027 1000 Protein (Album.) 1+ 1+ 2+ 2+ 1+ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies NEGATIV NEGATIV TRACE NEGATIV NEGATIV TRACE TRACE 1+ TRACE TRACE Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 324 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex Animal Number Day Number Appear ence 7f 86 24 CLEAR 87 24 CLEAR 88 24 CLEAR 89 24 CLEAR - - 2--4 90 CLEAR Urine Col or YELLOW YELLOW YELLOW YELLOW YELLOW pH Volume Value mL 3.7 6.5 3.8 6.0 3.3 6.0 4.4 6.5 4.4 6.0 Specific Weight g/L 1034 1036 1046 1029 1038 Prote in (Album.) TRACE 1+ 1+ TRACE 1+ Bili rubin NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Urobil i nogen Ketone Bodies NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Glucose NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV Blood (RBCs) NEGATIV NEGATIV NEGATIV NEGATIV NEGATIV * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 325 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats* 1 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 23 23 23 23 23 41 41 41 41 41 Erythro cytes 1-5 Leuco cytes 1-5 1-5 1-5 1-5 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Other Ep.CelIs Triple Phosphat x x x x x x x x x x Calcium Oxalate Sperms several several several several several several several Bacteria several several several several several several several several several several Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 326 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan 2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 23 23 23 23 23 41 41 41 41 41 Erythro cytes Leuco cytes 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Other Ep.CelIs Triple Phosphat x x x x x x x x x x Calcium Oxalate Sperms Bacteria several several several several several several several several several several Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 327 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 30 Day Number 23 23 23 23 23 41 41 41 41 41 Erythro cytes Leuco cytes 1-5 1-5 1-5 1-5 6-10 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Other Ep.CelIs <5 grn <5 grn Triple Phosphat x x x x x x Calcium Oxalate x Sperms several several several several several several several Bacteria several several several several several several several several several numers. Nominal Dose: Group 1 * = result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 328 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 23 23 23 23 23 41 41 41 41 41 Erythro cytes 31-50 Leuco cytes 6-10 1-5 1-5 1-5 1-5 1-5 1-5 6-10 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 1-5 Other Ep.Cells Triple Phosphat x x x x x x Calcium Oxalate Sperms Bacteria several numers. several several several several several several several several * = result to left has an ,associated comment or marker Nomi nal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mig/kg Group 5 - 3 mg/kg Page 329 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 -5 Day Number 24 24 24 24 25 Erythro cytes 6-10 1-5 Leuco cytes 1-5 1-5 1-5 1-5 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 Triple Phosphat x x x x x Calcium Oxalate Sperms several several several several Bacteri a several several several several several * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 330 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 24 24 24 24 88 Erythro cytes Leuco cytes 1-5 1-5 1-5 1-5 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 Triple Phosphat x x x x Calcium Oxalate Sperms Bacteri a several several several several several * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 331 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 24 24 24 24 88 Erythro cytes Leuco cytes 1-5 1-5 1-5 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 Triple Phosphat x x x x x Calcium Oxalate Sperms several several several several several Bacteri a several several several several several * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 332 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats* 4 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 24 24 24 24 99 Erythro cytes Leuco cytes 1-5 1-5 1-5 Squamous E.Cells 1-5 1-5 1-5 1-5 1-5 Triple Phosphat x x x x Calcium Oxalate x Sperms Bacteria several several several several several * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 333 Toxicology Study Report - PT02-0222 E X P L A N A T I O N OF U R I N A L Y S I S S Y M B O L S Semiquantitative Parameters Protein (Albumin) NEGATIVE TRACE 1+ 2+ 3+ 4+ = negative = trace = approx. 0.3 g/L = approx. 1.0 g/L = approx. 3.0 g/L >= 10.0 g/L Blood (Erythrocytes) NEGATIVE TRACE 1+ 2+ 3+ = negative = trace = small = moderate = large Glucose NEGATIVE TRACE 1+ 2+ 3+ = approx. 5.5 mmol/L = approx. 14.0 mmol/L = approx. 28.0 mmol/L => 55.0 mmol/L Ketone Bodies NEGATIVE TRACE 1+ 2+ 3+ 4+ = negative = trace = 1.5 mmol/L = 3.9 mmol/L = 7.8 mmol/L >= 15.6 mmol/L Bilirubin NEGATIVE 1+ 2+ 3+ = negative = small = moderate = large Urobilinogen NEGATIVE TRACE 1+ 2+ 3+ <= 3 pmol/L = 16 pmol/L = 33 pmol/L = 66 pmol/L >= 131 pmol/L Nitrite NEGATIVE POSITIVE = negative = positive Appearance CLEAR CLOUDY SL CLOUDY TURBID = clear = cloudy = slightly cloudy = turbid Colour AMBER DK YELLOW GREEN ORANGE = amber = Dark yellow = green = orange OTHER RED STRAW YELLOW = other = red = straw = yellow Page 334 Toxicology Study Report - PT02-0222 Erythrocytes Leucocytes per visual field 1- 5 6 - 10 11 - 20 21 - 30 31 - 50 51 - 100 > 100 per visual field 1- 5 6 - 10 11 - 20 21 - 30 31 - 50 51 - 100 > 100 TriplePhos Uric Acid Urates Ca Oxalate AmorphSalt Crystals = Triple Phosphate = Uric Acid = Urates = Calcium Oxalate = Amorphous Salt Sperms _____ per visual field_______ several = several numers. = numerous EXPLANATION OF U R I N A L Y S I S Sediment SYMBOLS Squamous Epithelial Cells per visual field 1- 5 6 - 10 11 - 20 21 - 30 31 - 50 > 50 Round Epithelial Cells per visual field 1- 5 6 - 10 11 - 20 21 - 30 31 - 50 > 50 Round Epith. Cells with large Nuclei No. per visual field 1- 5 6 - 10 11 - 20 21 - 30 31 - 50 > 50 < < > < < > Other Epithelial Cells 5 tld 10 tld 10 tld = 1= 6=> No. per visual field 5 tailed epithelial cells 10 tailed epithelial cells 10 tailed epithelial cells 5 grn 10 grn 10 grn = 1= 6=> 5 irregular forms, extreme granulated 10 irregular forms, extreme granulated 10 irregular forms, extreme granulated 2CaPhos 2MgPhos AmmonCl CaSulf HipAcid Hemtdin Leucine Tyrosn Miscellaneous = Dicalcium Phosphate = Dimagnesium Phosphate = Ammonium Chloride = Calcium Sulfate = Hippuric Acid = Hematoidin = Leucine = Tyrosine Cystine Cystein Cholest Carbte CPrecpt YstCell SqEpCCl MucThrd = Cystine = Cystein = Cholesterol = Carbonate = Compound Precipitate = Yeast Cells = Squamous Epithelial Cell Clusters = Mucous-Thread hyaline erythr. leucoc. epithel. granul. waxy cylind. fatty Casts = hyaline = erythrocytic = leucocytic = epithelial = granular = waxy = cylindrous = fatty several numers. Bacteria per visual field = several = numerous Eggs _____ per visual field______ Oxyuris = Oxyuris Trichus = Trichuris Page 335 Toxicology Study Report - PT02-0222 13.1.4 Organ weights Page 336 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 29 29 29 29 29 43 43 43 43 43 Heart Weight g 0.998 0.912 1.005 1.204 0.908 1.231 0.910 1.050 1.581 1.168 L iver Weight g 11.01 10.06 10.97 13.07 11.08 11.68 7.95 9.22 13.65 9.73 Kidneys Weight g 1.927 1.888 1.888 2.495 2.286 2.356 1.896 2.024 2.933 2.307 Adrenals Weight g 0.045 0.046 0.045 0.043 0.049 0.051 0.047 0.038 0.055 0.052 Spleen Weight g 0.682 0.878 0.726 1.040 0.757 0.794 0.727 0.631 0.970 0.740 Thymus Weight g 0.471 0.475 0.439 0.554 0.458 0.481 0.333 0.354 0.441 0.317 Brain Weight g 1.792 1.804 1.725 1.906 1.955 1.958 2.020 1.719 2.089 1.911 Testes Weight g 3.021 2.879 3.217 3.391 3.570 3.605 2.977 3.082 4.019 3.867 Epidi dymis Wt g 0.897 0.707 0.854 0.792 0.871 1.115 1.047 1.032 1.324 1.197 * _ result to left has an associated comment or marker Nomi nal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 - 3 mg/kg Page 337 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 2m Animal Number 11 12 13 14 -5 Day Number 29 29 29 29 55 Heart Weight g 0.857 0.796 0.843 1.034 0.855 L iver Weight g 11.15 9.49 12.30 11.44 11.04 Kidneys Weight g 1.944 2.167 2.124 2.130 2.161 Adrenals Weight g 0.050 0.040 0.041 0.043 0.039 Spleen Weight g 0.565 0.667 0.688 0.708 0.755 Thymus Weight g 0.513 0.424 0.375 0.335 50 5.5359565 Brain Weight g 1.628 1.789 1.709 1.792 515.5815055 Testes Weight g 2.986 3.070 3.572 3.476 53 5.5375 955 Epidi dymis Wt g 0.868 0.784 0.832 0.908 5 505 .5 7535955 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 338 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 29 29 29 29 20 Heart Weight g 0.798 0.902 1.024 1.040 0.900 L iver Weight g 10.93 11.96 13.93 14.54 13.16 Kidneys Weight g 1.822 2.395 2.300 2.456 2.173 Adrenals Weight g 0.051 0.043 0.051 0.047 0.043 Spleen Weight g 0.535 0.672 0.627 0.776 0.522 Thymus Weight g 0.504 0.336 0.407 0.534 0.444 Brain Weight g 1.714 1.746 1.800 1.916 1.622 Testes Weight g 3.235 3.401 3.544 4.025 23 2.20222 Epidi dymis Wt g 0.759 0.768 0.840 0.878 2 202 .28212822 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 339 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 Day Number 29 29 29 29 29 43 43 43 43 Heart Weight g 0.841 0.754 0.903 0.863 0.683 0.893 0.647 0.664 0.828 L iver Weight g 13.98 14.79 13.87 15.84 12.11 6.73 5.16 4.09 7.01 Kidneys Weight g 1.904 1.993 1.980 2.102 1.842 1.791 1.378 1.056 1.758 Adrenals Weight g 0.062 0.054 0.057 0.059 0.047 0.050 0.044 0.040 0.046 Spleen Weight g 0.590 0.596 0.494 0.722 0.513 0.494 0.385 0.275 0.558 Thymus Weight g 0.311 0.305 0.355 0.435 0.324 0.268 0.162 0.056 0.320 Brain Weight g 1.731 1.729 1.724 1.863 1.789 1.898 1.713 1.589 1.720 Testes Weight g 3.479 3.491 3.337 3.541 3.468 2.973 3.215 3.520 3.618 Epidi dymis Wt g 0.829 0.904 0.670 0.758 0.738 1.032 0.784 0.813 1.011 * _ result to left has an associated comment or marker Nomi nal Dose: Group 1 - 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 - 240 mg/kg Group 5 3 mg/kg Page 340 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 29 29 29 29 66 Heart Weight g 1.296 0.997 1.028 1.119 1.255 L iver Weight g 11.86 10.57 9.72 10.19 11.62 Kidneys Weight g 2.141 1.909 1.879 1.992 2.326 Adrenals Weight g 0.040 0.043 0.051 0.041 0.051 Spleen Weight g 0.619 0.805 0.701 0.735 0.956 Thymus Weight g 0.467 0.555 0.482 0.521 0.532 Brain Weight g 1.903 1.835 1.738 1.888 1.866 Testes Weight g 3.611 3.427 3.345 3.242 646.6096 166 Epidi dymis Wt g 0.867 0.777 0.901 0.826 6 606 .69636466 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 341 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 29 29 29 29 29 43 43 43 43 43 Heart Weight g 0.743 0.687 0.831 0.804 0.814 0.741 0.865 0.769 0.811 0.894 Liver Weight g 8.17 7.64 9.20 8.64 8.39 6.19 8.13 7.46 7.56 8.44 K idneys Weight g 1.472 1.307 1.466 1.463 1.596 1.553 1.696 1.521 1.569 1.521 Adrenals Weight g 0.077 0.055 0.060 0.055 0.055 0.070 0.061 0.073 0.056 0.058 Spleen Weight g 0.623 0.669 0.690 0.671 0.592 0.600 0.678 0.581 0.627 0.883 Thymus Weight g 0.300 0.400 0.387 0.437 0.509 0.348 0.328 0.281 0.413 0.380 Brain Weight g 1.846 1.703 1.769 1.812 1.773 1.718 1.887 1.868 1.825 1.889 Nominal Dose: Group 1 * result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 342 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 29 29 29 29 44 Heart Weight g 0.703 0.703 0.872 0.737 0.755 Liver Weight g 8.13 7.97 8.86 8.92 7.45 K idneys Weight g 1.529 1.547 1.556 1.610 1.325 Adrenals Weight g 0.061 0.068 0.053 0.051 0.062 Spleen Weight g 0.734 0.790 0.640 0.712 0.645 Thymus Weight g 0.418 0.363 0.392 0.546 40 4.434434 Brain Weight g 1.719 1.607 1 .777 1.850 41.464 74 744 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 343 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 29 29 29 29 55 Heart Weight g 0.740 0.695 0.695 0.746 0.600 Liver Weight g 9.73 10.65 9.62 8.86 10.06 K idneys Weight g 2.094 2.055 1.857 1.885 1.750 Adrenals Weight g 0.054 0.056 0.061 0.061 0.063 Spleen Weight g 0.652 0.577 0.531 0.535 0.600 Thymus Weight g 0.355 0.357 0.372 0.317 0.301 Brain Weight g 1.760 1.644 1.719 1.664 01.0 60 30 500 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 344 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 29 29 29 29 29 43 43 43 43 43 Heart Weight g 0.743 0.686 0.643 0.632 0.633 0.842 0.664 0.691 0.580 0.772 Liver Weight g 16.47 14.87 12.62 12.74 12.26 7.98 5.46 5.94 5.16 7.97 Ki dneys Weight g 1.713 1.645 1.510 1.845 1.496 1.568 1.264 1.362 1.222 1.646 Adrenals Weight g 0.073 0.063 0.057 0.052 0.053 0.058 0.053 0.060 0.035 0.051 Spleen Weight g 0.495 0.478 0.395 0.450 0.461 0.715 0.514 0.478 0.422 0.558 Thymus Weight g 0.384 0.270 0.323 0.353 0.217 0.409 0.299 0.328 0.235 0.283 Brain Weight g 1.730 1.742 1.559 1.734 1.532 1.869 1.747 1.763 1.691 1.800 Nominal Dose: Group 1 * result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 345 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 5f Animal Number 66 67 68 69 -0 Day Number 29 29 29 29 00 Heart Weight g 0.790 0.795 0.910 0.734 0.910 Liver Weight g 7.77 7.59 6.63 7.26 7.22 K idneys Weight g 1.398 1.271 1.282 1.246 1.321 Adrenals Weight g 0.055 0.054 0.054 0.051 0.060 Spleen Weight g 0.600 0.632 0.589 0.616 0.722 Thymus Weight g 0.483 0.392 0.380 0.403 0.325 Brain Weight g 1.659 1.687 1.843 1.602 1.222 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 - 3 mg/kg Page 346 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 -5 Day Number 29 29 29 29 29 Heart Weight g 1.248 1.340 0.826 1.219 1.222 L iver Weight g 13.38 13.01 10.04 12.25 12.43 Kidneys Weight g 2.439 2.670 2.089 2.432 2.427 Adrenals Weight g 0.054 0.052 0.039 0.056 0.055 Spleen Weight g 0.772 0.845 0.648 0.880 0.822 Thymus Weight g 0.586 0.528 0.445 0.758 0.535 Brain Weight g 1.890 1.904 1.792 1.839 1.922 Testes Weight g 3.899 3.619 3.406 3.620 23 2.2442822 Epidi dymis Wt g 0.951 0.903 0.857 0.920 2.222 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 347 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 29 29 29 29 88 Heart Weight g 1.096 1.258 1.083 1.149 1.388 L iver Weight g 11.88 13.67 9.25 12.08 81838.89898 Kidneys Weight g 2.236 2.888 2.080 2.320 882 8.86 82 878 Adrenals Weight g 0.047 0.056 0.045 0.039 8880 8.80 84868 Spleen Weight g 0.798 0.848 0.737 0.770 80 8.858988 Thymus Weight g 0.702 0.486 0.456 0.604 80 8.8687828 Brain Weight g 1.803 1.897 1.869 1.919 828.8018 188 Testes Weight g 3.393 3.826 3.349 3.382 83 8.8948 488 Epidi dymis Wt g 0.788 0.868 0.837 0.835 8 808 .898 18088 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 348 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 29 29 29 29 88 Heart Weight g 0.736 0.712 0.727 0.836 80 8.87888 Liver Weight g 7.05 6.87 6.02 6.99 7.81 K idneys Weight g 1.393 1.353 1.209 1.316 881 8.83 8788 Adrenals Weight g 0.049 0.066 0.048 0.063 8880 8.80 86848 Spleen Weight g 0.708 0.608 0.576 0.551 80 8.8628488 Thymus Weight g 0.350 0.309 0.259 0.244 80 8.8458808 Brain Weight g 1.625 1.740 1.588 1.784 81.8 8 68 388 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 349 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 29 29 29 29 99 Heart Weight g 0.709 0.830 0.824 0.733 90 9.9869 799 Liver Weight g 6.28 6.98 7.66 7.60 998 9.8998 9 K idneys Weight g 1.213 1.440 1.475 1.426 991 9.95 92999 Adrenals Weight g 0.045 0.063 0.061 0.052 9990 9.90 95969 Spleen Weight g 0.571 0.675 0.658 0.733 90 9.9759699 Thymus Weight g 0.339 0.509 0.313 0.401 90 9.9349929 Brain Weight g 1.641 1.812 1.875 1.763 91.9 69 9 399 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 350 Toxicology Study Report - PT02-0222 13.1.5 Neurotoxicological examinations 13.1.5.1 Grip strengh Page 351 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 1m Animal Number 1 2 3 4 5 6 7 8 9 10 Day Number 26 26 26 26 26 26 26 26 26 26 Str. of F.limbsl g 900 700 740 800 800 800 780 780 800 800 Str. of F.limbs2 g 840 800 800 840 820 800 800 760 900 880 Str. of H.limbsl g 350 300 320 300 270 320 300 280 300 290 Str. of H.limbs2 g 310 280 280 300 290 300 260 290 320 300 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 352 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 1f Animal Number 31 32 33 34 35 36 37 38 39 40 Day Number 22 22 22 22 22 22 22 22 22 22 Str. of F.limbsl g 740 800 700 700 800 800 800 720 700 800 Str. of F.limbs2 g 680 820 720 660 800 820 820 740 760 800 Str. of H.limbsl g 300 290 270 260 280 290 250 270 300 270 Str. of H.limbs2 g 280 270 270 280 270 270 270 290 300 300 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 353 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 2m Animal Number 11 12 13 14 15 Day Number 26 26 26 26 55 Str. of F.limbs1 g 800 700 800 800 800 Str. of F.limbs2 g 780 800 860 840 700 Str. of H.limbs1 g 280 300 260 260 280 Str. of H.limbs2 g 300 300 270 280 550 Nominal Dose: Group 1 0 mg/kg * ^ result to left has an associated comment or marker Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 354 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 2f Animal Number 41 42 43 44 45 Day Number 22 22 22 22 44 Str. of F.limbsl g 640 780 700 700 640 Str. of F.limbs2 g 640 760 680 720 680 Str. of H.limbsl g 260 280 290 240 250 Str. of H.limbs2 g 240 250 270 240 455 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 355 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 5 Group Sex 3m Animal Number 16 17 18 19 20 Day Number 26 26 26 26 22 Str. of F.limbs1 g 800 600 700 640 800 Str. of F.limbs2 g 760 700 780 680 800 Str. of H.limbs1 g 290 300 260 280 300 Str. of H.limbs2 g 300 250 300 290 200 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 356 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 6 Group Sex 3f Animal Number 46 47 48 49 50 Day Number 22 22 22 22 55 Str. of F.limbsl g 600 600 760 800 555 57050555 Str. of F.limbs2 g 680 700 720 800 700 Str. of H.limbsl g 280 270 260 260 270 Str. of H.limbs2 g 300 290 270 280 550 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 357 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 7 Group Sex 4m Animal Number 21 22 23 24 25 26 27 28 29 30 Day Number 26 26 26 26 26 26 26 26 26 26 Str. of F.limbsl g 700 600 620 700 780 740 600 620 620 700 Str. of F.limbs2 g 680 680 700 800 700 800 660 680 680 600 Str. of H.limbsl g 240 240 250 250 280 270 260 240 240 220 Str. of H.limbs2 g 250 260 260 270 270 250 250 240 270 250 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 358 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 8 Group Sex 4f Animal Number 51 52 53 54 55 56 57 58 59 60 Day Number 22 22 22 22 22 22 22 22 22 22 Str. of F.limbsl g 620 600 680 640 600 780 740 700 600 740 Str. of F.limbs2 g 700 700 600 700 640 780 780 740 600 780 Str. of H.limbsl g 240 270 200 220 230 270 240 260 250 200 Str. of H.limbs2 g 210 240 220 240 210 240 210 250 230 190 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 359 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 9 Group Sex 5m Animal Number 61 62 63 64 65 Day Number 23 23 23 23 66 Str. of F.limbsl g 800 680 700 780 666 67060666 Str. of F.limbs2 g 820 720 680 820 800 Str. of H.limbsl g 300 240 280 270 290 Str. of H.limbs2 g 320 250 280 300 655 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 360 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats 10 Group Sex 5f Animal Number 66 67 68 69 70 Day Number 23 23 23 23 23 Str. of F.limbsl g 660 700 700 680 720 Str. of F.limbs2 g 720 680 700 740 780 Str. of H.limbsl g 250 230 250 240 290 Str. of H.limbs2 g 270 260 260 280 250 Nominal Dose: Group 1 * ^ result to left has an associated comment or marker 0 mg/kg Group 2 - 15 mg/kg Group 3 - 60 mg/kg Group 4 240 mg/kg Group 5 3 mg/kg Page 361 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 1 Group Sex 6m Animal Number 71 72 73 74 75 Day Number 22 22 22 22 77 Str. of F.limbsl g 760 800 800 780 800 Str. of F.limbs2 g 800 800 840 800 780 Str. of H.limbsl g 270 290 280 300 300 Str. of H.limbs2 g 310 280 300 290 755 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 362 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 2 Group Sex 6f Animal Number 81 82 83 84 85 Day Number 22 22 22 22 88 Str. of F.limbsl g 720 800 800 720 888 87080888 Str. of F.limbs2 g 760 820 820 760 800 Str. of H.limbsl g 270 260 280 260 300 Str. of H.limbs2 g 280 300 300 290 855 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 363 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 3 Group Sex 7m Animal Number 76 77 78 79 80 Day Number 22 22 22 22 88 Str. of F.limbsl g 760 780 780 860 800 Str. of F.limbs2 g 820 820 780 800 840 Str. of H.limbsl g 310 300 270 250 290 Str. of H.limbs2 g 280 290 280 290 800 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 364 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats 4 Group Sex 7f Animal Number 86 87 88 89 90 Day Number 22 22 22 22 99 Str. of F.limbsl g 660 780 700 680 780 Str. of F.limbs2 g 700 800 800 780 720 Str. of H.limbsl g 280 250 270 250 300 Str. of H.limbs2 g 250 270 300 250 900 * = result to left has an associated comment or marker Nominal Dose: Group 6 - 0 mg/kg/d Group 7 - 0.3 mg/kg/d Page 365 Toxicology Study Report - PT02-0222 13.1.5.2 Motor activity (movements per 60 minutes) Page 366 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RON DATE: 2B-HAY-2003 SUMMARY AMD STATISTICAL EVALUATION STUDY t PT02-0222 - T-7758 - 4 weeJco oral toxicity in rato MOTOR ACTIVITY/INDIVIDUAL VALUES (NUMBER OF COUNTS PER SO-MINUTE-SESSION) ------------------------ MEASUREMENT-1 GROUP-1 S E X - F --------------------- - ANIMAL VALUE 31 405 32 477 33 406 34 679 35 451 36 648 37 169 38 751 39 607 40 729 ................... ..... MEASUREMENT-1 GROUP-1 S E X - M .................... ... ANIMAL VALUE 1 604 2 453 3 370 4 638 5 609 6 728 7 372 8 629 9 414 10 661 ------------------------ MEASUREMENT-1 GROUP-2 S E X - F ......... -............. ANIMAL VALUE 66 621 67 561 68 684 69 769 70 632 GROUP-2 S E X - M .......... ...... ....... ANIMAL VALUE 61 581 62 6S7 63 501 64 432 65 767 ........... .............MEASUREMENT-1 GROUP-3 S E X - F .......... ...... ....... ANIMAL VALUE 41 496 42 672 43 669 44 523 45 536 Page 367 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTXS RUN DATE: 28-MAY-20Q3 SUMMARY AMD STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats MOTOR ACTIVITY/INDIVIDUAL VALUES {NUMBER OF COUNTS PER 6 0 -MINUTE-SESSION) ...... MEASUREMENT-1 GROUP-3 SBX-H ----- ANIMAL VALUE 11 480 12 649 13 520 14 448 15 595 MEASUREMENT-1 GROUP-4 S E X - F ............ .... ....... ANIMAL VALUE 46 509 47 4?4 48 594 49 519 50 646 MEASUREMENT-1 GROUP-4 SSX-M ANIMAL VALUE 16 441 17 558 18 706 19 587 20 643 MEASUREMENT-1 GROUP-5 SKX-F ANIMAL VALUE 51 527 52 414 53 432 54 632 55 487 56 418 57 590 58 686 59 372 60 530 ........... ............ MEASUREMENT-1 GROUP-5 SKX-M ANIMAL VALUE 21 314 22 545 23 632 24 481 25 420 26 777 27 561 28 644 29 553 30 410 Page 368 Toxicology Study Report - PT02-0222 Page 369 Toxicology Study Report - PT02-0222 13.2 ADDITIONAL DATA 13.2.1 Composition of diet Page 370 Toxicology Study Report - PT02-0222 SSNIFF R/M-H: SOLE DIET FOR RATS AND MICE - Ingredients [average % content in the diet] Crude protein Crude fat Crude fiber Ash 19.00 3.00 5.20 6.70 Calcium Phosphorous Sodium Magnesium Potassium 1.10 0.80 0.25 0.20 1.00 Amino Acids [average % content in the diet] Lysine Methionine Cystine Glycine Leucine Isoleucine Arginine Phenylalanine Tryptophane Histidine Alanine Tyrosine Asparagine acid Glutamine acide Valine Page 371 MAINTENANCE 1.00 0.30 0.25 0.90 1.50 0.90 1.20 0.90 0.25 0.45 0.70 0.60 1.40 2.20 0.90 Vitamins [per kg diet] Vitamin A Vitamin D2 Vitamin E Vitamin C Vitamin B1 Vitamin B2 Vitamin B6 Vitamin B12 Biotin Pantothenic acid Choline Folic acid Nicotic acid Vitamin K3 Inosit 10 000 IU 1 280 IU 120 mg 500 mg 15 mg 25 mg 12 mg 50 (Jg 200 |jg 40 mg 1 600 mg 4 mg 100 mg 5 mg 50 mg Trace elements [per kg diet] Managanese Copper Zinc Iodine Iron Fluorine Metabolizable energy [per kg diet] ME 75.0 mg 12.0 mg 70.0 mg 1.5 mg 220.0 mg 10.0 mg 12.1 MJ Toxicology Study Report - PT02-0222 13.2.2 Historical control data Page 372 Toxicology Study Report - PT02-0222 Species: Rat S tra in : Hsd:SD Male animals ( Age: 10 - 16 weeks) Version from 26-Nov-2002 Parameter Unity Min Max Mean Red blood cell count Hemoglobin Hematocrit MCV MCH MCHC Reticulocytes Heinz Bodies White blood cell count Platelets Coagulation Time 1 0 12/l g /l 10-15 l 10-12 g g /l 109/l 109/l Seconds 7,44 145 0,43 55 18 307 0,007 0 9 783 99 8,27 160 0,5 63 20 354 0,045 0 12,7 1121 151 7,84 152,59 0,46 58,47 19,47 333,97 0,03 0,00 10,53 957,97 128,42 Sodium Potassium Calcium Chloride Phosphorus Total Bili rubin Direct Bilirubin Glucose Uric Acid Creatinine Urea Nitrogen Cholesterol Triglyceri des Total Protein Albumin ASAT ALAT G-Gluta.Transf. Alkaline Phosphatase mmol/l mmol/l mmol/l mmol/l mmol/l umol/l umol/l mmol/l umol/l umol/l mmol/l mmol/l mmol/l g /l g /l lU/l lU/l lU/l lU/l 135 4,55 2,27 99 2,53 2,4 0 9,24 35 37 3,54 1,57 0,48 49 21,8 42 30 2 294 144 7,17 2,51 104 3,6 10,6 1,4 23,66 146 67 7,74 2,5 1,08 59 29,4 131 82 4 471 140,16 5,57 2,40 101,09 2,89 4,87 0,14 15,14 65,29 51,28 6,21 2,06 0,79 53,69 25,60 90,34 41,09 3,00 354,47 Volume pH Value Specific Weight ml g /l 1,6 6 1027 6,9 8 1076 4,56 7,12 1041,39 Body weight Heart Weight Liver Weight Kidneys We ight Spleen Weight Testes Weight Epididymis Weight Adrenals Weight Brain Weight Thymus Wei ght Lung Weight Thyroid Gland Weight Pituitary Gland Weight g g g g g g g g g g g g g g/ k g 249 0,937 9,336 1,764 0,594 2,972 0,735 0,0334 1,676 0,404 1,195 0,0127 0,0068 309,2 1,141 12,125 2,329 0,857 3,631 0,906 0,5 1,897 0,553 1,725 0,016 0,0096 278,57 1,03 11,00 2,04 0,72 3,35 0,85 0,05 1,81 0,46 1,48 0,01 0,01 Heart Weight Liver Weight Kidneys We ight Spleen Weight Testes Weight Epididymis Weight Adrenals Weight Brain Weight Thymus Wei ght Lung Weight Thyroid Gland Weight Pituitary Gland Weight 3,371 35,964 6,437 2,294 10,923 2,832 0,1225 6,07 1,432 4,334 0,042 0,025 4,104 43,486 8,464 3,074 13,077 3,466 0,1845 7,121 1,985 5,928 0,0542 0,033 3,71 39,44 7,31 2,60 12,06 3,10 0,15 6,53 1,66 5,17 0,05 0,03 SD 0,22 3,57 0,02 1,68 0,57 10,16 0,01 0,00 1,05 78,29 13,79 2,03 0,48 0,06 1,17 0,21 2,32 0,35 2,58 21,39 7,34 0,82 0,19 0,14 2,32 2,08 24,07 10,49 0,82 43,64 1,45 0,52 12,18 14,45 0,05 0,77 0,17 0,06 0,14 0,05 0,08 0,05 0,04 0,17 0,00 0,00 0,20 1,84 0,49 0,19 0,56 0,19 0,01 0,29 0,15 0,49 0,00 0,00 Number of studies 32 32 32 32 32 32 32 29 32 31 31 32 32 32 32 32 32 30 32 31 32 32 32 32 32 23 32 32 22 32 23 31 23 32 32 32 32 32 32 22 32 32 23 9 10 10 32 32 32 32 32 22 32 32 23 9 10 10 Page 373 Toxicology Study Report - PT02-0222 Species: Rat S tra in : Hsd:SD Female animals ( Age: 10 - 16 weeks) Version from 26-Nov-2002 Parameter Unity Min Max Mean Red blood cell count Hemoglobin Hematocrit MCV MCH MCHC Reticulocytes Heinz Bodies White blood cell count Platelets Coagulation Time 1 0 12/l g /l 10-15 l 10-12 g g /l 109/l 109/l Seconds 6,96 132,00 0,40 55,00 18,00 320,00 0,01 0,00 5,30 818,00 107,00 8,03 154,00 0,46 61,00 21,00 358,00 0,08 0,00 11,40 1187,00 171,00 7,43 143,88 0,43 57,19 19,50 339,09 0,03 0,00 8,06 990,81 127,03 Sodium Potassium Calcium Chloride Phosphorus Total Bili rubin Direct Bilirubin Glucose Uric Acid Creatinine Urea Nitrogen Cholesterol Triglyceri des Total Protein Albumin ASAT ALAT G-Gluta.Transf. Alkaline Phosphatase mmol/l mmol/l mmol/l mmol/l mmol/l umol/l umol/l mmol/l umol/l umol/l mmol/l mmol/l mmol/l g /l g /l lU/l lU/l lU/l lU/l 137,00 4,32 2,28 101,00 2,31 2,10 0,00 7,70 56,00 38,00 4,80 1,63 0,40 48,00 22,20 40,00 27,00 2,00 189,00 144,00 6,60 2,53 107,00 3,46 9,90 1,10 18,04 160,00 73,00 6,76 2,69 1,09 60,00 30,20 133,00 57,00 4,00 380,00 140,50 5,33 2,39 103,38 2,78 5,03 0,15 13,01 78,74 53,13 5,86 2,10 0,60 54,41 27,07 93,28 37,06 3,05 269,75 Volume pH Value Specific Weight ml g /l Body weight Heart Weight Liver Weight Kidneys We ight Spleen Weight Adrenals Weight Brain Weight Thymus Wei ght Ovaries Weight Lung Weight Thyroid Gland Weight Pituitary Gland Weight g g g g g g g g g g g g 1,40 6,00 1024,00 173,60 0,69 6,22 1,23 0,46 0,04 1,60 0,27 0,11 0,95 0,01 0,01 6,40 4,03 8,00 6,85 1054,00 1036,35 210,40 0,91 8,29 1,61 0,70 0,06 1,80 0,43 0,14 1,39 0,11 0,01 197,50 0,78 7,38 1,36 0,62 0,05 1,71 0,34 0,13 1,21 0,02 0,01 g/kg Heart Weight Liver Weight Kidneys We ight Spleen Weight Adrenals Weight Brain Weight Thymus Wei ght Ovaries Weight Lung Weight Thyroid Gland Weight Pituitary Gland Weight 3,45 33,56 6,17 2,41 0,23 8,22 1,36 0,55 4,94 0,06 0,04 4,62 41,09 8,04 3,43 0,31 9,51 2,02 0,73 6,64 0,08 0,06 3,97 37,32 6,89 3,14 0,27 8,71 1,73 0,63 6,01 0,07 0,05 SD 0,26 5,53 0,02 1,67 0,62 9,43 0,01 0,00 1,35 93,59 13,15 1,93 0,49 0,07 1,48 0,27 2,35 0,29 1,94 22,33 7,16 0,50 0,25 0,12 2,73 2,15 23,80 6,22 0,72 42,61 1,23 0,50 8,14 8,74 0,05 0,57 0,10 0,06 0,00 0,06 0,04 0,01 0,13 0,03 0,00 0,24 1,99 0,43 0,23 0,02 0,34 0,15 0,05 0,58 0,01 0,01 Number of studies 32 32 32 32 32 32 32 29 32 31 31 32 32 32 32 32 32 30 32 31 32 32 32 32 32 23 32 32 22 32 23 31 22 32 32 32 32 32 32 30 23 12 9 10 10 32 32 32 32 32 32 23 12 9 10 10 Page 374 Toxicology Study Report - PT02-0222 13.3 REPORTS INCLUDING 13.3.1 Pathology report Page 375 PT0 2 - 0 2 2 2* 376 Patho lo g y R eport Study-No.: PT02-0222 T-7758 prepared by: Dr. Berndt Hein Pathologist SUMMARY PT0 2 0222* 377 Mortality: One recovery high-dose animal was found dead at study day 42. The cause of death was related to treatment with the test article. Necropsy Findings: Group 4 (D3; high dose, 240 mg/kg): K0/K0 animals: D is c o lo u r e d kidneys in three females and all 5 males, one e n la r g e d stomach, two e n la r g e d livers, and one o p a q u e eye. R l/R l animals: S m a ll accessory genital glands (prostate and/ or seminal vesicle) in three animals. Additionally, one male exhibited a s m a ll thymus and e n la r g e d adrenal glands. An irre g u la r su rfa c e could be observed on the kidney of one male as well as one female. R1/+1 animal (died): S m a ll accessory genital glands (prostate and seminal vesicle) in combination with sm a ll testes and epididymides. Group 3 (D2; mid-high dose, 60 mg/kg): K0/K0 animals: D is c o lo u r e d kidneys in four males, and four females, and a d is c o lo u r e d duodenum in one female. Group 2 (Dl; mid dose. 15 mg/kg): K0/K0 animals: D is c o lo u r e d kidneys in three males, and one female. Group 5 (D4; low-mid dose, 3 mg/kg): K0/K0 animals: T ra n sp a re n t m a rg in s in the liver of female animal no. 68. Microscopical Findings: Relevant histopathological findings were seen in the following organs: Liver: H y p e r tro p h y o f h e p a to c y te s in nearly all animals of the high dose group D3 at terminal necropsy. Spleen: L y m p h o c y te d e p le tio n in the animals of the high dose group D3: one male at terminal necropsy, and two male at recovery necropsy. Thymus: A tro p h y in three males of group D3 at recovery necropsy. PT0 2 -022 2* 378 Iliac lymph node: L y m p h o id c e ll d e p le tio n in animal no. 30 (group D3), which died during the recovery. Testes/ Epididymides: A tro p h y in animal no. 30 (unscheduled death). Prostate/ Seminal Vesicles: A tro p h y in three animals of group D3/ recovery necropsy. Findings in the kidneys were also noted and included tu b u la r c h a n g es. These findings were sporadically seen in males and females with special focus on group D3 and D2 at the terminal sacrifice. A n e p h ro b la sto m a could be detected in one female (no. 51). One male and one female of group D3 exhibited a ch ro n ic n e p h ro p a th y at recovery necropsy. Sporadic changes in form of c e llu la r in fd tr a te s / in fla m m a to ry f o c i were observed in the lungs and liver of some animals of different groups. In group D3 (terminal sacrifice) could be observed a s u b m u c o sa l e d e m a in the forestomach, a d ila ta tio n of the uterus, and an e n la r g e d e p ith eliu m of the cornea, in different animals. Conclusion: The 4-week oral gavage administration of the test article caused severe alterations in the target organs and unscheduled death in one high-dose male one day before the end of the experiment. One of the central organ systems involved in the toxicity of the test article were the "manufacturing plants" of white blood cells, particularly the thymus, but also spleen and lymph nodes, which exhibited a loss of white blood cells in the animals of the high dose group. This effect could only be observed in single males of the high dose group D3. A comparable effect (tubular atrophy) could be observed in the testes of one animal of the high dose group. Both kinds of tissue demonstrate this reaction during the recovery period. At terminal sacrifice the animals of the high dose group exhibited an increase of hepatocellular activity (hypertrophy caused by enzyme induction), wich had returned to normal after the 14day recovery period. The kidney was identified as another target organ of the test article. Although it showed a more or less diffuse picture regarding incidence and evidence of its tubular alterations - which is not uncommon in particular for the male Sprague Dawley rat - severity grades of these findings were distinctly higher in the dose groups D2 (60 mg/kg) and D3 (240 mg/kg). The other findings should be discussed as spontaneous, they occurred in the control group, too, or could relatively often be observed in historical controls. PTO 2 -0222* 379 MATERIAL AND METHODS GROUP DESIGN FOR PATHOLOGIC EVALUATION: Group No. 1 / Co 2/D1 3/D2 4/D3 5/D4 control mid mid-high high mid-low* Dose mg/kg bw. Animal-No.: (male) K0-Group Rl-Group Animal-No.: (female) K0-Group Rl-Group 0 1-5 6-10 31-35 36-40 15 11 - 15 - 41-45 - 60 16-20 - 46- 50 - 240 21 -25 26-30 51-55 56-60 3 61-65 - 66-70 - * the low dose D5 (0.3 mg/kg) is added in an addendum (no. 90222) to this report against another control group. ADMINISTRATION OF THE TEST ARTICLE The test article was orally administrated by means of a pharyngeal tube, 28 administrations for four weeks. NECROPSY AND HISTOPATHOLOGY All animals were killed by exsanguination (dissection of the V. cava cran.) after intraperitoneal anaesthesia with Ketamin-Hydrochloride and Xylazin at termination (KO-subgroup on day 29; R1-subgroup on day 43) and were subjected to necropsy. Sections of the following organs / tissues were examined microscopically from all male and female rats of terminal sacrifice (KO) group 1 (control), and group 4 (high dose) according to the protocol: Heart, lungs (incl. bronchi) and trachea, liver, kidneys, spleen, brain (cerebrum, cerebellum, stem, medulla oblongata), spinal cord (cervical), testes, epididymis, prostate, seminal vesicles, ovaries, uterus, urinary bladder, stomach, jejunum, colon, adrenals, thymus, bone marrow (sternum), sciatic nerve, thyroid and parathyroid gland; iliac and mandibular lymphnode; additionally all macroscopically visible changes in organs, and all organs of intercurrently died animals; also kidneys, liver, spleen and thymus of all animals, due to histopathological changes in the high dose group (KO or Rl). All tissue specimen subjected to histopathology were fixed in formalin, embedded in Paraffin, and stained with hematoxylin and eosin (HE). The lungs were additionally instilled with 4 % formaldehyde prior to embedding. PT 0 2 - 0 2 2 2* 3 8 0 DATA COMPILATION The animal data as well as the necropsy data were recorded in Provantis, during the section at ProTox Kastengrund Testing Facility, entered into the Pathdata computer system and transferred via electronic mail to the Test Site ProTox Marburg. The microscopic findings were recorded by the undersigned pathologist using on-line input into the Pathdata computer system. All macroscopic and microscopic findings are given for each animal in text form under Text of Gross and Microscopic Findings. Histopathologic changes were described, wherever possible, according to their distribution, severity, and morphologic character. Severity scores were assigned as given under Explanation of Codes and Symbols. In paired organs non-neoplastic lesions of different severity were scored as follows: grade 1/2or grade 1/3 grade 1/4or grade 2/3 or grade 2/4 grade 1/5or grade 2/5 or grade 3/4 or grade 3/5 grade 4/5 = grade 2 = grade 3 = grade 4 = grade 5 All incidence tables were created by the Pathdata computer system. RESULTS PT0 2 - 0 2 2 2 * 381 MORTALITY Animal no. 30 (group 4: high dose, recovery) was found dead one day before termination of the recovery period (study day 42). Although autolysis was evident, microscopic examination indicated severe lymphocytes depletion in spleen, thymus and lymph nodes as cause of death. This finding was considered test-article related NECROPSY FINDINGS Group 4 (D3; high dose, 240 mg/kg): K0/K0 animals: D is c o lo u r e d kidneys in three females (no. 52, 54, 55) and all 5 males, one e n la rg e d stomach (male no. 24), two e n la r g e d livers (females no. 51, 54), and one o p a q u e eye in female no. 55. R l/R l animals: S m a ll accessory genital glands (prostate and/ or seminal vesicle) in no. 26, 27 and 28. Additionally, male no. 28 exhibited a s m a ll thymus and e n la r g e d adrenal glands. An irre g u la r su rfa c e could be observed on the kidney of male no. 28 as well as female no. 59. R1/+1 animal (died): S m a ll accessory genital glands (prostate and seminal vesicle) in combination with sm a ll testes and epididymides. Group 3 (D2; mid-high dose, 60 mg/kg): K0/K0 animals: D is c o lo u r e d kidneys in four males (no. 17-20), and four females (no. 46, 47, 49, 50), and a d is c o lo u r e d duodenum in female no. 46. Group 2 (Dl; mid dose ,15 mg/kg): K0/K0 animals: D is c o lo u r e d kidneys in three males (no. 11,14 and 15), and female no. 45. Group 5 (D4; low-mid dose, 3 mg/kg): K0/K0 animals: T ra n sp a re n t m a rg in s in the liver of female animal no. 68. For details see also Text of Gross and Microscopic Findings. PT0 2 -022 2* 382 HISTOPATHOLOGY FINDINGS Relevant histopathological findings were seen in the following organs: Liver: H y p e r tro p h y o f h e p a to c y te s in nearly all animals of the high dose group D3 at terminal necropsy. Spleen: L y m p h o c y te d e p le tio n in the animals of the high dose group D3: one male at terminal necropsy, and two male at recovery necropsy. Thymus: A tro p h y in three males of high dose group D3 at recovery necropsy. Iliac lymph node: L y m p h o id c e ll d e p le tio n in one animal (high dose group D3), which died during the recovery. Testes/ Epididymides: A tro p h y in animal no. 30 (unscheduled death). Prostate/ Seminal Vesicles: A tro p h y in three animals of group D3/ recovery necropsy. Findings in the kidneys were also noted and included tu b u la r c h a n g es. These findings were sporadically seen in males and females with special focus on high dose group D3 and mid-high dose group D2 at the terminal sacrifice. A n e p h ro b la sto m a could be detected in one high dose (D3) female. One male and one female of group D3 exhibited a c h ro n ic n e p h ro p a th y at recovery necropsy. Sporadic changes in form of c e llu la r in filtra te s / in fla m m a to ry f o c i were observed in the lungs and liver of some animals of different groups. In group D3 (terminal sacrifice) could be observed a su b m u c o sa l e d e m a in the forestomach, a d ila ta tio n of the uterus, and an e n la r g e d ep ith eliu m of the cornea, in different animals. CONCLUSIONS The 4-week oral gavage administration of the test article caused severe alterations in the target organs and unscheduled death in one high-dose male (D3) one day before the end of the experiment. One of the central organ systems involved in the toxicity of the test article were the "manufacturing plants" of white blood cells, particularly the thymus, but also spleen and lymph nodes, which exhibited a loss of white blood cells in the animals of the high dose group. This effect could only be observed in single males of the high dose group D3. A comparable effect (tubular atrophy) could be observed in the testes of one animal of the high dose recovery group which was found dead on study day 42. Both kinds of tissue demonstrate this reaction during the recovery period. At terminal sacrifice the animals of the high dose group exhibited an increase of hepatocellular activity (hypertrophy caused by enzyme induction), wich had returned to normal after the 14day recovery period. PT0 2 - 0 2 2 2* 3 83 The kidney was identified as another target organ of the test article. Although it showed a more or less diffuse picture regarding incidence and evidence of its tubular alterations - which is not uncommon in particular for the male Sprague Dawley rat - severity grades of these findings were distinctly higher in the high dose groups (D2 and D3). The other findings should be discussed as spontaneous, they occurred in the control group, too, or could relatively often be observed in historical controls. /SC / }. Signature (Dr. B. Hein) Veterinary Pathologist Principal Investigator END OF REPORT SECTION PT02 -022 2* 384 PATHOLOGY REPORT PAGE 1 / 58 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb AUTHENTICATION I,the undersigned hereby declares that the histopathology data in this report were compiled by me, and that they reflect accurately the primary data records. ProTox Marburg Dr. Berndt Hein ProTox Marburg Aventis Pharma Deutschland GmbH Marburg P T0 2 - 0 2 2 2 3 8 5 PATHOLOGY REPO RT PAGE : 2/58 PT02-0222 TEST ARTICLE ; T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR ; 3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb STATEMENT OF COMPLIANCE The undersigned hereby declares that this study was performed according to the regulations of Good Laboratory Practice (GLP). (Study. Pathologist) ProTox Marburg Date : PT02 - 0 2 2 2 * 386 PATHOLOGY REPORT TEST ARTICLE TEST SYSTEM SPONSOR ;T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology EXPLANATION OF CODES AND SYMBOLS PAGE : 3/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb CODES AND SYMBOLS USED AT ANIMAL LEVEL: M = Male animal F = Female animal KO = Terminal sacrifice group R1...R9 = Recovery / post-treatment group 1...9 + = Intercurrent death/sacrificed moribund +1 = Found dead CODES AND SYMBOLS USED AT ORGAN LEVEL: A Severe autolysis, evaluation not possible G Gross observation checked off histologically ! Gross observt.not checked off histologically 0 Tissue not present for histologic examination I Histologic examination not required + Organ examined, findings present Organ examined, no pathologic findings noted (AOFT only) ( Only one of paired organs examined/present CODES AND SYMBOLS USED AT FINDING LEVEL: GRADE 2 = Slight / few / small GRADE 3 = Moderate / moderate number / moderate size GRADE 4 = Marked / many / large NO = Malignant neoplasm ( = Finding unilateral in pairedorgans * = Comment in text of individual animal data PT0 2 0222* 387 PATHOLOGY REPORT SUMMARY TABLES PAGE : 4/58 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology PATHOL. NO.; 02222 HE DATE 16-JUL-03 PathData System V5.lb NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: KO SEX DOSE GROUP NO.ANIMALS CO D1 D2 D3 D4 55555 MALE KIDNEYS - Atrophy:Tubular - Dilation:Tubular - Tubular Necrosis 55555 3 1- - - ---2- --1-- LIVER - Hypertrophy - Inflammatory Foci - Mixed Cell Infiltrat 55555 4 122 -1 LUNGS - Interstit.Infiltrat. 5 5- - - 1---- SPLEEN - Lymphocyte Depletion 55555 ---1- P T0 2 --0 2 2 2* 3 8 8 PATHOLOGY REPORT SUMMARY TABLES PAGE : 5/58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0 SEX DOSE GROUP NO.ANIMALS CO D1 D2 D3 D4 55555 FEMALE KIDNEYS - Atrophy:Tubular - Dilation:Tubular - Tubular Degeneration - Tubular Necrosis - Tubular Hyaline - Nephroblastoma 55555 - - 1- 1--- - - - 1- - 1- --- 1--- 1- LIVER - Hypertrophy - Inflammatory Foci 55555 ---5-----1- FORESTOMACH - Edema, submucosal 5 5_ - _ ---1- UTERUS - Dilatation 5 5- - -- ---1" EYES - Epithelization 1-- -- _ _ ---1- PTO 2 0 2 2 2 * 3 8 9 PATHOLOGY REPORT SUMMARY TABLES PAGE : 6/58 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: Rl, INCL. DEATHS SEX DOSE GROUP NO.ANIMALS CO D1 D2 D3 D4 5--5" MALE KIDNEYS - Chronic Nephropathy - Dilation:Tubular 5 4_ -- _ --- 1- 3----- LIVER - Inflammatory Foci 5 4- - _ ---1- SPLEEN - Lymphocyte Depletion 5 5- - - ---2- THYMUS - Atrophy 5 5-- _ _ ---3- ILIAC LYMPH NODE - Lymphocyte Depletion 1-- -- _ _ ---1- PROSTATE - Atrophy 3_ _ - _ ---3- SEMINAL VESICLES - Atrophy 4_ _ _ _ "--3- TESTES - Atrophy:Tubular 1_ _ _ _ ---1- EPIDIDYMIDES - Atrophy 1 1 PATHOLOGY REPORT SUMMARY TABLES PAGE 7/ 58 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology PATHOL. NO. ; 02222 HE DATE 16-JUL-03 PathData System V5.lb NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: Rl, INCL. DEATHS SEX DOSE GROUP NO.ANIMALS CO D1 D2 D3 D4 5--5- KIDNEYS ;5 -- _ 5 _ - Chronic Nephropathy 1-- 1- FEMALE PTO 2 0 2 2 2 * 391 PATHOLOGY REPORT SUMMARY TABLES PAGE : 8/58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0 SEX : DOSE GROUP: CO D1 D2 D3 D4 NO.ANIMALS: 55555 MALE KIDNEYS :5 5 5 5 5 - Atrophy:Tubular GRADE 2 : 31 TOTAL AFFECTED : MEAN SEVERITY : 31 - 2.0 2.0 - Dilation:Tubular GRADE 2 : 2 TOTAL AFFECTED : MEAN SEVERITY : 2 - 2.0 - Tubular Necrosis GRADE 2 : 1-- TOTAL AFFECTED : MEAN SEVERITY : 1 - 2.0 LIVER :5 5555 - Hypertrophy GRADE 2 : 4 TOTAL AFFECTED : MEAN SEVERITY : 4 - 2.0 PTO 2 0 2 2 2 * 3 9 2 PATHOLOGY REPORT SUMMARY TABLES PAGE : 9/58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0 SEX : DOSE GROUP: CO D1 D2 D3 D4 NO.ANIMALS : 5 5 5 5 5 FEMALE KIDNEYS :5 5 5 5 5 - Atrophy:Tubular GRADE 2 : - - 1 -- - TOTAL AFFECTED : _ _ 1 _ _ MEAN SEVERITY : - - 2.0 - - - Dilation :Tubular GRADE 2 : 1 - - - - TOTAL AFFECTED : 1 _ _ _ -- MEAN SEVERITY : 2.0 - - - - - Tubular Degeneration GRADE 2 : - - - 1 - TOTAL AFFECTED : - - - 1 _ MEAN SEVERITY : - - - 2.0 - - Tubular Necrosis GRADE 2 : - - 1 " - TOTAL AFFECTED : -- -- 1 _ _ MEAN SEVERITY : -- -- 2.0 - - - Tubular Hyaline GRADE 2 : " - - 1 - TOTAL AFFECTED : _ -- -- 1 _ MEAN SEVERITY : - - - 2 . 0 - LIVER :5 5 5 5 5 - Hypertrophy GRADE 2 : - - - 3- GRADE 3 : " - " 2 - TOTAL AFFECTED : _ _ _ 5 -- MEAN SEVERITY : - - - 2.4 - PATHOLOGY REPORT SUMMARY TABLES PAGE 10/ 58 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System VS.lb SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: Rl, INCL. DEATHS SEX : DOSE GROUP: CO D1 D2 D3 D4 NO.ANIMALS: 5 5 MALE KIDNEYS :5 _ - 4_ - Chronic Nephropathy GRADE 3 : - - - 1 - TOTAL AFFECTED : - - - 1 MEAN SEVERITY : - -- -- 3.0 -- - Dilation :Tubular GRADE 2 : 3 - - - - TOTAL AFFECTED : 3 _ -- - _ MEAN SEVERITY : 2.0 - - - - THYMUS :5_ -- 5 _ - Atrophy GRADE 2 : - - - 1 - GRADE 3 : - - - 1 - GRADE 4 : - - - 1 - TOTAL AFFECTED : _ _ _ 3 _ MEAN SEVERITY : - - - 3.0 - PROSTATE : 3_ _ -- _ - Atrophy GRADE 3 : - - - 3 - TOTAL AFFECTED : 3_ _ _ MEAN SEVERITY : - - - 3.0 - SEMINAL VESICLES : 4_ _ _ _ - Atrophy GRADE 3 : - - - 3 - TOTAL AFFECTED : _ _ _ 3 _ MEAN SEVERITY : - - - 3.0 - PT O 2 - 0 2 2 2* 394 PATHOLOGY REPO RT SUMMARY T A B L E S TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: Rl, INCL. DEATHS SEX : DOSE GROUP: CO D1 D2 D3 D4 NO.ANIMALS: 5 5- TESTES : - Atrophy:Tubular GRADE 3 : _ 1--1- TOTAL AFFECTED : MEAN SEVERITY : 1 - 3.0 - - PAGE : 11/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE PT0 2 - 0 2 2 2 * 395 PATHOLOGY REPO RT SUMMARY T A B L E S PAGE : 12/ 58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb SUMMARY INCIDENCE OF GRADINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: Rl, INCL. DEATHS SEX : DOSE GROUP: CO D1 D2 D3 D4 NO.ANIMALS : 5 - - 5 - FEMALE KIDNEYS :5_ - 5- - Chronic Nephropathy GRADE 2 : 1 - - - - GRADE 4 : - - - 1 - TOTAL AFFECTED : 1 - - 1 MEAN SEVERITY : 2.0 - - 4.0 - PT0 2 0222* 396 PATHOLOGY REPORT IN D IV ID U A L A N IM A L DATA PAGE 13/ 58 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month , Oral Gavage SPONSOR : 3M Corporate Toxicology PATHOL. NO.; 02222 HE DATE ; 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : CO, control ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MKO MKO MKO MKO MKO MRI MRI MR1 MRI MR1 HEART -- _ 11f 11 KIDNEYS - Dilation: Tubular ------ +++ 2. 2. 2. LIVER - Inflammatory Foci --+ 2. ----" " ---- LUNGS - Interstit.Infiltrat. "+ 2. _f t f ! T SPLEEN -- - - THYMUS -- - - TRACHEA -- _ f 11f 1 ILIAC LYMPH NODE -- _ ! 1 T1 MANDIBULAR LYMPH NO. -- _ f f 11T FORESTOMACH -- _ 1f 1t 1 GLANDULAR STOMACH -- _ 1f 111 JEJUNUM -- _ f f ! 11 COLON -- -- til 1f CEREBRUM -- _ 1f 111 CEREBELLUM -- _ ! f 1t MEDULLA OBLONGATA -- _ 11! 11 SPINAL CORD, CERVIC. -- _ f 11! 1 SCIATIC NERVE -- _ 1f 11 PTO 2 0 2 2 2 * 3 9 7 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 14/ 58 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : CO, control ANIMAL NUMBER : ADRENAL CORTEX ADRENAL MEDULLA THYROID GLAND 123456789 10 MK0 MK0 MK0 MK0 MK0 MR1 MR1 MR1 MR1 MR1 ---- -- - - --- -1 -1 -1 11 f1 f1 1I 11 1! PARATHYROID GLANDS URINARY BLADDER -- - --- - - - 1! f! 1 11 111 PROSTATE ----- 11T11 SEMINAL VESICLES - - - - - t 1T11 TESTES EPIDIDYMIDES --------- 11111 f1 1 11 BONE MARROW PTO 2 0 2 2 2 * 3 9 8 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 15/ 58 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : CO, control ANIMAL NUMBER : HEART 31 32 33 34 35 36 37 38 39 40 FKO FKO FKO FKO FKO FRI FRI FRI FR1 FR1 - - 11111 KIDNEYS - Chronic Nephropathy - Dilation:Tubular + 2. . + 2. LIVER LUNGS - -- - - - Ill I1 SPLEEN - -- - THYMUS TRACHEA ILIAC LYMPH NODE MANDIBULAR LYMPH NO. FORESTOMACH GLANDULAR STOMACH JEJUNUM COLON CEREBRUM CEREBELLUM MEDULLA OBLONGATA SPINAL CORD, CERVIC. SCIATIC NERVE ADRENAL CORTEX - -- - - 0 fill 1 - - fill 1 - - fill 1 - - fill 1 - - fill 1 - - fill 1 - - fill 1 - - fill 1 - - fill 1 - - fill 1 - 011111 - - III! 1 - - 1111 1 PT0 2 - 0 2 2 2 * 399 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 16/ 58 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : CO, control ANIMAL NUMBER : ADRENAL MEDULLA THYROID GLAND PARATHYROID GLANDS URINARY BLADDER OVARIES UTERUS BONE MARROW 31 32 33 34 35 36 37 38 39 40 FKO FKO FKO FKO FKO FRI FRI FRI FRI FRI ----- f 1 1 fI ----- 1 1 1 1 1 ----- 1 1 1 1 1 0-- -- 1 1 1 ! ----- 11111 - - -- - 1 1 1 11 ----- T1111 PTO 2 0222* 400 PATHOLOGY REPO RT IN D IV ID U A L A N IM A L DATA PAGE : 17/ 58 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : Dl, mid dose ANIMAL NUMBER : 11 12 13 14 15 41 42 43 44 45 MKO MKO MKO MKO MKO FK0 FK0 FK0 FK0 FK0 KIDNEYS -G - - -G -G - - - -G LIVER -------- - SPLEEN - ------- - THYMUS -------- - PTO 2 0222* 401 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 18/ 58 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM Rat , 1 month, Oral Gavage SPONSOR 3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16- JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D2, mid-high dose ANIMAL NUMBER : 16 17 18 19 20 46 47 48 49 50 MKO MKO MKO MKO MKO FK0 FK0 FKO FK0 FKO KIDNEYS - Atrophy :Tubular - Tubular Necrosis + -G +G +G +G -G -G 2. 2. 2 . 2. +G +G 2. 2. LIVER - Inflammatory Foci -- ++- 2. 2. - SPLEEN -- ------- THYMUS -- ------- SMALL INTESTINE -G1 1 1 T f ! ''' PT0 2 0222* 402 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 19/ 58 PT02-0222 TEST ARTICLE ;T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose ANIMAL NUMBER : HEART 21 22 23 24 25 26 27 28 29 30 MK0 MK0 MKO MK0 MKO MR1 MR1 MR1 MR1 MR1 + - - - T 1 1 I- KIDNEYS +G -G +G -G -G - - Chronic Nephropathy - Atrophy: Tubular 2. - Dilation:Tubular 2. 2. LIVER - Hypertrophy - Inflammatory Foci LUNGS - ++++ 2* 2* 2* 2* --- - - 1 SPLEEN - - Lymphocyte Depletion - THYMUS - Atrophy TRACHEA - +- - - 3. - - - +G - A 3* A- - + 2. 111 - - +- + 3. 4 . + +G - 2. 4. + 3. ILIAC LYMPH NODE - Lymphocyte Depletion ..... . . '+ 3. MANDIBULAR LYMPH NO. STOMACH FORESTOMACH GLANDULAR STOMACH JEJUNUM COLON CEREBRUM ----- 1 'G ! --------------------- !f1 1A 1A 1A 1A 1- CEREBELLUM PTO 2 0222* 403 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 20/ 58 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose ANIMAL NUMBER : MEDULLA OBLONGATA SPINAL CORD, CERVIC. SCIATIC NERVE ADRENAL GLANDS ADRENAL CORTEX ADRENAL MEDULLA THYROID GLAND PARATHYROID GLANDS URINARY BLADDER PROSTATE - Atrophy SEMINAL VESICLES - Atrophy TESTES - Atrophy:Tubular EPIDIDYMIDES - Atrophy BONE MARROW 21 22 23 24 25 26 27 28 29 30 MK0 MK0 MK0 MK0 MK0 MR1 MR1 MR1 MR1 MR1 + - - - - - 1 1 f 1- - - - - - 1 1 f I- - - - - - T 1 1 1- 1 1 1 f 1 1 1 'G 1 ? - - - - - f ? - 1- - - - - - f f- 1- - - (- - - f f 1 1 - - - (- - - f 1 1 1 - - - - - - 1 T f 10 - - - -- 1 +G +G 1 +G 3. 3. 3. - - - - - -G +G +G y +G 3. 3. 3. - - - - - 1 1 1 y +G 3. - - - - - f f 1 y +G - 3. - - - - - 1 1 ! y- PTO 2 0222* 404 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 21/ 58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 ;Rat, 1 month, Oral Gavage :3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose ANIMAL NUMBER : HEART 51 52 53 54 55 56 57 58 59 60 FK0 FK0 FK0 FK0 FK0 FRI FRI FRI FRI FRI ----- yyyy KIDNEYS - Chronic Nephropathy - Tubular Degeneration - Tubular Hyaline - Nephroblastoma + (NO. LIVER - Hypertrophy - Inflammatory Foci +G 3* LUNGS - -G + +G 2. 2. ++ 2* 2* 2. -- +G 2* - -G - . - . . . - +G 4* +3* - - 1y -- . yy . . . - y SPLEEN ---------- THYMUS TRACHEA ILIAC LYMPH NODE MANDIBULAR LYMPH NO. FORESTOMACH - Edema, submucosal GLANDULAR STOMACH JEJUNUM COLON CEREBRUM CEREBELLUM ---------- ----- !y y yy ----- 1y y y y ----- 1y y yy - - +- - y y y y y 2. ----- y y y yy ----- y y y y 1 ----- 1y y y 1 ----- y y y y y --- -yyyyy MEDULLA OBLONGATA PTO 2 0 2 2 2 * 4 0 5 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 22/ 58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage ;3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose ANIMAL NUMBER : SPINAL CORD, CERVIC. SCIATIC NERVE ADRENAL CORTEX ADRENAL MEDULLA THYROID GLAND PARATHYROID GLANDS URINARY BLADDER OVARIES UTERUS - Dilatation BONE MARROW EYES - Epithelization 51 52 5 3 54 5 5 56 57 58 59 60 FK0 FK0 FK0 FK0 FKO FRI FRI FRI FRI FRI - --- - 111f 1 ----- 111!f ----- !1111 - - - - - 1111f ----- 11 1!f - - (- - (- 1 1 1 1 1 ----- 11111 ----- 11f T1 +- - - - !11T1 2. ----_ 1 1 1 f 1 1 1 t 1 +G ' ' ' ' 2. P TO2 --0 2 2 2* 4 0 6 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 23/ 58 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral Gavage 3M Corporate Toxicology PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D4, mid-low dose ANIMAL NUMBER 61 62 63 64 65 66 67 68 69 70 MKO MKO MKO MKO MKO FK0 FKO FK0 FK0 FKO KIDNEYS - ------ LIVER - Inflammatory Foci - Mixed Cell Infiltrat +--+ 2* . . 2 * . . .2. - - -G , SPLEEN ---------- THYMUS ---------- BRAIN ' ' ' ' ' ' ' '! ' ' PTO 2 0 2 2 2 * 4 0 7 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ;T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology ANIMAL HEADING DATA DOSE GROUP : CO, control PAGE : 24/ 58 PT02-0222 PATHOL. NO. : 02222 HE DATE : 16-JUL-03 PathData System V5.lb ANIMAL SEX NUMBER M/F 1M 2M 3M 4M 5M 6M 7M 8M 9M 10 M 31 F 32 F 33 F 34 F 35 F 36 F 37 F 38 F 39 F 40 F DEFINED AND FINAL STATE OF NECROPSY KO KO KO KO KO KO KO KO KO KO RI RI RI RI RI RI RI RI RI RI KO KO KO KO KO KO KO KO KO KO RI RI RI RI RI RI RI RI RI RI TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 PT0 2 - 0 2 2 2* 4 0 8 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : CO, control PAGE : 25/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.1b MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 3 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LIVER: -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 LUNGS : -Interstitial infiltration (mononuclear)/ pneumonia, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS: -Tubular dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 7 PTO 2 0 2 2 2 * 4 0 9 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ;T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : CO, control PAGE : 26/ 58 PT02-0222 PATHOL. NO. : 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 43 ANIMAL NO. : 8 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS: -Tubular dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS: -Tubular dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 9 PTO 2 0 2 2 2* 41 O PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : CO, control PAGE : 27/58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 31 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS URINARY BLADDER: Tissue not present for histologic examination ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: KO DAYS ON TEST : 29 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS : -Tubular dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 33 PTO 2 0 2 2 2 * 411 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : CO, control PAGE : 28/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 ANIMAL NO. : 35 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TRACHEA: Tissue not present for histologic examination SPINAL CORD (CERVICAL SEGMENT): Tissue not present for histologic examination ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS : -Chronic nphropathie foci, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 40 PTO 2 0 2 2 2 * 4 1 2 PATHOLOGY REPO RT IN D IV ID U A L A N IM A L DATA TEST ARTICLE : T-7758 TEST SYSTEM Rat, 1 month, Oral Gavage SPONSOR 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : CO, control PAGE : 29/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.1b FEMALE ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PTO 2 O 2 2 2 413 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral Gavage 3M Corporate Toxicology ANIMAL HEADING DATA DOSE GROUP : Dl, mid dose PAGE : 30/ 58 PT02-0222 PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb ANIMAL SEX NUMBER M/F 11 M 12 M 13 M 14 M 15 M 41 F 42 F 43 F 44 F 45 F DEFINED AND FINAL STATE OF NECROPSY KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ; T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : Dl, mid dose PAGE* 31/ 58 PT02-0222 PATHOL. NO.; 02222 HE DATE ; 16-JUL-03 PathData System V5.1b MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 11 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no . 01. NO MICROSCOPIC FINDINGS NOTED. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 14 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. PTO 2 0 2 2 2 * 415 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : Dl, mid dose PAGE 32/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: KO DAYS ON TEST : 29 * ANIMAL NO. : 15 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. PTO 2 0 2 2 2 * 4 1 6 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : Dl, mid dose PAGE : 33/ 58 PT02-0222 PATHOL. NO. : 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 ANIMAL NO. : 45 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PTO 2 0222* 417 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology ANIMAL HEADING DATA DOSE GROUP : D2, mid-high dose PAGE : 34/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb ANIMAL SEX NUMBER M/F 16 M 17 M 18 M 19 M 20 M 46 F 47 F 48 F 49 F 50 F DEFINED AND FINAL STATE OF NECROPSY KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 PTO 2 0 2 2 2 * 41 8 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D2, mid-high dose PAGE : 35/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 16 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS: -Tubular necrosis, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 17 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. PTO 2 0222* 419 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D2, mid-high dose PAGE : 36/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16- JUL-03 PathData System V5. lb MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 18 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. -Tubular atrophy, focal/multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.* * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 19 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. -Tubular atrophy, focal/multifocal, bilateral, grade 2 LIVER: -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 PT0 2 0222* 420 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR ; 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D2, mid-high dose PAGE : 37/ 58 PT02-0222 PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE CONT./FF. ANIMAL NO. : 19 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 ANIMAL NO. : 20 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED* * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. -Tubular atrophy, focal/multifocal, bilateral, grade 2 LIVER: -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT0 2 - 0 2 2 2 * 421 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D2, mid-high dose PAGE : 38/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.1b FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 46 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. SMALL INTESTINE: 01: Duodenum, Mucous Membrane: Discolored, white. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. SMALL INTESTINE: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * ANIMAL NO. : 47 P T0 2 0222* 422 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ; T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC: FINDINGS DOSE GROUP : D2, mid-high dose PAGE : 39/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE CONT./FF. ANIMAL NO. : 47 * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED.* * STATE AT NECROPSY: K0 DAYS ON TEST : 29 ANIMAL NO. : 49 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. -Tubular atrophy, focal/multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PTO2 - 0 2 2 2* 4 2 3 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D2, mid-high dose PAGE : 40/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 ANIMAL NO. : 50 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS : No microscopic finding corresponding to necropsy observation no. 01. -Tubular necrosis, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PTO 2 0 2 2 2* 424 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology ANIMAL HEADING DATA DOSE GROUP : D3, high dose PAGE : 41/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.1b ANIMAL SEX NUMBER M/F 21 M 22 M 23 M 24 M 25 M 26 M 27 M 28 M 29 M 30 M 51 F 52 F 53 F 54 F 55 F 56 F 57 F 58 F 59 F 60 F DEFINED AND FINAL STATE OF NECROPSY KO KO KO KO KO KO KO KO KO KO RI RI RI RI RI RI RI RI RI +1 KO KO KO KO KO KO KO KO KO KO RI RI RI RI RI RI RI RI RI RI TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 42 17-OCT-02 27-NOV-02 27-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 29 17-OCT-02 14-NOV-02 14-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 43 17-OCT-02 28-NOV-02 28-NOV-02 P T O2 0 2 2 2* 425 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ; T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 42/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: KO DAYS ON TEST : 29 * ANIMAL NO. : 21 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. -Tubular dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: KO DAYS ON TEST : 29 * ANIMAL NO. : 22 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED* * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. LIVER: -Hypertrophy, centrolobular, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasma) PTO 2 - 0 2 2 2* 4 2 6 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 43/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.1b MALE CONT./FF. ANIMAL NO. : 22 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: KO DAYS ON TEST : 29 * ANIMAL NO. : 23 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS : No microscopic finding corresponding to necropsy observation no. 01. -Tubular atrophy, focal/multifocal, bilateral, grade 2 -Tubular dilation, multifocal, bilateral, grade 2 LIVER: -Hypertrophy, diffuse, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasma) THYROID GLAND: Only one of paired organs examined/present PARATHYROID GLANDS: Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PTO 2 0 2 2 2* 427 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ; T-7758 TEST SYSTEM ; Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 44/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.1b MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 24 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. STOMACH: 01: Large. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. LIVER: -Hypertrophy, diffuse, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasms) STOMACH: No microscopic finding corresponding to necropsy observation no. 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * ANIMAL NO. : 25 PTO 2 0 2 2 2* 428 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 45/ 58 PT02-0222 PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE CONT./FF. ANIMAL NO. : 25 * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. LIVER: -Hypertrophy, centrolobular, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasma) SPLEEN: -Lymphocyte depletion, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * ANIMAL NO. : 26 * NECROPSY FINDINGS SEMINAL VESICLES: 01: Small. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS SEMINAL VESICLES: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. PTO 2 0 2 2 2* 429 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral Gavage 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 46/58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: R1 DAYS ON TEST : 43 ANIMAL NO. : 27 * NECROPSY FINDINGS PROSTATE: 01: Small. SEMINAL VESICLES: 01: Small. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS THYMUS : -Atrophy, grade 2 PROSTATE: -Atrophy, grade 3 This finding corresponds to necropsy observation no: 01. SEMINAL VESICLES: -Atrophy, bilateral, grade 3 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * NECROPSY FINDINGS KIDNEYS: 01: Surface changed, irregular. THYMUS: 01: Small. * ANIMAL NO. : 28 PTO2 - 0 2 2 2* 430 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 47/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE CONT./FF. ANIMAL NO. : 28 ADRENAL GLANDS: 01: Large. PROSTATE: 01: Small. SEMINAL VESICLES: 01: Small. NO OTHER NECROPSY OBSERVATIONS NOTED* * MICROSCOPIC FINDINGS KIDNEYS : -Chronic nphropathie foci, bilateral, grade 3 (degenerative alterations mainly in the tubuli, with round cellular infiltrations in the interstitium) This finding corresponds to necropsy observation no: 01. SPLEEN: -Lymphocyte depletion, grade 3 THYMUS: -Atrophy, grade 4 This finding corresponds to necropsy observation no: 01. ADRENAL GLANDS: No microscopic finding corresponding to necropsy observation no. 01. PROSTATE: -Atrophy, grade 3 This finding corresponds to necropsy observation no: 01. SEMINAL VESICLES: -Atrophy, bilateral, grade 3 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PTO 2 0 2 2 2* 431 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 48/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb MALE CONT./FF. ANIMAL NO. : 28 * REMARKS THYMUS: Thymus submitted in large capsule * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * ANIMAL NO. : 29 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LIVER: -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: R1/+1 DAYS ON TEST : 42 * NECROPSY FINDINGS PROSTATE: 01: Small. SEMINAL VESICLES: 01: Small. TESTES: 01: Small. * ANIMAL NO. : 30* PT0 2 0 2 2 2* 432 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM ; Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 49/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb MALE CONT./FF. ANIMAL NO. : 30 EPIDIDYMIDES : 01: Small. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: Severe autolysis, evaluation not possible LIVER: Severe autolysis, evaluation not possible SPLEEN: -Lymphocyte depletion, grade 4 THYMUS: -Atrophy, grade 3 ILIAC LYMPH NODE: -Depletion of lymphocytes, grade 3 FORESTOMACH: Severe autolysis, evaluation not possible GLANDULAR STOMACH: Severe autolysis, evaluation not possible JEJUNUM : Severe autolysis, evaluation not possible COLON : Severe autolysis, evaluation not possible URINARY BLADDER: Tissue not present for histologic examination PROSTATE: -Atrophy, grade 3 This finding corresponds to necropsy observation no: 01. SEMINAL VESICLES: -Atrophy, bilateral, grade 3 This finding corresponds to necropsy observation no: 01. TESTES : -Tubular atrophy, multifocal, bilateral, grade 3 This finding corresponds to necropsy observation no: 01. PT0 2 0222* 433 PATHOLOGY REPO RT IN D IV ID U A L A N IM A L DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 50/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE CONT./FF. ANIMAL NO. : 30 EPIDIDYMIDES : -Atrophy, bilateral, grade 3 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * REMARKS THYMUS: Thymus submitted in capsule 1 URINARY BLADDER: submitted in capsule 1 PT O2 0 2 2 2* 434 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 51/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 ANIMAL NO. : 51 * NECROPSY FINDINGS LIVER: 01: Large. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS : -Nephroblastoma, unilateral (malignant neoplasm) LIVER: -Hypertrophy, diffuse, grade 3 (= hepatocytes with pale, mostly fine granulated cytoplasma) This finding corresponds to necropsy observation no: 01. UTERUS : -Dilatation, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * ANIMAL NO. : 52 PT0 2 0222* 435 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral Gavage :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 52/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb FEMALE CONT./FF. ANIMAL NO. : 52 * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. LIVER: -Hypertrophy, diffuse, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasma) -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS: -Hyaline resorption bodies, tubular, focal, bilateral, LIVER: -Hypertrophy, diffuse, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasma) FORESTOMACH : -Submucosal inflammatory edema, focal, grade 2 PARATHYROID GLANDS: Only one of paired organs examined/present grade 2 53 PTO 2 O 2 2 2 4 36 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ; T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 53/ 58 PT02-0222 PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE CONT./FF. ANIMAL NO. : 53 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 54 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. LIVER: 01: Large. NO OTHER NECROPSY OBSERVATIONS NOTED* * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. -Tubular degeneration, multifocal, bilateral, grade 2 LIVER: -Hypertrophy, centrolobular, grade 2 (= hepatocytes with pale, mostly fine granulated cytoplasma) This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PTO2 - 0 2 2 2* 437 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ; T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 54/58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 55 * NECROPSY FINDINGS KIDNEYS: 01: Discolored, light brown. EYES : 01: RIGHT, Opaque, Both eyes submittet in large Capsule. NO OTHER NECROPSY OBSERVATIONS NOTED* * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. LIVER: -Hypertrophy, centrolobular, grade 3 (= hepatocytes with pale, mostly fine granulated cytoplasma) PARATHYROID GLANDS: Only one of paired organs examined/present EYES: -Epithelium of the cornea enlarged (4 layers), bilateral, grade 2 This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. P TQ2 0222* 438 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR ; 3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D3, high dose PAGE : 55/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE ; 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: R1 DAYS ON TEST : 43 * ANIMAL NO. : 59 * NECROPSY FINDINGS KIDNEYS: 01: Surface changed, irregular. NO OTHER NECROPSY OBSERVATIONS NOTED* * MICROSCOPIC FINDINGS KIDNEYS : -Chronic nphropathie foci, bilateral, grade 4 (degenerative alterations mainly in the tubuli, with round cellular infiltrations in the interstitium) This finding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PTO 2 0 2 2 2* 439 PATHOLOGY REPORT IN D IV ID U A L A N IM A L DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral Gavage SPONSOR : 3M Corporate Toxicology ANIMAL HEADING DATA DOSE GROUP : D4, mid-low dose PAGE : 56/ 58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb ANIMAL SEX NUMBER M/F 61 M 62 M 63 M 64 M 65 M 66 F 67 F 68 F 69 F 70 F DEFINED AND FINAL STATE OF NECROPSY KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 29 18-NOV-02 16-DEC-02 16-DEC-02 PTO 2 0 2 2 2* 4 4 0 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR :3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D4, mid-low dose PAGE : 57/58 PT02-0222 PATHOL. NO.: 02222 HE DATE : 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 61 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LIVER: -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 with necrotic hepatocytes. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29* * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LIVER: -Microgranuloma, focal/multifocal (inflammatory foci), grade 2 + single cell necrosis -Mixed cell infiltration, in the portal area, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 64 PT0 2 0 2 2 2 * 441 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral Gavage SPONSOR ;3M Corporate Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D4, mid-low dose PAGE : 58/ 58 PT02-0222 PATHOL. NO.; 02222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29* ANIMAL NO. : 68 * NECROPSY FINDINGS LIVER: 01: Margins changed, partly, transparent. BRAIN: 01: DAMAGED. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS LIVER: No microscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PT0 2 - 0 2 2 2* 442 Pathology Report Study-No.: PT02-0222 T-7758 PathData-No. 90222 prepared by: Dr. Berndt Hein Pathologist PT0 2 - 0 2 2 2* 443 SUMMARY Mortality: There were no unscheduled deaths during the course of the experiment. Necropsy Findings: There were no gross pathology findings, which could be related to administration of the test compound in all dose groups. Microscopical Findings: There were no histopathological findings, which could be related to administration of the test compound in all animals investigated. Conclusion: All the observed findings could sporadically be observed in various organs of animals from different groups. They occurred at an incidence and severity historically seen at the testing facility for rats of their age and strain. Therefore, they were n o t c o n s id e r e d r e la te d to treatm ent. MATERIAL AND METHODS PT O2 - 0 2 2 2* 4 4 4 GROUP DESIGN FOR PATHOLOGIC EVALUATION: Group No. * Animal-No.: male Animal-No.: female Dose (mg/kg) C l / 06 Control 71-75 81-85 0 D5 / 07 Low Dose 76-80 86-90 0.3 * the dose groups D1 to D4 (15 - 60 - 240 -3 mg/kg) incl. a control group are reported in no. 02222) ADMINISTRATION OF THE TEST ARTICLE The test article was orally administrated by means of a pharyngeal tube, 28 administrations for four weeks. NECROPSY AND HISTOPATHOLOGY All animals were killed by exsanguination (dissection of the V. cava cran.) after intraperitoneal anaesthesia with Ketamin-Hydrochloride and Xylazin at termination and were subjected to necropsy. Sections of the following organs / tissues were examined microscopically from all male and female rats according to the protocol and its changes: Heart, lungs (incl. bronchi) and trachea, liver, kidneys, spleen, brain (cerebrum, cerebellum, stem, medulla oblongata), spinal cord (cervical), testes, epididymis, prostate, seminal vesicles, ovaries, uterus, urinary bladder, stomach, small (jejunum) and large intestine (colon), adrenals, thymus, bone marrow (sternum), sciatic nerve, thyroid and parathyroid gland, iliac and mandibular lymphnode;.additionally all macroscopically changes organs. All tissue specimen subjected to histopathology were fixed in formaline, embedded in Paraffin, and stained with hematoxylin and eosin (HE). The lungs were additionally instilled with 4 % formaldehyde prior to embedding. PT02 - 0 2 2 2 * 445 DATA COMPILATION The animal data as well as the necropsy data were recorded in Provantis, during the section at ProTox Kastengrund Testing Facility, entered into the Pathdata computer system and transferred via electronic mail to the Test Site ProTox Marburg. The microscopic findings were recorded by the undersigned pathologist using on-line input into the Pathdata computer system. All macroscopic and microscopic findings are given for each animal in text form under Text of Gross and Microscopic Findings. Histopathologic changes were described, wherever possible, according to their distribution, severity, and morphologic character. Severity scores were assigned as given under Explanation of Codes and Symbols. In paired organs non-neoplastic lesions of different severity were scored as follows: grade 1/2 or grade1/3 grade 1/4 or grade2/3 or grade 2/4 grade 1/5 or grade2/5 or grade 3/4 or grade 3/5 grade 4/5 = grade 2 = grade 3 = grade 4 - grade 5 All incidence tables were created by the Pathdata computer system. RESULTS PT0 2 - 0 2 2 2* 446 MORTALITY There were no unscheduled deaths during the course of the experiment. NECROPSY FINDINGS There were no gross pathology findings, which could be related to administration of the test compound in all dose groups. HISTOPATHOLOGY FINDINGS There were no histopathological findings, which could be related to administration of the test compound in all animals investigated. Sporadic changes in form of d ila ta tio n and cellu la r infiltration could be observes in the uterus of animal no. 89 (group D5/07). Single control animals (group Cl/06) exhibited tubular d ila ta tio n in the kidney (no. 71), or cellu la r in filtration s in the lungs (no. 83) or glandular stomach (no. 75) For further details see also N umber of Animals with Microscopic Findings, Table of Individual Microscopic Findings, and Text of Gross and Microscopic Findings. CONCLUSIONS PT0 2 - 0 2 2 2* 4 4 7 All the observed findings could sporadically be observed in various organs of animals from different groups. They occurred at an incidence and severity historically seen at the testing facility for rats of their age and strain. Therefore, they were n o t c o n s id e r e d r e la te d to treatm ent. Signature (Dr. B. Hein) Veterinary Pathologist Principal Investigator END OF REPORT SECTION PTO 2 0 2 2 2* 448 PATHOLOGY REPORT PAGE 1/ 17 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral gavage 3M Corporated Toxicology PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb AUTHENTICATION I,the undersigned hereby declares that the histopathology data in this report were compiled by me, and that they reflect accurately the primary data records. ProTox Marburg Dr. Berndt Hein ProTox Marburg Aventis Pharma Deutschland GmbH Marburg PT0 2 - 0 2 2 2* 449 PATHOLOGY REPORT PAGE : 2/ 17 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral gavage SPONSOR : 3M Corporated Toxicology PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb STATEMENT OF COMPLIANCE The undersigned hereby declares that this study was performed according to the regulations of Good Laboratory Practice (GLP). (Study Pathologist) ProTox Marburg Date : y S C / ) ' ^ PTO 2 0 2 2 2* 4 5 0 PATHOLOGY REPO RT TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral gavage 3M Corporated Toxicology EXPLANATION OF CODES AND SYMBOLS PAGE : 3/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb CODES AND SYMBOLS USED AT ANIMAL LEVEL: M = Male animal F = Female animal KO = Terminal sacrifice group CODES AND SYMBOLS USED AT ORGAN LEVEL: ' = Histologic examination not required + = Organ examined, findings present = Organ examined, no pathologic findings noted (AOFT only) ( = Only one of paired organs examined/present CODES AND SYMBOLS USED AT FINDING LEVEL: GRADE 2 = Slight / few / small PTO 2 0 2 2 2 * 451 PATHOLOGY REPORT SUMMARY TABLES PAGE : 4/17 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral gavage SPONSOR :3M Corporated Toxicology PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0 DOSE GROUP SEX NO.ANIMALS Cl MF 55 D5 MF 55 KIDNEYS - Dilation:Tubular 5555 1- - - LUNGS - Interstit.Infiltrat. 5555 - 1-- GLANDULAR STOMACH - Mixed cell.infiltrat 5555 1--- UTERUS - Dilatation - PMN cell.infiltrat. - 5- 5 1- - - - -1 PT0 2 0222* 452 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 5/17 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral gavage :3M Corporated Toxicology PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.1b TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : Cl, Sixth group ANIMAL NUMBER : 71 72 73 74 75 81 82 83 84 85 MKO MKO MKO MKO MKO FKO FKO FKO FKO FKO HEART ---------- KIDNEYS - Dilation:Tubular +- - - - - - - - 2. LIVER ---------- LUNGS - - + -- - - - - - - Interstit.Infiltrat. 2. SPLEEN ---------- THYMUS ---------- TRACHEA ---------- ILIAC LYMPH NODE ---------- MANDIBULAR LYMPH NO. ---------- FORESTOMACH ---------- GLANDULAR STOMACH + -- - - - _ --_ - Mixed cell.infiltrat 2. JEJUNUM ---------- COLON CEREBRUM ------------------- CEREBELLUM ---------- MEDULLA OBLONGATA ---------- SPINAL CORD, CERVIC. ---------- SCIATIC NERVE ---------- PTO 2 0 2 2 2 * 4 5 3 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 6/17 PT02-0222 TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral gavage SPONSOR :3M Corporated Toxicology PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : Cl, Sixth group ANIMAL NUMBER : 71 72 73 74 75 81 82 83 84 85 MKO MKO MKO MKO MKO FKO FKO FKO FKO FKO ADRENAL CORTEX - - ----- --- ADRENAL MEDULLA - - ----- --- THYROID GLAND PARATHYROID GLANDS URINARY BLADDER - - ----- -- - (- (- - - ----- - (- (-- - PROSTATE ----- SEMINAL VESICLES --- TESTES ----- EPIDIDYMIDES --- OVARIES - --- UTERUS - --- BONE MARROW - - ----- --- PT0 2 0222* 454 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA PAGE : 7/17 PT02-0222 TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral gavage :3M Corporated Toxicology PATHOL. NO.; 90222 HE DATE : 16-JUL-03 PathData System V5.lb TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D5, Seventh group ANIMAL NUMBER : 76 77 78 79 80 86 87 88 89 90 MKO MKO MKO MKO MKO FK0 FK0 FK0 FK0 FK0 HEART ---------- KIDNEYS ---------- LIVER ---------- LUNGS ---------- SPLEEN ---------- THYMUS ---------- TRACHEA ---------- ILIAC LYMPH NODE ---------- MANDIBULAR LYMPH NO. ---------- FORESTOMACH ---------- GLANDULAR STOMACH ---------- JEJUNUM ---------- COLON ---------- CEREBRUM ---------- CEREBELLUM ---------- MEDULLA OBLONGATA ---------- SPINAL CORD, CERVIC. ---------- SCIATIC NERVE ---------- ADRENAL CORTEX ---------- ADRENAL MEDULLA ---------- PTO 2 0 2 2 2 * 4 5 5 PATHOLOGY REPORT IN D IV ID U A L A N IM A L DATA PAGE : 8/17 PT02-0222 TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral gavage SPONSOR : 3M Corporated Toxicology PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.1b TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS DOSE GROUP : D5, Seventh group ANIMAL NUMBER : 76 77 78 79 80 86 87 88 89 90 MKO MKO MKO MKO MKO FKO FKO FKO FKO FKO THYROID GLAND - - ----- PARATHYROID GLANDS URINARY BLADDER (- - - (- (- - - - - <- - ----- PROSTATE -- SEMINAL VESICLES -- TESTES -- EPIDIDYMIDES -- OVARIES ----- UTERUS - Dilatation - PMN cell.infiltrat. 2. 2. BONE MARROW - - ----- PO 2 0 2 2 2 * 456 PATHOLOGY REPO RT IN D IV ID U A L A N IM A L DATA TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral gavage 3M Corporated Toxicology ANIMAL HEADING DATA DOSE GROUP : Cl, Sixth group PAGE : 9/17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb ANIMAL SEX NUMBER M/F 71 M 72 M 73 M 74 M lb M 81 F 82 F 83 F 84 F 85 F DEFINED AND FINAL STATE OF NECROPSY KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 PTO 2 0 2 2 2* 457 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE :T-7758 TEST SYSTEM :Rat, 1 month, Oral gavage SPONSOR :3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : Cl, Sixth group PAGE : 10/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb MALE * STATE AT NECROPSY: KO DAYS ON TEST : 29 ANIMAL NO. : 71 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KIDNEYS : -Tubular dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS GLANDULAR STOMACH: -Mixed cellular infiltration, in the submucosal area, grade 2 PARATHYROID GLANDS: Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 75 PTO 2 0 2 2 2* 4 5 8 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral gavage 3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : Cl, Sixth group * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS PARATHYROID GLANDS: Only one of paired organs examined/present NO MICROSCOPIC FINDINGS NOTED. PAGE : 11/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE ANIMAL NO. : 81 * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNGS: -Interstitial infiltration (mononuclear)/ pneumonia, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. 83 PTO 2 0 2 2 2* 4 59 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE ;T-7758 TEST SYSTEM :Rat, 1 month, Oral gavage SPONSOR :3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : Cl, Sixth group * STATE AT NECROPSY: KO DAYS ON TEST : 29 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS THYROID GLAND: Only one of paired organs examined/present PARATHYROID GLANDS: Only one of paired organs examined/present NO MICROSCOPIC FINDINGS NOTED. PAGE : 12/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE ANIMAL NO. : 84 - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PTO 2 O2 2 2 4 6 0 PATHOLOGY REPORT IN D IV ID U A L A N IM A L DATA TEST ARTICLE TEST SYSTEM SPONSOR T-7758 Rat, 1 month, Oral qavaqe 3M Corporated Toxicology ANIMAL HEADING DATA DOSE GROUP D5, Seventh group PAGE : 13/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE 16-JUL-03 PathData System V5.Ib ANIMAL SEX NUMBER M/F 76 M 77 M 78 M 79 M 80 M 86 F 87 F 88 F 89 F 90 F DEFINED AND FINAL STATE OF NECROPSY K0 KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO KO TEST DAYS FIRST AND LAST DAY UNDER TEST DATE OF NECROPSY 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 29 28-JAN-03 25-FEB-03 25-FEB-03 P T O2 0 2 2 2 * 461 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral gavage :3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D5, Seventh group * STATE AT NECROPSY: KO DAYS ON TEST : 29 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS PARATHYROID GLANDS: Only one of paired organs examined/present NO MICROSCOPIC FINDINGS NOTED. PAGE : 14/17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb MALE ANIMAL NO. : 76 * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS PARATHYROID GLANDS: Only one of paired organs examined/present NO MICROSCOPIC FINDINGS NOTED. 79 PT0 2 Q2 2 2* 4 6 2 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA TEST ARTICLE TEST SYSTEM SPONSOR :T-7758 :Rat, 1 month, Oral gavage :3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D5, Seventh group PAGE : 15/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.1b MALE * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 80 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS PARATHYROID GLANDS: Only one of paired organs examined/present NO MICROSCOPIC FINDINGS NOTED. PTO 2 - 0 2 2 2 463 PATHOLOGY REPORT IN D IV ID U A L A N IM A L DATA TEST ARTICLE : T-7758 TEST SYSTEM : Rat, 1 month, Oral gavage SPONSOR : 3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D5, Seventh group PAGE : 16/17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.1b FEMALE * STATE AT NECROPSY: KO DAYS ON TEST : 29 * ANIMAL NO. : 89 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS UTERUS : -Dilatation, grade 2 -Infiltration with polymorphnuclear cells, endometrial, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS PARATHYROID GLANDS: Only one of paired organs examined/present NO MICROSCOPIC FINDINGS NOTED. 90 PTO 2 -0222* 464 PATHOLOGY REPORT IN D IV ID U A L A N IM A L DATA TEST ARTICLE : T-7758 TEST SYSTEM Rat, 1 month, Oral gavage SPONSOR 3M Corporated Toxicology TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : D5, Seventh group PAGE : 17/ 17 PT02-0222 PATHOL. NO.: 90222 HE DATE : 16-JUL-03 PathData System V5.lb FEMALE ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS -