Document Z4n3Qey19QpqowooxENVqOYYL

} 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 (quantivtative 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 diet ............................................................................................................... 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 evalution and 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 evalution and 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 of the in-life phase of 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 Toxinogy Study Report -PTO20222 2 STATEMENTS T7758 Rat repeat dose 28-day oral toxiity + 14-days recovery 21 SCHEDULING Date of protocol approval 11-06t:2002 Date of initiation 17-0ct:2002 Date of termination 25-Feb-2003 TPHRIASCTSITCUEDYREWGAUSLACTOINODNUSCTED IN ACCORDANCE WITH GOOD LABORATORY tNhoe ustnufdoyr.eseen circumstances were observed which might have affected the quality or integrity of 22 APPROVALS STUDY DIRECTOR APPROVED BY sovwontor 4 : Dr. G. Ehiing b% Dr. W. Mueller THeesatdinogfFParcoilTiotxy M-aGneargmeamneynt N-ig Hoos Date Cy 21 202 Dale ( Dr. A. M. Su cacaIt N) o sen) d Aetye_132003 Pages Toxicology Study Report- PT02.0222 23 STATEMENT OF GOOD LABORATORY PRACTICE STUDY NUMBER: TITLE: PT02-0222 T7758 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 8% 2001, published in Bundesgesetzblatt Jahrgang 2001 Teil I Nr. 21, in GBoonond, LoanboMraatyor1y4"P,ra2c0t0i1ce, aasfopruebmleinstheidonoend Mlaawrcihs t2h3e",im1p9l9e9me(natsarteivoinseodf itnhePrOinEcCipDle P1ri9n9c9i/pl1e1s/EoUf of March 8", 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 specimens of laboratory investigation. reference sample, protocol, report, all raw data and DTHEISSCRSITBUEDDY AWNADS TCHOINSDRUECPTOERDTINFUALCLCYORADNADNCAECCWUIRTAHTTEHLEY PRREOFCLEEDCUTRSETSHHEERREAIWN DATA GENERATED IN THE STUDY. . Dr. G. Fling Study Director Mf,As Kod Dae Page 10 Tology Study Repon- P1022 2.4 QUALITY ASSURANCE STATEMENT STUDY NUMBER: PT02-0222 TITLE: T-7758 Rat repeat dose 28-day oral toxicity + 14-days recovery "This study was periodically inspected and properly signed recordsofthese 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 dataofthe study. Dates of Inspection Study Phase Dates of Report to Study Director and Management 14001-2002 17002002 18-Oct-2002 22.00t:2002 07-Nov-2002 14Nov-2002 18-Nov-2002 061a0:2003 2600:2003 225:-MFaeyb--22000033 22-May-2003 22-May-2003 - 03-Jun-2003 2267-:MMaayy--22000033 08-Aug-2003 study plan study condet `study conduct study conduct sty condut studyconduct study conduct study conduct study conduct sctoudnytcoennducretport contributor report draft report cocnotntrriibbuuttoorr rreeppoorrtt final report 14-0ct:2002 17062002 18-Oct-2002 22.012002 07-Nov-2002 14Nov-2002 18:Nov2002 06.1an:2003 26.1m:2003 225:-MFaeyb--22000033 22-May-2003 03-Jun-2003 2267--MMaayy--22000033 08-Aug-2003 C. lus CQ.uaElhirtlyiAchssurance (GLP) 08 lug - 9003 Date page 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 F12 O3 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 Food : at least five days : 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 of animals (mg/kg/bw./d) main groups 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 5 5 7** 0.3 5 5 * = 1st additional dose group ( group 5) ** = 2nd d additional dose group (group 7) and corresponding 2nd control group (group 6) Nubmer of animals recovery groups male female 5 5 - - - - 5 5 - - - - - - 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: Group 1 2 3 4 5 6 7 Table 2: Number of animals / Animal numbers Dose (mg/kg bw.) 0.0 15.0 60.0 240.0 3.0 0.0 0.3 Number of Animals males females 10 10 5 5 5 5 10 10 5 5 5 5 5 5 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 -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: Urinalysis - Semiquantitative parameters evaluated Appearence Bilirubin Blood Color Glucose Ketone bodies Microscopic Examination (Sediment)* pH Protein Urobilinogen * 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 Parameters 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 Table 13: Results of dose suspension analysis Dose level (mg/kg/day) 00 0.3 3 15 60 240 Concentration (mg/ml) 00 0.06 0.6 3 12 48 Analysed content (mean %) Day 1 n.d. n.d. 99 95 107 114 108 n.d. = not detected The anticipated concentrations were satisfactorily confirmed. (Analytical report archived with the raw data) 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: mg / kg bw. / d Table 14: Designation of the dose groups (1 - 5) for individual data 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 of 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 Hematocrit Hematocrit Hemoglobin Hemoglobin MCH Mean Corpuscular Hemoglobin MCHC Mean Corpuscular Hemoglobin Concentration MCV Mean Corpuscular Volume Red cell count Red blood cell count (Erythrocyte count) Reticulocytes 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 Methodology/Instrumentation Unity Advia 120 Bayer Diagnostics GmbH 109/l Advia 120 Bayer Diagnostics GmbH 10.1.1.3 Blood coagulation Abbreviation Parameter Platelets 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. (-GT) ALAT Albumin Alb/Glob Ratio AP ASAT Total Biliru. Calcium (Ca) Chloride (Cl) Cholesterol Creatinine Globulin Glucose Phosphorus Potassium (K) Sodium (Na) Total Protein Triglycerides Urea Nitrogen Uric Acid Parameter -Glutamyltranspeptidase Units U/l Alanine Aminotransferase U/l Albumin g/l Albumin Globulin Ratio 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 Bilirubin Blood (RBCs) Urobilinogen Microscopy of Sediment Parameter Urine Color Appearence of Urine pH Value (sq) Protein (Albumine) (sq) Glucose (sq) Ketone Bodies (sq) Bilirubin (sq) Blood (RBCs) (sq) Urobilinogen (sq) Units 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. min. N (n) Rpm S.D. STATS K0/K0 animals R1/R1 animals R1/+1 animal : Approximately : Body weight : Day : Male : Female : Good Laboratory Practice : Gas Chromatograph : Identification : Includes : Life Animal Safety Welfare : Maximum : 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 Page 46 Toxicology Study Report - PT02-0222 11.3 FOOD CONSUMPTION (GROUPS 1 - 5) Page 47 Toxicology Study Report - PT02-0222 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 Page 52 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 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 Date: 16-Dec-2002 Page: 1 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 1m 1 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 2 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 3 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 4 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 5 No Abnormalities Detected X X X X . . . . X X X X X X X X X X X X X X Respiratory sounds . . . . X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 6 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 7 No Abnormalities Detected X X X X X X X X X X . . X X X X X X X X X X Respiratory sounds . . . . . . . . . . X X . . . . . . . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 8 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 9 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 10 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 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 64 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 2 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 1m 1 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 2 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 3 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 4 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 5 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Respiratory sounds . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 6 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 7 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Respiratory sounds . . . . . . . . . . . . . . . . . . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 8 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 9 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 10 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 65 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 3 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 1f 31 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 32 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 33 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 34 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 35 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 36 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 37 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 38 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 39 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 40 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 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 66 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 4 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 1f 31 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 32 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 33 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 34 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 35 No Abnormalities Detected X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 36 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 37 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 38 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 39 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 40 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 67 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 5 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 2m 11 No Abnormalities Detected X X X X X X X . . . . X X X X . . . . . . . Gait stilted . . . . . . . . . . . . . . . X X X X X X X Respiratory sounds . . . . . . . X X X X . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 12 No Abnormalities Detected X X X X X X X X X X X X X X . . . . . . . . Gait uncoordinated . . . . . . . . . . . . . . X X X X X X X X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 13 No Abnormalities Detected X X X X X X X X X X X X X X X X . . . . . . Gait stilted . . . . . . . . . . . . . . . . X X X . . . Gait uncoordinated . . . . . . . . . . . . . . . . . . . X X X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 14 No Abnormalities Detected X X X X X X X X X X X X X X . . . . . . . . Gait uncoordinated . . . . . . . . . . . . . . X X X X X X X X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 15 No Abnormalities Detected X X X X X X X X X X X X X X . . . . . . . . Gait uncoordinated . . . . . . . . . . . . . . X X X X X X X X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 6 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 2m 11 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Respiratory sounds . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 12 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 13 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 14 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 15 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 7 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 2f 41 No Abnormalities Detected X X X X X X X X X X X X X X . . . . . . . . Gait stilted . . . . . . . . . . . . . . X X X X X X X X Gait uncoordinated . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 42 No Abnormalities Detected X X X X X X X X X X X X X X . . . . . . . . Gait stilted . . . . . . . . . . . . . . X X X X X X X X Gait uncoordinated . . . . . . . . . . . . . . . . . . . . . X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 43 No Abnormalities Detected X X X X X X X X X X X X X X X . . . . . . . Gait uncoordinated . . . . . . . . . . . . . . . X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . X X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 44 No Abnormalities Detected X X X X X X X X X X X X X X X X . . . . . . Gait uncoordinated . . . . . . . . . . . . . . . . X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 45 No Abnormalities Detected X X X X X X X X X X X X X X X X . . . . . . Gait uncoordinated . . . . . . . . . . . . . . . . X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . X X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 8 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 2f 41 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated . . . X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 42 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 43 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 44 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture . . . . . . X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 45 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 9 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3m 16 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . . X X X X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . X X X Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 17 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . . . . X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . . X Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 18 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . X X X X X X X X . . . . . . . . . . Gait uncoordinated . . . . . . . . . . . . X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . X X X Feces discolored . . . . Y Y . . . . . . . . . . . . . . . . Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 19 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . . . . . . . . X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . . X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . . X Feces discolored . . . . . Y . . . . . . . . . . . . . . . . Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 10 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 3m 16 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 17 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 18 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 19 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 73 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 11 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3m 20 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . X X X X X X X . . . . . . . . . . . Gait uncoordinated . . . . . . . . . . . X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . . . Feces discolored . . . . . Y Y . . . . . . . . . . . . . . . Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 12 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 3m 20 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture . . . X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 13 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3f 46 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . X X . . . . . . . . . . . . . . . Gait uncoordinated . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . X X X Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 47 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . . . . X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . . . . . . . X X X Squatting posture . . . . . . . . . . . . . . . . . . X X X X Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 48 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . X X Gait uncoordinated . . . . . X X X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . X . . . . . . . . Squatting posture . . . . . . . . . . . . . X X X X X X X X X Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 49 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . X X . . . . . . . . . . . . . . . Gait stilted . . . X X X X X X X X X X . . . . . . . X X Gait uncoordinated . . . . . . . . . . . . X X X X X X X X X X Squatting posture . . . . X X X X X X X X X X X X X X X X X X Feces discolored . . . . Y Y . . . . . . . . . . . . . . . . Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 76 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 14 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 3f 46 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 47 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 48 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen . . . . . . . . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 49 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 15 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3f 50 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . . . X X X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . X X Tray / bedding discolored . . . Y Y Y Y Y Y Y Y Y Y Y . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 16 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 3f 50 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Tray / bedding discolored . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 79 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 17 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4m 21 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . 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 Abdomen swollen . . . . . . . X X X X X X X X X X X X X X X 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 22 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . 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 . . . . . . . . . . . X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . . X Feces discolored . . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 23 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . 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 . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . X X X X Feces discolored . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 18 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4m 21 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 22 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 23 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 19 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4m 24 No Abnormalities Detected 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 . . . . . . . . X X X X X X X X X X X X X X Squatting posture . . . . X X X X . . . . . . . . . . X X X X 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 25 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . 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 . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . X X X X X X X . . . X X X X X X X X Feces discolored . . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 26 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . X X X X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . X X X X X X X 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 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 82 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 20 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4m 24 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 25 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 26 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . X X X X X X X X Gait uncoordinated X X X X X X X X X X X X . . . . . . . . . Abdomen swollen X X X X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 Date: 16-Dec-2002 Page: 21 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 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 . . . . . . . . X X X X X X X X X X X X X X Squatting posture . . . . X X X X X X X X X . X X X X X X X X 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 . . . . . . . . . . . . . . . . . . . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 28 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . 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 . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . . . . . . X X 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 Date: 16-Dec-2002 Page: 22 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4m 27 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . . . X X Gait stilted . . . . . . . . . . . . . X X X 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 X X X Abdomen swollen X X X X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Snout encrusted blood-colored . . . . . . . . . . . . . . . . . X X . . Snout swollen . . . . . . . . . . . . . . . . . X X . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 28 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . X X X X Gait stilted . . . X X X X X . . X X X X X X 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 X X X Abdomen swollen X X X X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Lower incisor(s) broken off . . . . X X X . . . . . . . . . . . . . . Upper incisor(s) broken off . . . . . . . . . . . . . . . . . . . . X Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 85 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 23 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4m 29 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . 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 . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . X X X . . . . . . . . . . . X X X X 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 30 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X X X X X X . . . . . . . . X X Gait uncoordinated . . . . X X X X X X X . X X X X X X X X X X Abdomen swollen . . . . . . . . . . X X X X X X X X X X X X Squatting posture . . . X X X X X X X X . . . X X X X X X X X Stupor . . . . . . . . . . . . . . . . . . . . . . Coat bristling . . . . . . . . . . . . . . . . . . . . . . Feces discolored . . . 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 . . . . . . . . . . . . . . . . . . . . . . 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 Date: 16-Dec-2002 Page: 24 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4m 29 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X 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 X X X Abdomen swollen X X X X X X X X X X X X . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 30 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . X X X X X X X X X X X X X X X X . . Gait stilted X X X X X X X X X X X X X X X X X X X . . Gait uncoordinated X X X X X X X X X . . . . . . . . X X . . Abdomen swollen X X X X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X . . Stupor . . . . . . . . . . . . . . . . . X X . . Coat bristling . . . . . . . . . . . . . . . . . X X . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Snout encrusted blood-colored . . . . . . . . . . . . . . . . . X X X . Snout swollen . . . . . . . . . . . . . . . . . X X X . Lower incisor(s) broken off . . . X X X X . . . . . . . . . . . . . . Found dead . . . . . . . . . . . . . . . . . . . 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 87 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 25 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4f 51 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X . . . . . . . . . . . . X X X Gait uncoordinated . . . . . . X X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . X X X X X X X X Feces discolored . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 52 No Abnormalities Detected 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 . . . . . . . . . . . . . . . . . . X X X X Squatting posture . . . . X X X . . . . . . . . . . . X X X X Feces discolored . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 53 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated . . . . X X X X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . . . X . . . . . . . . X X X X X X X Feces discolored . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 26 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4f 51 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 52 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 53 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 27 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4f 54 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X 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 . . . . . . . . . . . X X . X X X X X X X X Squatting posture . . . . X X X X X X X . . . X X X X X X X X Feces discolored . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 55 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X X . . . . . . X X X X X X X X Gait uncoordinated . . . . . . X X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . X X X X X . . . . . . . . . . Squatting posture . . . . . . . . . . . . . . X X X X X X X X Feces discolored . . . 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 Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 56 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . . . . . . . . . . . . . . . . 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 . . . . . . . . X X X X X X X X X X X X X X Squatting posture . . . . . . . . . . . . . . . X X X X X X X Feces discolored . . . 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 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 90 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 28 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4f 54 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 55 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Gait uncoordinated X X X X X X X . . . . . . . . . . . . . . Abdomen swollen . . . . . . . . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 56 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . X X X X X X X X X Gait uncoordinated X X X X X X X X X X X X . . . . . . . . . Abdomen swollen X X X X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 Date: 16-Dec-2002 Page: 29 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4f 57 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X X . . . . . . . . . . . . . X Gait uncoordinated . . . . . . . . X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . . . . . . . X X X Squatting posture . . . . X X X X X X X X X X X X X X X X X X Feces discolored . . . 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 58 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . . X X X . . . . . . . . . . . . . . X Gait uncoordinated . . . . . . . X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . . . X X X X X X X Squatting posture . . . . X X X X X X X X X X X X X X X X X X Feces discolored . . . 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 Killed: end of recovery . . . . . . . . . . . . . . . . . . . . . . 59 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . X X . . . . . . . . . . . . . . Gait stilted . . . X X X X X X X X X X X X X X X X X X X Gait uncoordinated . . . . . X X X X X X X X X X X X X X X X X Abdomen swollen . . . . . . . . . . . . . . . . . . X X X X Squatting posture . . . . X X X X X X X X X X X X X X X X X X Feces discolored . . . 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) trimmed . . . . . . . . . . . . . . . . . . . . . . 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 92 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 30 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4f 57 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X X X X X X X X X X X X X X X Gait uncoordinated X X X X X X X X X X X X . . . . . . . . . Abdomen swollen X X . . . . . . . . . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 58 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . . . X X Gait stilted X X X X X X X X X X X X X X X X X X X X X Gait uncoordinated X X X X X X X X X X X X . . . . . . . . . Abdomen swollen X X X X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . X 59 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Flanks drawn in . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X X X X X X X X X X 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 X X X Abdomen swollen X X . . . . . . . . . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Lower incisor(s) broken off . . . . . X X X X X X X X X X . . . . . . Upper incisor(s) trimmed . . . . . . . . . . . . X . . . . . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 93 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 31 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 4f 60 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . . Gait stilted . . . 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 . . . . . . . X X X X X X X X X X X X X X X Squatting posture . . . . X X X . . . . . . . X X X X X X X X Feces discolored . . . 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 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 94 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 32 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4f 60 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . 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 X X X Abdomen swollen X X . X X X X X X X . . . . . . . . . . . Squatting posture X X X X X X X X X X X X X X X X X X X X X Feces discolored . . . . . . . . . . . . . . . . . . . . . Tray / bedding discolored Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y . . . . Killed: end of recovery . . . . . . . . . . . . . . . . . . . . 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 95 Toxicology Study Report - PT02-0222 RTA001-01/04 PROVANTIS Date: 16-Dec-2002 Page: 33 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 5m 61 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 Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 62 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 Gait stilted . . . . . . . . . . . . . . . . . . . . . . Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 63 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 Gait stilted . . . . . . . . . . . . . . . . . . . . . . Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 64 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 Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 65 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 Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 34 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 5m 61 No Abnormalities Detected X . . . . . . . . . . . . . . . . . . . . Squatting posture . X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 62 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . . X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 63 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted . . X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 64 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . Squatting posture . . . X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 65 No Abnormalities Detected X X X . . . . . . . . . . . . . . . . . . Squatting posture . . . X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 16-Dec-2002 Page: 35 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 5f 66 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 Gait stilted . . . . . . . . . . . . . . . . . . . . . X Squatting posture . . . . . . . . . . . . . . . . . . . . . X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 67 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 Gait stilted . . . . . . . . . . . . . . . . . . . . . . Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 68 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 Gait stilted . . . . . . . . . . . . . . . . . . . . . . Squatting posture . . . . . . . . . . . . . . . . . . . . . . Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 69 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 Gait stilted . . . . . . . . . . . . . . . . . . . . . X Squatting posture . . . . . . . . . . . . . . . . . . . . . X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . 70 No Abnormalities Detected X X X X X X X X X X X X X X X X X X X X X . Gait stilted . . . . . . . . . . . . . . . . . . . . . X Squatting posture . . . . . . . . . . . . . . . . . . . . . X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . * = 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 Date: 16-Dec-2002 Page: 36 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date (continued) Group Animal Sex Number Clinical Sign 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 5f 66 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 67 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Squatting posture . . X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 68 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 69 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . X . . . . . . . . . . . . . . 70 No Abnormalities Detected . . . . . . . . . . . . . . . . . . . . . Gait stilted X X X X X X X . . . . . . . . . . . . . . Squatting posture X X X X X X X . . . . . . . . . . . . . . Killed: end of study . . . . . . 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 Date: 28-May-2003 Page: 1 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X * = 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 Date: 28-May-2003 Page: 2 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X * = 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 Date: 28-May-2003 Page: 3 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X * = 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 Date: 28-May-2003 Page: 4 Clinical Observations - Clinical Signs by Animal Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Group Animal Sex Number Clinical Sign 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X 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 X Killed: end of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . X * = 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 RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- SDTAUYDY -0003 NE MSE.ADN. N 1165..74 10 1122..29 5 1232..72 5 1271..98 5 1241..99 9 +0001 MSE.ADN. N 1387..43 10 1343..05 5 1445..21 5 1438..46 5 1465..22 + 9 +0004 MSE.ADN. N 1524..81 M 5 +0005 MSE.ADN. N 15184..48 10 16121..25 5 1435..67 5 11309..38 9 +0008 MSE.ADN. N 17177..29 10 1835..24 5 18102..47 5 1649..61 5 1568..40 9 +0011 MSE.ADN. N 2059..01 M 5 +0012 MSE.ADN. N 20240..32 10 20183..48 5 19101..22 5 1788..36 9 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 106 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- SDTAUYDY +0015 MSE.ADN. N 22149..95 10 22181..06 5 22132..07 5 20193..00 5 19142..91 9 +0018 MSE.ADN. N 24144..46 M 5 +0019 MSE.ADN. N 24253..25 10 24123..47 5 23125..04 5 21152..65 9 +0022 MSE.ADN. N 25276..05 10 26136..08 5 25112..04 5 24107..64 5 21192..35 9 +0025 MSE.ADN. N 27158..85 M 5 +0026 MSE.ADN. N 23606..40 10 21558..32 5 21499..90 5 21277..50 9 +0029 MSE.ADN. N 27391..63 10 27198..84 5 26193..88 5 26211..26 5 23107..79 9 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 107 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- SDTAUYDY +0033 MSE.ADN. N 29453..87 5 22128..38 4 +0036 MSE.ADN. N 30444..24 5 20284..86 4 +0040 MSE.ADN. N 31498..64 5 20330..07 4 +0043 MSE.ADN. N 32500..08 5 19345..09 4 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 108 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----F-E-M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- SDTAUYDY -0003 NE MSE.ADN. N 1134..16 10 1063..69 5 1143..60 5 1154..22 5 1142..82 10 +0001 MSE.ADN. N 1294..25 10 1202..66 5 1313..04 5 1332..26 5 1265..64 10 +0004 MSE.ADN. N 1343..44 M 5 +0005 MSE.ADN. N 1475..19 10 1453..69 5 13113..09 5 1268..10 10 +0008 MSE.ADN. N 1588..21 10 1482..86 5 1565..84 5 14182..21 5 13192..23 10 +0011 MSE.ADN. N 1574..81 M 5 +0012 MSE.ADN. N 1699..59 10 1664..23 5 16130..25 5 15141..40 10 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 109 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----F-E-M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- SDTAUYDY +0015 MSE.ADN. N 1788..04 10 1685..41 5 1765..81 5 1729..42 5 16121..88 10 +0018 MSE.ADN. N 1766..24 M 5 +0019 MSE.ADN. N 1868..76 10 1894..21 5 1849..24 5 17152..06 10 +0022 MSE.ADN. N 1939..36 10 1844..83 5 1934..06 5 18181..40 5 17182..42 10 +0025 MSE.ADN. N 1904..80 M 5 +0026 MSE.ADN. N 20141..39 10 2062..00 5 11908..42 5 11843..19 10 +0029 MSE.ADN. N 21112..80 10 1954..09 5 2055..80 5 1998..87 5 18260..01 10 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFESREENATNDFROONME-CTOANITLREODLT(EPST<S 0F.O0R5)L.OWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 110 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----F-E-M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- SDTAUYDY +0033 MSE.ADN. N 22104..49 5 19236..62 5 +0036 MSE.ADN. N 22114..62 5 19279..26 5 +0040 MSE.ADN. N 22168..49 5 19287..48 5 +0043 MSE.ADN. N 22157..65 5 18299..49 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). 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 RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ SDTAUYDY -0004 NE MSE.ADN. N 1064..20 5 1083..86 5 +0001 MSE.ADN. N 1393..28 5 1424..21 5 +0004 MSE.ADN. N 1603..03 5 1635..67 5 +0008 MSE.ADN. N 1884..00 5 1916..24 5 +0011 MSE.ADN. N 2124..46 5 21150..65 5 +0015 MSE.ADN. N 2368..64 5 24121..43 5 +0018 MSE.ADN. N 25133..54 5 26146..00 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 113 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ SDTAUYDY +0022 MSE.ADN. N 27106..45 5 28222..84 5 +0025 MSE.ADN. N 28137..41 5 29220..04 5 +0029 MSE.ADN. N 29157..65 5 30275..84 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLAT(ISSTTAITCIASLTIECVAALLUAANTAILOYNSIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 114 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----F-E-M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ SDTAUYDY -0004 NE MSE.ADN. N 1044..81 5 1023..64 5 +0001 MSE.ADN. N 1244..67 5 1254..22 5 +0004 MSE.ADN. N 1345..49 5 1395..26 + 5 +0008 MSE.ADN. N 1458..03 5 1508..47 5 +0011 MSE.ADN. N 1567..86 5 1618..45 5 +0015 MSE.ADN. N 1668..06 5 1729..62 5 +0018 MSE.ADN. N 1748..09 5 17180..42 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFESREENATNDFROONME-CTOANITLREODLT(EPST<S 0F.O0R5)L.OWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). Page 115 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------- B-O-D-Y--W-E-I-G-H-T-----F-E-M-A-L-E--A-N-I-M-A-L-S---(-g-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ SDTAUYDY +0022 MSE.ADN. N 1818..02 5 18170..83 5 +0025 MSE.ADN. N 1849..03 5 1898..96 5 +0029 MSE.ADN. N 1909..68 5 19191..07 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDIPFOFSESRIEBNLTE FRONME C:ONNTOROSLTA(TSITSATTIICSATLICEAVLALAUNAATLIYOSNIS BASED ON CHANGES VERSUS PRELIMINARY VALUES). 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 PROVANTIS Date: 16-Dec-2002 Page: 1 Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group From: -3 1 5 8 12 15 19 22 26 29 33 36 40 -3 Sex To: 1 5 8 12 15 19 22 26 29 33 36 40 43 43 1m Mean S.D. N 2m Mean S.D. N 3m Mean S.D. N 4m Mean S.D. N 119.69 5.84 10 -----119.22 3.87 5 -----117.50 7.31 5 -----185.28 72.41 9 ------ 103.52 6.90 10 -----99.73 4.77 5 -----82.03 3.93 5 -----60.97 11.40 9 ------ 97.74 9.41 10 -----91.04 6.52 5 -----89.29 4.36 5 -----83.31 4.33 9 ------ 90.97 9.05 10 -----84.42 5.78 5 -----88.73 5.19 5 -----87.61 4.51 9 ------ 87.17 7.98 10 -----76.57 4.65 5 -----85.43 5.31 5 -----82.27 4.55 9 ------ 81.33 7.56 10 -----72.81 4.07 5 -----80.10 5.40 5 -----81.71 4.85 9 ------ 72.03 7.96 10 -----68.25 3.60 5 -----74.22 5.41 5 -----76.29 4.57 9 ------ 60.49 8.00 10 -----55.71 3.07 5 -----57.06 4.54 5 -----63.09 4.22 9 ------ 62.89 6.90 10 -----61.26 3.44 5 -----70.16 5.95 5 -----61.68 6.43 9 ------ 72.48 10.73 5 ------ . . . -----. . . -----73.77 5.97 4 ------ 69.67 10.52 5 ------ . . . -----. . . -----45.85 4.91 4 ------ 67.74 10.29 5 ------ . . . -----. . . -----38.68 5.52 4 ------ 53.36 8.38 5 -----. . . -----. . . -----45.62 7.97 4 ------ 82.98 7.74 10 -----81.00 4.09 5 -----82.72 4.97 5 -----81.04 3.97 9 ------ 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 118 Toxicology Study Report - PT02-0222 RTA075-01/00 PROVANTIS Date: 16-Dec-2002 Page: 2 Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group From: -3 1 5 8 12 15 19 22 26 29 33 36 40 -3 Sex To: 1 5 8 12 15 19 22 26 29 33 36 40 43 43 1f Mean S.D. N 2f Mean S.D. N 3f Mean S.D. N 4f Mean S.D. N 106.88 3.83 10 -----109.17 2.66 5 -----114.39 2.98 5 -----106.26 4.58 10 ------ 105.09 3.86 10 -----100.20 2.57 5 -----70.58 4.08 5 -----72.17 3.96 10 ------ 91.44 4.45 10 -----90.01 2.65 5 -----91.44 9.55 5 -----88.67 7.08 10 ------ 80.62 4.77 10 -----79.31 2.36 5 -----80.33 6.35 5 -----87.40 7.80 10 ------ 74.24 3.94 10 -----74.29 1.97 5 -----76.50 4.81 5 -----84.68 7.50 10 ------ 73.49 3.59 10 -----71.89 1.76 5 -----72.50 3.89 5 -----81.33 6.47 10 ------ 72.05 4.99 10 -----70.84 1.55 5 -----75.68 4.25 5 -----78.45 5.71 10 ------ 65.54 3.84 10 -----60.29 1.64 5 -----61.98 3.62 5 -----71.88 7.94 10 ------ 62.67 3.54 10 -----64.12 1.76 5 -----65.45 3.25 5 -----66.72 8.25 10 ------ 78.52 5.51 5 -----. . . -----. . . -----92.02 15.44 5 ------ 66.90 4.47 5 -----. . . -----. . . -----77.93 13.29 5 ------ 67.94 5.23 5 -----. . . -----. . . -----75.08 13.17 5 ------ 60.21 5.09 5 -----. . . -----. . . -----44.55 7.60 5 ------ 79.24 3.97 10 -----80.01 1.84 5 -----78.76 4.41 5 -----80.39 6.60 10 ------ 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 119 Toxicology Study Report - PT02-0222 RTA075-01/00 PROVANTIS Date: 16-Dec-2002 Page: 1 Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group From: -3 1 4 8 11 15 18 22 25 -3 Sex To: 1 4 8 11 15 18 22 25 29 29 5m Mean S.D. N 123.54 3.04 5 ------ 106.52 2.88 5 ------ 102.44 2.77 5 ------ 95.24 3.54 5 ------ 86.99 4.16 5 ------ 76.39 4.18 5 ------ 74.72 4.58 5 ------ 63.32 4.17 5 ------ 51.47 3.41 5 ------ 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 PROVANTIS Date: 16-Dec-2002 Page: 2 Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group From: -3 1 4 8 11 15 18 22 25 -3 Sex To: 1 4 8 11 15 18 22 25 29 29 5f Mean S.D. N 108.64 3.10 5 ------ 96.77 2.26 5 ------ 90.07 1.81 5 ------ 78.73 1.48 5 ------ 76.38 2.16 5 ------ 68.93 2.21 5 ------ 69.01 1.85 5 ------ 60.02 1.30 5 ------ 57.05 1.30 5 ------ 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: 1 Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group From: -4 1 4 8 11 15 18 22 25 -4 Sex To: 1 4 8 11 15 18 22 25 29 29 6m Mean S.D. N 7m Mean S.D. N 118.26 3.67 5 -----118.79 3.21 5 ------ 112.34 2.56 5 -----110.40 3.43 5 ------ 109.23 2.15 5 -----105.51 3.60 5 ------ 102.60 2.18 5 -----101.75 4.22 5 ------ 89.81 2.51 5 -----86.17 4.00 5 ------ 79.86 3.72 5 -----78.12 4.27 5 ------ 69.87 4.15 5 -----70.33 5.15 5 ------ 58.44 3.68 5 -----54.06 4.22 5 ------ 72.06 4.52 5 -----66.18 5.32 5 ------ 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: 2 Food Consumption By Animal - Intergroup Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group From: -4 1 4 8 11 15 18 22 25 -4 Sex To: 1 4 8 11 15 18 22 25 29 29 6f Mean S.D. N 7f Mean S.D. N 114.35 4.42 5 -----115.11 3.85 5 ------ 92.26 3.69 5 -----101.47 3.76 5 ------ 88.23 4.60 5 -----92.73 4.74 5 ------ 88.12 4.76 5 -----84.45 4.79 5 ------ 82.58 4.26 5 -----77.42 4.25 5 ------ 66.02 3.38 5 -----65.88 3.67 5 ------ 67.73 3.26 5 -----60.49 3.30 5 ------ 56.36 2.68 5 -----53.61 2.86 5 ------ 70.08 3.53 5 -----70.86 3.89 5 ------ 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 RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----R-E-D--C-E-L-L--C-O-U-N-T--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- R(e1d0Eb1l2o/oLd) cell count MSE.ADN. N 70..7266 5 70..9151 5 70..8335 5 70..8307 5 70..5463 5 H(egm/oLg)lobin MSE.ADN. N 1504 1564 1503 1485 1498 5 5 5 5 5 H(eumnaittoyc)rit MSE.ADN. N 00..4051 5 00..4061 5 00..4052 5 00..4052 5 00..4042 5 M(C1V0E-15 L) MSE.ADN. N 571 581 581 581 581 5 5 5 5 5 M(C1H0E-12 g) NE MSE.ADN. N 201 201 191 190 200 5 5 5 5 5 M(CgH/CL) NE MSE.ADN. N 3398 3423 3349 3264 3384 5 5 5 5 5 R(eutniictuyl)ocytes MSE.ADN. N 00..002091 5 00..002093 5 00..002062 5 00..002092 5 00..002065 5 H(euinniztyB)odies NE MSE.ADN. N 00..000000 5 00..000000 5 00..000000 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 126 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----R-E-D--C-E-L-L--C-O-U-N-T--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP153 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- R(e1d0Eb1l2o/oLd) cell count MSE.ADN. N 70..1391 5 70..5310 5 70..4653 4 70..4400 5 60..9285 4 H(egm/oLg)lobin MSE.ADN. N 1386 1494 11401 1453 1340 5 5 4 5 4 H(eumnaittoyc)rit MSE.ADN. N 00..4012 5 00..4032 5 00..4023 4 00..4022 5 00..3092 4 M(C1V0E-15 L) MSE.ADN. N 561 571 561 571 562 5 5 4 5 4 M(C1H0E-12 g) NE MSE.ADN. N 190 200 190 201 191 5 5 4 5 4 M(CgH/CL) NE MSE.ADN. N 3405 3496 3413 34100 3335 5 5 4 5 4 R(eutniictuyl)ocytes MSE.ADN. N 00..002094 5 00..003035 5 00..002065 4 00..000269 5 00..000259 4 H(euinniztyB)odies NE MSE.ADN. N 00..000000 5 00..000000 5 00..000000 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 127 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----R-E-D--C-E-L-L--C-O-U-N-T--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ R(e1d0Eb1l2o/oLd) cell count MSE.ADN. N 80..6287 5 90..2321 + 4 H(egm/oLg)lobin MSE.ADN. N 1607 1673 5 4 H(eumnaittoyc)rit MSE.ADN. N 00..4082 5 00..5001 4 M(C1V0E-15 L) MSE.ADN. N 552 542 5 4 M(C1H0E-12 g) NE MSE.ADN. N 181 181 5 4 M(CgH/CL) NE MSE.ADN. N 3344 3355 5 4 R(eutniictuyl)ocytes MSE.ADN. N 00..002140 5 00..000085 4 H(euinniztyB)odies NE MSE.ADN. N 00..000000 5 00..000000 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 128 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----R-E-D--C-E-L-L--C-O-U-N-T--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ R(e1d0Eb1l2o/oLd) cell count MSE.ADN. N 80..0079 5 80..4453 5 H(egm/oLg)lobin MSE.ADN. N 1494 1567 5 5 H(eumnaittoyc)rit MSE.ADN. N 00..4041 5 00..4062 5 M(C1V0E-15 L) MSE.ADN. N 541 541 5 5 M(C1H0E-12 g) NE MSE.ADN. N 191 181 5 5 M(CgH/CL) NE MSE.ADN. N 3445 3413 5 5 R(eutniictuyl)ocytes MSE.ADN. N 00..002003 5 00..001054 5 H(euinniztyB)odies NE MSE.ADN. N 00..000000 5 00..000000 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 129 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----W-H-I-T-E--C-E-L-L--C-O-U-N-T--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- W(h1i0tEe9/bLl)ood cell count MMEEADNIAN SX.MDA.X XNMIN 1101..84 112..66 8.25 1133..58 116..82 11.35 1123..91 125..03 11.05 1111..14 113..94 9.05 99..14 112..84 7.85 N(euuntirtoyp)hils NE MXEMDIINAN XNMAX 00..1008 0.125 00..1008 0.115 00..0086 0.085 00..1018 0.125 00..1029 0.155 E(ousniintoyp)hils NE MXEMDIINAN XNMAX 00..0000 0.025 00..0010 0.025 00..0000 0.015 00..0000 0.015 00..0000 0.015 B(ausnoipthyi)ls NE MXEMDIINAN XNMAX 00..0011 0.025 00..0011 0.015 00..0000 0.015 00..0000 0.005 00..0000 0.015 L(yumnpihtoyc)ytes NE MXEMDIINAN XNMAX 00..8875 0.885 00..8854 0.885 00..8899 0.925 00..8874 0.895 00..8851 0.875 M(ounnoictyyt)es NE MXEMDIINAN XNMAX 00..0021 0.025 00..0021 0.035 00..0011 0.025 00..0011 0.035 00..0022 0.025 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTLTYHEDIHFIFGEHREESNTTDFORSOEMACNODNTORNOEL-T(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 130 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----W-H-I-T-E--C-E-L-L--C-O-U-N-T--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- W(h1i0tEe9/bLl)ood cell count MMEEADNIAN 77..96 1111..12 190..81 88..50 77..99 SX.MDA.X 110..30 102..82 100..84 111..63 19..34 XNMIN 6.45 10.15 8.64 7.45 6.54 N(euuntirtoyp)hils NE MXEMDIINAN XNMAX 00..0086 0.105 00..0097 0.145 00..0075 0.074 00..0097 0.115 00..0086 0.094 E(ousniintoyp)hils NE MXEMDIINAN XNMAX 00..0000 0.015 00..0011 0.025 00..0010 0.014 00..0000 0.015 00..0011 0.014 B(ausnoipthyi)ls NE MXEMDIINAN XNMAX 00..0000 0.015 00..0000 0.015 00..0000 0.004 00..0000 0.050 00..0000 0.040 L(yumnpihtoyc)ytes NE MXEMDIINAN XNMAX 00..9807 0.925 00..8882 0.895 00..9920 0.944 00..8897 0.915 00..9809 0.914 M(ounnoictyyt)es NE MXEMDIINAN XNMAX 00..0011 0.015 00..0021 0.045 00..0011 0.014 00..0011 0.025 00..0011 0.024 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 131 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----W-H-I-T-E--C-E-L-L--C-O-U-N-T--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ W(h1i0tEe9/bLl)ood cell count MMEEDAINAN SX.MDA.X XNMIN 99..71 111..19 7.05 55..44 61..42 4.24 N(euuntirtoyp)hils NE MXEMDIINAN XNMAX 00..1019 0.145 00..1018 0.384 E(ousniintoyp)hils NE MXEMDIINAN XNMAX 00..0010 0.015 00..0011 0.014 B(ausnoipthyi)ls NE MXEMDIINAN XNMAX 00..0000 0.015 00..0000 0.004 L(yumnpihtoyc)ytes NE MXEMDIINAN XNMAX 00..8864 0.875 00..8579 0.914 M(ounnoictyyt)es NE MXEMDIINAN XNMAX 00..0022 0.035 00..0011 0.024 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 132 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----W-H-I-T-E--C-E-L-L--C-O-U-N-T--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ W(h1i0tEe9/bLl)ood cell count MMEEADNIAN SX.MDA.X XNMIN 77..54 78..70 08..99 19..73 6.65 5.35 N(euuntirtoyp)hils NE MXEMDIINAN XNMAX 00..0076 0.105 00..0086 0.135 E(ousniintoyp)hils NE MXEMDIINAN XNMAX 00..0011 0.015 00..0011 0.015 B(ausnoipthyi)ls NE MXEMDIINAN XNMAX 00..0000 0.050 00..0000 0.050 L(yumnpihtoyc)ytes NE MXEMDIINAN XNMAX 00..9807 0.925 00..8893 0.925 M(ounnoictyyt)es NE MXEMDIINAN XNMAX 00..0011 0.025 00..0021 0.025 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 133 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----B-L-O-O-D--C-O-A-G-U-L-A-T-I-O-N--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- P(l1a0tEe9l/eLt)s MSE.ADN. N 1013304 1017270 111412 108557 99787 5 5 5 5 5 C(oSaegcuolnadtsi)on Time MSE.ADN. N 1014 15183 1119 1118 10143 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 134 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----B-L-O-O-D--C-O-A-G-U-L-A-T-I-O-N--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- P(l1a0tEe9l/eLt)s MSE.ADN. N 1016607 5 1122784 5 105895 4 1112240 5 1113080 4 C(oSaegcuolnadtsi)on Time MSE.ADN. N 13110 16101 5 5 997 5 10251 5 1046 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 135 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----B-L-O-O-D--C-O-A-G-U-L-A-T-I-O-N--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ P(l1a0tEe9l/eLt)s MSE.ADN. N 1015251 293385 5 4 C(oSaegcuolnadtsi)on Time MSE.ADN. N 13193 12179 5 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 136 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----B-L-O-O-D--C-O-A-G-U-L-A-T-I-O-N--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ P(l1a0tEe9l/eLt)s MSE.ADN. N 104520 5 1220850 5 C(oSaegcuolnadtsi)on Time MSE.ADN. N 15115 13157 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 137 Toxicology Study Report - PT02-0222 12.7.2 Hematology (Groups 6 - 7) Page 138 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----R-E-D--C-E-L-L--C-O-U-N-T--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ R(e1d0Eb1l2o/oLd) cell count MSE.ADN. N 07..2999 5 07..2973 5 H(egm/oLg)lobin MSE.ADN. N 1568 1542 5 5 H(eumnaittoyc)rit MSE.ADN. N 00..4062 5 00..4050 5 M(C1V0E-15 L) MSE.ADN. N 581 572 5 5 M(C1H0E-12 g) NE MSE.ADN. N 191 191 5 5 M(CgH/CL) NE MSE.ADN. N 3374 3383 5 5 R(eutniictuyl)ocytes MSE.ADN. N 00..000332 5 00..000353 5 H(euinniztyB)odies NE MSE.ADN. N 00..000000 5 00..000000 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFICFOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 139 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----R-E-D--C-E-L-L--C-O-U-N-T--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ R(e1d0Eb1l2o/oLd) cell count MSE.ADN. N 70..8226 5 07..1675 5 H(egm/oLg)lobin MSE.ADN. N 1493 1473 5 5 H(eumnaittoyc)rit MSE.ADN. N 00..4041 5 00..4031 5 M(C1V0E-15 L) MSE.ADN. N 561 561 5 5 M(C1H0E-12 g) NE MSE.ADN. N 190 190 5 5 M(CgH/CL) NE MSE.ADN. N 3432 3474 5 5 R(eutniictuyl)ocytes MSE.ADN. N 00..002063 5 00..003038 5 H(euinniztyB)odies NE MSE.ADN. N 00..000000 5 00..000000 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNROEL-T(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 140 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----W-H-I-T-E--C-E-L-L--C-O-U-N-T--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ W(h1i0tEe9/bLl)ood cell count MMEEADNIAN SX.MDA.X XNMIN 1123..50 127..85 10.15 1111..92 123..13 7.85 N(euuntirtoyp)hils NE MXEMDIINAN XNMAX 00..1120 0.155 00..1009 0.115 E(ousniintoyp)hils NE MXEMDIINAN XNMAX 00..0011 0.015 00..0011 0.015 B(ausnoipthyi)ls NE MXEMDIINAN XNMAX 00..0000 0.005 00..0000 0.005 L(yumnpihtoyc)ytes NE MXEMDIINAN XNMAX 00..8824 0.865 00..8846 0.885 M(ounnoictyyt)es NE MXEMDIINAN XNMAX 00..0021 0.035 00..0022 0.035 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 141 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----W-H-I-T-E--C-E-L-L--C-O-U-N-T--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ W(h1i0tEe9/bLl)ood cell count MMEEADNIAN 1101..85 78..92 SX.MDA.X 112..96 18..28 XNMIN 7.75 6.05 N(euuntirtoyp)hils NE MXEMDIINAN XNMAX 00..0086 0.105 00..0098 0.125 E(ousniintoyp)hils NE MXEMDIINAN XNMAX 00..0021 0.025 00..0011 0.025 B(ausnoipthyi)ls NE MXEMDIINAN XNMAX 00..0000 0.005 00..0000 0.005 L(yumnpihtoyc)ytes NE MXEMDIINAN XNMAX 00..8887 0.905 00..8884 0.895 M(ounnoictyyt)es NE MXEMDIINAN XNMAX 00..0021 0.025 00..0011 0.052 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 142 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----B-L-O-O-D--C-O-A-G-U-L-A-T-I-O-N--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ P(l1a0tEe9l/eLt)s MSE.ADN. N 1113521 5 114447 5 C(oSaegcuolnadtsi)on Time MSE.ADN. N 14121 15271 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 143 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- H-E-M-A-T-O-L-O-G-Y-----B-L-O-O-D--C-O-A-G-U-L-A-T-I-O-N--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ P(l1a0tEe9l/eLt)s MSE.ADN. N 1113049 5 107798 5 C(oSaegcuolnadtsi)on Time MSE.ADN. N 1266 13111 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL 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 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- S(omdmioulm/L) MSE.ADN. N 1412 1382 1401 1411 1421 5 5 5 5 5 P(omtmaosls/iLu)m MSE.ADN. N 60..0373 5 50..9420 5 60..1224 5 50..5285 5 50..9511 5 C(amlmcoilu/mL) MSE.ADN. N 20..4023 5 20..4034 5 20..3017 5 20..3036 5 20..3048 5 C(hmlmoorli/dLe) MSE.ADN. N 1031 1022 1011 1012 1012 5 5 5 5 5 P(hmomsoplh/oLr)us MSE.ADN. N 30..0157 5 30..1211 5 30..2113 5 20..8273 5 20..9184 5 T(outmaoll/BLi)lirubin MSE.ADN. N 50..13 40..53 50..85 61..22 50..55 5 5 5 5 5 G(lmumcools/eL) MSE.ADN. N 192..4885 5 170..1781 5 191..8565 5 161..6740 5 162..1902 5 U(ruimcolA/cLi)d MSE.ADN. N 337 273 5120 6230 5118 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 146 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- C(ruemaotli/nLi)ne MSE.ADN. N 472 463 525 474 435 5 5 5 5 5 U(rmemaolN/iLt)rogen MSE.ADN. N 60..1807 5 60..3668 5 50..7582 5 50..5464 5 70..0986 5 C(hmomloels/tLe)rol MSE.ADN. N 20..0007 5 20..0102 5 10..9261 5 10..9189 5 10..8169 5 T(rmimgolly/cLe)rides MSE.ADN. N 00..5019 5 00..4064 5 00..4107 5 00..4078 5 00..3172 5 T(ogt/aLl) Protein MSE.ADN. N 522 502 532 541 521 5 5 5 5 5 A(lgb/uLm)in MSE.ADN. N 261..00 5 241..04 5 260..28 5 260..45 5 261..61 5 A(SIAUT/L) MSE.ADN. N 8119 8111 10132 10187 10126 5 5 5 5 5 A(LIAUT/L) MSE.ADN. N 424 4140 453 594 + 6140 + 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 147 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- G(-IGUl/uLt)a.Transf. NE MSE.ADN. N 3 0 3 0 3 0 3 0 4 1 5 5 5 5 5 A(lIkUa/lLi)ne Phosphatase MSE.ADN. N 49765 36584 47744 58607 412243 5 5 5 5 5 Albumin/Globulin Ratio MSE.ADN. N 00..9093 5 00..9017 5 00..9084 5 00..9065 5 10..0055 5 G(lgo/bLu)lin MSE.ADN. N 261 262 272 271 251 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 148 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROU2P450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- S(omdmioulm/L) MSE.ADN. N 1412 1402 1402 1472 + 1452 + 5 5 5 5 5 P(omtmaosls/iLu)m MSE.ADN. N 50..1399 5 50..7267 5 60..0387 5 50..1470 5 50..8767 5 C(amlmcoilu/mL) MSE.ADN. N 20..3012 5 20..4037 5 20..3065 5 20..2032 5 20..2153 5 C(hmlmoorli/dLe) MSE.ADN. N 1042 1051 1041 1029 1015 5 5 5 5 5 P(hmomsoplh/oLr)us MSE.ADN. N 20..7242 5 20..8358 5 30..1183 5 20..8027 5 30..1331 5 T(outmaoll/BLi)lirubin MSE.ADN. N 60..04 50..03 60..34 61..94 50..97 5 5 5 5 5 G(lmumcools/eL) MSE.ADN. N 132..3061 5 131..3662 5 161..3687 5 131..9843 5 141..5442 5 U(ruimcolA/cLi)d MSE.ADN. N 4190 6296 6125 8136 112180 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 149 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROU2P405 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- C(ruemaotli/nLi)ne MSE.ADN. N 482 535 515 474 466 5 5 5 5 5 U(rmemaolN/iLt)rogen MSE.ADN. N 50..8247 5 50..8629 5 60..0621 5 15..3732 5 05..8842 5 C(hmomloels/tLe)rol MSE.ADN. N 10..9206 5 20..1287 5 20..2084 5 20..7245 5 20..3486 5 T(rmimgolly/cLe)rides MSE.DAN. N 00..4098 5 00..3054 5 00..3065 5 00..3096 5 00..4123 5 T(ogt/aLl) Protein MSE.ADN. N 542 553 522 612 563 5 5 5 5 5 A(lgb/uLm)in MSE.ADN. N 271..06 5 271..41 5 251..45 5 321..02 5 303..05 5 A(SIAUT/L) MSE.ADN. N 10113 10158 11202 1038 9165 5 5 5 5 5 A(LIAUT/L) MSE.ADN. N 414 414 487 465 536 + 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFICFOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 150 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- G(-IGUl/uLt)a.Transf. NE MSE.ADN. N 3 0 3 0 3 0 3 0 61 + 5 5 5 5 5 A(lIkUa/lLi)ne Phosphatase MSE.ADN. N 40239 39533 32608 37474 45889 5 5 5 5 5 Albumin/Globulin Ratio MSE.ADN. N 00..9095 5 10..0014 5 00..9075 5 10..1014 + 5 10..1166 + 5 G(lgo/bLu)lin MSE.ADN. N 271 272 261 291 261 5 5 5 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 151 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ S(omdmioulm/L) MSE.ADN. N 1391 1441 + 5 4 P(omtmaosls/iLu)m MSE.ADN. N 60..0218 5 40..9202 4 C(amlmcoilu/mL) MSE.ADN. N 20..2191 5 20..3019 4 C(hmlmoorli/dLe) MSE.ADN. N 1021 1072 + 5 4 P(hmomsoplh/oLr)us MSE.ADN. N 02..2944 5 02..1747 4 T(outmaoll/BLi)lirubin MSE.ADN. N 50..47 61..40 5 4 G(lmumcools/eL) MSE.ADN. N 203..1688 5 61..2034 4 U(ruimcolA/cLi)d MSE.ADN. N 4114 5154 5 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 152 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ C(ruemaotli/nLi)ne MSE.ADN. N 475 554 5 4 U(rmemaolN/iLt)rogen MSE.ADN. N 60..9980 5 115..5135 4 C(hmomloels/tLe)rol MSE.ADN. N 10..8141 5 10..9150 4 T(rmimgolly/cLe)rides MSE.ADN. N 00..4180 5 00..2160 M 3 T(ogt/aLl) Protein MSE.ADN. N 503 584 + 5 4 A(lgb/uLm)in MSE.ADN. N 231..41 5 271..89 + 4 A(SIAUT/L) MSE.ADN. N 10146 10189 5 4 A(LIAUT/L) MSE.ADN. N 499 386 5 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 153 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ G(-IGUl/uLt)a.Transf. NE MSE.ADN. N 3 0 3 0 5 4 A(lIkUa/lLi)ne Phosphatase MSE.ADN. N 32332 21641 - 5 4 Albumin/Globulin Ratio MSE.ADN. N 00..8075 5 00..9015 4 G(lgo/bLu)lin MSE.ADN. N 272 312 + 5 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 154 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ S(omdmioulm/L) MSE.ADN. N 1430 1422 5 5 P(omtmaosls/iLu)m MSE.ADN. N 40..7266 5 05..3659 + 5 C(amlmcoilu/mL) MSE.ADN. N 20..3083 5 20..3005 5 C(hmlmoorli/dLe) MSE.ADN. N 1051 1071 5 5 P(hmomsoplh/oLr)us MSE.ADN. N 20..4149 5 30..0262 + 5 T(outmaoll/BLi)lirubin MSE.ADN. N 50..26 50..55 5 5 G(lmumcools/eL) MSE.ADN. N 121..7602 5 124..6260 5 U(ruimcolA/cLi)d MSE.ADN. N 6211 6270 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APILE<D0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 155 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ C(ruemaotli/nLi)ne MSE.ADN. N 554 568 5 5 U(rmemaolN/iLt)rogen MSE.ADN. N 50..7420 5 84..5146 5 C(hmomloels/tLe)rol MSE.ADN. N 10..8344 5 10..8282 5 T(rmimgolly/cLe)rides MSE.ADN. N 00..4151 5 00..2190 5 T(ogt/aLl) Protein MSE.ADN. N 582 522 - 5 5 A(lgb/uLm)in MSE.ADN. N 281..41 5 240..28 5 A(SIAUT/L) MSE.ADN. N 9260 10304 5 5 A(LIAUT/L) MSE.AD.N N 345 2413 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 156 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 27-JAN-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROU2P405 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ G(-IGUl/uLt)a.Transf. NE MSE.ADN. N 3 0 3 0 5 5 A(lIkUa/lLi)ne Phosphatase MSE.ADN. N 22560 18752 5 5 Albumin/Globulin Ratio MSE.ADN. N 00..9085 5 00..8063 5 G(lgo/bLu)lin MSE.ADN. N 292 281 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 157 Toxicology Study Report - PT02-0222 12.7.4 Clinical chemistry (Groups 6 - 7) Page 158 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ S(omdmioulm/L) MSE.ADN. N 1381 1401 + 5 5 P(omtmaosls/iLu)m MSE.ADN. N 50..6171 5 50..0291 5 C(amlmcoilu/mL) MSE.ADN. N 20..4095 5 20..4056 5 C(hmlmoorli/dLe) MSE.ADN. N 1021 1021 5 5 P(hmomsoplh/oLr)us MSE.ADN. N 30..1100 5 20..7183 5 T(outmaoll/BLi)lirubin MSE.ADN. N 40..83 50..02 5 5 G(lmumcools/eL) MSE.ADN. N 191..3122 5 125..2712 5 U(ruimcolA/cLi)d MSE.ADN. N 247 3135 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 159 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ C(ruemaotli/nLi)ne MSE.ADN. N 473 473 5 5 U(rmemaolN/iLt)rogen MSE.ADN. N 50..9982 5 50..5749 5 C(hmomloels/tLe)rol MSE.ADN. N 20..0102 5 20..1183 5 T(rmimgolly/cLe)rides MSE.ADN. N 00..5057 5 00..6105 5 T(ogt/aLl) Protein MSE.ADN. N 521 552 + 5 5 A(lgb/uLm)in MSE.ADN. N 240..88 5 270..65 + 5 A(SIAUT/L) MSE.ADN. N 908 7184 5 5 A(LIAUT/L) MSE.ADN. N 448 406 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 160 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ G(-IGUl/uLt)a.Transf. NE MSE.ADN. N 4 0 4 0 5 5 A(lIkUa/lLi)ne Phosphatase MSE.ADN. N 36350 44288 + 5 5 Albumin/Globulin Ratio MSE.ADN. N 00..9035 5 10..0007 5 G(lgo/bLu)lin MSE.ADN. N 217 228 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 161 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ S(omdmioulm/L) MSE.ADN. N 1412 1411 5 5 P(omtmaosls/iLu)m MSE.ADN. N 50..6423 5 50..1193 5 C(amlmcoilu/mL) MSE.ADN. N 20..4111 5 20..4025 5 C(hmlmoorli/dLe) MSE.ADN. N 1062 1062 5 5 P(hmomsoplh/oLr)us MSE.ADN. N 30..0126 5 20..6085 5 T(outmaoll/BLi)lirubin MSE.ADN. N 50..35 50..28 5 5 G(lmumcools/eL) MSE.DAN. N 152..1526 5 142..1026 5 U(ruimcolA/cLi)d MSE.ADN. N 606 6222 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 162 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ C(ruemaotli/nLi)ne MSE.ADN. N 494 525 5 5 U(rmemaolN/iLt)rogen MSE.ADN. N 50..0625 5 50..1764 5 C(hmomloels/tLe)rol MSE.ADN. N 20..3261 5 20..2282 5 T(rmimgolly/cLe)rides MSE.ADN. N 00..4080 5 00..3077 5 T(ogt/aLl) Protein MSE.ADN. N 553 591 5 5 A(lgb/uLm)in MSE.ADN. N 271..04 5 281..81 5 A(SIAUT/L) MSE.ADN. N 11284 11138 5 5 A(LIAUT/L) MSE.ADN. N 433 434 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 163 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- C-L-I-N-I-C-A-L--C-H-E-M-I-S-T-R-Y--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ G(-IGUl/uLt)a.Transf. NE MSE.ADN. N 4 0 4 0 5 5 A(lIkUa/lLi)ne Phosphatase MSE.ADN. N 30677 312086 5 5 Albumin/Globulin Ratio MSE.ADN. N 00..9054 5 00..9075 5 G(lgo/bLu)lin MSE.ADN. N 282 301 5 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(AIPLE<D0T.E0S5T)S. FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 164 Toxicology Study Report - PT02-0222 12.7.5 Urinalysis (Groups 1 - 5) Page 165 Toxicology Study Report - PT02-0222 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- U-R-I-N-A-L-Y-S-I-S--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- V(omlLu)me MSE.ADN. N 21..91 21..90 20..58 41..04 51..32 + 5 5 5 5 5 pH Value (sq) NE MXEMDIINAN XMAX 7 7 7 6 7 6 6 6 7 6 7 7 7 7 7 S(pge/cLi)fic Weight MSE.ADN. N 105194 5 106120 5 106111 5 10507 5 10398 5 WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 166 Toxicology Study Report - PT02-0222 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- U-R-I-N-A-L-Y-S-I-S--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- V(omlLu)me MSE.ADN. N 31..15 30..18 40..83 31..72 63..26 5 5 5 5 5 pH Value (sq) NE MXEMDIINAN XMAX 7 6 7 7 7 7 7 6 6 6 8 7 7 8 6 S(pge/cLi)fic Weight MSE.ADN. N 103190 4 104170 5 10327 5 10362 5 103143 5 WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNTOROSLTATISTICAL EVALUATION Page 167 Toxicology Study Report - PT02-0222 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- U-R-I-N-A-L-Y-S-I-S--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ V(omlLu)me MSE.ADN. N 43..97 42..29 5 4 pH Value (sq) NE MXEMDIINAN XMAX 7 7 8 8 8 8 S(pge/cLi)fic Weight MSE.ADN. N 104290 5 104118 M 3 WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 168 Toxicology Study Report - PT02-0222 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- U-R-I-N-A-L-Y-S-I-S--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ V(omlLu)me MSE.ADN. N 52..92 42..73 5 5 pH Value (sq) NE MXEMDIINAN XMAX 7 7 6 7 8 7 S(pge/cLi)fic Weight MSE.ADN. N 10339 5 104110 5 WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 169 Toxicology Study Report - PT02-0222 12.7.6 Urinalysis (Groups 6 - 7) Page 170 Toxicology Study Report - PT02-0222 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- U-R-I-N-A-L-Y-S-I-S--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ V(omlLu)me MSE.ADN. N 30..78 52..93 5 5 pH Value (sq) NE MXEMDIINAN XMAX 7 6 7 6 7 7 S(pge/cLi)fic Weight MSE.ADN. N 10447 5 103152 5 WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNROEL-T(APILE<D0T.E0S5T)S. FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 171 Toxicology Study Report - PT02-0222 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- U-R-I-N-A-L-Y-S-I-S--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ V(omlLu)me MSE.ADN. N 41..07 30..95 5 5 pH Value (sq) NE MXEMDIINAN XMAX 6 6 6 6 7 7 S(pge/cLi)fic Weight MSE.ADN. N 103180 5 10376 5 WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL 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 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- BODY WEIGHT (g) NE MSE.ADN. N 27243..02 5 27198..84 5 26193..88 5 26211..26 5 23119..29 5 H(ega)rt Weight MSE.ADN. N 10..010250 5 10..112294 5 00..807914 5 00..903998 5 00..800899 5 L(igv)er Weight MSE.ADN. N 111..213086 5 100..799220 5 111..008149 5 121..940645 + 5 141..131782 + 5 K(igd)neys Weight MSE.ADN. N 20..029779 5 20..014895 5 20..100952 5 20..222591 5 10..906948 5 S(pgl)een Weight MSE.ADN. N 00..811475 5 00..715038 5 00..607760 5 00..604911 5 00..508930 5 T(egs)tes Weight MSE.ADN. N 30..221767 5 30..534335 5 30..229576 5 30..438313 5 30..406736 5 E(pgi)didymis Weight MSE.ADN. N 00..802746 5 00..806612 5 00..802667 5 00..801530 5 00..708900 5 A(dgr)enals Weight MSE.ADN. N 00..00405262 5 00..00405524 5 00..00402464 5 00..00407400 5 00..00505587 + 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 174 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- B(rga)in Weight MSE.ADN. N 10..803963 5 10..805608 5 10..704766 5 01..078794 5 01..076607 5 T(hgy)mus Weight MSE.ADN. N 00..407494 5 00..501316 5 00..400697 5 00..404759 5 00..304563 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 175 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-F-E-M-A-L-E-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- BODY WEIGHT (g) NE MSE.ADN. N 2109..64 5 1954..09 5 2055..80 5 1998..87 5 18141..67 5 H(ega)rt Weight MSE.ADN. N 00..707660 5 00..802789 5 00..705740 5 00..701302 5 00..606478 5 L(igv)er Weight MSE.ADN. N 80..450786 5 70..249346 5 80..354067 5 90..860646 + 5 131..789124 + 5 K(igd)neys Weight MSE.ADN. N 10..416013 5 10..300549 5 10..511131 5 10..912492 + 5 10..614426 + 5 S(pgl)een Weight MSE.ADN. N 00..604490 5 00..604713 5 00..701536 5 00..508511 5 00..405368 5 A(dgr)enals Weight MSE.ADN. N 00..00600945 5 00..00504383 5 00..00509700 5 00..00509308 5 00..00508966 5 B(rga)in Weight MSE.ADN. N 10..708514 5 10..700993 5 10..702963 5 10..608543 5 10..615095 5 T(hgy)mus Weight MSE.ADN. N 00..400776 5 00..309594 5 00..403700 5 00..305242 5 00..300697 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 176 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ BODY WEIGHT (g) NE MSE.ADN. N 32500..08 5 19345..09 4 H(ega)rt Weight MSE.ADN. N 10..128582 5 00..715281 4 L(igv)er Weight MSE.ADN. N 102..424368 5 51..734783 4 K(igd)neys Weight MSE.ADN. N 20..340031 5 01..344986 4 S(pgl)een Weight MSE.ADN. N 00..717225 5 00..412285 4 T(egs)tes Weight MSE.ADN. N 30..541604 5 30..323924 4 E(pgi)didymis Weight MSE.ADN. N 10..114230 5 00..911300 4 A(dgr)enals Weight MSE.ADN. N 00..00408666 5 00..00405402 4 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< 0F.O0R5)L.OWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 177 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ B(rga)in Weight MSE.ADN. N 10..913490 5 10..713207 4 T(hgy)mus Weight MSE.ADN. N 00..037825 5 00..121072 4 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 178 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-F-E-M-A-L-E-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ BODY WEIGHT (g) NE MSE.ADN. N 22157..65 5 18299..49 5 H(ega)rt Weight MSE.ADN. N 00..801664 5 00..170110 5 L(igv)er Weight MSE.ADN. N 70..585664 5 61..530723 5 K(igd)neys Weight MSE.ADN. N 10..507722 5 10..411827 5 S(pgl)een Weight MSE.ADN. N 00..617243 5 00..513171 5 A(dgr)enals Weight MSE.ADN. N 00..00603765 5 00..00501949 5 B(rga)in Weight MSE.ADN. N 10..803772 5 10..707646 5 T(hgy)mus Weight MSE.ADN. N 00..305500 5 00..031614 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 179 Toxicology Study Report - PT02-0222 12.9 ORGAN WEIGHTS (GROUPS 6 - 7) Page 180 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ BODY WEIGHT (g) NE MSE.ADN. N 29157..65 5 30275..84 5 H(ega)rt Weight MSE.ADN. N 10..117919 5 10..118185 5 L(igv)er Weight MSE.ADN. N 121..232021 5 121..187843 5 K(igd)neys Weight MSE.ADN. N 20..421018 5 20..433204 5 S(pgl)een Weight MSE.ADN. N 00..800914 5 00..800522 5 T(egs)tes Weight MSE.ADN. N 30..519984 5 30..527893 5 E(pgi)didymis Weight MSE.ADN. N 00..808586 5 00..804485 5 A(dgr)enals Weight MSE.ADN. N 00..00501720 5 00..00406661 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 181 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ B(rga)in Weight MSE.ADN. N 10..808735 5 10..900706 5 T(hgy)mus Weight MSE.ADN. N 00..151760 5 00..151804 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPTS< F0O.R05L)O.WER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 182 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- O-R-G-A-N--W-E-I-G-H-T-S--(-F-E-M-A-L-E-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ BODY WEIGHT (g) NE MSE.ADN. N 1909..68 5 19191..07 5 H(ega)rt Weight MSE.ADN. N 00..707784 5 00..709638 5 L(igv)er Weight MSE.ADN. N 60..964387 5 70..498601 5 K(igd)neys Weight MSE.ADN. N 01..037352 5 01..142117 5 S(pgl)een Weight MSE.ADN. N 00..601630 5 00..607792 5 A(dgr)enals Weight MSE.ADN. N 00..00508807 5 00..00505742 5 B(rga)in Weight MSE.ADN. N 10..712103 5 10..705973 5 T(hgy)mus Weight MSE.ADN. N 00..302823 5 00..037891 5 ------------------------------------------------------------------------------------------------------------------------ TI-FTEASLTL.HTIWGOH-ETRAIDLOESDESTEASRTE FSOIRGNTIHFEICHAINGTHLEYSTDIDFOFSEEREANNTDFORNOEM-TCAOINLTERDOLTE(SPT<S 0F.O0R5)L.OWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 183 Toxicology Study Report - PT02-0222 12.10 RELATIVE ORGAN WEIGHTS (GROUPS 1 - 5) Page 184 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- BODY WEIGHT (g) NE MSE.ADN. N 27243..02 5 27198..84 5 26193..88 5 22611..62 5 21391..92 5 Heart Weight MSE.ADN. N 30..616839 5 40..022474 5 30..233307 5 30..518194 5 30..419856 5 Liver Weight MSE.ADN. N 400..998735 5 380..593963 5 411..092805 5 491..360210 + 5 612..066510 + 5 Kidneys Weight MSE.ADN. N 70..653994 5 70..321884 5 70..851296 5 80..563720 5 80..455213 5 Spleen Weight MSE.ADN. N 20..937930 5 20..639765 5 20..520471 5 20..425419 5 20..522803 5 Testes Weight MSE.ADN. N 111..706278 5 102..764610 5 102..523161 5 103..934487 + 5 115..309752 + 5 Epididymis Weight MSE.ADN. N 30..032535 5 30..028654 5 30..026771 5 30..111075 5 30..349847 5 Adrenals Weight MSE.ADN. N 00..10617864 5 00..10622435 5 00..10518932 5 00..10821414 5 00..20411238 + 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 185 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- Brain Weight MSE.ADN. N 60..742777 5 60..622558 5 60..448651 5 60..841443 5 70..678185 + 5 Thymus Weight MSE.ADN. N 10..705701 5 10..813746 5 10..522935 5 10..731326 5 10..419761 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 186 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--F-E-M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP 23 GROUP135 GROUP640 GROUP2450 ----------------------------------------------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g----------m-g-/-k-g-------------- BODY WEIGHT (g) NE MSE.ADN. N 2109..64 5 1954..09 5 2055..80 5 1998..87 5 18141..67 5 Heart Weight MSE.ADN. N 30..628651 5 40..255042 5 30..636680 5 30..526600 5 30..611461 5 Liver Weight MSE.ADN. N 392..912495 5 371..348636 5 401..583899 5 492..077987 + 5 745..571100 + 5 Kidneys Weight MSE.ADN. N 60..965425 5 60..638380 5 70..334841 5 90..665791 + 5 80..970127 + 5 Spleen Weight MSE.ADN. N 30..018019 5 30..249012 5 30..426636 5 20..910863 5 20..406976 5 Adrenals Weight MSE.ADN. N 00..20858528 5 00..20821033 5 00..20837725 5 00..20926810 5 00..30232216 5 Brain Weight MSE.ADN. N 80..457211 5 80..767885 5 80..338664 5 80..433189 5 80..939656 5 Thymus Weight MSE.ADN. N 10..933616 5 20..024522 5 20..038193 5 10..707734 5 10..637477 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 187 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ BODY WEIGHT (g) NE MSE.ADN. N 32500..08 5 19345..09 4 Heart Weight MSE.ADN. N 30..629438 5 30..933642 4 Liver Weight MSE.ADN. N 322..404119 5 291..398284 4 Kidneys Weight MSE.ADN. N 70..139444 5 70..655789 4 Spleen Weight MSE.ADN. N 20..422434 5 20..127627 4 Testes Weight MSE.ADN. N 110..072844 5 174..607055 + 4 Epididymis Weight MSE.ADN. N 30..630352 5 40..743216 + 4 Adrenals Weight MSE.ADN. N 00..10513911 5 00..20325752 + 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 188 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ Brain Weight MSE.ADN. N 60..196534 5 91..028786 + 4 Thymus Weight MSE.ADN. N 10..210473 5 00..947582 4 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 189 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 17-DEC-2002 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -R-E-C-O-V-E-R-Y--V-A-L-U-E----------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--F-E-M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP2450 --------------------------------------------------------------------m-g-/-k-g--------------------------------m-g-/-k-g------------ BODY WEIGHT (g) NE MSE.ADN. N 22157..65 5 18299..49 5 Heart Weight MSE.ADN. N 30..612700 5 30..716912 5 Liver Weight MSE.ADN. N 333..511205 5 343..232190 5 Kidneys Weight MSE.ADN. N 06..499934 5 07..653026 5 Spleen Weight MSE.ADN. N 20..947191 5 20..823835 5 Adrenals Weight MSE.ADN. N 00..20855740 5 00..20731650 5 Brain Weight MSE.ADN. N 80..613778 5 19..353393 + 5 Thymus Weight MSE.ADN. N 10..514597 5 10..624133 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 190 Toxicology Study Report - PT02-0222 12.11 RELATIVE ORGAN WEIGHTS (GROUPS 6 - 7) Page 191 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ BODY WEIGHT (g) NE MSE.ADN. N 29157..65 5 30275..84 5 Heart Weight MSE.ADN. N 30..944903 5 30..826539 5 Liver Weight MSE.ADN. N 412..246444 5 393..358339 5 Kidneys Weight MSE.ADN. N 80..135300 5 70..889154 5 Spleen Weight MSE.ADN. N 20..720359 5 20..611339 5 Testes Weight MSE.ADN. N 120..148950 5 110..685364 5 Epididymis Weight MSE.ADN. N 30..010578 5 20..726360 5 Adrenals Weight MSE.ADN. N 00..10712786 5 00..10522321 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 192 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ Brain Weight MSE.ADN. N 06..337875 5 06..417909 5 Thymus Weight MSE.ADN. N 10..932349 5 10..829717 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 193 Toxicology Study Report - PT02-0222 ATOX 10.2 PROVANTIS RUN DATE: 05-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- R-E-L-A-T-I-V-E--O-R-G-A-N--W-E-I-G-H-T-S--F-E-M-A-L-E-S--(-g-/-k-g--b-d-w-t-)- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ BODY WEIGHT (g) NE MSE.ADN. N 1909..68 5 19191..07 5 Heart Weight MSE.ADN. N 40..027577 5 30..928017 5 Liver Weight MSE.ADN. N 361..359442 5 373..409115 5 Kidneys Weight MSE.ADN. N 60..928275 5 70..131646 5 Spleen Weight MSE.ADN. N 30..232128 5 30..420259 5 Adrenals Weight MSE.ADN. N 00..30033872 5 00..20738237 5 Brain Weight MSE.ADN. N 90..022927 5 80..865506 5 Thymus Weight MSE.ADN. N 10..638636 5 10..931962 5 ------------------------------------------------------------------------------------------------------------------------ WIIFLCAOLXLONH-ITGEHSETR.DTOWSOE-STAAIRLEEDSITGENSITFIFCOARNTTLHYEDHIIFGFHEERSETNTDOFSREOMANCDONOTNREO-LT(APIL<ED0.T0E5S)T.S FOR LOWER DOSES, +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL EVALUATION Page 194 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 Page 198 Toxicology Study Report - PT02-0222 12.12.3 Motor activity (Groups 1 - 5) Page 199 Toxicology Study Report - PT02-0222 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 RUN DATE: 11-MAR-2003 SUMMARY AND STATISTICAL EVALUATION STUDY : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -F-I-N-A-L--V-A-L-U-E-------------------------------------------------------------------------------------------------------------- N-E-U-R-O-T-O-X-I-C-O-L-O-G-I-C-A-L--E-V-A-L-U-A-T-I-O-N- GROUP 10 GROUP0.23 ------------------------------------------------------------------m-g-/-k-g-/-d------------------------------m-g-/-k-g-/-d------------ N(UMMABLEERS)OF MOVEMENTS MSE.ADN. N 53748..46 5 61455..64 5 N(UFMEBMEARLEOSF) MOVEMENTS MSE.ADN. N 57889..60 5 614229..60 5 ------------------------------------------------------------------------------------------------------------------------ WILCOXON-TEST. SEQUENTIALLY REJECTIVE MULTIPLE COMPARISONS (P < 0.05). +M/- :: SEIVGANLIUFAITCIAONNTLNYOTDPIOFSFSEIRBELNET FRNOEM :CONNOTRSOTLATISTICAL 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 Date: 16-Dec-2002 Page: 1 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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 . . . . . 6 119 142 173 192 219 241 265 279 293 304 324 333 356 . 353 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 116.7 138.4 158.4 177.2 204.3 224.9 245.2 257.0 266.0 279.6 295.8 304.2 319.6 . 320.0 S.D. 5.4 7.3 14.8 17.9 20.2 19.5 23.5 26.5 30.4 31.3 43.7 44.4 48.4 . 50.8 N 10 10 10 10 10 10 10 10 10 10 5 5 5 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 204 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 2 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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 1f 31 110 126 143 147 152 168 175 178 188 199 . . . . . 32 119 133 149 158 173 177 183 188 201 210 . . . . . 33 109 127 148 159 172 182 194 198 210 221 . . . . . 34 117 135 155 170 180 188 197 202 214 219 . . . . . 35 111 125 141 154 165 173 184 189 196 204 . . . . . 36 111 127 141 155 167 174 186 194 202 204 212 214 218 . 213 37 118 132 152 162 176 187 199 206 224 233 239 235 237 . 238 38 110 123 139 146 155 163 173 179 187 193 200 201 197 . 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 113.1 129.2 147.1 158.2 169.5 178.0 186.7 193.3 204.3 211.8 220.4 221.6 226.4 . 225.6 S.D. 4.6 4.5 5.9 8.1 9.9 8.4 8.6 9.6 11.9 12.0 14.9 14.2 18.9 . 17.5 N 10 10 10 10 10 10 10 10 10 10 5 5 5 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 205 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 3 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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. 3.7 5.1 11.5 12.7 13.8 12.7 13.7 12.4 15.3 13.8 . . . . . N 5 5 5 5 5 5 5 5 5 5 0 0 0 0 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 Page 206 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 4 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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. 3.0 3.4 3.9 5.4 4.3 5.1 4.1 4.6 6.0 5.0 . . . . . N 5 5 5 5 5 5 5 5 5 5 0 0 0 0 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 Page 207 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 5 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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. 7.9 8.6 5.7 9.1 11.2 13.0 15.4 17.4 19.9 21.6 . . . . . N 5 5 5 5 5 5 5 5 5 5 0 0 0 0 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 Page 208 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 6 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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. 4.2 2.6 13.9 12.1 10.5 9.2 9.4 11.0 10.4 8.7 . . . . . N 5 5 5 5 5 5 5 5 5 5 0 0 0 0 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 Page 209 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 7 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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 . . . . . 26 125 148 144 156 181 199 220 226 241 243 235 226 222 . 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 120.8 145.0 138.2 153.9 176.1 191.6 212.8 215.9 221.1 224.9 214.6 201.8 191.2 133.0 194.0 S.D. 5.8 6.3 10.9 11.0 10.8 15.4 14.7 16.0 24.9 24.8 23.6 26.4 37.5 . 35.9 N 10 10 10 10 10 10 10 10 10 10 5 5 5 1 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 210 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 8 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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 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 . . . . . 54 107 120 112 130 150 153 164 169 178 182 . . . . . 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 . 218 57 116 130 126 145 156 167 181 181 190 197 198 201 204 . 186 58 115 131 130 146 158 172 185 189 198 203 207 212 207 . 184 59 105 118 115 110 129 140 153 160 161 140 149 146 150 . 144 60 113 127 131 142 157 165 174 175 182 188 197 206 210 . 215 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 112.2 126.6 126.1 139.2 154.4 162.8 175.0 178.4 183.9 186.0 193.6 197.2 198.4 . 189.4 S.D. 4.8 5.4 8.0 12.3 11.0 11.8 12.6 12.2 14.1 20.1 26.2 29.6 27.8 . 29.9 N 10 10 10 10 10 10 10 10 10 10 5 5 5 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 211 Toxicology Study Report - PT02-0222 RTA051-02/00 PROVANTIS Date: 16-Dec-2002 Page: 1 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Bodyweights (g) --------------- Day numbers relative to Start Date Group Animal Sex Number -3 1 4 8 11 15 18 22 25 29 5m 61 112 137 157 190 215 238 260 274 290 298 62 108 128 146 177 195 213 232 250 262 272 63 116 135 153 179 197 219 229 243 253 256 64 113 134 155 183 205 231 242 264 277 274 65 112 136 153 187 213 239 259 284 297 299 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 112.2 134.0 152.8 183.2 205.0 228.0 244.4 263.0 275.8 279.8 S.D. 2.9 3.5 4.1 5.4 9.1 11.6 14.6 16.8 18.5 18.4 N 5 5 5 5 5 5 5 5 5 5 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ * = 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 PROVANTIS Date: 16-Dec-2002 Page: 2 Bodyweights - Individual Bodyweights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Bodyweights (g) --------------- Day numbers relative to Start Date Group Animal Sex Number -3 1 4 8 11 15 18 22 25 29 5f 66 112 124 137 148 159 170 174 185 191 198 67 107 122 137 151 163 175 181 189 196 200 68 101 117 129 146 152 161 166 180 186 188 69 107 120 133 147 159 169 179 189 193 197 70 106 120 136 152 156 167 181 181 188 192 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 106.6 120.6 134.4 148.8 157.8 168.4 176.2 184.8 190.8 195.0 S.D. 3.9 2.6 3.4 2.6 4.1 5.1 6.4 4.3 4.0 4.9 N 5 5 5 5 5 5 5 5 5 5 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ * = 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 PROVANTIS Date: 03-Mar-2003 Page: 1 Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Bodyweights (g) --------------- Day numbers relative to Start Date Group Animal Sex Number -4 1 4 8 11 15 18 22 25 29 6m 71 107 139 161 189 214 245 267 286 296 307 72 100 133 156 185 211 241 259 284 297 311 73 111 141 159 183 205 223 231 245 256 268 74 106 140 159 190 216 239 257 270 290 303 75 107 143 165 193 216 235 253 267 278 289 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 106.2 139.2 160.0 188.0 212.4 236.6 253.4 270.4 283.4 295.6 S.D. 4.0 3.8 3.3 4.0 4.6 8.4 13.5 16.5 17.1 17.5 N 5 5 5 5 5 5 5 5 5 5 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ * = 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 PROVANTIS Date: 03-Mar-2003 Page: 2 Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Bodyweights (g) --------------- Day numbers relative to Start Date Group Animal Sex Number -4 1 4 8 11 15 18 22 25 29 6f 81 106 127 138 151 161 171 173 182 184 191 82 110 128 132 141 155 164 173 181 184 189 83 99 117 125 133 145 153 162 169 172 176 84 103 123 138 146 158 166 175 181 182 194 85 106 128 139 154 165 176 187 192 198 203 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 104.8 124.6 134.4 145.0 156.8 166.0 174.0 181.0 184.0 190.6 S.D. 4.1 4.7 5.9 8.3 7.6 8.6 8.9 8.2 9.3 9.8 N 5 5 5 5 5 5 5 5 5 5 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ * = 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 PROVANTIS Date: 03-Mar-2003 Page: 3 Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Bodyweights (g) --------------- Day numbers relative to Start Date Group Animal Sex Number -4 1 4 8 11 15 18 22 25 29 7m 76 105 141 164 191 215 242 265 282 294 308 77 105 137 155 183 204 237 260 288 288 312 78 113 141 162 187 207 227 240 246 261 266 79 110 148 167 197 223 250 272 292 300 319 80 111 144 170 198 229 256 283 306 317 334 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 108.8 142.2 163.6 191.2 215.6 242.4 264.0 282.8 292.0 307.8 S.D. 3.6 4.1 5.7 6.4 10.5 11.3 16.0 22.4 20.4 25.4 N 5 5 5 5 5 5 5 5 5 5 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ * = 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 PROVANTIS Date: 03-Mar-2003 Page: 4 Bodyweights - Individual Bodyweights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Bodyweights (g) --------------- Day numbers relative to Start Date Group Animal Sex Number -4 1 4 8 11 15 18 22 25 29 7f 86 97 118 130 137 148 157 165 175 174 185 87 105 125 142 156 163 179 186 191 193 201 88 105 128 138 147 159 172 172 186 188 195 89 104 128 142 153 168 176 179 184 187 197 90 102 127 144 159 169 179 190 203 201 217 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ Mean 102.6 125.2 139.2 150.4 161.4 172.6 178.4 187.8 188.6 199.0 S.D. 3.4 4.2 5.6 8.7 8.5 9.2 10.2 10.3 9.9 11.7 N 5 5 5 5 5 5 5 5 5 5 ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ ------ * = 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 PROVANTIS Date: 16-Dec-2002 Page: 1 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 1m 1 2 3 4 5 6 7 8 9 10 ------ ---- Mean S.D. N ------ ---- 118.75 127.20 123.58 116.48 115.15 116.99 124.63 127.75 109.83 116.54 -----119.69 5.84 10 ------ 100.33 110.11 104.45 97.13 108.93 97.46 110.83 112.87 92.75 100.33 -----103.52 6.90 10 ------ 91.43 101.91 95.81 88.40 109.22 90.59 109.49 110.22 84.79 95.57 -----97.74 9.41 10 ------ 88.58 98.03 92.33 84.71 100.58 82.48 102.73 99.12 75.33 85.82 -----90.97 9.05 10 ------ 85.10 92.10 87.73 79.09 91.19 81.16 101.45 95.00 74.82 84.08 -----87.17 7.98 10 ------ 79.70 84.97 82.16 72.29 82.34 76.28 96.50 88.33 70.96 79.75 -----81.33 7.56 10 ------ 69.38 73.41 71.56 61.39 69.95 69.12 89.74 79.49 63.95 72.31 -----72.03 7.96 10 ------ 57.17 60.42 58.45 49.06 56.50 59.44 77.98 68.55 54.49 62.85 -----60.49 8.00 10 ------ 64.25 68.29 66.01 55.03 64.13 57.17 75.35 66.02 51.87 60.74 -----62.89 6.90 10 ------ . . . . . 65.92 87.90 77.82 60.35 70.41 -----72.48 10.73 5 ------ . . . . . 62.51 84.15 76.19 58.09 67.43 -----69.67 10.52 5 ------ . . . . . 60.23 81.85 73.84 56.39 66.40 -----67.74 10.29 5 ------ . . . . . 47.20 64.61 58.41 43.86 52.70 -----53.36 8.38 5 ------ 83.85 90.72 86.90 78.18 88.67 74.35 92.86 87.20 69.04 78.07 -----82.98 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 PROVANTIS Date: 16-Dec-2002 Page: 2 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 1f 31 32 33 34 35 36 37 38 39 40 ------ ---Mean S.D. N ------ ---- 110.17 103.17 110.17 103.17 110.17 108.12 102.93 110.44 100.92 109.50 -----106.88 3.83 10 ------ 108.18 103.19 105.82 100.34 109.40 107.84 101.76 110.31 99.31 104.71 -----105.09 3.86 10 ------ 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 ------ 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 -----78.52 5.51 5 ------ . . . . . 69.17 62.17 73.48 64.34 65.34 -----66.90 4.47 5 ------ . . . . . 70.14 64.19 76.13 63.79 65.44 -----67.94 5.23 5 ------ . . . . . 62.80 56.98 68.01 56.51 56.74 -----60.21 5.09 5 ------ 85.14 79.85 79.40 76.21 82.63 79.74 73.90 84.46 74.46 76.58 -----79.24 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 PROVANTIS Date: 16-Dec-2002 Page: 3 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 ------ ---Mean S.D. N ------ ---- 119.75 125.43 114.98 117.97 117.97 -----119.22 3.87 5 ------ 105.54 102.69 93.27 97.13 100.00 -----99.73 4.77 5 ------ 100.87 91.91 83.29 87.51 91.64 -----91.04 6.52 5 ------ 92.90 86.28 77.12 82.37 83.42 -----84.42 5.78 5 ------ 82.33 80.13 70.67 74.85 74.85 -----76.57 4.65 5 ------ 76.30 77.52 67.60 71.76 70.86 -----72.81 4.07 5 ------ 70.59 72.89 63.64 67.74 66.40 -----68.25 3.60 5 ------ 57.29 60.08 52.12 54.95 54.11 -----55.71 3.07 5 ------ 62.65 66.39 57.31 60.31 59.64 -----61.26 3.44 5 ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ 85.36 84.81 75.56 79.40 79.88 -----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 PROVANTIS Date: 16-Dec-2002 Page: 4 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 ------ ---Mean S.D. N ------ ---- 107.63 108.50 105.93 111.67 112.13 -----109.17 2.66 5 ------ 100.00 100.00 96.52 100.73 103.75 -----100.20 2.57 5 ------ 88.89 91.58 87.18 88.60 93.79 -----90.01 2.65 5 ------ 78.53 81.27 77.11 77.34 82.32 -----79.31 2.36 5 ------ 74.68 74.68 72.14 72.76 77.17 -----74.29 1.97 5 ------ 71.86 71.08 70.51 71.08 74.93 -----71.89 1.76 5 ------ 70.30 70.30 70.49 69.58 73.55 -----70.84 1.55 5 ------ 60.10 59.80 60.10 58.48 62.96 -----60.29 1.64 5 ------ 63.90 63.58 63.90 62.22 67.01 -----64.12 1.76 5 ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ 79.54 80.09 78.21 79.16 83.07 -----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 PROVANTIS Date: 16-Dec-2002 Page: 5 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 ------ ---Mean S.D. N ------ ---- 127.32 118.12 110.17 121.35 110.56 -----117.50 7.31 5 ------ 88.01 82.46 79.66 82.46 77.56 -----82.03 3.93 5 ------ 96.04 89.47 89.18 87.75 84.00 -----89.29 4.36 5 ------ 96.91 89.71 87.22 86.98 82.85 -----88.73 5.19 5 ------ 93.66 87.63 82.73 82.73 80.38 -----85.43 5.31 5 ------ 88.66 82.24 76.86 76.69 76.03 -----80.10 5.40 5 ------ 82.98 75.94 71.00 70.01 71.15 -----74.22 5.41 5 ------ 64.06 59.02 54.09 52.85 55.27 -----57.06 4.54 5 ------ 79.11 73.10 65.93 64.61 68.07 -----70.16 5.95 5 ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ 90.75 84.19 79.65 80.60 78.43 -----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 PROVANTIS Date: 16-Dec-2002 Page: 6 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 ------ ---Mean S.D. N ------ ---- 118.33 114.98 110.08 114.98 113.60 -----114.39 2.98 5 ------ 69.92 69.66 66.67 77.50 69.14 -----70.58 4.08 5 ------ 86.46 89.52 85.01 108.26 87.96 -----91.44 9.55 5 ------ 75.91 78.80 77.57 91.54 77.81 -----80.33 6.35 5 ------ 73.56 74.42 75.07 85.05 74.42 -----76.50 4.81 5 ------ 71.07 71.47 69.92 79.38 70.68 -----72.50 3.89 5 ------ 73.65 74.43 73.07 83.23 74.04 -----75.68 4.25 5 ------ 59.16 60.20 60.97 68.29 61.28 -----61.98 3.62 5 ------ 62.05 64.68 64.52 70.84 65.16 -----65.45 3.25 5 ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ . . . . . -----. . . ------ 76.68 77.57 75.88 86.56 77.12 -----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 PROVANTIS Date: 16-Dec-2002 Page: 7 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 4m 21 22 23 24 25 26 27 28 29 30 ------ ---Mean S.D. N ------ ---- 121.26 128.22 116.20 129.72 126.77 254.95 269.77 265.65 254.95 284.08 -----195.16 75.08 10 ------ 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 ------ 76.77 85.59 84.44 83.61 87.96 79.11 89.90 83.27 79.11 93.07 -----84.28 5.11 10 ------ 79.45 87.61 87.35 84.30 90.63 87.83 95.48 90.52 85.30 103.14 -----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 -----77.61 10.03 5 ------ . . . . . 42.52 46.12 52.69 42.06 54.75 -----47.63 5.82 5 ------ . . . . . 35.04 39.45 46.18 34.06 49.37 -----40.82 6.76 5 ------ . . . . . 40.44 48.14 55.71 38.18 63.95 -----49.28 10.71 5 ------ 77.18 83.24 80.23 78.84 87.10 77.15 84.92 84.40 76.30 94.50 -----82.39 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 PROVANTIS Date: 16-Dec-2002 Page: 8 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ 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 4f 51 52 53 54 55 56 57 58 59 60 ------ ---Mean S.D. N ------ ---- 100.26 103.95 112.19 112.19 105.23 105.88 102.44 102.44 113.00 105.00 -----106.26 4.58 10 ------ 66.04 69.14 72.84 76.29 69.41 70.57 73.05 71.65 80.26 72.48 -----72.17 3.96 10 ------ 83.69 88.72 91.83 97.52 87.73 79.45 85.61 84.06 103.11 84.98 -----88.67 7.08 10 ------ 80.83 85.19 88.46 90.36 86.64 79.08 85.38 84.54 107.53 85.95 -----87.40 7.80 10 ------ 75.96 78.53 84.49 84.49 82.85 79.62 86.27 84.44 103.59 86.54 -----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 -----92.02 15.44 5 ------ . . . . . 68.19 74.85 71.28 101.24 74.11 -----77.93 13.29 5 ------ . . . . . 65.84 71.85 69.45 98.31 69.95 -----75.08 13.17 5 ------ . . . . . 38.57 43.42 43.31 57.60 39.84 -----44.55 7.60 5 ------ 75.76 78.58 85.29 85.38 81.85 72.30 77.08 75.19 94.73 77.76 -----80.39 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: 1 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group Animal From: -3 1 4 8 11 15 18 22 25 -3 Sex Number To: 1 4 8 11 15 18 22 25 29 29 5m 61 62 63 64 65 ------ ---- Mean S.D. N ------ ---- 122.09 128.81 121.12 123.08 122.58 -----123.54 3.04 5 ------ 103.85 111.44 106.02 105.65 105.65 -----106.52 2.88 5 ------ 99.14 106.50 103.61 101.78 101.18 -----102.44 2.77 5 ------ 91.19 99.28 98.23 95.19 92.33 -----95.24 3.54 5 ------ 83.00 92.16 90.38 86.24 83.19 -----86.99 4.16 5 ------ 72.29 80.90 80.36 76.11 72.29 -----76.39 4.18 5 ------ 70.79 78.42 80.08 74.70 69.61 -----74.72 4.58 5 ------ 60.28 66.41 68.55 62.85 58.52 -----63.32 4.17 5 ------ 48.47 53.37 55.99 51.72 47.82 -----51.47 3.41 5 ------ 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: 2 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group Animal From: -3 1 4 8 11 15 18 22 25 -3 Sex Number To: 1 4 8 11 15 18 22 25 29 29 5f 66 67 68 69 70 ------ ---- Mean S.D. N ------ ---- 104.52 107.71 113.15 108.66 109.14 -----108.64 3.10 5 ------ 94.51 95.24 100.27 97.50 96.35 -----96.77 2.26 5 ------ 89.47 88.54 92.73 91.07 88.54 -----90.07 1.81 5 ------ 78.61 76.86 80.98 78.87 78.35 -----78.73 1.48 5 ------ 75.68 73.67 79.55 75.91 77.09 -----76.38 2.16 5 ------ 68.99 66.67 72.58 68.20 68.20 -----68.93 2.21 5 ------ 69.36 67.30 71.97 67.66 68.78 -----69.01 1.85 5 ------ 59.93 58.53 61.57 58.99 61.07 -----60.02 1.30 5 ------ 56.56 55.56 58.82 56.41 57.89 -----57.05 1.30 5 ------ 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: 1 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group Animal From: -4 1 4 8 11 15 18 22 25 -4 Sex Number To: 1 4 8 11 15 18 22 25 29 29 6m 71 72 73 74 75 ------ ---- Mean S.D. N ------ ---- 117.89 124.46 115.08 117.89 116.00 -----118.26 3.67 5 ------ 112.00 116.26 112.00 112.37 109.09 -----112.34 2.56 5 ------ 108.57 111.44 111.11 108.88 106.15 -----109.23 2.15 5 ------ 101.90 103.70 105.84 101.15 100.41 -----102.60 2.18 5 ------ 87.80 89.16 94.16 88.57 89.36 -----89.81 2.51 5 ------ 76.30 78.13 86.05 78.76 80.05 -----79.86 3.72 5 ------ 66.00 67.22 76.68 69.26 70.19 -----69.87 4.15 5 ------ 55.44 55.54 64.40 57.62 59.20 -----58.44 3.68 5 ------ 68.99 68.42 79.39 70.15 73.37 -----72.06 4.52 5 ------ 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: 2 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group Animal From: -4 1 4 8 11 15 18 22 25 -4 Sex Number To: 1 4 8 11 15 18 22 25 29 29 6f 81 82 83 84 85 ------ ---- Mean S.D. N ------ ---- 112.45 110.08 121.30 115.93 111.97 -----114.35 4.42 5 ------ 90.06 91.79 98.62 91.44 89.39 -----92.26 3.69 5 ------ 85.12 90.11 95.35 86.62 83.96 -----88.23 4.60 5 ------ 85.04 89.64 95.44 87.28 83.18 -----88.12 4.76 5 ------ 80.12 83.39 89.26 82.10 78.01 -----82.58 4.26 5 ------ 65.12 66.47 71.11 65.69 61.71 -----66.02 3.38 5 ------ 67.61 67.80 72.51 67.42 63.32 -----67.73 3.26 5 ------ 56.10 56.26 60.22 56.57 52.65 -----56.36 2.68 5 ------ 69.87 70.24 75.29 69.68 65.34 -----70.08 3.53 5 ------ 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: 3 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group Animal From: -4 1 4 8 11 15 18 22 25 -4 Sex Number To: 1 4 8 11 15 18 22 25 29 29 7m 76 77 78 79 80 ------ ---- Mean S.D. N ------ ---- 121.14 123.14 117.32 115.50 116.86 -----118.79 3.21 5 ------ 110.60 115.53 111.33 107.09 107.43 -----110.40 3.43 5 ------ 105.35 110.65 107.16 102.75 101.63 -----105.51 3.60 5 ------ 101.81 106.80 104.91 98.41 96.80 -----101.75 4.22 5 ------ 86.21 89.34 90.78 83.30 81.24 -----86.17 4.00 5 ------ 77.84 79.41 84.51 75.61 73.22 -----78.12 4.27 5 ------ 70.02 69.89 78.81 67.91 65.03 -----70.33 5.15 5 ------ 53.70 53.70 61.01 52.25 49.65 -----54.06 4.22 5 ------ 65.61 65.83 74.95 63.81 60.68 -----66.18 5.32 5 ------ 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: 4 Food Consumption By Animal - Individual Food Consumption Relative To Bodyweight Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Day numbers relative to Start Date Mean Group Animal From: -4 1 4 8 11 15 18 22 25 -4 Sex Number To: 1 4 8 11 15 18 22 25 29 29 7f 86 87 88 89 90 ------ ---- Mean S.D. N ------ ---- 121.86 113.91 112.45 112.93 114.41 -----115.11 3.85 5 ------ 108.06 100.37 100.75 99.26 98.89 -----101.47 3.76 5 ------ 100.37 89.93 94.04 90.85 88.45 -----92.73 4.74 5 ------ 92.16 82.34 85.84 81.83 80.08 -----84.45 4.79 5 ------ 84.59 75.44 77.95 75.00 74.14 -----77.42 4.25 5 ------ 71.64 63.20 67.05 64.98 62.51 -----65.88 3.67 5 ------ 65.00 58.62 61.73 60.88 56.23 -----60.49 3.30 5 ------ 57.69 52.43 53.83 54.27 49.83 -----53.61 2.86 5 ------ 76.32 69.54 71.54 71.35 65.55 -----70.86 3.89 5 ------ 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 Page 234 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 7.53 -------- 8.16 -------- 7.57 -------- 7.85 -------- 7.68 -------- 8.63 -------- 8.35 -------- 8.85 -------- 9.04 -------- 8.54 154 ------ 153 ------ 147 ------ 146 ------ 151 ------ 155 ------ 158 ------ 167 ------ 167 ------ 152 0.44 ------ 0.47 ------ 0.44 ------ 0.44 ------ 0.44 ------ 0.47 ------ 0.48 ------ 0.49 ------ 0.50 ------ 0.45 59 -------- 57 -------- 58 -------- 55 -------- 57 -------- 54 -------- 58 -------- 56 -------- 55 -------- 53 20 -------- 19 -------- 20 -------- 19 -------- 20 -------- 18 -------- 19 -------- 19 -------- 18 -------- 18 348 ----330 ----338 ----335 ----346 ----332 ----328 ----337 ----336 ----336 0.030 -------- 0.029 -------- 0.028 -------- 0.029 -------- 0.030 -------- 0.023 -------- 0.041 -------- 0.019 -------- 0.019 -------- 0.016 0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 ---------------------------------------------------------------+ 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 235 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 7.32 -------- 7.56 -------- 7.28 -------- 7.07 -------- 6.74 -------- 8.05 -------- 8.10 -------- 8.16 -------- 7.93 -------- 8.11 140 ------ 146 ------ 136 ------ 137 ------ 130 ------ 143 ------ 149 ------ 153 ------ 150 ------ 151 0.42 ------ 0.43 ------ 0.41 ------ 0.40 ------ 0.39 ------ 0.42 ------ 0.44 ------ 0.45 ------ 0.43 ------ 0.44 57 -------- 56 -------- 56 -------- 56 -------- 57 -------- 52 -------- 54 -------- 55 -------- 54 -------- 54 19 -------- 19 -------- 19 -------- 19 -------- 19 -------- 18 -------- 18 -------- 19 -------- 19 -------- 19 337 ----343 ----335 ----346 ----338 ----338 ----341 ----344 ----351 ----345 0.033 -------- 0.030 -------- 0.028 -------- 0.022 -------- 0.030 -------- 0.022 -------- 0.019 -------- 0.022 -------- 0.021 -------- 0.016 0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 ---------------------------------------------------------------- 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 236 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 29 ---- 29 ---- 29 ---- 29 ---- 29 7.33 -------- 7.84 -------- 8.11 -------- 7.66 -------- 8.19 148 ------ 150 ------ 148 ------ 150 ------ 155 0.43 ------ 0.45 ------ 0.46 ------ 0.44 ------ 0.47 59 -------- 58 -------- 56 -------- 57 -------- 58 20 -------- 19 -------- 18 -------- 20 -------- 19 344 ----331 ----323 ----343 ----328 0.029 -------- 0.027 -------- 0.023 -------- 0.025 -------- 0.024 --------------------- ----------------------------- 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 237 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 29 ---- 29 ---- 29 ---- 29 ---- 29 . * -------- 8.12 -------- 7.76 -------- 6.67 -------- 7.23 . * ------ 153 ------ 143 ------ 128 ------ 140 . * ------ 0.45 ------ 0.43 ------ 0.37 ------ 0.41 . * -------- 56 -------- 55 -------- 56 -------- 57 . * -------- 19 -------- 19 -------- 19 -------- 19 . * ----339 ----338 ----344 ----343 . * -------- 0.028 -------- 0.018 -------- 0.028 -------- 0.029 --------------------- ----------------------------- 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 238 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 29 ---- 29 ---- 29 ---- 29 ---- 29 8.26 -------- 8.12 -------- 7.53 -------- 7.63 -------- 7.44 151 ------ 154 ------ 143 ------ 146 ------ 144 0.47 ------ 0.48 ------ 0.44 ------ 0.44 ------ 0.44 57 -------- 59 -------- 59 -------- 58 -------- 59 18 -------- 19 -------- 19 -------- 19 -------- 19 323 ----323 ----324 ----332 ----329 0.027 -------- 0.030 -------- 0.030 -------- 0.031 -------- 0.027 --------------------- ----------------------------- 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 239 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 29 ---- 29 ---- 29 ---- 29 ---- 29 7.15 -------- 7.60 -------- 8.00 -------- 7.21 -------- 7.03 140 ------ 142 ------ 149 ------ 145 ------ 137 0.40 ------ 0.44 ------ 0.44 ------ 0.42 ------ 0.39 56 -------- 57 -------- 56 -------- 58 -------- 56 20 -------- 19 -------- 19 -------- 20 -------- 20 347 ----326 ----335 ----345 ----349 0.035 -------- 0.030 -------- 0.019 -------- 0.028 -------- 0.031 --------------------- ----------------------------- 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 240 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 8.25 -------- 7.16 -------- 7.61 -------- 7.28 -------- 7.48 -------- 9.04 -------- 9.16 -------- 9.68 -------- 9.00 160 ------ 140 ------ 151 ------ 144 ------ 148 ------ 165 ------ 164 ------ 171 ------ 167 0.47 ------ 0.41 ------ 0.45 ------ 0.43 ------ 0.44 ------ 0.50 ------ 0.49 ------ 0.50 ------ 0.50 58 -------- 57 -------- 59 -------- 59 -------- 58 -------- 56 -------- 53 -------- 52 -------- 55 19 -------- 20 -------- 20 -------- 20 -------- 20 -------- 18 -------- 18 -------- 18 -------- 19 337 ----343 ----338 ----333 ----340 ----328 ----337 ----339 ----337 0.025 -------- 0.031 -------- 0.031 -------- 0.026 -------- 0.019 -------- 0.010 -------- 0.003 -------- 0.005 -------- 0.013 0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -------------------------------------------------+ -------- 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 241 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 . * -------- 7.02 -------- 7.32 -------- 6.73 -------- 6.86 -------- 8.16 -------- 8.30 -------- 9.07 -------- 8.71 -------- 8.02 . * ------ 135 ------ 131 ------ 125 ------ 127 ------ 153 ------ 155 ------ 167 ------ 157 ------ 147 . * ------ 0.41 ------ 0.40 ------ 0.37 ------ 0.38 ------ 0.45 ------ 0.45 ------ 0.48 ------ 0.46 ------ 0.44 . * -------- 59 -------- 54 -------- 55 -------- 56 -------- 55 -------- 55 -------- 53 -------- 53 -------- 54 . * -------- 19 -------- 18 -------- 19 -------- 19 -------- 19 -------- 19 -------- 18 -------- 18 -------- 18 . * ----326 ----332 ----338 ----334 ----339 ----342 ----346 ----342 ----338 . * -------- 0.032 -------- 0.023 -------- 0.034 -------- 0.025 -------- 0.014 -------- 0.019 -------- 0.010 -------- 0.011 -------- 0.019 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -----0.000 -------------------------------------------------+ -------+ -------- 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 242 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 9 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 29 ---- 29 ---- 29 ---- 29 ---- 29 8.03 -------- 7.88 -------- 7.87 -------- 8.07 -------- 7.69 155 ------ 152 ------ 156 ------ 162 ------ 156 0.45 ------ 0.45 ------ 0.46 ------ 0.47 ------ 0.45 57 -------- 57 -------- 58 -------- 58 -------- 59 19 -------- 19 -------- 20 -------- 20 -------- 20 341 ----339 ----340 ----346 ----346 0.028 -------- 0.030 -------- 0.031 -------- 0.025 -------- 0.032 0.000 -----0.000 -----0.000 -----0.000 -----0.000 ----------------------------- 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 243 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 10 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 29 ---- 29 ---- 29 ---- 29 ---- 29 7.14 -------- 7.75 -------- 7.28 -------- 7.84 -------- 7.54 144 ------ 153 ------ 145 ------ 152 ------ 150 0.40 ------ 0.45 ------ 0.42 ------ 0.44 ------ 0.43 57 -------- 58 -------- 58 -------- 56 -------- 57 20 -------- 20 -------- 20 -------- 19 -------- 20 358 ----343 ----346 ----349 ----351 0.030 -------- 0.032 -------- 0.034 -------- 0.029 -------- 0.041 0.000 -----0.000 -----0.000 -----0.000 -----0.000 ----------------------------- 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 244 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 11 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Red Cell Count Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Comments and Markers -------------------- Group Animal Day Sex Number Number Measurement Marker Comment ------------------------------------------------------------------------------------------------------------------------------ 2f 41 29 Red blood cell count Hemoglobin Hematocrit MCV MCH MCHC Reticulocytes 4f 51 29 Red blood cell count Hemoglobin Hematocrit MCV MCH MCHC Reticulocytes Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated Marker = E implies value excluded from means Page 245 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 1 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 29 ---- 29 ---- 29 ---- 29 ---- 29 8.30 -------- 7.58 -------- 7.82 -------- 8.16 -------- 8.08 166 ------ 146 ------ 151 ------ 161 ------ 156 0.49 ------ 0.44 ------ 0.44 ------ 0.48 ------ 0.47 59 -------- 58 -------- 56 -------- 59 -------- 58 20 -------- 19 -------- 19 -------- 20 -------- 19 337 ----334 ----344 ----335 ----335 0.030 -------- 0.028 -------- 0.030 -------- 0.036 -------- 0.035 0.000 -----0.000 -----0.000 -----0.000 -----0.000 ----------------------------- * = 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: 2 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 29 ---- 29 ---- 29 ---- 29 ---- 29 7.52 -------- 7.68 -------- 8.21 -------- 7.92 -------- 7.75 150 ------ 148 ------ 153 ------ 149 ------ 144 0.44 ------ 0.44 ------ 0.45 ------ 0.43 ------ 0.42 58 -------- 57 -------- 55 -------- 55 -------- 55 20 -------- 19 -------- 19 -------- 19 -------- 19 344 ----338 ----342 ----344 ----340 0.023 -------- 0.030 -------- 0.022 -------- 0.027 -------- 0.026 0.000 -----0.000 -----0.000 -----0.000 -----0.000 ----------------------------- * = 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: 3 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 29 ---- 29 ---- 29 ---- 29 ---- 29 8.20 -------- 7.73 -------- 8.22 -------- 7.84 -------- 7.65 155 ------ 152 ------ 154 ------ 152 ------ 156 0.46 ------ 0.45 ------ 0.45 ------ 0.45 ------ 0.45 56 -------- 59 -------- 55 -------- 57 -------- 59 19 -------- 20 -------- 19 -------- 19 -------- 20 336 ----335 ----340 ----338 ----343 0.036 -------- 0.038 -------- 0.026 -------- 0.033 -------- 0.032 0.000 -----0.000 -----0.000 -----0.000 -----0.000 ----------------------------- * = 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: 4 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Red cell count 10E12/L Hemo globin g/L Hemato crit unity MCV 10E-15 L MCH 10E-12 g MCHC g/L Reticulo cytes unity Heinz Bodies unity Hyper chromas. 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 29 ---- 29 ---- 29 ---- 29 ---- 29 7.67 -------- 7.80 -------- 7.50 -------- 7.46 -------- 7.84 144 ------ 149 ------ 148 ------ 143 ------ 151 0.43 ------ 0.43 ------ 0.42 ------ 0.41 ------ 0.45 55 -------- 55 -------- 56 -------- 56 -------- 57 19 -------- 19 -------- 20 -------- 19 -------- 19 339 ----349 ----353 ----345 ----336 0.028 -------- 0.029 -------- 0.025 -------- 0.045 -------- 0.038 0.000 -----0.000 -----0.000 -----0.000 -----0.000 --------------+ --------------- * = 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 12.55 -------- 8.24 -------- 11.41 -------- 10.40 -------- 11.48 -------- 9.70 -------- 6.99 -------- 11.14 -------- 10.37 -------- 7.25 0.08 ------ 0.12 ------ 0.10 ------ 0.11 ------ 0.08 ------ 0.09 ------ 0.14 ------ 0.09 ------ 0.11 ------ 0.11 0.88 ------ 0.85 ------ 0.87 ------ 0.86 ------ 0.88 ------ 0.87 ------ 0.84 ------ 0.87 ------ 0.86 ------ 0.84 0.02 ----0.01 ----0.02 ----0.02 ----0.01 ----0.02 ----0.02 ----0.02 ----0.02 ----0.03 0.00 ------ 0.00 ------ 0.00 ------ 0.00 ------ 0.02 ------ 0.00 ------ 0.00 ------ 0.01 ------ 0.01 ------ 0.01 0.02 ----0.01 ----0.01 ----0.01 ----0.01 ----0.01 ----0.00 ----0.00 ----0.00 ----0.00 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 250 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 6.41 -------- 7.95 -------- 7.41 -------- 9.99 -------- 7.55 -------- 6.95 -------- 7.74 -------- 7.37 -------- 6.58 -------- 8.85 0.08 ------ 0.06 ------ 0.10 ------ 0.08 ------ 0.09 ------ 0.08 ------ 0.10 ------ 0.07 ------ 0.07 ------ 0.06 0.90 ------ 0.92 ------ 0.87 ------ 0.90 ------ 0.88 ------ 0.89 ------ 0.87 ------ 0.91 ------ 0.90 ------ 0.92 0.01 ----0.01 ----0.01 ----0.01 ----0.01 ----0.01 ----0.02 ----0.01 ----0.02 ----0.01 0.00 ------ 0.00 ------ 0.01 ------ 0.00 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 0.00 ----0.01 ----0.00 ----0.01 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 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 251 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 29 ---- 29 ---- 29 ---- 29 ---- 29 15.31 -------- 11.50 -------- 14.99 -------- 10.99 -------- 12.87 0.08 ------ 0.06 ------ 0.06 ------ 0.08 ------ 0.08 0.89 ------ 0.92 ------ 0.92 ------ 0.89 ------ 0.89 0.01 ----0.01 ----0.01 ----0.02 ----0.02 0.01 ------ 0.00 ------ 0.00 ------ 0.00 ------ 0.00 0.01 ----0.00 ----0.00 ----0.00 ----0.00 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 252 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 29 ---- 29 ---- 29 ---- 29 ---- 29 . * -------- 10.35 -------- 8.55 -------- 9.97 -------- 10.23 . * ------ 0.06 ------ 0.07 ------ 0.05 ------ 0.07 . * ------ 0.92 ------ 0.91 ------ 0.94 ------ 0.90 . * ----0.01 ----0.01 ----0.01 ----0.01 . * ------ 0.01 ------ 0.01 ------ 0.00 ------ 0.01 . * ----0.00 ----0.00 ----0.00 ----0.00 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 253 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 29 ---- 29 ---- 29 ---- 29 ---- 29 10.49 -------- 11.05 -------- 8.98 -------- 13.41 -------- 13.20 0.11 ------ 0.12 ------ 0.09 ------ 0.08 ------ 0.11 0.86 ------ 0.84 ------ 0.88 ------ 0.89 ------ 0.87 0.02 ----0.03 ----0.01 ----0.01 ----0.01 0.00 ------ 0.00 ------ 0.01 ------ 0.01 ------ 0.00 0.00 ----0.00 ----0.00 ----0.00 ----0.00 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 254 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 29 ---- 29 ---- 29 ---- 29 ---- 29 8.24 -------- 11.30 -------- 8.04 -------- 7.76 -------- 7.36 0.07 ------ 0.08 ------ 0.09 ------ 0.09 ------ 0.11 0.91 ------ 0.90 ------ 0.88 ------ 0.89 ------ 0.87 0.01 ----0.01 ----0.02 ----0.02 ----0.01 0.00 ------ 0.01 ------ 0.00 ------ 0.00 ------ 0.01 0.00 ----0.00 ----0.00 ----0.00 ----0.00 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 255 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 7.99 -------- 9.83 -------- 9.05 -------- 7.82 -------- 12.36 -------- 4.42 -------- 6.44 -------- 4.24 -------- 6.44 0.13 ------ 0.09 ------ 0.12 ------ 0.11 ------ 0.15 ------ 0.14 ------ 0.08 ------ 0.38 ------ 0.08 0.85 ------ 0.87 ------ 0.85 ------ 0.86 ------ 0.81 ------ 0.84 ------ 0.91 ------ 0.59 ------ 0.89 0.02 ----0.02 ----0.02 ----0.02 ----0.02 ----0.01 ----0.01 ----0.02 ----0.01 0.00 ------ 0.01 ------ 0.00 ------ 0.00 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 0.01 ----0.00 ----0.01 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 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 256 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 . * -------- 7.27 -------- 6.48 -------- 8.58 -------- 9.40 -------- 8.98 -------- 5.29 -------- 9.31 -------- 6.76 -------- 7.99 . * ------ 0.09 ------ 0.07 ------ 0.08 ------ 0.06 ------ 0.06 ------ 0.09 ------ 0.13 ------ 0.07 ------ 0.08 . * ------ 0.89 ------ 0.91 ------ 0.89 ------ 0.91 ------ 0.92 ------ 0.88 ------ 0.83 ------ 0.91 ------ 0.89 . * ----0.01 ----0.01 ----0.02 ----0.01 ----0.01 ----0.02 ----0.02 ----0.01 ----0.02 . * ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 . * ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 ----0.00 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 257 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 9 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 29 ---- 29 ---- 29 ---- 29 ---- 29 13.80 -------- 11.31 -------- 13.77 -------- 12.51 -------- 16.22 0.11 ------ 0.08 ------ 0.10 ------ 0.11 ------ 0.10 0.84 ------ 0.88 ------ 0.86 ------ 0.84 ------ 0.85 0.03 ----0.02 ----0.01 ----0.02 ----0.03 0.01 ------ 0.00 ------ 0.01 ------ 0.02 ------ 0.01 0.01 ----0.01 ----0.01 ----0.01 ----0.01 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 258 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 10 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 29 ---- 29 ---- 29 ---- 29 ---- 29 11.22 -------- 10.56 -------- 12.18 -------- 11.30 -------- 10.12 0.09 ------ 0.11 ------ 0.08 ------ 0.14 ------ 0.07 0.89 ------ 0.82 ------ 0.88 ------ 0.82 ------ 0.89 0.01 ----0.04 ----0.02 ----0.02 ----0.02 0.01 ------ 0.01 ------ 0.01 ------ 0.02 ------ 0.01 0.00 ----0.01 ----0.00 ----0.01 ----0.00 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 259 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 11 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Comments and Markers -------------------- Group Animal Day Sex Number Number Measurement Marker Comment ------------------------------------------------------------------------------------------------------------------------------ 2f 41 29 White blood cell count Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils (%) 4f 51 29 White blood cell count Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%) Basophils (%) Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample Sample coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated coagulated Marker = E implies value excluded from means Page 260 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 29 ---- 29 ---- 29 ---- 29 ---- 29 12.54 -------- 10.07 -------- 17.52 -------- 13.10 -------- 11.84 0.13 ------ 0.12 ------ 0.15 ------ 0.11 ------ 0.10 0.82 ------ 0.84 ------ 0.82 ------ 0.86 ------ 0.86 0.03 ----0.03 ----0.01 ----0.02 ----0.02 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 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: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 29 ---- 29 ---- 29 ---- 29 ---- 29 12.63 -------- 11.49 -------- 10.34 -------- 7.73 -------- 11.85 0.10 ------ 0.09 ------ 0.08 ------ 0.08 ------ 0.06 0.87 ------ 0.87 ------ 0.88 ------ 0.88 ------ 0.90 0.02 ----0.02 ----0.01 ----0.02 ----0.02 0.01 ------ 0.02 ------ 0.02 ------ 0.02 ------ 0.01 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: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 29 ---- 29 ---- 29 ---- 29 ---- 29 12.31 -------- 11.00 -------- 7.75 -------- 13.26 -------- 11.88 0.11 ------ 0.11 ------ 0.09 ------ 0.09 ------ 0.10 0.86 ------ 0.84 ------ 0.88 ------ 0.86 ------ 0.86 0.02 ----0.03 ----0.02 ----0.03 ----0.02 0.01 ------ 0.01 ------ 0.01 ------ 0.01 ------ 0.01 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: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - White Cell Count (rel. values) Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number White cell cnt 10E9/L Neutro phils unity Lympho cytes unity Mono cytes unity Eosino phils unity Baso phils unity 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 29 ---- 29 ---- 29 ---- 29 ---- 29 5.96 -------- 8.80 -------- 8.19 -------- 8.81 -------- 7.68 0.09 ------ 0.08 ------ 0.09 ------ 0.08 ------ 0.12 0.88 ------ 0.89 ------ 0.88 ------ 0.88 ------ 0.84 0.01 ----0.01 ----0.01 ----0.01 ----0.02 0.01 ------ 0.01 ------ 0.01 ------ 0.02 ------ 0.01 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 100 ------- 96 ------- 99 ------- 102 ------- 106 ------- 129 ------- 126 ------- 137 ------- 144 ------- 159 1119 -----1049 -----1021 -----1153 ------ 810 -----1179 ------ 844 -----1077 -----1101 -----1056 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 265 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 135 ------- 115 ------- 133 ------- 142 ------- 132 ------- 151 ------- 145 ------- 176 ------- 138 ------- 147 849 -----1006 -----1184 ------ 992 -----1270 -----1065 -----1076 ------ 978 -----1051 -----1081 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 266 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 29 ---- 29 ---- 29 ---- 29 ---- 29 102 ------- 106 ------- 111 ------- 126 ------- 112 1132 -----1098 -----1066 -----1087 -----1173 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 267 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 29 ---- 29 ---- 29 ---- 29 ---- 29 105 ------- 96 ------- 88 ------- 105 ------- 102 . * -----1095 -----1087 -----1007 -----1149 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 268 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 29 ---- 29 ---- 29 ---- 29 ---- 29 124 ------- 105 ------- 108 ------- 115 ------- 104 1103 -----1177 -----1042 -----1060 -----1042 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 269 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 29 ---- 29 ---- 29 ---- 29 ---- 29 68 ------- 106 ------- 112 ------- 120 ------- 119 1093 -----1029 -----1324 -----1016 -----1136 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 270 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 124 ------- 101 ------- 97 ------- 90 ------- 106 ------- 148 ------- 132 ------- 125 ------- 102 960 ------ 942 -----1050 ------ 930 -----1108 ------ 904 -----1012 ------ 627 -----1195 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 271 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 96 ------- 108 ------- 98 ------- 111 ------- 105 ------- 153 ------- 122 ------- 153 ------- 125 ------- 121 . * -----1258 -----1173 ------ 988 ------ 982 -----1206 -----1316 -----1443 ------ 967 -----1470 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 272 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 9 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 29 ---- 29 ---- 29 ---- 29 ---- 29 179 ------- 157 ------- 157 ------- 150 ------- 145 1141 -----1229 -----1088 ------ 980 ------ 910 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 273 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 10 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 29 ---- 29 ---- 29 ---- 29 ---- 29 173 ------- 153 ------- 164 ------- 146 ------- 164 1299 -----1503 ------ 815 ------ 957 -----1066 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 274 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 11 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Comments and Markers -------------------- Group Animal Day Sex Number Number Measurement Marker Comment ------------------------------------------------------------------------------------------------------------------------------ 2f 41 29 Platelets 4f 51 29 Platelets Sample coagulated Sample coagulated Marker = E implies value excluded from means Page 275 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 29 ---- 29 ---- 29 ---- 29 ---- 29 133 ------- 132 ------- 159 ------- 147 ------- 139 966 -----1170 -----1322 -----1093 -----1204 * = 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: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 29 ---- 29 ---- 29 ---- 29 ---- 29 126 ------- 129 ------- 118 ------- 134 ------- 122 1122 -----1104 ------ 996 -----1147 -----1300 * = 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: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 29 ---- 29 ---- 29 ---- 29 ---- 29 167 ------- 168 ------- 181 ------- 132 ------- 137 1088 -----1158 -----1143 -----1211 -----1133 * = 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: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Blood Coagulation Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Coagul. Time sec Plate lets 10E9/L 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 29 ---- 29 ---- 29 ---- 29 ---- 29 135 ------- 123 ------- 148 ------- 119 ------- 131 1143 -----1088 -----1166 -----1001 ------ 998 * = 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 142 ------ 142 ------ 139 ------ 139 ------ 141 ------ 139 ------ 137 ------ 139 ------ 141 ------ 139 5.74 ------ 5.89 ------ 5.85 ------ 6.39 ------ 6.46 ------ 5.80 ------ 6.20 ------ 6.40 ------ 5.90 ------ 5.75 2.39 ------- 2.46 ------- 2.42 ------- 2.45 ------- 2.40 ------- 2.21 ------- 2.18 ------- 2.27 ------- 2.42 ------- 2.39 105 -------- 104 -------- 102 -------- 102 -------- 104 -------- 102 -------- 102 -------- 103 -------- 103 -------- 101 2.90 ------ 2.86 ------ 3.05 ------ 3.18 ------ 3.25 ------ 2.53 ------ 3.01 ------ 3.12 ------ 3.08 ------ 2.96 18.5 ------- 18.8 ------- 18.1 ------- 24.5 ------- 17.5 ------- 17.0 ------- 19.8 ------- 21.6 ------- 25.7 ------- 16.8 37 ------ 21 ------ 36 ------ 34 ------ 38 ------ 38 ------ 60 ------ 49 ------ 24 ------ 35 44 ------ 47 ------ 50 ------ 47 ------ 45 ------ 54 ------ 46 ------ 51 ------ 42 ------ 42 5.5 -------- 5.4 -------- 5.5 -------- 6.9 -------- 7.2 -------- 6.9 -------- 5.9 -------- 8.3 -------- 6.5 -------- 7.3 38 ---46 ---45 ---38 ---45 ---42 ---49 ---60 ---56 ---39 67 ----- 69 ----105 ----- 66 ----- 98 ----111 ----116 ----116 ----- 80 ----- 95 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 281 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 515 -------- 450 -------- 396 -------- 532 -------- 588 -------- 364 -------- 307 -------- 327 -------- 337 -------- 279 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 4 51 ------- 54 ------- 50 ------- 53 ------- 53 ------- 49 ------- 48 ------- 51 ------- 55 ------- 49 1.9 ------ 2.1 ------ 2.0 ------ 2.0 ------ 2.0 ------ 1.7 ------ 1.8 ------ 1.9 ------ 2.0 ------ 1.8 0.53 -------- 0.35 -------- 0.53 -------- 0.56 -------- 0.59 -------- 0.57 -------- 0.38 -------- 0.55 -------- 0.54 -------- 0.38 25 ------- 27 ------- 25 ------- 26 ------- 27 ------- 22 ------- 23 ------- 24 ------- 25 ------- 23 26 -------- 27 -------- 25 -------- 27 -------- 26 -------- 27 -------- 25 -------- 27 -------- 30 -------- 26 0.96 -------- 1.00 -------- 1.00 -------- 0.96 -------- 1.04 -------- 0.81 -------- 0.92 -------- 0.89 -------- 0.83 -------- 0.88 4.7 ------- 5.4 ------- 5.3 ------- 4.9 ------- 5.0 ------- 6.0 ------- 6.1 ------- 5.6 ------- 4.4 ------- 5.0 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 282 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 142 ------ 142 ------ 138 ------ 140 ------ 141 ------ 144 ------ 143 ------ 143 ------ 143 ------ 143 4.65 ------ 5.05 ------ 5.35 ------ 5.18 ------ 5.71 ------ 4.84 ------ 4.41 ------ 4.66 ------ 4.75 ------ 5.12 2.30 ------- 2.29 ------- 2.31 ------- 2.30 ------- 2.34 ------- 2.37 ------- 2.39 ------- 2.41 ------- 2.40 ------- 2.34 104 -------- 105 -------- 101 -------- 106 -------- 103 -------- 106 -------- 106 -------- 106 -------- 104 -------- 105 2.54 ------ 2.76 ------ 3.05 ------ 2.51 ------ 2.83 ------ 2.42 ------ 2.44 ------ 2.26 ------ 2.35 ------ 2.75 12.2 ------- 15.5 ------- 14.7 ------- 10.5 ------- 13.9 ------- 10.5 ------- 12.2 ------- 12.2 ------- 14.3 ------- 14.3 47 ------ 59 ------ 33 ------ 54 ------ 51 ------ 90 ------ 33 ------ 52 ------ 58 ------ 72 51 ------ 49 ------ 46 ------ 45 ------ 48 ------ 58 ------ 48 ------ 54 ------ 58 ------ 58 5.6 -------- 5.5 -------- 6.0 -------- 6.1 -------- 6.0 -------- 5.7 -------- 5.3 -------- 5.4 -------- 5.9 -------- 6.3 43 ---35 ---39 ---42 ---46 ---38 ---29 ---36 ---33 ---38 114 ----- 97 ----- 87 ----- 91 ----115 ----124 ----- 71 ----- 98 ----- 85 ----102 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 283 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 419 -------- 380 -------- 442 -------- 404 -------- 372 -------- 201 -------- 306 -------- 241 -------- 209 -------- 175 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 -------- 4 56 ------- 53 ------- 51 ------- 55 ------- 56 ------- 61 ------- 59 ------- 55 ------- 56 ------- 57 2.0 ------ 2.0 ------ 1.5 ------ 1.8 ------ 2.2 ------ 2.4 ------ 1.5 ------ 1.8 ------ 1.7 ------ 1.8 0.49 -------- 0.49 -------- 0.44 -------- 0.63 -------- 0.42 -------- 0.27 -------- 0.49 -------- 0.41 -------- 0.55 -------- 0.52 28 ------- 26 ------- 25 ------- 27 ------- 29 ------- 30 ------- 29 ------- 28 ------- 28 ------- 27 28 -------- 27 -------- 26 -------- 28 -------- 27 -------- 31 -------- 30 -------- 27 -------- 28 -------- 30 1.00 -------- 0.96 -------- 0.96 -------- 0.96 -------- 1.07 -------- 0.97 -------- 0.97 -------- 1.04 -------- 1.00 -------- 0.90 6.5 ------- 5.8 ------- 5.5 ------- 6.4 ------- 5.9 ------- 5.3 ------- 6.3 ------- 4.9 ------- 5.0 ------- 4.7 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 284 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 29 ---- 29 ---- 29 ---- 29 ---- 29 140 ------ 140 ------ 139 ------ 141 ------ 139 6.20 ------ 6.35 ------ 5.88 ------ 6.32 ------ 5.85 2.40 ------- 2.23 ------- 2.26 ------- 2.32 ------- 2.32 101 -------- 102 -------- 102 -------- 101 -------- 101 3.27 ------ 3.35 ------ 3.06 ------ 3.29 ------ 3.08 17.4 ------- 19.5 ------- 21.1 ------- 21.2 ------- 20.1 58 ------ 51 ------ 46 ------ 64 ------ 39 50 ------ 55 ------ 47 ------ 59 ------ 47 6.6 -------- 5.8 -------- 5.5 -------- 5.8 -------- 5.2 47 ---40 ---48 ---46 ---43 110 ----- 98 ----- 97 ----119 ----- 90 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 285 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 29 ---- 29 ---- 29 ---- 29 ---- 29 516 -------- 380 -------- 553 -------- 412 -------- 507 3 -------- 3 -------- 3 -------- 3 -------- 3 51 ------- 54 ------- 50 ------- 55 ------- 55 1.7 ------ 1.8 ------ 2.1 ------ 2.0 ------ 2.2 0.48 -------- 0.18 -------- 0.62 -------- 0.37 -------- 0.33 26 ------- 26 ------- 25 ------- 27 ------- 27 25 -------- 28 -------- 25 -------- 28 -------- 28 1.04 -------- 0.93 -------- 1.00 -------- 0.96 -------- 0.96 5.9 ------- 5.2 ------- 6.3 ------- 6.4 ------- 5.4 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 286 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 29 ---- 29 ---- 29 ---- 29 ---- 29 142 ------ 141 ------ 141 ------ 140 ------ 138 5.67 ------ 6.15 ------ 6.64 ------ 5.84 ------ 6.09 2.41 ------- 2.30 ------- 2.40 ------- 2.31 ------- 2.38 106 -------- 104 -------- 104 -------- 104 -------- 103 3.33 ------ 3.12 ------ 3.30 ------ 3.04 ------ 3.11 15.7 ------- 15.3 ------- 14.6 ------- 18.4 ------- 17.9 57 ------ 67 ------ 82 ------ 40 ------ 66 47 ------ 53 ------ 57 ------ 46 ------ 52 6.3 -------- 6.7 -------- 6.3 -------- 5.2 -------- 5.6 47 ---44 ---60 ---45 ---43 98 ----112 ----148 ----- 91 ----102 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 287 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 29 ---- 29 ---- 29 ---- 29 ---- 29 307 -------- 296 -------- 243 -------- 428 -------- 325 3 -------- 3 -------- 3 -------- 3 -------- 3 53 ------- 54 ------- 52 ------- 50 ------- 49 2.3 ------ 2.2 ------ 2.3 ------ 2.3 ------ 2.3 0.34 -------- 0.35 -------- 0.30 -------- 0.42 -------- 0.41 26 ------- 27 ------- 26 ------- 25 ------- 23 27 -------- 27 -------- 26 -------- 25 -------- 26 0.96 -------- 1.00 -------- 1.00 -------- 1.00 -------- 0.88 6.5 ------- 6.8 ------- 6.1 ------- 5.7 ------- 6.3 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 288 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 9 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 29 ---- 29 ---- 29 ---- 29 ---- 29 140 ------ 142 ------ 141 ------ 141 ------ 142 5.75 ------ 5.76 ------ 5.25 ------ 5.36 ------ 5.78 2.31 ------- 2.25 ------- 2.41 ------- 2.34 ------- 2.35 102 -------- 102 -------- 103 -------- 99 -------- 101 3.05 ------ 2.82 ------ 2.48 ------ 3.00 ------ 3.00 14.9 ------- 16.9 ------- 16.2 ------- 15.8 ------- 19.4 87 ------ 76 ------ 36 ------ 58 ------ 56 49 ------ 41 ------ 46 ------ 50 ------ 48 5.7 -------- 6.2 -------- 5.1 -------- 5.2 -------- 5.6 58 ---64 ---58 ---53 ---60 127 ----102 ----- 83 ----111 ----119 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 289 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 10 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 29 ---- 29 ---- 29 ---- 29 ---- 29 608 -------- 533 -------- 606 -------- 661 -------- 491 3 -------- 3 -------- 3 -------- 3 -------- 3 54 ------- 53 ------- 53 ------- 54 ------- 55 2.0 ------ 1.9 ------ 2.1 ------ 2.2 ------ 1.7 0.44 -------- 0.36 -------- 0.49 -------- 0.51 -------- 0.56 26 ------- 27 ------- 26 ------- 26 ------- 27 28 -------- 26 -------- 27 -------- 28 -------- 28 0.93 -------- 1.04 -------- 0.96 -------- 0.93 -------- 0.96 6.0 ------- 7.6 ------- 4.9 ------- 7.3 ------- 5.4 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 290 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 11 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 29 ---- 29 ---- 29 ---- 29 ---- 29 145 ------ 146 ------ 147 ------ 149 ------ 146 5.11 ------ 5.56 ------ 5.46 ------ 5.43 ------ 5.42 2.20 ------- 2.25 ------- 2.25 ------- 2.24 ------- 2.23 109 -------- 108 -------- 106 -------- 109 -------- 111 2.77 ------ 2.81 ------ 2.81 ------ 2.79 ------ 2.94 12.3 ------- 13.5 ------- 15.5 ------- 12.2 ------- 16.2 107 ------ 66 ------ 74 ------ 89 ------ 78 45 ------ 46 ------ 53 ------ 49 ------ 44 4.3 -------- 6.9 -------- 7.1 -------- 5.9 -------- 4.4 43 ---49 ---45 ---53 ---42 95 ----- 99 ----104 ----115 ----100 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 291 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 12 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 29 ---- 29 ---- 29 ---- 29 ---- 29 377 -------- 409 -------- 382 -------- 412 -------- 304 3 -------- 3 -------- 3 -------- 3 -------- 3 62 ------- 62 ------- 62 ------- 60 ------- 58 2.9 ------ 3.1 ------ 2.5 ------ 2.6 ------ 2.6 0.30 -------- 0.46 -------- 0.40 -------- 0.37 -------- 0.40 32 ------- 33 ------- 33 ------- 32 ------- 30 30 -------- 29 -------- 29 -------- 28 -------- 28 1.07 -------- 1.14 -------- 1.14 -------- 1.14 -------- 1.07 6.4 ------- 8.6 ------- 5.5 ------- 8.0 ------- 5.9 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 292 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 13 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 143 ------ 144 ------ 141 ------ 141 ------ 141 ------ 144 ------ 145 ------ 144 ------ 144 5.50 ------ 5.71 ------ 6.66 ------ 5.46 ------ 6.20 ------ 5.18 ------ 4.80 ------ 4.94 ------ 4.67 2.24 ------- 2.37 ------- 2.45 ------- 2.35 ------- 2.27 ------- 2.34 ------- 2.31 ------- 2.18 ------- 2.40 101 -------- 102 -------- 102 -------- 100 -------- 104 -------- 106 -------- 107 -------- 109 -------- 105 2.86 ------ 2.86 ------ 3.20 ------ 2.99 ------ 2.97 ------ 2.88 ------ 2.65 ------ 2.64 ------ 2.90 15.2 ------- 18.5 ------- 12.4 ------- 14.8 ------- 19.6 ------- 7.3 ------- 5.6 ------- 5.1 ------- 6.9 59 ------ 36 ------ 50 ------ 33 ------ 77 ------ 52 ------ 73 ------ 55 ------ 38 40 ------ 38 ------ 50 ------ 42 ------ 47 ------ 54 ------ 59 ------ 55 ------ 50 7.3 -------- 5.8 -------- 7.8 -------- 6.4 -------- 8.1 -------- 8.1 -------- 11.8 -------- 18.7 -------- 7.5 66 ---77 ---68 ---59 ---51 ---42 ---44 ---32 ---32 87 ----107 ----127 ----- 88 ----100 ----111 ----108 ----130 ----- 84 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 293 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 14 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 382 -------- 469 -------- 303 -------- 615 -------- 351 -------- 266 -------- 243 -------- 127 -------- 219 4 -------- 4 -------- 3 -------- 3 -------- 4 -------- 3 -------- 3 -------- 3 -------- 3 51 ------- 54 ------- 52 ------- 52 ------- 51 ------- 59 ------- 61 ------- 53 ------- 60 1.6 ------ 2.0 ------ 1.8 ------ 1.8 ------ 2.1 ------ 2.0 ------ 2.0 ------ 1.8 ------ 2.0 0.20 -------- 0.50 -------- 0.33 -------- 0.48 -------- 0.36 -------- 0.31 -------- 0.15 -------- . * -------- 0.33 26 ------- 28 ------- 27 ------- 27 ------- 25 ------- 29 ------- 28 ------- 25 ------- 29 25 -------- 26 -------- 25 -------- 25 -------- 26 -------- 30 -------- 33 -------- 28 -------- 31 1.04 -------- 1.08 -------- 1.08 -------- 1.08 -------- 0.96 -------- 0.97 -------- 0.85 -------- 0.89 -------- 0.94 5.5 ------- 5.0 ------- 5.2 ------- 5.5 ------- 6.4 ------- 7.4 ------- 6.5 ------- 6.6 ------- 5.1 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 294 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 15 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 148 ------ 144 ------ 145 ------ 143 ------ 143 ------ 141 ------ 143 ------ 142 ------ 144 ------ 140 6.10 ------ 5.55 ------ 7.07 ------ 5.51 ------ 5.07 ------ 5.23 ------ 6.11 ------ 5.55 ------ 5.96 ------ 5.62 2.45 ------- 2.22 ------- 2.32 ------- 2.15 ------- 2.12 ------- 2.37 ------- 2.27 ------- 2.24 ------- 2.28 ------- 2.34 105 -------- 107 -------- 105 -------- 105 -------- 103 -------- 106 -------- 109 -------- 106 -------- 106 -------- 106 3.38 ------ 2.86 ------ 3.55 ------ 2.95 ------ 2.91 ------ 2.83 ------ 3.07 ------ 2.88 ------ 3.13 ------ 3.38 16.0 ------- 12.2 ------- 14.5 ------- 14.8 ------- 15.2 ------- 16.1 ------- 11.2 ------- 12.3 ------- 6.6 ------- 17.1 322 ------ 80 ------ 100 ------ 49 ------ 89 ------ 39 ------ 85 ------ 86 ------ 69 ------ 57 54 ------ 50 ------ 38 ------ 42 ------ 45 ------ 45 ------ 64 ------ 61 ------ 61 ------ 50 6.8 -------- 4.9 -------- 6.0 -------- 5.0 -------- 6.4 -------- 6.4 -------- 7.3 -------- 8.8 -------- 15.5 -------- 4.7 53 ---49 ---60 ---47 ---58 ---31 ---29 ---80 ---43 ---32 82 ----119 ----101 ----- 82 ----- 94 ----- 68 ----- 97 ----152 ----111 ----- 71 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 295 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 16 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 437 -------- 328 -------- 556 -------- 443 -------- 524 -------- 229 -------- 111 -------- 112 -------- 199 -------- 274 5 -------- 5 -------- 8 -------- 7 -------- 6 -------- 3 -------- 3 -------- 3 -------- 3 -------- 3 61 ------- 56 ------- 56 ------- 55 ------- 52 ------- 53 ------- 51 ------- 50 ------- 54 ------- 53 3.1 ------ 2.3 ------ 2.1 ------ 2.5 ------ 1.9 ------ 2.1 ------ 2.1 ------ 1.8 ------ 1.6 ------ 1.8 0.60 -------- 0.48 -------- 0.36 -------- 0.39 -------- 0.25 -------- 0.39 -------- 0.19 -------- 0.24 -------- 0.25 -------- 0.40 36 ------- 29 ------- 29 ------- 29 ------- 27 ------- 25 ------- 24 ------- 23 ------- 25 ------- 24 25 -------- 27 -------- 27 -------- 26 -------- 25 -------- 28 -------- 27 -------- 27 -------- 29 -------- 29 1.44 -------- 1.07 -------- 1.07 -------- 1.12 -------- 1.08 -------- 0.89 -------- 0.89 -------- 0.85 -------- 0.86 -------- 0.83 7.2 ------- 5.5 ------- 5.8 ------- 5.4 ------- 5.8 ------- 4.9 ------- 5.4 ------- 5.3 ------- 6.3 ------- 5.4 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 296 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 17 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 29 ---- 29 ---- 29 ---- 29 ---- 29 136 ------ 137 ------ 138 ------ 139 ------ 140 6.33 ------ 6.08 ------ 6.20 ------ 5.52 ------ 5.47 2.39 ------- 2.39 ------- 2.42 ------- 2.45 ------- 2.48 99 -------- 101 -------- 103 -------- 104 -------- 104 3.43 ------ 2.91 ------ 3.17 ------ 2.95 ------ 3.11 17.8 ------- 16.4 ------- 16.6 ------- 18.0 ------- 17.1 25 ------ 31 ------ 25 ------ 30 ------ 26 48 ------ 46 ------ 50 ------ 44 ------ 44 7.3 -------- 6.4 -------- 6.7 -------- 5.7 -------- 5.7 33 ---42 ---41 ---45 ---61 67 ----- 81 ----- 98 ----- 79 ----- 82 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 297 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 18 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 29 ---- 29 ---- 29 ---- 29 ---- 29 347 -------- 390 -------- 371 -------- 292 -------- 438 3 -------- 3 -------- 3 -------- 3 -------- 3 53 ------- 47 ------- 50 ------- 51 ------- 51 1.9 ------ 1.9 ------ 2.0 ------ 2.0 ------ 2.2 0.54 -------- 0.44 -------- 0.44 -------- 0.43 -------- 0.46 25 ------- 22 ------- 25 ------- 25 ------- 23 28 -------- 25 -------- 25 -------- 26 -------- 28 0.89 -------- 0.88 -------- 1.00 -------- 0.96 -------- 0.82 4.3 ------- 4.5 ------- 5.0 ------- 4.4 ------- 4.5 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 298 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 19 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 29 ---- 29 ---- 29 ---- 29 ---- 29 139 ------ 142 ------ 138 ------ 141 ------ 140 5.36 ------ 5.67 ------ 5.77 ------ 5.97 ------ 6.05 2.39 ------- 2.42 ------- 2.55 ------- 2.44 ------- 2.37 104 -------- 106 -------- 104 -------- 107 -------- 105 2.39 ------ 2.53 ------ 3.28 ------ 2.98 ------ 3.09 11.2 ------- 12.5 ------- 13.4 ------- 14.3 ------- 15.4 78 ------ 90 ------ 91 ------ 58 ------ 29 48 ------ 61 ------ 54 ------ 54 ------ 49 6.2 -------- 5.0 -------- 5.6 -------- 5.5 -------- 6.8 46 ---42 ---42 ---43 ---34 104 ----100 ----129 ----113 ----- 81 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 299 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 20 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 29 ---- 29 ---- 29 ---- 29 ---- 29 411 -------- 387 -------- 435 -------- 304 -------- 427 3 -------- 3 -------- 3 -------- 3 -------- 3 54 ------- 54 ------- 54 ------- 59 ------- 52 2.2 ------ 2.2 ------ 2.0 ------ 2.6 ------ 1.9 0.30 -------- 0.30 -------- 0.39 -------- 0.38 -------- 0.37 27 ------- 28 ------- 27 ------- 29 ------- 26 27 -------- 26 -------- 27 -------- 30 -------- 26 1.00 -------- 1.08 -------- 1.00 -------- 0.97 -------- 1.00 4.7 ------- 4.9 ------- 5.6 ------- 5.0 ------- 5.0 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 300 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 21 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 29 ---- 29 ---- 29 ---- 29 ---- 29 138 ------ 139 ------ 137 ------ 139 ------ 137 5.51 ------ 5.80 ------ 5.67 ------ 5.62 ------ 5.75 2.44 ------- 2.51 ------- 2.43 ------- 2.56 ------- 2.50 102 -------- 101 -------- 101 -------- 102 -------- 102 3.14 ------ 3.09 ------ 2.95 ------ 3.12 ------ 3.21 18.4 ------- 18.5 ------- 20.1 ------- 18.7 ------- 20.9 21 ------ 23 ------ 30 ------ 15 ------ 32 48 ------ 46 ------ 51 ------ 47 ------ 44 7.5 -------- 5.1 -------- 5.6 -------- 6.1 -------- 5.6 46 ---40 ---38 ---57 ---41 97 ----- 93 ----- 95 ----- 82 ----- 81 * = 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 302 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 29 ---- 29 ---- 29 ---- 29 ---- 29 338 -------- 412 -------- 341 -------- 366 -------- 369 4 -------- 4 -------- 4 -------- 4 -------- 4 52 ------- 53 ------- 51 ------- 51 ------- 51 1.9 ------ 1.9 ------ 2.0 ------ 2.2 ------ 2.0 0.52 -------- 0.57 -------- 0.47 -------- 0.52 -------- 0.65 24 ------- 26 ------- 25 ------- 24 ------- 25 28 -------- 27 -------- 26 -------- 27 -------- 26 0.86 -------- 0.96 -------- 0.96 -------- 0.89 -------- 0.96 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: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 29 ---- 29 ---- 29 ---- 29 ---- 29 138 ------ 141 ------ 140 ------ 143 ------ 141 5.69 ------ 5.63 ------ 6.12 ------ 5.73 ------ 4.93 2.29 ------- 2.42 ------- 2.31 ------- 2.48 ------- 2.56 104 -------- 106 -------- 108 -------- 108 -------- 105 3.15 ------ 2.96 ------ 2.96 ------ 2.82 ------ 3.21 16.1 ------- 18.0 ------- 16.2 ------- 11.3 ------- 14.0 57 ------ 60 ------ 65 ------ 51 ------ 65 54 ------ 50 ------ 49 ------ 46 ------ 44 5.7 -------- 5.3 -------- 4.8 -------- 4.0 -------- 5.3 45 ---41 ---46 ---38 ---44 134 ----128 ----141 ----101 ----- 85 * = 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 304 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 29 ---- 29 ---- 29 ---- 29 ---- 29 312 -------- 275 -------- 370 -------- 209 -------- 367 4 -------- 4 -------- 4 -------- 4 -------- 4 54 ------- 55 ------- 52 ------- 57 ------- 59 2.4 ------ 2.1 ------ 2.2 ------ 2.5 ------ 2.6 0.34 -------- 0.37 -------- 0.34 -------- 0.39 -------- 0.54 26 ------- 26 ------- 26 ------- 28 ------- 29 28 -------- 29 -------- 26 -------- 29 -------- 30 0.93 -------- 0.90 -------- 1.00 -------- 0.97 -------- 0.97 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: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 29 ---- 29 ---- 29 ---- 29 ---- 29 140 ------ 141 ------ 139 ------ 139 ------ 142 5.45 ------ 4.97 ------ 5.03 ------ 4.95 ------ 5.05 2.47 ------- 2.48 ------- 2.34 ------- 2.47 ------- 2.50 103 -------- 102 -------- 103 -------- 102 -------- 102 2.80 ------ 2.97 ------ 2.82 ------ 2.65 ------ 2.67 13.9 ------- 14.5 ------- 14.2 ------- 17.0 ------- 19.0 57 ------ 34 ------ 31 ------ 27 ------ 16 46 ------ 46 ------ 48 ------ 52 ------ 43 6.2 -------- 5.7 -------- 4.2 -------- 5.6 -------- 6.0 34 ---45 ---41 ---47 ---35 79 ----- 78 ----- 90 ----- 88 ----- 55 * = 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 306 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 29 ---- 29 ---- 29 ---- 29 ---- 29 428 -------- 442 -------- 484 -------- 416 -------- 468 4 -------- 4 -------- 4 -------- 4 -------- 4 54 ------- 57 ------- 53 ------- 57 ------- 56 2.2 ------ 2.1 ------ 2.1 ------ 2.4 ------ 2.1 0.60 -------- 0.60 -------- 0.50 -------- 0.47 -------- 0.84 28 ------- 27 ------- 27 ------- 28 ------- 28 26 -------- 30 -------- 26 -------- 29 -------- 28 1.08 -------- 0.90 -------- 1.04 -------- 0.97 -------- 1.00 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: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Sodium mmol/L Potas sium mmol/L Calcium mmol/L Chloride mmol/L Phos phorus mmol/L Glucose mmol/L Uric Acid umol/L Creati nine umol/L Urea Nitrogen mmol/L ALAT IU/L ASAT IU/L 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 29 ---- 29 ---- 29 ---- 29 ---- 29 141 ------ 140 ------ 142 ------ 140 ------ 143 5.35 ------ 5.25 ------ 5.13 ------ 5.22 ------ 5.00 2.36 ------- 2.45 ------- 2.48 ------- 2.40 ------- 2.39 107 -------- 104 -------- 105 -------- 107 -------- 108 2.64 ------ 2.64 ------ 2.68 ------ 2.77 ------ 2.67 13.9 ------- 11.8 ------- 12.7 ------- 17.0 ------- 15.2 67 ------ 91 ------ 72 ------ 40 ------ 40 52 ------ 58 ------ 50 ------ 45 ------ 54 5.3 -------- 5.6 -------- 6.0 -------- 4.1 -------- 4.8 40 ---45 ---46 ---36 ---46 114 ----127 ----123 ----- 83 ----119 * = 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 308 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 11-Mar-2003 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Clinical Chemistry Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ (continued) Group Sex Animal Number Day Number Alk.Phos phatase IU/L G-Gluta. Transf. IU/L Total Protein g/L Chole sterol mmol/L Triglyce rides mmol/L Albumin g/L Globulin g/L Alb/Glob Ratio Total Biliru. umol/L 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 29 ---- 29 ---- 29 ---- 29 ---- 29 227 -------- 486 -------- 283 -------- 260 -------- 382 4 -------- 4 -------- 4 -------- 4 -------- 4 57 ------- 60 ------- 59 ------- 58 ------- 59 2.1 ------ 2.4 ------ 2.1 ------ 2.6 ------ 2.2 0.30 -------- 0.36 -------- 0.33 -------- 0.40 -------- 0.48 28 ------- 30 ------- 30 ------- 28 ------- 28 29 -------- 30 -------- 29 -------- 30 -------- 31 0.97 -------- 1.00 -------- 1.03 -------- 0.93 -------- 0.90 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLOUDY ------CLEAR ------CLEAR ------CLOUDY ------CLEAR ------CLEAR DK YELL -------DK YELL -------YELLOW -------YELLOW -------DK YELL -------YELLOW -------DK YELL -------DK YELL -------YELLOW -------YELLOW 3.0 ------ 1.8 ------ 3.2 ------ 4.5 ------ 1.9 ------ 7.6 ------ 1.7 ------ 1.3 ------ 9.8 ------ 3.9 6.5 ----- 6.5 ----- 6.5 ----- 7.0 ----- 6.5 ----- 7.5 ----- 6.5 ----- 6.5 ----- 7.5 ----- 7.0 1061 -------- 1068 -------- 1056 -------- 1036 -------- 1072 -------- 1031 -------- 1069 -------- 1071 -------- 1029 -------- 1047 3+ -------2+ -------2+ -------1+ -------2+ -------1+ -------3+ -------4+ -------2+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------TRACE -------NEGATIV -------TRACE -------NEGATIV -------TRACE -------TRACE -------NEGATIV -------NEGATIV 1+ -------1+ -------1+ -------TRACE -------1+ -------TRACE -------1+ -------2+ -------1+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 311 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 CLEAR ------CLEAR ------- * ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR DK YELL -------YELLOW -------- * -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 2.1 ------ 3.5 ------ 1.2 ------ 3.9 ------ 5.0 ------ 5.0 ------ 5.2 ------ 2.9 ------ 8.0 ------ 8.2 6.0 ----- 7.5 ----- . * ----- 6.5 ----- 6.5 ----- 7.0 ----- 7.0 ----- 6.5 ----- 7.0 ----- 7.5 1054 -------- 1034 -------- . * -------- 1034 -------- 1034 -------- 1031 -------- 1036 -------- 1048 -------- 1027 -------- 1024 1+ -------1+ -------- * -------1+ -------TRACE -------NEGATIV -------1+ -------NEGATIV -------1+ -------TRACE NEGATIV -------NEGATIV -------- * -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------- * -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------- * -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------- * -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------- * -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 312 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 23 ---- 23 ---- 23 ---- 23 ---- 23 CLEAR ------CLOUDY ------CLEAR ------CLOUDY ------CLEAR DK YELL -------DK YELL -------DK YELL -------DK YELL -------DK YELL 1.8 ------ 2.2 ------ 3.5 ------ 1.9 ------ 3.3 6.0 ----- 6.5 ----- 6.5 ----- 6.5 ----- 6.5 1079 -------- 1065 -------- 1053 -------- 1053 -------- 1054 2+ -------2+ -------3+ -------2+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------TRACE -------TRACE -------TRACE TRACE -------1+ -------1+ -------1+ -------TRACE NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 313 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 23 ---- 23 ---- 23 ---- 23 ---- 23 CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 5.0 ------ 4.8 ------ 4.3 ------ 4.7 ------ 5.0 7.0 ----- 6.5 ----- 7.0 ----- 6.5 ----- 7.0 1027 -------- 1041 -------- 1024 -------- 1038 -------- 1030 1+ -------1+ -------TRACE -------1+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------TRACE -------TRACE -------TRACE NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 314 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 23 ---- 23 ---- 23 ---- 23 ---- 23 CLEAR ------CLOUDY ------CLEAR ------CLEAR ------CLOUDY YELLOW -------YELLOW -------DK YELL -------YELLOW -------DK YELL 2.9 ------ 4.5 ------ 3.4 ------ 6.2 ------ 3.0 6.0 ----- 6.0 ----- 6.5 ----- 6.0 ----- 6.0 1051 -------- 1044 -------- 1058 -------- 1042 -------- 1057 2+ -------1+ -------2+ -------1+ -------2+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------TRACE -------NEGATIV -------TRACE TRACE -------1+ -------1+ -------1+ -------TRACE NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 315 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 23 ---- 23 ---- 23 ---- 23 ---- 23 CLEAR ------CLEAR ------CLOUDY ------CLEAR ------CLOUDY YELLOW -------YELLOW -------DK YELL -------DK YELL -------DK YELL 4.6 ------ 5.3 ------ 2.8 ------ 3.0 ------ 2.6 7.0 ----- 6.5 ----- 6.5 ----- 8.0 ----- 6.0 1035 -------- 1036 -------- 1039 -------- 1036 -------- 1035 2+ -------1+ -------1+ -------1+ -------2+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 1+ -------1+ -------1+ -------1+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 316 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 ------ 30 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 CLEAR ------CLOUDY ------CLOUDY ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------- * ------CLEAR ------CLEAR YELLOW -------YELLOW -------YELLOW -------DK YELL -------YELLOW -------YELLOW -------DK YELL -------- * -------YELLOW -------YELLOW 5.7 ------ 5.1 ------ 7.1 ------ 4.9 ------ 3.8 ------ 7.8 ------ 3.0 ------ 1.1 ------ 4.8 ------ 2.4 7.0 ----- 6.0 ----- 6.5 ----- 6.5 ----- 6.5 ----- 7.5 ----- 7.5 ----- . * ----- 7.5 ----- 6.0 1029 -------- 1039 -------- 1028 -------- 1044 -------- 1048 -------- 1022 -------- 1058 -------- . * -------- 1044 -------- 1066 1+ -------1+ -------1+ -------1+ -------1+ -------1+ -------1+ -------- * -------TRACE -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------- * -------NEGATIV -------NEGATIV NEGATIV -------TRACE -------NEGATIV -------TRACE -------TRACE -------NEGATIV -------TRACE -------- * -------NEGATIV -------NEGATIV 1+ -------1+ -------1+ -------1+ -------1+ -------NEGATIV -------TRACE -------- * -------TRACE -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------- * -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------- * -------NEGATIV -------NEGATIV 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 317 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 CLEAR ------TURBID ------CLOUDY ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR DK YELL -------DK YELL -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 4.4 ------ 3.7 ------ 4.9 ------ 12.5 ------ 5.4 ------ 8.4 ------ 4.5 ------ 3.7 ------ 2.3 ------ 4.8 6.0 ----- 6.0 ----- 6.0 ----- 6.0 ----- 6.0 ----- 6.5 ----- 6.5 ----- 7.0 ----- 6.0 ----- 7.0 1044 -------- 1045 -------- 1035 -------- 1013 -------- 1034 -------- 1028 -------- 1039 -------- 1035 -------- 1053 -------- 1048 1+ -------1+ -------TRACE -------NEGATIV -------TRACE -------1+ -------TRACE -------1+ -------2+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 1+ -------1+ -------2+ -------1+ -------1+ -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------TRACE NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------2+ -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 318 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 9 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 26 ---- 26 ---- 26 ---- 26 ---- 26 CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLOUDY DK YELL -------DK YELL -------DK YELL -------DK YELL -------DK YELL 3.1 ------ 1.5 ------ 2.6 ------ 3.2 ------ 4.1 6.5 ----- 6.0 ----- 6.5 ----- 6.0 ----- 6.5 1064 -------- 1075 -------- 1055 -------- 1069 -------- 1049 2+ -------2+ -------2+ -------2+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------TRACE -------TRACE -------TRACE -------TRACE TRACE -------TRACE -------1+ -------TRACE -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 319 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 10 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 26 ---- 26 ---- 26 ---- 26 ---- 26 CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 2.7 ------ 3.0 ------ 3.4 ------ 4.2 ------ 2.0 6.5 ----- 6.5 ----- 6.5 ----- 6.5 ----- 7.0 1057 -------- 1042 -------- 1043 -------- 1035 -------- 1057 2+ -------1+ -------1+ -------1+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------NEGATIV -------NEGATIV -------NEGATIV -------TRACE TRACE -------NEGATIV -------TRACE -------TRACE -------TRACE NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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 320 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 11 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urinalysis (semiquant. Params) Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats -----------------------------------------------------------------------------------------------------------------------------------Comments and Markers -------------------- Group Animal Day Sex Number Number Measurement Marker Comment ------------------------------------------------------------------------------------------------------------------------------ 1f 33 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) 4m 28 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) Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - not examined Sample too small - 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: 1 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 24 ---- 24 ---- 24 ---- 24 ---- 24 CLOUDY ------CLEAR ------CLEAR ------CLEAR ------CLEAR YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 3.0 ------ 4.7 ------ 3.3 ------ 3.0 ------ 4.5 6.0 ----- 6.5 ----- 6.5 ----- 6.5 ----- 6.5 1052 -------- 1039 -------- 1040 -------- 1051 -------- 1036 4+ -------1+ -------3+ -------4+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV TRACE -------NEGATIV -------NEGATIV -------TRACE -------NEGATIV TRACE -------TRACE -------TRACE -------TRACE -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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: 2 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 24 ---- 24 ---- 24 ---- 24 ---- 24 CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 3.8 ------ 3.1 ------ 1.9 ------ 4.9 ------ 6.4 6.0 ----- 6.0 ----- 6.0 ----- 7.0 ----- 6.5 1037 -------- 1046 -------- 1049 -------- 1029 -------- 1027 1+ -------1+ -------1+ -------TRACE -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------TRACE -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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: 3 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 24 ---- 24 ---- 24 ---- 24 ---- 24 CLEAR ------CLEAR ------CLOUDY ------CLEAR ------CLEAR YELLOW -------YELLOW -------DK YELL -------YELLOW -------YELLOW 7.1 ------ 4.8 ------ 2.4 ------ 7.2 ------ 8.0 6.5 ----- 6.0 ----- 6.5 ----- 6.5 ----- 6.5 1028 -------- 1038 -------- 1055 -------- 1027 -------- 1029 1+ -------1+ -------2+ -------2+ -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------TRACE -------NEGATIV -------NEGATIV TRACE -------TRACE -------1+ -------TRACE -------TRACE NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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: 4 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Appear ence Urine Color Volume mL pH Value Specific Weight g/L Protein (Album.) Bili rubin Urobili nogen Ketone Bodies Glucose Blood (RBCs) 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 24 ---- 24 ---- 24 ---- 24 ---- 24 CLEAR ------CLEAR ------CLEAR ------CLEAR ------CLEAR YELLOW -------YELLOW -------YELLOW -------YELLOW -------YELLOW 3.7 ------ 3.8 ------ 3.3 ------ 4.4 ------ 4.4 6.5 ----- 6.0 ----- 6.0 ----- 6.5 ----- 6.0 1034 -------- 1036 -------- 1046 -------- 1029 -------- 1038 TRACE -------1+ -------1+ -------TRACE -------1+ NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV -------NEGATIV 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Other Ep.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 ------------------------1-5 ------------------------------- --------1-5 ----1-5 ----1-5 --------1-5 --------1-5 ----- 1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 ---------------------------------------------------------------- x -------x -------x -------x -------x -------x -------x -------x -------x -------x ------------------------------------------------------- --------------several --------------several -------several -------several -------several -------several -------several several -------several -------several -------several -------several -------several -------several -------several -------several -------several 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 326 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Other Ep.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 ------------------------------------------------------- 1-5 ----1-5 ----1-5 ----1-5 ----1-5 --------1-5 --------1-5 ----1-5 1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 ---------------------------------------------------------------- x -------x -------x -------x -------x -------x -------x -------x -------x -------x ------------------------------------------------------- ---------------------------------------------------------------- several -------several -------several -------several -------several -------several -------several -------several -------several -------several 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 327 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Other Ep.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 ------ 30 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 ------------------------------------------------------- 1-5 ----1-5 ----1-5 ----1-5 ----6-10 ----1-5 ----------------- 1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------<5 grn -------<5 grn -------------------------------------------------- x -----------------------------------x -------x -------x -------x -------x ------------------------------------------------x ------- several ---------------------several -------several -------several -------several --------------several -------several several -------several -------several -------several -------several -------several -------several -------several -------several -------numers. 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 328 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 27-Jan-2003 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Other Ep.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 23 ---- 23 ---- 23 ---- 23 ---- 23 ---- 41 ---- 41 ---- 41 ---- 41 ---- 41 ------31-50 ------------------------------------------------- 6-10 ----1-5 ----1-5 ----1-5 ----1-5 ----1-5 --------1-5 ----6-10 ----1-5 1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 -------1-5 ---------------------------------------------------------------- ---------------------x --------------x -------x -------x -------x -------x ------------------------------------------------------- ---------------------------------------------------------------- several -------numers. -------several -------several -------several -------several -------several -------several -------several -------several 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 329 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 24 ---- 24 ---- 24 ---- 24 ---- 24 6-10 ------------------1-5 ------- 1-5 ----1-5 ----1-5 ----1-5 ----1-5 1-5 -------1-5 -------1-5 -------1-5 -------1-5 x -------x -------x -------x -------x ------------------------- several -------several -------several --------------several 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: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 24 ---- 24 ---- 24 ---- 24 ---- 24 ------------------------- 1-5 ----1-5 ----1-5 ----1-5 ----1-5 1-5 -------1-5 -------1-5 -------1-5 -------1-5 x -------x --------------x -------x ------------------------- ----------------------------- 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: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 24 ---- 24 ---- 24 ---- 24 ---- 24 ------------------------- 1-5 --------1-5 ----1-5 ----1-5 1-5 -------1-5 -------1-5 -------1-5 -------1-5 x -------x -------x -------x -------x ------------------------- several -------several -------several -------several -------several 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: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Urine Sediment Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Erythro cytes Leuco cytes Squamous E.Cells Triple Phosphat Calcium Oxalate Sperms Bacteria 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 24 ---- 24 ---- 24 ---- 24 ---- 24 ------------------------- 1-5 --------1-5 ----1-5 ----- 1-5 -------1-5 -------1-5 -------1-5 -------1-5 x --------------x -------x -------x ------------------x ------- ----------------------------- 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 EXPLANATION OF URINALYSIS SYMBOLS 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 Bilirubin NEGATIVE 1+ 2+ 3+ Blood (Erythrocytes) NEGATIVE TRACE 1+ 2+ 3+ = negative = trace = small = moderate = large Glucose NEGATIVE TRACE 1+ 2+ 3+ = negative = small = moderate = large Urobilinogen NEGATIVE TRACE 1+ 2+ 3+ <= 3 mol/L = 16 mol/L = 33 mol/L = 66 mol/L >= 131 mol/L = 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 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 URINALYSIS 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 < > 5 tld 10 tld 10 tld = 1= 6=> 5 grn 10 grn 10 grn = 1= 6=> 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 several numers. Bacteria per visual field = several = numerous Other Epithelial Cells No. per visual field 5 tailed epithelial cells 10 tailed epithelial cells 10 tailed epithelial cells 5 irregular forms, extreme granulated 10 irregular forms, extreme granulated 10 irregular forms, extreme granulated hyaline erythr. leucoc. epithel. granul. waxy cylind. fatty Casts = hyaline = erythrocytic = leucocytic = epithelial = granular = waxy = cylindrous = fatty 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 0.998 -----0.912 -----1.005 -----1.204 -----0.908 -----1.231 -----0.910 -----1.050 -----1.581 -----1.168 11.01 -----10.06 -----10.97 -----13.07 -----11.08 -----11.68 ------ 7.95 ------ 9.22 -----13.65 ------ 9.73 1.927 ------- 1.888 ------- 1.888 ------- 2.495 ------- 2.286 ------- 2.356 ------- 1.896 ------- 2.024 ------- 2.933 ------- 2.307 0.045 -------- 0.046 -------- 0.045 -------- 0.043 -------- 0.049 -------- 0.051 -------- 0.047 -------- 0.038 -------- 0.055 -------- 0.052 0.682 -----0.878 -----0.726 -----1.040 -----0.757 -----0.794 -----0.727 -----0.631 -----0.970 -----0.740 0.471 -----0.475 -----0.439 -----0.554 -----0.458 -----0.481 -----0.333 -----0.354 -----0.441 -----0.317 1.792 -----1.804 -----1.725 -----1.906 -----1.955 -----1.958 -----2.020 -----1.719 -----2.089 -----1.911 3.021 -----2.879 -----3.217 -----3.391 -----3.570 -----3.605 -----2.977 -----3.082 -----4.019 -----3.867 0.897 -------- 0.707 -------- 0.854 -------- 0.792 -------- 0.871 -------- 1.115 -------- 1.047 -------- 1.032 -------- 1.324 -------- 1.197 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 337 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 29 ---- 29 ---- 29 ---- 29 ---- 29 0.857 -----0.796 -----0.843 -----1.034 -----0.824 11.15 ------ 9.49 -----12.30 -----11.44 -----11.04 1.944 ------- 2.167 ------- 2.124 ------- 2.130 ------- 2.161 0.050 -------- 0.040 -------- 0.041 -------- 0.043 -------- 0.039 0.565 -----0.667 -----0.688 -----0.708 -----0.752 0.513 -----0.424 -----0.375 -----0.335 -----0.396 1.628 -----1.789 -----1.709 -----1.792 -----1.810 2.986 -----3.070 -----3.572 -----3.476 -----3.379 0.868 -------- 0.784 -------- 0.832 -------- 0.908 -------- 0.739 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 338 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 29 ---- 29 ---- 29 ---- 29 ---- 29 0.798 -----0.902 -----1.024 -----1.040 -----0.930 10.93 -----11.96 -----13.93 -----14.54 -----13.16 1.822 ------- 2.395 ------- 2.300 ------- 2.456 ------- 2.173 0.051 -------- 0.043 -------- 0.051 -------- 0.047 -------- 0.043 0.535 -----0.672 -----0.627 -----0.776 -----0.594 0.504 -----0.336 -----0.407 -----0.534 -----0.444 1.714 -----1.746 -----1.800 -----1.916 -----1.692 3.235 -----3.401 -----3.544 -----4.025 -----3.202 0.759 -------- 0.768 -------- 0.840 -------- 0.878 -------- 0.818 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 339 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 0.841 -----0.754 -----0.903 -----0.863 -----0.683 -----0.893 -----0.647 -----0.664 -----0.828 13.98 -----14.79 -----13.87 -----15.84 -----12.11 ------ 6.73 ------ 5.16 ------ 4.09 ------ 7.01 1.904 ------- 1.993 ------- 1.980 ------- 2.102 ------- 1.842 ------- 1.791 ------- 1.378 ------- 1.056 ------- 1.758 0.062 -------- 0.054 -------- 0.057 -------- 0.059 -------- 0.047 -------- 0.050 -------- 0.044 -------- 0.040 -------- 0.046 0.590 -----0.596 -----0.494 -----0.722 -----0.513 -----0.494 -----0.385 -----0.275 -----0.558 0.311 -----0.305 -----0.355 -----0.435 -----0.324 -----0.268 -----0.162 -----0.056 -----0.320 1.731 -----1.729 -----1.724 -----1.863 -----1.789 -----1.898 -----1.713 -----1.589 -----1.720 3.479 -----3.491 -----3.337 -----3.541 -----3.468 -----2.973 -----3.215 -----3.520 -----3.618 0.829 -------- 0.904 -------- 0.670 -------- 0.758 -------- 0.738 -------- 1.032 -------- 0.784 -------- 0.813 -------- 1.011 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 340 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 29 ---- 29 ---- 29 ---- 29 ---- 29 1.296 -----0.997 -----1.028 -----1.119 -----1.203 11.86 -----10.57 ------ 9.72 -----10.19 -----11.62 2.141 ------- 1.909 ------- 1.879 ------- 1.992 ------- 2.326 0.040 -------- 0.043 -------- 0.051 -------- 0.041 -------- 0.051 0.619 -----0.805 -----0.701 -----0.735 -----0.904 0.467 -----0.555 -----0.482 -----0.521 -----0.532 1.903 -----1.835 -----1.738 -----1.888 -----1.888 3.611 -----3.427 -----3.345 -----3.242 -----4.091 0.867 -------- 0.777 -------- 0.901 -------- 0.826 -------- 0.934 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 341 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 0.743 -----0.687 -----0.831 -----0.804 -----0.814 -----0.741 -----0.865 -----0.769 -----0.811 -----0.894 8.17 ------ 7.64 ------ 9.20 ------ 8.64 ------ 8.39 ------ 6.19 ------ 8.13 ------ 7.46 ------ 7.56 ------ 8.44 1.472 ------- 1.307 ------- 1.466 ------- 1.463 ------- 1.596 ------- 1.553 ------- 1.696 ------- 1.521 ------- 1.569 ------- 1.521 0.077 -------- 0.055 -------- 0.060 -------- 0.055 -------- 0.055 -------- 0.070 -------- 0.061 -------- 0.073 -------- 0.056 -------- 0.058 0.623 -----0.669 -----0.690 -----0.671 -----0.592 -----0.600 -----0.678 -----0.581 -----0.627 -----0.883 0.300 -----0.400 -----0.387 -----0.437 -----0.509 -----0.348 -----0.328 -----0.281 -----0.413 -----0.380 1.846 -----1.703 -----1.769 -----1.812 -----1.773 -----1.718 -----1.887 -----1.868 -----1.825 -----1.889 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 342 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 29 ---- 29 ---- 29 ---- 29 ---- 29 0.703 -----0.703 -----0.872 -----0.737 -----0.757 8.13 ------ 7.97 ------ 8.86 ------ 8.92 ------ 7.85 1.529 ------- 1.547 ------- 1.556 ------- 1.610 ------- 1.322 0.061 -------- 0.068 -------- 0.053 -------- 0.051 -------- 0.062 0.734 -----0.790 -----0.640 -----0.712 -----0.687 0.418 -----0.363 -----0.392 -----0.546 -----0.433 1.719 -----1.607 -----1.777 -----1.850 -----1.677 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 343 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 29 ---- 29 ---- 29 ---- 29 ---- 29 0.740 -----0.695 -----0.695 -----0.746 -----0.673 9.73 -----10.65 ------ 9.62 ------ 8.86 -----10.16 2.094 ------- 2.055 ------- 1.857 ------- 1.885 ------- 1.753 0.054 -------- 0.056 -------- 0.061 -------- 0.061 -------- 0.063 0.652 -----0.577 -----0.531 -----0.535 -----0.610 0.355 -----0.357 -----0.372 -----0.317 -----0.371 1.760 -----1.644 -----1.719 -----1.664 -----1.635 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 344 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 29 ---- 29 ---- 29 ---- 29 ---- 29 ---- 43 ---- 43 ---- 43 ---- 43 ---- 43 0.743 -----0.686 -----0.643 -----0.632 -----0.633 -----0.842 -----0.664 -----0.691 -----0.580 -----0.772 16.47 -----14.87 -----12.62 -----12.74 -----12.26 ------ 7.98 ------ 5.46 ------ 5.94 ------ 5.16 ------ 7.97 1.713 ------- 1.645 ------- 1.510 ------- 1.845 ------- 1.496 ------- 1.568 ------- 1.264 ------- 1.362 ------- 1.222 ------- 1.646 0.073 -------- 0.063 -------- 0.057 -------- 0.052 -------- 0.053 -------- 0.058 -------- 0.053 -------- 0.060 -------- 0.035 -------- 0.051 0.495 -----0.478 -----0.395 -----0.450 -----0.461 -----0.715 -----0.514 -----0.478 -----0.422 -----0.558 0.384 -----0.270 -----0.323 -----0.353 -----0.217 -----0.409 -----0.299 -----0.328 -----0.235 -----0.283 1.730 -----1.742 -----1.559 -----1.734 -----1.532 -----1.869 -----1.747 -----1.763 -----1.691 -----1.800 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 345 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 29 ---- 29 ---- 29 ---- 29 ---- 29 0.790 -----0.795 -----0.910 -----0.734 -----0.910 7.77 ------ 7.59 ------ 6.63 ------ 7.26 ------ 7.22 1.398 ------- 1.271 ------- 1.282 ------- 1.246 ------- 1.321 0.055 -------- 0.054 -------- 0.054 -------- 0.051 -------- 0.060 0.600 -----0.632 -----0.589 -----0.616 -----0.769 0.483 -----0.392 -----0.380 -----0.403 -----0.335 1.659 -----1.687 -----1.843 -----1.602 -----1.755 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 346 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 29 ---- 29 ---- 29 ---- 29 ---- 29 1.248 -----1.340 -----0.826 -----1.219 -----1.220 13.38 -----13.01 -----10.04 -----12.25 -----12.43 2.439 ------- 2.670 ------- 2.089 ------- 2.432 ------- 2.427 0.054 -------- 0.052 -------- 0.039 -------- 0.056 -------- 0.055 0.772 -----0.845 -----0.648 -----0.880 -----0.858 0.586 -----0.528 -----0.445 -----0.758 -----0.535 1.890 -----1.904 -----1.792 -----1.839 -----1.992 3.899 -----3.619 -----3.406 -----3.620 -----3.448 0.951 -------- 0.903 -------- 0.857 -------- 0.920 -------- 0.809 * = 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: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g Testes Weight g Epidi dymis Wt g 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 29 ---- 29 ---- 29 ---- 29 ---- 29 1.096 -----1.258 -----1.083 -----1.149 -----1.353 11.88 -----13.67 ------ 9.25 -----12.08 -----13.99 2.236 ------- 2.888 ------- 2.080 ------- 2.320 ------- 2.627 0.047 -------- 0.056 -------- 0.045 -------- 0.039 -------- 0.046 0.798 -----0.848 -----0.737 -----0.770 -----0.859 0.702 -----0.486 -----0.456 -----0.604 -----0.672 1.803 -----1.897 -----1.869 -----1.919 -----2.011 3.393 -----3.826 -----3.349 -----3.382 -----3.944 0.788 -------- 0.868 -------- 0.837 -------- 0.835 -------- 0.910 * = 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 29 ---- 29 ---- 29 ---- 29 ---- 29 0.736 -----0.712 -----0.727 -----0.836 -----0.878 7.05 ------ 6.87 ------ 6.02 ------ 6.99 ------ 7.81 1.393 ------- 1.353 ------- 1.209 ------- 1.316 ------- 1.387 0.049 -------- 0.066 -------- 0.048 -------- 0.063 -------- 0.064 0.708 -----0.608 -----0.576 -----0.551 -----0.624 0.350 -----0.309 -----0.259 -----0.244 -----0.450 1.625 -----1.740 -----1.588 -----1.784 -----1.863 * = 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: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - Organ Weights Study : PT02-0222 /1 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Heart Weight g Liver Weight g Kidneys Weight g Adrenals Weight g Spleen Weight g Thymus Weight g Brain Weight g 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 29 ---- 29 ---- 29 ---- 29 ---- 29 0.709 -----0.830 -----0.824 -----0.733 -----0.867 6.28 ------ 6.98 ------ 7.66 ------ 7.60 ------ 8.88 1.213 ------- 1.440 ------- 1.475 ------- 1.426 ------- 1.529 0.045 -------- 0.063 -------- 0.061 -------- 0.052 -------- 0.056 0.571 -----0.675 -----0.658 -----0.733 -----0.756 0.339 -----0.509 -----0.313 -----0.401 -----0.342 1.641 -----1.812 -----1.875 -----1.763 -----1.693 * = 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: 1 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 1m 1 ------ 2 ------ 3 ------ 4 ------ 5 ------ 6 ------ 7 ------ 8 ------ 9 ------ 10 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 900 -------- 700 -------- 740 -------- 800 -------- 800 -------- 800 -------- 780 -------- 780 -------- 800 -------- 800 840 -------- 800 -------- 800 -------- 840 -------- 820 -------- 800 -------- 800 -------- 760 -------- 900 -------- 880 350 -------- 300 -------- 320 -------- 300 -------- 270 -------- 320 -------- 300 -------- 280 -------- 300 -------- 290 310 -------- 280 -------- 280 -------- 300 -------- 290 -------- 300 -------- 260 -------- 290 -------- 320 -------- 300 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 352 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 2 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 1f 31 ------ 32 ------ 33 ------ 34 ------ 35 ------ 36 ------ 37 ------ 38 ------ 39 ------ 40 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 740 -------- 800 -------- 700 -------- 700 -------- 800 -------- 800 -------- 800 -------- 720 -------- 700 -------- 800 680 -------- 820 -------- 720 -------- 660 -------- 800 -------- 820 -------- 820 -------- 740 -------- 760 -------- 800 300 -------- 290 -------- 270 -------- 260 -------- 280 -------- 290 -------- 250 -------- 270 -------- 300 -------- 270 280 -------- 270 -------- 270 -------- 280 -------- 270 -------- 270 -------- 270 -------- 290 -------- 300 -------- 300 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 353 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 3 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 2m 11 ------ 12 ------ 13 ------ 14 ------ 15 26 ---- 26 ---- 26 ---- 26 ---- 26 800 -------- 700 -------- 800 -------- 800 -------- 800 780 -------- 800 -------- 860 -------- 840 -------- 700 280 -------- 300 -------- 260 -------- 260 -------- 280 300 -------- 300 -------- 270 -------- 280 -------- 260 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: 4 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 2f 41 ------ 42 ------ 43 ------ 44 ------ 45 22 ---- 22 ---- 22 ---- 22 ---- 22 640 -------- 780 -------- 700 -------- 700 -------- 640 640 -------- 760 -------- 680 -------- 720 -------- 680 260 -------- 280 -------- 290 -------- 240 -------- 250 240 -------- 250 -------- 270 -------- 240 -------- 240 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 355 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 5 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 3m 16 ------ 17 ------ 18 ------ 19 ------ 20 26 ---- 26 ---- 26 ---- 26 ---- 26 800 -------- 600 -------- 700 -------- 640 -------- 800 760 -------- 700 -------- 780 -------- 680 -------- 800 290 -------- 300 -------- 260 -------- 280 -------- 300 300 -------- 250 -------- 300 -------- 290 -------- 250 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 356 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 6 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 3f 46 ------ 47 ------ 48 ------ 49 ------ 50 22 ---- 22 ---- 22 ---- 22 ---- 22 600 -------- 600 -------- 760 -------- 800 -------- 700 680 -------- 700 -------- 720 -------- 800 -------- 700 280 -------- 270 -------- 260 -------- 260 -------- 270 300 -------- 290 -------- 270 -------- 280 -------- 250 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 357 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 7 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 4m 21 ------ 22 ------ 23 ------ 24 ------ 25 ------ 26 ------ 27 ------ 28 ------ 29 ------ 30 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 ---- 26 700 -------- 600 -------- 620 -------- 700 -------- 780 -------- 740 -------- 600 -------- 620 -------- 620 -------- 700 680 -------- 680 -------- 700 -------- 800 -------- 700 -------- 800 -------- 660 -------- 680 -------- 680 -------- 600 240 -------- 240 -------- 250 -------- 250 -------- 280 -------- 270 -------- 260 -------- 240 -------- 240 -------- 220 250 -------- 260 -------- 260 -------- 270 -------- 270 -------- 250 -------- 250 -------- 240 -------- 270 -------- 250 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 358 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 8 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 4f 51 ------ 52 ------ 53 ------ 54 ------ 55 ------ 56 ------ 57 ------ 58 ------ 59 ------ 60 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 ---- 22 620 -------- 600 -------- 680 -------- 640 -------- 600 -------- 780 -------- 740 -------- 700 -------- 600 -------- 740 700 -------- 700 -------- 600 -------- 700 -------- 640 -------- 780 -------- 780 -------- 740 -------- 600 -------- 780 240 -------- 270 -------- 200 -------- 220 -------- 230 -------- 270 -------- 240 -------- 260 -------- 250 -------- 200 210 -------- 240 -------- 220 -------- 240 -------- 210 -------- 240 -------- 210 -------- 250 -------- 230 -------- 190 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 359 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 9 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 5m 61 ------ 62 ------ 63 ------ 64 ------ 65 23 ---- 23 ---- 23 ---- 23 ---- 23 800 -------- 680 -------- 700 -------- 780 -------- 700 820 -------- 720 -------- 680 -------- 820 -------- 800 300 -------- 240 -------- 280 -------- 270 -------- 290 320 -------- 250 -------- 280 -------- 300 -------- 300 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 360 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 17-Dec-2002 Page: 10 Generalised Results By Animal - Animals Against Parameters - Multiple Times Activity : - FOB - Clinical Part Study : PT02-0222 - T-7758 - 4 weeks oral toxicity in rats ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 5f 66 ------ 67 ------ 68 ------ 69 ------ 70 23 ---- 23 ---- 23 ---- 23 ---- 23 660 -------- 700 -------- 700 -------- 680 -------- 720 720 -------- 680 -------- 700 -------- 740 -------- 780 250 -------- 230 -------- 250 -------- 240 -------- 290 270 -------- 260 -------- 260 -------- 280 -------- 250 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 361 Toxicology Study Report - PT02-0222 RTA053-01/04 PROVANTIS Date: 03-Mar-2003 Page: 1 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 6m 71 ------ 72 ------ 73 ------ 74 ------ 75 22 ---- 22 ---- 22 ---- 22 ---- 22 760 -------- 800 -------- 800 -------- 780 -------- 800 800 -------- 800 -------- 840 -------- 800 -------- 780 270 -------- 290 -------- 280 -------- 300 -------- 300 310 -------- 280 -------- 300 -------- 290 -------- 280 * = 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: 2 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 6f 81 ------ 82 ------ 83 ------ 84 ------ 85 22 ---- 22 ---- 22 ---- 22 ---- 22 720 -------- 800 -------- 800 -------- 720 -------- 700 760 -------- 820 -------- 820 -------- 760 -------- 800 270 -------- 260 -------- 280 -------- 260 -------- 300 280 -------- 300 -------- 300 -------- 290 -------- 280 * = 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: 3 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 7m 76 ------ 77 ------ 78 ------ 79 ------ 80 22 ---- 22 ---- 22 ---- 22 ---- 22 760 -------- 780 -------- 780 -------- 860 -------- 800 820 -------- 820 -------- 780 -------- 800 -------- 840 310 -------- 300 -------- 270 -------- 250 -------- 290 280 -------- 290 -------- 280 -------- 290 -------- 300 * = 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: 4 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 ------------------------------------------------------------------------------------------------------------------------------------ Group Sex Animal Number Day Number Str. of F.limbs1 g Str. of F.limbs2 g Str. of H.limbs1 g Str. of H.limbs2 g 7f 86 ------ 87 ------ 88 ------ 89 ------ 90 22 ---- 22 ---- 22 ---- 22 ---- 22 660 -------- 780 -------- 700 -------- 680 -------- 780 700 -------- 800 -------- 800 -------- 780 -------- 720 280 -------- 250 -------- 270 -------- 250 -------- 300 250 -------- 270 -------- 300 -------- 250 -------- 260 * = 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 Page 367 Toxicology Study Report - PT02-0222 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 - MAINTENANCE Ingredients [average % content in the diet] Crude protein Crude fat Crude fiber Ash 19.00 3.00 5.20 6.70 Calcium 1.10 Phosphorous 0.80 Sodium 0.25 Magnesium 0.20 Potassium 1.00 Amino Acids [average % content in the diet] Lysine 1.00 Methionine 0.30 Cystine 0.25 Glycine 0.90 Leucine 1.50 Isoleucine 0.90 Arginine 1.20 Phenylalanine 0.90 Tryptophane 0.25 Histidine 0.45 Alanine 0.70 Tyrosine 0.60 Asparagine acid 1.40 Glutamine acide 2.20 Valine 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 g 200 g 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 Page 371 Toxicology Study Report - PT02-0222 13.2.2 Historical control data Page 372 Toxicology Study Report - PT02-0222 Species: Rat Strain: 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 1012/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 Bilirubin Direct Bilirubin Glucose Uric Acid Creatinine Urea Nitrogen Cholesterol Triglycerides 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 IU/l IU/l IU/l IU/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 ml pH Value Specific Weight g/l 1,6 6 1027 6,9 8 1076 4,56 7,12 1041,39 Body weight g Heart Weight g Liver Weight g Kidneys Weight g Spleen Weight g Testes Weight g Epididymis Weight g Adrenals Weight g Brain Weight g Thymus Weight g Lung Weight g Thyroid Gland Weight g Pituitary Gland Weight g g/kg 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 Weight Spleen Weight Testes Weight Epididymis Weight Adrenals Weight Brain Weight Thymus Weight 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 Strain: 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 1012/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 Bilirubin Direct Bilirubin Glucose Uric Acid Creatinine Urea Nitrogen Cholesterol Triglycerides 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 IU/l IU/l IU/l IU/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 ml pH Value Specific Weight g/l 1,40 6,00 1024,00 6,40 8,00 1054,00 4,03 6,85 1036,35 Body weight g Heart Weight g Liver Weight g Kidneys Weight g Spleen Weight g Adrenals Weight g Brain Weight g Thymus Weight g Ovaries Weight g Lung Weight g Thyroid Gland Weight g Pituitary Gland Weight g 173,60 0,69 6,22 1,23 0,46 0,04 1,60 0,27 0,11 0,95 0,01 0,01 210,40 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 Weight Spleen Weight Adrenals Weight Brain Weight Thymus Weight 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 PT02 -0222+ 376 PATHOLOGY REPORT Study-No.: PT02-0222 T-7758 prepared by: DR. BERNDT HEIN Pathologist SUMMARY PT02 -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): KO/KO animals: Discoloured Kidneys in three females and all 5 males, one enlarged stomach, two enlarged livers, and one opague eye. RURI animals: Small accessory genital glands (prostate and/ or seminal vesicle) in three animals Additionally, one male exhibited a small thymus and enlarged adrenal glands. An irregular surface could be observed on the kidney of one male as well as one female. R1/+1 animal (died): `Small accessory genital glands (prostate and seminal vesicle) in combination with small testes and epididymides Group 3 (D2; mid-high dose, 60 mg/kg): KO/KO animals: Discoloured kidneys in four males, and four females, and a discoloured duodenum in one female. Gro2u(Dp1; mid dose. 15 mg/kg): KO/KO animals: Discoloured kidneys in three males, and one female. Group 5 (D4; low-mid dose, 3 mg/kg): KO/KO animals: Transparent margins in the liveroffemale animal no. 68. Microscopical Findings: Relevant histopathological findings were seen in the following organs: Liver: Hypertrophyof hepatocytes in nearly all animals of the high dose group D3 at terminal necropsy. Spleen: Lymphocyte depletion in the animals of the high dose group D3: one male at terminal necropsy, and two male at recovery necropsy. Thymus: Atrophy in three malesofgroup D3 at recovery necropsy. PT02 =0222 378 Tiiac lymph node: Lymphoid cell depletion in animal no. 30 (group D3), which died during the recovery. Testes! Epididymides: Atrophy in animal no. 30 (unscheduled death). Prostate/ Seminal Vesicles: Atrophy in three animals of group 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 on group D3 and D2 at the terminal sacrifice. A nephroblastoma could be detected in one female (no. 51). One male and one femaleofgroup D3 exhibited a chronic nephropathy at recovery necropsy. Sporadic changes in form of cellular infiltrates / inflammatoryfoci were observed in the lungs and liver of some animals of different groups. In group D3 (terminal sacrifice) could be observed a submucosal edema in the forestomach, a dilatation of the uterus, and an enlarged epithelium 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 endofthe 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 lossofwhite 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 kindsoftissue demonstrate this reaction during the recovery period. At terminal sacrifice the animalsofthe high dose group exhibited an increaseof hepatocellular activity (hypertrophy caused by enzyme induction), wich had returned to normal after the 14day recovery period. The kidney was identified as another target organofthe 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. PTO2 =-0222+ 379 MATERIAL AND METHODS GROUP DESIGN FOR PATHOLOGIC EVALUATION: Group No. Dose Animal-No.: (male) Animal-No.: (female) mg/kgbw. K0-Group RI-Group KO-Group RI-Group 1/Co control 0 1-5 6-10 31-35 36-40 2/D1 mid 15 3/D2 mid-high 60 4/D3 high 240 5/D4 mid-low* 3 1-15 - 41-45 - 16-20 - 46-50 - 21-25 26-30 51-55 56-60 61-65 - 66-70 - control grtohupe.low dose D5 (0.3 mghkg) is added in an addendum (no. 90222)to ths report against another ADMINISTRATION OF THE TEST ARTICLE `The test article was orally administrated by means ofa pharyngeal tube, 28 administrations for four weeks. NECROPSY AND HISTOPATHOLOGY All animals were killed by exsanguination (dissection ofthe V. cava cran.) after intraperitoneal anaesthesia with Ketamin-Hydrochloride and Xylazin at termination (K0-subgroup on day 29; RI-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, vsetseimc,lesm,edouvalrliaes,obultoenrguast,a)u,rinsapriynabllacdodrerd, (scteormviaccahl,),jetjeustneusm,,ecpoildoind,ymaidsr,enaplrso,sttahtye,muss,embionnael marrow (sternum), sciatic nerve, thyroid and parathyroid gland; iliac and mandibular Iymphnode; addideidtiaonniamlallys;alallmsaockriodsnceoypsi,clailvlery, visible spleen changes in organs, and and thymusofall anima all ls, organs due to of intercurrently histopathological changes in the high dose group (KO or R1). 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. PT02 =-0222+ 380 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 lesionsofdifferent severity were scored as follows: grade 1/2 orgrad1/e3 =grade2 grade1/4orgrade2/3orgrade 2/4 =grad3e grade 1/5 or grade 2/5 or grade 3/4 or grade 3/5 = grade 4 o grade d/s = grade 5 All incidence tables were created by the PATHDATA computer system. RESULTS PT02 =-0222+ 381 MORTALITY Animal no. 30 (group 4: high dose, recovery) was found dead one day before termination of itnhdeirceactoedvesreyvepreerilodym(pshtoucdyytdeasyd4e2p)l.etiAolnthinousgphleaeunt,oltyhsyismuwsasanedvildyemntp,hmniocdreosscaospiccauesxeamoifndaetaitohn. This finding was considered test-artcle related NECROPSY FINDINGS Group 4 (D3; high dose, 240 mg/kg): KO/KO animals: Discoloured kidneys in three females (no. 52, 54, 55) and all males, one enlarged stomach (male no. 24), two enlarged livers (females no. 51, 54), and one opague eye in female no. 55. RURI 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. RI/+1 animal (died) Small accessory genital glands (prostate and seminal vesicle) in combination with small testes and epididymides. Group 3 (D2; mid-high dose, 60 mg/kg): KO/KO 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 (DI; mid dose ,15 mg/kg): KO/KO animals: Discoloured kidneys in three males (no. 11, 14 and 15), and female no. 45. Group (D4; low-mid dose, 3 mg/kg): KO/KO animals: Transparent margins in the liveroffemale animal no. 68. For details see also TEXT OF GROSS AND MICROSCOPIC FINDINGS. PT02 =-0222+ 382 HISTOPATHOLOGY FINDINGS Relevant histopathological findings were seen in the following organs: Liver: Hypertrophyof hepatocytes in nearly all animals of the high dose group D3 at terminal necropsy. Spleen: Lymphocyte depletion in the animalsofthe high dose group D3: one male at terminal necropsy, and two male at recovery necropsy. Thymus: Atrophy in three malesofhigh dose group D3 at recovery necropsy. Tiiac lymph node: Lymphoid cell depletion in one animal (high dose group D3), which died during the recovery. Testes/ Epididymides: Atrophy in animal no. 30 (unscheduled death) Prostate/ Seminal Vesicles: Atrophy in three animals of group D3/ recovery necropsy. Findings in the kidneys were also noted and included fubular changes. 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 nephroblastoma could be detected in one high dose (D3) female. One male and one femaleofgroup D3 exhibited a chronic nephropathy at recovery necropsy. Sporadic changes in form of cellular infiltrates / inflammatoryfoci were observed in the lungs and liver of some animals of different groups. In group D3 (terminal sactifice) could be observed a submucosal edema in the forestomach,a dilatation of the uterus, and an enlarged epithelium of the cornea, in different animals. CONCLUSIONS `The 4-week oral gavage administrationofthe 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 Iymph nodes, which exhibited a lossofwhite blood cells in the animals of the high dose group. "This effect could only be observed in single malesofthe high dose group D3. A comparable effect (tubular atrophy) could be observed in the testesofone 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 animalsofthe high dose group exhibited an increaseofhepatocellular dacatyivrietcyo(vheyrpyepretrrioopdh.y caused by enzyme induction), wich had returned to normal after the 14- PT02 -0222+ 383 `The kidney was identified as another target organofthe 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. Lov AClF0n Signature (Dr. B. Hein) Veterinary Pathologist Principal Investigator _ [END OF REPORT SECTION PTO02 -0222% 384 oxsioer somone me sruos S RENTLLi teovotrpuree Tfamaonr. eNoe.LeLszeeve, fr SSdrna ithieSa oper vere cotmplrindbyenSe,aS na i soto vazoors Y/R oEporr.TeesOroreMaISdtTeYinvscntand Guo PT02 -0222+ 385 samme sevens wee: erot2lozssss TTSeoosrtoASwRoTsIrGoeHEn1 1RSau7t,5Co8r3pmoornatthe, TOorxailsoGtaovsayge BtPaahtrohnoa.tsMNoOos.ysT5te7e2in72.Vo55.s51b [rg ---- Sin fmsigirralebayseddrsiynes Seherk SiiLnS aso 2E 0% PELI, TEED (studyLPiatehologist) proton Marburg ae: CC 09.07 PT02 -0222+ 384 PATHOLOGY REPORT TTEESSTT ASYRSTTIaCMLE:: 1Ra-t7,781 month, Oral Gavage Sponsor } 30 Corporate Toxicology EXPLANATION OF CODES AND SYHBOLS eace L1u03-022s2e DPaArTeHOL. NO.: 1062-207021-F0E3 Pathbatao system V5.1b CODES AND SYMBOLS USED AT ANIMAL ISVEL: W:Xo "==iTFaeelrmemailneaanliamnaislmaaclrifice grow Rfh1...R9 -= RIrenoctaoedvrecraayrerse/ntposdte-attrhe/astamcernitficgerdoumpor1i.b..u5nd CODES AND SYMBOLS USED AT ORGAN LEVEL: AG; =S= eGGvrrooessrsseooabbusstesorrlvvyaasttii.son,notechvcaahclekuceskdteidoonfofffnohtihsiptsootslosoliagbgilicecaallllyy .: Z=~ GThriiotsatanouleoegxniaocmtinpeerxdea,smeinnftaitnidfooirnngshnoitsprteorsleeoqngutiicreedxamination :t == Onrlgyanoneexamoifnepda,irendo poartghanoslogeixcamifniendd/ipnrgessennotted (AOFT only) CODES AND SYMBOLS USED AT FINDING LEVEL: GGRRAADDEE 23 =- SHloidganrtate/ f/emwod/ersamatlelnumber / moderate size GNRoADE 4 -2 MMaarlkiegdnan/tmamneycpl/aslmarge :( == CFoimnmdeinntg uinniltaetxetraolf iinndipvaiidrueadloragnainmsal data PT02 -0222+ 387 eSaomaomLsorcyTARBLEEpSoRT ence Cearozs-02e22 TTeEsStT aSnyrSiTcEiNs : 1Ra1t7,881 monch, Oral Gavage Sponsor {Su Corporate Toxicology aoPaamrcishobrs.tsoNo.s:y| st0fe2en2c2a2vusn.#o1Esb SStOaMtBuEsR AOTF ANENCTRWOAPLSSY:WITKHO MICROSCOPIC FINDINGS BY ORGAN/GROUP/SE SBooxse crower!: co bi 02 53 bt wie TT Koreepshyimubsiar T oT S T 5 1 C r TD libet iarwr eresis E oo o1 fo TCuaevmperttropehy roi T1TY1r-o2o4l; rr rE LE owes rTTI Seimzpehocyte Depletion;TE STo E 1 PT02 -0222+ 388 SPAaTHrOLrOGTYARBELEPSORT TTEoSsTt ASyRsTtIaCwLE:; R1a-t1,7581 month, Oral Gavage SroNsoR 3M Corporate Toxicology. SSTOAMTBUESR AOTF NAENCIRMOAPLSSY:WITKHO WICROSCOPIC FINDINGS sYDeoOxS.EANGMRAoLvSP,:: CO5 DI5 Dz5 035 KIMDtNrEoYpShyitubutar CDilatiomamuiar 1 CE-T1TEoo 1 o-oo ITulbiuoullaarr Tubular NhDeeyegareionisensreastion;i+.=o-oo-- 1= .1 -1 Z Nephroblavtoma i = I 1 p"rhyypertrophy TC Imfammatory Foci FSOfRGEeSnTaO,NACsHwmicosal SE'bRiSlatation Sseepsithelization F CEA TTE + - oi iT ooTTT- 1 TTRonoTTT T : - T oT i oce L#1s032023os7e oaPATTEHOL. No.:: 10262-27201-H0E3 Fathbatso System VS. 1b BY ORGAN/GROUZ/SEX Dd PEALE 8 === == = = PT02 =-0222+ 389 PSAUTMHMOALROYGYTARBLEEPSORT eAGE sP1e02-022se2 TEESSTT ASRYTSICTLEEM:: 1R-at7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology DaPtATsHOL. NO.: 01262-2021-H0E3 PathDatao System VS.1b NSUTMABTEURS OATF ANENCTRVOAPLSSY:WITRlH, MIICNCRLO.SCODPEIACTHSFINDINGS BY ORGAN/GROU/SEX sDeOxS.E GROUP:: CO D1 D2 D3 D4 ALE NOANIMALS: 5 - = 5 =~ KICDhNrEoYnSic Nephropathy:cos- o-- == a1 == - Dilation:Tubular : 3 = = = = LIVIEnRflammatory Foei ci os- == == 41 == seLeEn cos = = 5 = = Lymphocyte Depletion: = = = 2 = T~HAYMtUrSophy sE s E = = 5 = I-LILAyCmpLhYoMcPyHteNODDeEpletion: o- .=oo= %1 -= P~ RAOtSrToApThEy P s- o - o - l so ~SEAMItNrAoLphVyESICLES so. - =a = EE -88A7tErSophysTubular L i - T = T = 1 = EPIDIDYMIDES ~ Atrophy T ---1 EE PTO2 =-0222% 390 PSAoTaHaOrLyOGYTARBLEEPSORT eace s#1a02-022s2e TTEoSsTt ASRyTsItCLeE;: 1Ra-t7,581 month, Oral Gavage SeoNsoR 3M Corporate Toxicology PbaaTtheoL. No.: 01262-2a201-H0E3 FathData System US. ib NSOTVABTEURS OATF ANENCIRAOLPSSY:WITRHl, MIICNCRLO.SCOOPAITCHSFINDINGS BY ORGAN/GROUE/SEX SDoOxSE Grove:: co D1 bz D3 De FEwALE No.ANIMALS: 5-5 KiHoenhervonsic wephropatny:C1E-T-T1E= PT02 -0222+ 391 SPAaTHrOLrOGYTARBELPEOSRT TTEESSTT ASRyTsItCLeE;: 1R-at1,7581 month, Oral Gavage Seonsor 34 Corporate Toxicology SSUTMAITAURSYATINNCEICDREONPCSEY:OFKOGRADINGS BY ORGAN/GROVE/SEX SDeOxSE Grove:; co D1 bz 03 Dd No.ANIMALS: 5 5 5 5 5 ence er02e-0s22e2 DTaATTHEoL. No.} 10262-2720-H0E3 Pachbatao system VS. 1b iE Ki~bAntervosphy: Tubular CETTE GaE 2: - = 3 1 - TEoAmNL ASFEFVEECRTIETDY +iC= -- 2.03 2.01 -oR GadE 2: - = = 2 - oMEmAaNL ASFEFVEECRTIETDY +1 =oo= =C2.2 -ET are nes ara sess nen aE 2: = = 1 = - tVoEmNaL ASFEFVEECRTIETDY +i =- = 2.01 -= -- Li"hvyeprertrophyGace CETTE 2: - = = 4 - TVoEL ASFEFVEECRTIETDY:+ =- =- =1 2.04 -= PTO2 -0222+ 392 SeaammioaLrocyABsLEEpSoRT ence eroezos22s2 TToEsStT aSmYzSicTiEsM:: 1Ra7t7,581 month, oral Gavage Sronson | SW Corporate' Toicology DEaarmeon. Now:{0l22e22eisE bathvatad system vib SSTOAMTRURSYATINNCEICORBONBGSEY:OFKoGRADING BY ORGAN/GROSUERX SSSooxosnaartoevr:!: cossoy 022 5350%bd fev = oAnterrosphy: TubuSlhaore TTT 2: <= 1 - = oma AerecTED =1=- pe LE Shor 2: 1 = = teonm SAevseERcITTeYD 201 o= C- o= C- Ran bia Te Ts Shor 2. = = 1. teoam aSeerevceTErDt:a s sor-es = sCo2r0t1 s-a-ns ses ssmsassssvmassss Shor 2: <= 1 - = hba omiaiSsaeseT cTreD: CC= 201T -oC= Ghee 2: o-oo - 1 - reoama ASevveemcTrEvD i =0 C201 -- pHrE percrophy TTT GGowse 23:: -o-oo= -173 -= tom aesEcTED =-5- PT02 =-0222+ 393 PSAUTMHMOALROYGYTARBELPEOSRT TTEESSTT ASRYTSITCELME:: 1Ra-t7,7581 month, Oral Gavage SPONSOR + 34 Corporate Toxicology SSTUAMTMUASRYATINNCEICDREONPCSEY:OFRIG,RADIINCNLG.S BDYEAOTRHGSAN/GROUP/SEX sDeOxSE GROUP:: CO DI D2 D3 DA NOANIWALS: 5 - = 5 = K~IDCNhErYoSnic NephropathyCs - aC GRADE 3: = = = 1 = TMOETAANL ASEFVFEERCITTEYD :: LILA -- =- =- 3.01 =- GRADE 2: 3 - = = = TM0ETAANL ASEFVFEERCITTEYD :: 2.03 =- =- =- =- T- HAMtUrSophy GRADE 2:Ps- -- o - s1 -= GGRRAADDEE 43:: -- -- -- 11 -- TMoETAANL ASEFVFEERCITTEYD +: -- == == 3 3.0 = - PR- OaStTrAoTpEhy so. = a. GRADE 3: - = = 3 = TMOETAANL ASEFVFEERCITTEYD :: -- =- =- 3.03 -- SEMINAL VESICLES vo Ta = Atrophy GRADE 3: - ~~ 3 = TMOETAANL ASEFVFEERCITTEYD 1 : - = - =3 = 3.0 = - eAGE PT0102/-022se2 DPaAtTsHOL. NO.: 01262-2021-H0E3 PathDatao System VS.1b ALE PT02 -0222+ 394 PSAUTMHMOALROYGYTARBELPEOSRT TTEESSTT ASRYTSICTLEEM:: TRa-t7,7581 month, Oral Gavage sronsor 31 Corporate Toxicology SSUTMAMTAURSYATINNCEICDREONPCSEY:OFRlG,RADIINCNLG.S BDYEAOTRHGSAN/GROUB/SEX DseOxSE GROUP:: CO D1 D2 D3 D4 NO.ANIMALS: 5 - - 5 = T-EAStTrEoSphy:Tubular vo. - STA GRADE 3: - - - 1 = TMOETAANL ASFEFVEECRTIETDY :: -- =- =- 3.01 =- PAGE. 2P11012-022s2e DPaAtTsHOL. No.:`1062-22021-H0E3 PathData System S.1b ALE PT02 =-0222% 395 PSAUTMHMOALROYGTYARBELPEOSRT ETESSTT ASRYTSICTLEEM:: 1Ra-t7,7581 month, Oral Gavage SPONSOR + 3u Corporate Toxicology SSTUAMTMUASRYATINNCEICDREONPCSEY:OFRlG,RADIINCNLG.S BDYEAOTRHGSAN/GROUP/SEX seDxO.SE GROUP:: CO DI D2 D3 D4 NOANDMALS: 5 - = 5 - K-IDCNhErYoSnic Nephropathy cos = = 5s = GGRRAADDEE 24:: -1 -- -- =1 =- TMOETAANL ASEFVFEERCITTEYD :: 2.01 -= =- 4.01 == ence P10122/-022s2s oaPtATsHOL. NO.:: 01262-2021-H0E3 PathData System V5.1b FEMALE PT02 =-0222+ 396 PIANTDHIOVLIODGUYARLEAPNOIRMTAL DATA AGE 1012-30/25282 TTEESSTT ASRYSTTIECML:E :RT-a 17158t mon, th, Oral Gavage SPONSOR + 34 Corporate Toxicology DPaArTHeOL. NO.:} 01262-2J20L-H0E3 PathData System V5.1b TDOASBELEGROOFUP:INDIVICDOUA,L McIoCnRtOroSlCOPIC FINDINGS ANIMALNOMBER : MKO 1MK2O MKO3 KO4 MKO5 MRI 6 MRL7 MRL8 MRL3 MAL10 Hb EART e - ee ee ee ~Dhiilmaatt ion:Tubur lar e Lo e hlnL L a T 2 2 -soIdnaflammatory Foci 2 D, L Te Te ~aItnatemrstit.Infiltrat.et. . 2. . EG RRR ER Lh Rb RLiR Ro A Lf EORSRAGE TT ALA SRGLf ES ERR RELL LAMERA LL SL RGR TL RS RR ee PT02 =-0222% 397 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA PAGE 1012-a022s2s TTEESSTT ASRYTSICTLEEM::R1-a 7718t mon, th, Oral Gavage SPONSOR 3u Corporate Toxicology DaPArTeHOL. NO.:: 01262-2320-H0E3 PathData System S.1b DTOASBELEGORFOIUNDPI:VIDCUOA,L McoInCtRrOoSlCOPIC FINDINGS ANIMALNUMBER : MKO1MK2O MKO3 MKO4 MKO5s MRL6 MRL7 MRI8 MRL 5 MRL10 ADRRENAALLCBOSRGTLELXAT L CTT f TT T TTT RGIS BLA HOLD SLAG RRR BLALf SRSA RAL SSL I EER RRL I ERG PTO2 -0222+ 398 eTaNmDiIoVLIoDoOyALRAupNoTRATL DATA ence eroaas-022s2s ToTessTt aSnYtSiTcEsM: 1| 1R75a18mtontsh, oral Gavage oeaarTieoL. Ro.:{ 0l2e0-2g2ouAoEs Sponsor | SW Corporate' Toicotoy Fachbacao systen vs. 1b AB0B5EooroFurINDIVI1 DUcoA,L MCoInCtRrOoSsCOPIC FINDINGS Ravn Nowe | 03 mo.3 FO3f:o FO3 FL3 PRL3 FRIwRmRL FRIwo io CI en LL NCoonheo Nreepuhiraorpathy + So. la. no. nn4 oI LLL LL ee LL LL pro oS Oo AA A Tr CA aT er mse serge riser bigdog So et seeantsssosmsesmespsgrrsessgases asegenssges RE at ar serene esr Ns tf m4 ot 2021ses g CET ron SAR Th 41m ns sss MH OTEraiigas mre semen essr espe eegessegassagesesgeserie ae agar essegeessgean a sageesegesesgon I GEE er sv srtesssseseeepsuess easgoeesgrassgeasnguassgersse EE eeeen teases tvs srmeeps eeesass sagesesges io PT02 =-0222+ 399 PIANTDHIOVLIODGUYALRAEPNOTRMTAL DATA PAGE 021-60/25282 TTEESSTT ASYRSTTIECML:E :R T-7a 7518t mon, th, Oral Gavage SPONSOR : 3 Corporate Toxicology DPAATTEHOL. NO.: 01262-2320-H0E3 Pathata System V5.1b TDOASBELEGROOFUP:INDIVICDOUA,L McIoCnRtOroSlCOPIC FINDINGS ANIMAL NOMBER : FKO31 FKO32 EKO33 FKO34 FKO35 FR136 FRl37 FRI38 FRL39 FR40 ADRRSENIADLMG EDULLA TLT T oT p TTT RR Sle GRRE BAER TTL pe RRL pe GRRL fe PT02 -0222+ 400 IPANTDHIOVLIODGUYALRAENPODRMTAL DATA PAGE. 10127-7022s2s TTEESSTT ASRYTSITCELME :: R71a-t7,7581 month, Oral Gavage SPONSOR + 3M Corporate Toxicology DAPATTEHOL. NO.:: 01262-2021-H0E3 PathData System V5.1b DTOASBELEGORFOIUNDPI:VIDUD1A,L mMiIdCROdSoCsOePIC FINDINGS ANIMAL NOMBER : MKO11MK2O MKO13 MKO14 MKO15 FKOa1 EKO42 FKO43 EKO44 EKO4s L KIDiNEYgS a - - %- - - - = an ET PT02 =-0222+ 401 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA eAGE PT0128-022s2e ETESSTT ASRYTSICTLEEM:: 1R-at7,7581 month, Oral Gavage SPONSOR 34 Corporate Toxicology DPaAtTeHOL. No.: 10262-2321-H0E3 Pathpatao System V5.1b TDAOBSLEEGORFOIUNDPI:VIDUD2A,L MmiIdC-RhOiSgChOPIdCoseFINDINGS ANIMAL NUMBER : MKO16 MKO17 MKO18 MKO19 MKO20 FKO46 FKO47 FKO48 FKO43 EKO50 KI- DANtErYoSphy: Tubular +6026 426 4a6 <60 6 - 4al6 4G f - Tubulr ar Necroa sis t 2 Dl T lTTlLL DLa l ~m Inflammatory Focie C ent e 2Ln Df EL a eee PT02 =-0222+ 402 PIANTDHIOVLIODGUYALRAENPTORMTAL DATA PAGE PT0129-022se2 TTEESSTT ASRYSTTIECML:E :R 1-7a 7518t mon, th, Oral Gavage SPONSOR : 34 Corporate Toxicology DAPATTEHOL. NO.:: 10262-2021-H0E3 PathData System V5.1b TDAOBSLEEGROOFUP:INDIVIDD3UA,L MhIiCghROSdCoOsPeIC FINDINGS ANIMAL NOMBER : MKO21 MKO22 MKO23 MKO24 MKO25 MRl26 MRL21 MRL28 MR129 MRl3+0 HEM ART T e CITT g T TTT --ACthrroopnhiyciTuNbeuplharropathy L . o. d_. . . .EE. 3%. -f bilation:Tubua lar EI te DnD i h L + eo. ~- HIynpfelratmrmoapthoyry Foci fics C5 ae522 o2es L + L+L7 Df LL hm e - Lymphocyte Depletion e . . . . 3e . . 3.LL 4 -rAtardoiphay Lo he L aL ea CEH RRs C `LymphI ocyteHS i DeplA etion o . . . . s 3 Shedd gp RSeT re CARRSRS TTL SER aT Lf CRE CEREAL I PT02 =-0222% 403 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA AcE PT0202/-022528 TTEESSTT ASYRSTTIECML:E :Ra1t-7,7581 month, Oral Gavage SPONSOR + 3u Corporate' Toxicology DPaArTeHOL. NO.: 10262-2021-H0E3 PathData System US.1b TDAOBSLEEGROOFUPI:NDIVIDD3UA,L hMiIgChROSdCosOePIC FINDINGS ANIMAL NUMBER : MKO21 MKO22 MKO23 MKO24 MKO25 MRI26 MRL21 MR128 MRI29 MRL3+0 MEDUALLLASOoBSL.ONGATA TTL[E TIT LT gene RRRRL SR ae RAL form RAL BELLA LL FTEHT IpTL geese neoe RRS STL I LL rere CRI BLASER SSSR ~SAtRroLphy SIL eee EIEN 3 s =Atropa hy mee. r Seen LL. l TRe E e3 -sAhttreopihbyi:nTgubular e Te a h . 3 =SAotvroAphRyG So he In PT02 =-0222+ 404 PIANTDHIOVLIODGUYARLEAPNOTRMTAL DATA PAGE. Pr20127-022s2e TEST TEST ASYRSTTIECML:E R :T-7a 7518t mon, th, Oral Gavage SPONSOR : 34 Corporate Toxicology PATHOL. DATE NO.::02162-2321-H0E3 PathData System V5.1b DTOASBELEGROOFUEINDIV:IDDU3A,L MhIiCghROSdCoOsPeIC FINDINGS ANIMAL NOMBER : E HEART RT FKO51 FKO52 EKO53 EKO54 FKO55 FR156 FR51 FRI58 FRI59 FRI60 TTT TTT I LL -- TCuhbruolnairc DNeegpehnreorpaattihoyn .. .. .. 2. ... .. .. .1.4% --f TNeupbhurloabrlaHsytaolmiane i wo!DonDoOnv DDThonn e DL Le : ~- HIynpfelratmrmoapthoyry Foci 3Co2a aeoo2 3TL oL nL gy Lf hab EG RRR IR LE Rh RIHS h fA o ERR TT R - EdeL ma, sBubamucdosal . Te CT. T. SR Ca RR RRL oie SOREL PT02 -0222+ 405 PIANTDHIOVLIODGUYARLEAPNOTRMTAL DATA PAGE Pr0222/-022528 TTEESSTT ASRYTSITCELME:: TR-7a 7518tmon, th, Oral Gavage SPONSOR 3u Corporate' Toxicology DPaATsHOL. NO.: 10262-2320-H0E3 Pathbata System V5.1b TDAOBSLEEGROOFUPI:NDIVIDD3UA,L MhiIgChROSdCoOsPeIC FINDINGS ANIMALNOMBER : FKO51 FKO52 FKO53 FXOsa FKO55 FRI56 FRl51 FRI58 FRI59 FRI60 SCPRINAR L CORD, CERVIC. R - = = = L = tt to RRL Gh RR ALL ERS BAR SR SLETR TL LL pI ge CRRA Baga TL GRRL GRRL ~sordeilaatoatnion 2. . . gf - Epithelization 2. PT02 -0222% 406 PIANTDHIOVLIODGUYALRAENPOIRMTAL DATA PAGE 2 P10223-022s2e TTEESSTT ASRYTSICTLEEM::T-Ra7t7,581 month, Oral Gavage sponsor 3u Corporate Toxicology pPaAtTHeOL. NO.:: 10262-2021-H0E3 PathDatao System VS.1b TDAOBSLEEGORFOIUNDPI:VIDUD4A,L MmIiCdR-OlSoCwOPdIoCseFINDINGS ANIMAL NUMBER : MKO61 MKO62 MKO63 MKO61 MKO65 FKO66 FKO61 FKO68 EKO69 FKO10 FKEIDNEYS C CETTE PTEPPT PTPPP ERPS T PARLPPRIOR --MiInxfeldamCmealtloryInfFioclitrat 2. L . o. e2... . . | ane Ll LL De LL BGT A PT02 -0222+ 407 PIANTDHIOVLIODGUYALRAENPIORMTAL DATA TTEESSTT ASRYTSITCELME:: 1Ra-t7,7581 month, Oral Gavage Seonsor iM Corporate Toxicology ADNOISNEALGRREOAUDIPNG: DCAOT,A control ence P10a2u-022s2e DPAATTHEOL. No.: 10262-2020-A0E3 Fathbata System Us.1b AWNOIMMGAELR MS/EFX SDTEAFTIENEODFANNDECRFOIPNSAYL ziSouwu Kw o o k w0 IsER uu o M0 owm 7ouu a Homm 150M HHoomm H2BUTETEFwToTwR Rooeww H3 orFwow ooww oOfFr ommowm om 33worffFF ommm oommom TDEASYTS DFAIYRSTUNADNERD LTAESSTT 5Z5s5571137100l6C01c07100057s 32i593 1117775-000G0C1110-00077 33 11770:C016-10-70 3$3 11770005.70075 Lllia4-t-NiNooovhv-iooos2 2l18i4---NNNooovvv---000222 ZJee--NNoovv--0022 7see--Nnoovv--002z 533553" 111737o00t0G1l1-o00s77 Llle4a--tNNhooovvn--i0oozs 3355 1177.-00810-1007 1lii--NNoovv--002o 343 1177--00CC11--0072 Zzoe--NNoovv--0022 1$333 111771--7000000-1000:7 ZZ2eo8---NNNooovvv---000222 NDEACTREOPOSFY 1l14ea--lNnuoobvvv--i00o3ss 112448---NNooovvv---000323 2268--NNoovv--0023 2288--NNoovv--0025 11a44l--uNNboovvvi--o00s75 1144--NNoovv--0073 2288--NNo0vv--002Z 222880---NNwooovvv---00032s PT02 -0222+ 408 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TEST ARTICLE : T-7758 TSEPSOTNSSORYSTEM: R3aut,Cor1pmoornatthe, TOorxailcolGoavgayge TDEOXSTE OGFRGORUOSPS:ANDCO,MIcCoRnOtSrCoOlPIC FINDINGS RE 10225-/022s28 PATHOL. No.: 02222 HE DPaartehbata Sy st1e6m-3V05-.013b ALE + DSATYASTEOANTTNEESCTROPSY:i KO 29 + ANIMAL NO. 3 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS IMviecsr:ogranuloma, focal/multifocal (inflammatory foci), grade 2 LOINnGtSe:rstitial infiltration (mononuclear)/ pneumonia, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + SDTAAYSTEOANTTNEECSROTPS:Y: R1 43 + ANIMAL NO. : kl + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KI"DTNuEbYuSl:ar dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL' TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 =-0222+ 409 PIANTDHIOVLIODGUYALRAENPOIRMTAL DATA TTEESSTT ASRYTSITCELME:: TRa-t7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDCO,MICcRoOnStrCoOlPIC FINDINGS PAGE 10226-/022528 DPaATzHeOL. NO.:: 01262-2021-H0E3 PathData System V5.1b als * DSATYASTEOANTTENSETCROPSY:i R1 43 + ANDMAL NO. 8 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KITDuNbEuYlSa:r dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL' TISSUES WITHOUT PATHOLOGIC FINDINGS. * SDTAAYSTEOANTTNEECSROTPS:Y: R1 43 + ANIMAL NO. : 9 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KI"DTNuEbYuSl:ar dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL' TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 =-0222+ 410 PIANTDHIOVLIODGUYALRAEPNOTRATL DATA EST TEST ASYRSTTIECMLE:: 71-7758 Rat, 1 month, Oral Gavage SPONSOR 3M Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDCO,MICcRoOnStrCoOlPIC FINDINGS eAcE Pr02127-022s2e PATHOL. NO.: 02222 HE DPAaTtEhData Sy:st1e6m-0V15-.013b FEvALE + SDATYASTEOANTTENSETCROPSY:i KO 29 * ANIMAL NO. : n + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS URITNiAsRsYueBLnAoDtDEpRr:esent for histologic examination ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * SDATYASTEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 33 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KITDuNbEuYlSa:r dilation, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL' TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 =-0222+ 411 PIANTDHIOVLIODGUYALRAENPOIRMTAL DATA TEST ARTICLE : T-7758 STErSoTNSSORYSTEM:+ R3aut,Cor1pomronatthe, TOorxailcoGlaovgayge TDEOXSTE OGFRGORUOSPS:ANDC0,MICcRoOnStrCoOlPIC FINDINGS PAGE P12082/-022s2e pPaAtTeHOL. NO.: 01262-2021-H0E3 PathData System V5.1b FEMALE + SDTAAYTSEOnATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 35 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS TRATCiHsEsAu:e not present for histologic examination SPTIiNsAsLueCORnoDt (pCrEeRsVeInCtALfSorEGhMiEsNtTo:)logic examination ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + DSATYASTEOANTTNEECSROTPS:Y: RL 43 + ANIMAL NO. : 0 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS KICDhNrEoYnSi:c nephropathic foci, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 =-0222% 412 PIANTDHIOVLIODGUYALRAENPODRMTAL DATA TTEESSTT ASRYTSITCELME :: 1Ra-t7,7581 month, Oral Gavage SPONSOR 34 Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDCO,MICcRoOnStrCoOlPIC FINDINGS PAGE P12092/-022528 DPAATTEHOL. NO.:: 01262-2021-HE0.3 PathData System V5.1b FEMALE - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PT02 =-0222% 413 PIANTDHIOVLIODGUYALRAENPOTRMTAL DATA TTEESSTT ASRYTSICTLEEM:: TRa-t7,7581 month, Oral Gavage SPONSOR : 34 Corporate Toxicology ADNOISEMALGRHEOAUDIPNG: DDA1T,A mid dose PAGE + PT0302/-022se2 DPAATTEHOL. NO.:: 01262-2021-H0E3 PathData System VS.1b ANNOIMMBAELR SME/XF 1123 wuow f1r5 ou 23 =oF a PE E DSTEAFTIENEDOFANNDECRFOIPNSAYL KKoo K0o KKoO KKoo KKoo KKoo KKOo KKoo TDEASYTS FDAIYRSTUNADNEDR LTAESSTT NDEACTREOPOSFY FRPPITN 2299 1177--00CCTT--0022 1144--NNOOVV--0022 1144--NNoovv--0022 2299 1177--00C07T--0022 1144--NNOOVV--0022 11l44--NNoOvV--0022 RIFT PHP PPRPPI YY 2299 1177--00CC77--0022 1144--NNOOVV--0022 1144--NNoovv--0022 2299 1177--00CCT7--0022 1144--NNOOVV--0022 1144--NNOoVv--0022 PT02 =-0222+ 414 PIANTDHIOVLIODGUYALRAEPNOIRMTAL DATA TTEESSTT ASRYTSICTLEEM:: RTa-t1,7581 month, Oral Gavage SPONSOR + 3M Corporate Toxicology DTOESXET GOFRGORUOSPS:ANDDI,MImCiRdOSCdOoPsIeC FINDINGS PAGE 2P3T012-022s2e DPAATTEHOL. NO.:: 01262-2021-H0E3 PathData System V5.1b MALE + DSATYASTEONATTNEECSROTPS:Y: KO 29 + ANTMAL NO. : n + NECROPSY FINDINGS KID0N1E:YSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. + SDTAYASTEOANTTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 1 * NECROPSY FINDINGS KID0N1E:YSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. PT02 -0222+ 415 eTaNmDiIoVvIoDcRyLRAzNpToWRATL DATA T7o5s5t7 aSYrSTcEMs:| 1Ra7t7,581 month, Oral Gavage Sronson {SW Corporate' Toxicotony T3E0R5T% OGFROVGEross A+ NDbl,MICmRiOdSCdOoPsIeC FINDINGS ence sersos-0s220 oaFarrson. Now:| 0l2e2-2s2ou7o%s Pacbstso syscen VS.1b wie + sSahtieonanmweErcROPSY: KO 2 + mma vo. 1s + necropsy FrDINGS NxOao0nO1eTvHsED:RiscNoElCoRrOePdS,Y OlBiSghEtRVAbTroIwOnN.S NOTED + wrcRoscoprc FromiGs NoOvNeoMrImCsiR:sOrSoCsOcPoTpEicSTNfDiInNiGnSgNOcToErDr:esponding to necropsy cbeervation no. Ol. PT02 -0222+ 416 PIANTDHIOVLIODGUYALRAENPOTRMTAL DATA TTEESSTT SARYTSITCELME :: 1Ra-t7,7581 month, Oral Gavage SPONSOR 3M Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDDI,MImCiRdOSCdOosPeIC FINDINGS AGE Pr0323-022528 DPAATTEHOL. No.: 01262-2020-H0E3 Pathbata System V5.1b FEMALE * DSATYASTEOANTTENSETCROPSY:i KO 29 + ANIMAL NO. as + NECROPSY FINDINGS KID0N1:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PT02 =0222+ 417 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT SARYTSICTLEEM:: 1R-at7,7581 month, Oral Gavage SPONSOR 3u Corporate' Toxicology ADNOISMEALGRHEOAUDIPN:G DDA2T,A mid-high dose PAGE PT0324-/025282 DaPArTeHOL. NO.: 10262-2320-H0E3 Pathbata System V5.1b ANNOIMNBAELR MSE/XF 1187mm 2109mu ias EF 0oFEF SDTEAFTIENEODFANNDECRFOIPNSAYL 00 0KO KKoO 00 KKOo KKoO KKOO KKoo TDEASYTS DFRIYRSTUNDAENRD TLEASSTT NDAETCEROPOSFY es 2295 1177--00CCTT--0022 1144--NNOOVV--0022 1144--NNoOvV--0022 2209 1177--00CCTT--0022 1144--NNOOVV--0022 1144--NNoovv--0022 es 2299 1177--00CCTT--0022 1144--NNOOVV--0022 1144--NNoOvV--0022 2299 1177--00CCTT--0022 1144--NNOOVV--0022 1144--NNoovv--0022 PT02 =-0222+% 418 PIANTDHIOVLIODGUYALRAEPNOIRMTAL DATA TTEESSTT ASRYTSICTLEEM:: TRa-t7,7581 month, Oral Gavage SPONSOR : 34 Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD2,MImCiRdO-ShCiOPgIhCdoFsIeNDINGS PAGE + 10325-/022s2e DPaAtTHeOL. No.:: 01262-2021-H0E3 PathData System US.1b vaLE * SDTAAYSTEOANTTNEECSROTPS:Y: KO 29 + ANIMAL NO. 16 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KITDuNbEuYlSa:r necrosis, multifocal, bilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * SDTAAYSTEOANTTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 1 * NECROPSY FINDINGS KID0N1:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. PT02 =-0222+ 419 PIANTDHIOVLIODGUYALRAENPOTRMTAL DATA TTEESSTT ASRYTSICTLEEM:: 1Ra-t7,7581 month, Oral Gavage SPONSOR + 34 Corporate Toxicology TDOESXET OGFROGURPOSS A: NDD2,MImCiRdO-ShCiOPgIhCdoFsIeNDINGS PAGE +31062-022s2e pPaAtTsHOL. NO.: 01262-2021-H0E3 PathData System V5.1b MALE * DSATYASTEOANTTNEESCTROPSY:i KO 29 + ANIMAL NO. 18 + NECROPSY FINDINGS KID0N1:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01 ATLLubOuTlHaErR aPtRrOoTpOhCyO,L TfIoScSaUlE/SmulWtIiTfHoOcUaTl,PAbTiHlOaLtOeGrIaCl,FIgNDrIaNdGeS.2 * SDTAAYSTEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 19 * NECROPSY FINDINGS KIo0N1:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. LI-VTEuRb:ular atrophy, focal/multifocal, bilateral, grade 2 -ticrogranulona, focal/multifocal (inflammatory foci), grade 2 PTO2 -0222+ 420 eINaDmIiVoIrDoUcAyLsAupNoTRAsL DATA STTresos7ntsaoSnnyrsitceins :| } 7fSau-t1,C7o5r3pmoornatteh', TOorwailcotGoanvyage T0E0R5E% OGFROGUrEoss A+NDD2,MIiCRdO-SnCiOgPhICdoFsIeNDINGS ence + Fro3z-022se0 baEPaartmehobna.caoNous:y| s0tT7ee2n2s2vs5i7.%e1 wie cont./FE. ANTAL Yo. 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + STATE AT=NECROPSY: KO + an vo. 2 + uecRopsY FrDINGS c50o0v1Oe:TrHsED:RiscNoElCoRrOePdS,Y OlBiSghEtRVAbTrIowOnN.S NOTED + vicRoscoeic FrvoINGs TaYapobemlsia:csrosatcrooppihcy,finfdoicnagl/cmoirtrietsopcoanld,ingBiltaotenreaclr,opsgyraocebservation no. Oi. LAiiLvcernOo:TgHErRa.nsPlROoTnOaC,OLfToIcSaSlU/EmSulNtIiTfoHcOaUlT P(AiTnHfOlLaOmGmIaCt,orEyNDfIoNcGiS)., grade 2 PT02 -0222+ 421 IPANTDHIOVLIODGUYALRAENPDOMRTAL DATA TTEESSTT ASRYTSICTLEEM:: R71a-t7,7581 month, Oral Gavage SPONSOR + 34 Corporate Toxicology DTOESXET GOFRGORUOSPS:ANDD2,MImCiRdO-ShCiOPgIhCdoFsIeNDINGS PAGE PT0328-022s2e DPAATTEHOL. No.:: 01262-2021-H0E3 PathData System V5.1b FEMALE * DSATYASTEONATTNEECSROTPS:Y: KO 29 * ANIMAL NO. : 6 + NECROPSY FINDINGS KID0N1E:YSD:iscolored, light brown. SMA0L1:L DIuNoTdEeSnTuInN,E: Mucous Membrane: Discolored, white. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. SMANLoLmiIcNrTEoSsTcIoNpEi:c finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. * DSATYASTEONATTNEECSROTPS:Y: KO 29 * NECROPSY FINDINGS KID01N:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + ANDMAL NO. a PT02 -0222+ 422 IPANTDHIOVLIODGUYALRAENPIOMRTAL DATA TEST TEST SARYTSICTLEEM:: RTa-t7,7581 month, Oral Gavage SPONSOR 3M Corporate Toxicology DTOESXET GOFRGORUOSPS:ANDD2,MICmRiOdS-ChOiPgIhCdoFsIeNDINGS PAGE 2P31092-022s2e DPaAtTeHOL. No.: : 02222 HE 16-01-03 PathData System V5.1b FEMALE CONT./FE. ANIMAL NO. : o + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. NO MICROSCOPIC FINDINGS NOTED. * SDTAYASTEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 4 * NECROPSY FINDINGS KID0N1E:YSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. AL-LTuObTulHaErR PatRrOoTpOhCyO,L TfIoScSaUlE/mSulWtIiTfHoOcUaTl,PATbiHlOaLtOeGrIaCl,FIgNDrIaNdGeS.2 PT02 -0222+ 423 IPANTDHIOVLIODGUYALRAENPOTRMTAL DATA TTEESSTT ASRYTSITCELME :: 7R1a-t7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD2,MImCiRdO-ShCiOPgIhCdoFsIeNDINGS ence 1042-00/25282 DPaAtTeHOL. NO.: 10262-2021-H0E3 PathData System VS.1b FEMALE * SDATYASTEOANTTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 50 + NECROPSY FINDINGS KID0N1E:YSb:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KINDNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. AL"LTubOuTlHaErR nPeRcOrToOsCiOsL, TmIuSlStUiEfSocWaIlT,HOUbTilaPtAeTrHaOlL,OGIgCradFeIND2INGS. - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PT02 =-0222+ 424 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT ASRYTSICTLEEM:: TR-at7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology ADNOISMEALGRHEOAUDIPNG: DDA3T,A high dose ence Pr0a21-022s2e DPaATrHeOL. NO.:: 01262-2021-H0E3 Pathata System V5.1b ANNOIMMBAELR MS/EXF 22127 mu 223 mu 225 u 2278 2390 wu 5 52 EoF 55:3 FoF 5S556 EoFF 5EE oF 5690 EoFF DSTEAFTIENEODFANNDECRFOIPNSAYL "K0o x00 KKoo KKoo KRoL KRoL RRlL rRRL RRlL R+L KKOo KKoO KKoO KKOO KRol KRLo RRll RRIL RRlL RRLI TDEASYTS FDAIYRSTUNADNEDR LTAESSTT ~ 22579" 11372-00cC1T0-0022" 11a4N-oNvO=V0-20"2 2239 1177--00CCTT--0022 1144--NNOOVV--0022 2139 1177--00CCTT--0022 1246--NNOOVV=-0022 4433 1177--00CCTT--0022 2288--NNOOVV--0022 4423 1177--00CCTT--0022 2267--NNOOVV-=0022 22957131270-601C0T0-30"2 2299 1177--00CCT7--0022 2493 1177--00CCTT--0022 4433 1177--00CCTT--0022 4433 1177--00CCTT--0022 1144-N%OV0-022" 1144--NNOOVV--0022 2184--NNOOVV--0022 2268--NNOOVV--0022 2286--NNOOVV--0022 DNAETCEROOBFSY 1144--NNoovv--0022 1144--NNOoVv--0022 2184--NNOoVv--0022 2288--NNoOvV--0022 2287--NNoovv--0022 T1a4c-nNoovv--0022 1144--NNoovv--0022 2184--NNoovv--0022 2288--NNoovv--0022 2288--NNoovv--0022 PT02 -0222+ 425 IPANTDHIOVLIODGUYALRAENPIOMRATL DATA TEESSTT ASRYTSICTLEEM:: R71a-t7,7581 month, Oral Gavage SPONSOR + 3u Corporate Toxicology DTEOXSTE GOFROUGPROSS A: NDD3,MIChRiOghSCOdPoIsCe FINDINGS PAGE PT0a22-022s2e bPaAtTsHOL. NO.:: 01262-2021-H0E3 PathData System V5.1b vaLE * SDTAAYTSEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 2 + NECROSY FINDINGS KID0N1:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01 ALTLubOuTlHaErR dPiRlOaTtOiCoOnL, TImuSlStUiEfSocWaIlT,HOUbTilaPtAeTrHaOlL,OGIgCradFeIND2INGS. + DSATYASTEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 22 + NECROPSY FINDINGS KID0N1:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation mo. OL. LI"VHEyRp:ertrophy, centrolobular, grade 2 c(y=tohpelpaastnoac)ytes with pale, mostly fine granulated PT02 -0222+ 426 PIANTDHIOVLIODGUYALRAENPIOMRTAL DATA TTEESSTT ASRYTSICTLEEM:: 7R1a-t7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD3,MIChRiOghSCOdPoIsCe FINDINGS PAGE 2P4T032-022se2 DaPtATsHOL. No.: 01262-2021-H0E3 PathData System U5.1b HALE CONT. /FE. ANIMAL NO. : 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + DSATYASTEOANTTENSETCROPSY:: KO 29 + ANIMAL NO. 23 + NECROPSY FINDINGS KID01N:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. TTuubbuullaarr adtirloapthiyo,n, fmouclatli/fmouclatli,focbaill,atebrialla,tergarla,degr2ade 2 LIHVyEpRe:rtrophy, diffuse, grade 2 C(y=tohpelpaastnoaclytes with pale, mostly fine granulated THOYnRlOyIDonGeLANoDf: paired organs examined/present PAORnAlTyHYRonOeIDofGLApNaDiSr:ed organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 =-0222+ 427 IPNADTIHVOILDOUGAYLRAENPDOMRATL DATA 7T5ESSTT SARYTSICTLEEM:: TR-at7,7581 month, Oral Gavage SPONSOR 34 Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD3,MIChRiOghSCOdPosIeC FINDINGS eAGE 10a2-u022s2s DaPtATeHOL. NO.: 10262-2021-H0E3 Pathbata System V5.1 ALE + DSATYASTEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. 21 + NECROPSY FINDINGS KID0N1:EYSD:iscolored, light brown. `ST0O1M:ACHL:arge. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KINDNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. LI"VHEyRp:ertrophy, diffuse, grade 2 c(y=tohpelpaastmoac)ytes with pale, mostly fine granulated STNOMoACmHi:croscopic finding corresponding to necropsy observation no. 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS + DSATYASTEONATTNEECSROTPS:Y: KO 29 + NECRORSY FINDINGS KID01N:EYSD:iscolored, light brown. NO OTHER NECROPSY OBSERVATIONS NOTED + ANIMAL NO. : 25 PT02 =-0222+ 428 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT ASRYTSITCELME :: 1R7a-t7,7581 month, Oral Gavage SPONSOR 34 Corporate Toxicology TDEOXSTE OGFROGURPOSS A: NDD3,MIChRiOghSCOdPoIsCe FINDINGS PAGE PT042s-022528 DaPtATeHOL. NO.: 10262-2021-H0E3 PathData System S.1b vALE CONT./FE. ANTAL NO. : 25 + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. LIHVyEpRe:rtrophy, centrolobular, grade 2 (= hepatocytes cytoplasna) with pale, mostly fine granulated SPLLyEmEpNh:ocyte depletion, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * DSATYASTEOANTTNEECSROTPS:Y: RL 43 + ANDMAL NO. 26 * NECROPSY FINDINGS SE0M1I:NALsmaVlElS.ICLES: NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS SEMNIoNAmLicVrEoSsIcCoLpEiSc: finding corresponding to necropsy observation no. Ol. NO MICROSCOPIC FINDINGS NOTED. PT02 =-0222+ 429 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT ASRYTSITCELME :: TRa-t7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD3,MIhCiRgOhSCOdPosIeC FINDINGS AGE Pro426-/025282 DPaAtTeHOL. NO.:: 01262-2021-H0E3 Pathata System V5.1b vaLe + DSATYASTEOANTTENSETCROPSY:: RL 43 + ANIMAL NO. 2 + NECROPSY FINDINGS PRO01S:TATSEm:al. SE0M1I:NALsmaVlElS.ICLES: NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS T-HAOtrSo:phy, grade 2 PR-OAStrToApThEy:, grade 3 SETMhIiNsALfViEnSdIiCnLgESc:orresponds to necropsy observation no: 01. -ATthriosphfyi,ndbiinlgatceorrarle,spognrdasdeto3 necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. * DSATYASTEONATTNEECSROTPS:Y: RL 43 + NECROPSY FINDINGS KID01N:EYSS:urface changed, irregular. THY0M1U:S:Small. + ANIMAL NO. : 28 PT02 =-0222+ 430 PIANTDHIOVLIODGUYALRAEPNOIRMTAL DATA TTEESSTT ASRYTSITCELME:: 7R1a-t7,7581 month, Oral Gavage SPONSOR + 3M Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD3,MIChRiOghSCOdPoIsCe FINDINGS PAGE 2 PT0421-022s2e DPAATTEHOL. NO.:: 01262-2021-H0E3 PathData System V5.1b MALE CONT./FE. ANTMAL NO. : 2 ADR0E1:NALLarGgLeA.NDS: PRO0S1:TATSEm:all. SEM0I1:NALSmaVlElS.ICLES: NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KICDhNrEoYnS:ic nephropathic foci, bilateral, grade 3 r(oduengdenceerlaltiuvlearalitnefrialttiroantsionmsainilnythien tihnetertsutbiutlii,um)with seLTEhEiNs: finding corresponds to necropsy observation no: Ol. TH-YLMyUmSp:hocyte depletion, grade 3 -TAhtirosphfyi,ndignrgadecor4responds to necropsy observation no: Ol. ADRNEoNAmLicrGLoAsNcDoSp:ic finding corresponding to necropsy observation no. 01. PR-OAStTrAoTpEh:y, grade 3 SEMTIhNiAsLfViEnSdIiCnLgESc:orresponds to necropsy observation no: 01. "TAhtriosphfyi,ndbiinlgatceorrarle,spognrdasdeto3 necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 -0222+ 431 eTaNTDHIOVLIODGOYNLRAEPNOTRATL DATA TTSreooeTnrsoaSnnYtSiTcEsM;| TRa7t7,581 onth, Oral Gavage 34 Corporate' Tonicotosy TSoosTE OGFroGuross A+Db,MICiRoOnSCOdPoIsCe FINDINGS ence . eraoze022s2s oEFaaarmtrzhobra.taoNoS.y{sl0t7ee2nn22Uts.efe1s5 wate cont./FE. ANIVAL 0. 2 + ewanks THUS: Thymus submitted in large capsule + sSovasrsoavrmweeecrRopsT: 71a + ana vo. 2 + vecaopsy FroiNGs O NECROPSY OBSERVATIONS NOTED. + uicroscoeic FnwomiGs LAadLvLiecrGr:ToaggrhanPuRiOoTnOsC,OLfToIcSaSlU/EmSultWiIfToHcOaUlT P(AiTnHfOlLaOmGmIaCt,orFyINDfIoNcGiS)., grade 2 + SSTeAsTEonaTmweEeCrRORSY: R1/+a1 + vecropsy FronNGs sexaoGusintaasTSeh:avnEas.icies: Tes(Ot1e5sT:SmaTll. - ma vo. : 2 PT02 =-0222% 432 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA T1E8SSTT ASRYTSICTLEEM:: TRa-t7,7581 month, Oral Gavage SPONSOR : 34 Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD3,MIChRiOghSCOdPoIsCe FINDINGS PAGE 02a-90)22528 DaPAtTeHOL. NO.: 01262-2320-H0E3 Pathbata System V5.1b MALE CONT./FE. ANIMAL XO. : 30 EPI01D:IDYSMmIaDllE.S: NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDSNeEvYeSr:e autolysis, evaluation not possible LIVSEeRv:ere autolysis, evaluation not possible SP-LLEyEmNp:hocyte depletion, grade 4 TH-YAMtUrSo:phy, grade 3 IDLIeApCleLtYiMoPnH NofODEl:ymphocytes, grade 3 FOSReEvSeTOrMeACaHu:tolysis, evaluation not possible GLSAeNvDeUrLeARauStToOlMyAsCiHs:, evaluation not possible JEJSUeNvUeMr:e autolysis, evaluation not possible coLSoeNv:ere autolysis, evaluation not possible URITNiAsRsYueBLnAoDtDEpRr:esent for histologic examination PAROtSrToApThEy:, grade 3 SEMThIiNsALfViEnSdIiCnLgESc:orresponds to necropsy observation no: Ol. -TAhtirosphfyi,ndibniglatceorrarle,spognrdasdeto3 necropsy observation no: 01. Te"sTTuEbSu:lar atrophy, multifocal, bilateral, grade 3 This finding corresponds to necropsy observation no: 01. PTO2 -0222+ 433 eIaNmDHIoVLIoDGUYALRAEPNOTRATL DATA TTeesstt aSnyrsitceis :| 1Ra1t7,581 month, Oral Gavage Sronson {SW Corporate' Toxicology T20S3T8 oGRFOUGPr.oss A+ D03,MIChRiOghSCOdPoIsCe FINDINGS once + Prosozs-022se0 beaarmneor. Nou: e0s22s2o2n1o%s Pachbatao systen VS.15 wis cont./ee. mma No. 50 sCeiTrthorirospohmfyii,nedsbi:inlgatceorrarles,pognrdas.deto3 necropsy observation no: Ol. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + rewnnes HURWINSAR:Y TBhLyAmDuDsERsusbumbimtittetdedinincapcsauplseuleI I PT02 -0222x 434 IPANTDHIOVLIODGUYALRAEPNOTRATL DATA STTpEEoSSnTTsoASrRYTSITCELME 1 : 3RTa07t7,C5o8r1pmoornatthe, TOorxailcoGlaovgayge TBEOXSTE GORFOUGPROSS A+NDD3,MIChRiOghSCOdPoIsCe FINDINGS ence + eraszy-022s2e DPeaaatTceHhObLa.teoNoS.yst012e62n-20V20S.-H0E13b rose + SSaTvAeTEonATTENESCTROPSY:i KO 2 mma vo. : a + NECROPSY. FINDINGS NLOav01eO:rTH:ELRa.rgNeE.CROPSY OBSERVATIONS NOTED + ucRoscopIC FINDINGS LKI"aVNoEewRge:hsr:oblastona, unilateral (malignant neoplasm) "hc(yy"ptheoerpptiaratosponhcay)y,tesdifwfiutshe,palger,ademos3tly fine granulated um"EbTRihDliSsa:taftiinodni,nggrcaordrees2ponds to necropsy cbservation no: OL. ALL OTHER PROTOCOL TISSUES WITHOUT ATHOLOGIC FINDINGS. + DSaTvAeTEonATTENESCTROPSY:i KO 29 + NECROPSY FINDINGS NKOro01nO:TeHvEsDR:i'scNoElCoRrOePdS,Y OlBiSgEhtRVAbTroIwOnN.S NOTED + ANAL No. : s2 PT02 -0222% 435 IPNADTIHVOILDOUGAYLRAENPIOMRATL DATA TEESSTT SARYTSICTLEEM:: TR-at7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology TDEOXSTE GOFRGORUOSPS:ANDD3,MIhCiRgOhSCOdPosIeC FINDINGS eAGE Pr0s2z-022s2s DPaAtTeHOL. NO.: 10262-2320-H0E3 Pathbata System V5.1b FEMALE CONT./FE. ANIMAL NO. : 52 * MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. LI"VHEyRp:ertrophy, diffuse, grade 2 c(y=tohpelpaastnoac)ytes with pale, mostly fine granulated AL-LiicOrToHgErRanPuRlOoTmOaC,OLfToIcSaSlU/EmSultWiIfToHcOaUlT P(AiTnHfOlLaOmGmIaCtorFyINDfIoNciG)S,. grade 2 + DSATYASTEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 53 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS KI"DhNyEaYlSi:ne resorption bodies, tubular, focal, bilateral, grade 2 LI"VHEyRp:ertrophy, diffuse, grade 2 c(y=tohpelpaastnoac)ytes with pale, mostly fine granulated FO-RSEuSbTmOuMcAoCsHa:l inflammatory edema, focal, grade 2 PAORnAlTyHYRoOnIeDofGLApNaDiSr:ed organs exanined/present PT02 -0222% 436 `IPNADTIHVOILDOUGAYLRAENPOTRMTAL DATA TTEESSTT ASRYTSITCELME :: 7Ra-t7,7581 month, Oral Gavage SPONSOR + 34 Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD3,MIChRiOghSCOdPoIsCe FINDINGS AcE 1052-3022528 DPAATTEHO.L. NO.:: 01262-2320L-H0E3 Pathata System V5.1b FEMALE CONT./FF. ANIMAL NO. : 53 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + DSATYASTEOANTTNEECSROTPS:Y: KO 29 + ANIMAL NO. : st + NECROPSY FINDINGS KID0N1:EYSb:iscolored, light brown. LIV0E1:R: Large. NO OTHER NECROPSY OBSERVATIONS NOTED + MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. LITVuEbRu:lar degeneration, multifocal, bilateral, grade 2 "H(y=pehretpraotpohcyy,tescenwtirtohlopbaullea,r,mosgtrlaydef2ine granulated cThyitsoplfaisnndai)ng corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 -0222+ 437 IPANTDHIOVLIODGUYALRAENPOIRMTAL DATA TTEESSTT ASRYTSICTLEEM:: R1a-t7,7581 month, Oral Gavage SPONSOR + 34 Corporate Toxicology DTOESXET GOFRGORUOSPS:ANDD3,MIChRiOghSCOdPoIsCe FINDINGS PAGE Pr0524-022528 DPAATTHEOL. No.:: 01262-2021-H0E3 PathData System V5.1b FEMALE * DSATYASTEONATTNEECSROTPS:Y: KO 29 + ANDMAL NO. : 55 + NECROPSY FINDINGS KID0N1:EYSD:iscolored, light brown. sxE0s1:: RIGHT, Opaque, Both eyes submittet in large Capsule. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNNoEYmSi:croscopic finding corresponding to necropsy observation no. 01. LI"VHEyRp:ertrophy, centrolobular, grade 3 c(y=tohpelpaastmoac)ytes with pale, mostly fine granulated PAORnAlTyHYRonOeIDofGLApNaDiSr:ed organs examined/present s"sEsp:ithelium of the cornea enlarged (4 layers), bilateral, gThriasdef2inding corresponds to necropsy observation no: 01. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 =-0222+ 438 eINaDmIiVoIrDoUcAyLsAzpNoTRAsL DATA TToEsStT aSYnStTEiMcs:| 7Ra1t7s581 month, Oral Gavage Sronson | SW Corporate' Toxicology T20K5% OGFroGuRoSS A+N3D,MIChRiOghSCOdPeIsCe FINDINGS ence eroszs-022s2e Toaarrso. Now:{ 0T2e2t22an1oEs Pacnbatso systen vs.1b rows + sSavtssoarnEecRoRsY: TL as + mm vo. ss + wecropsy FrDINGS wYooG1Oe:TsHES:RurfNaEcCeROPchSaYngGeBdS,ERViArTrIeOgNulSarN.orED + uicRoscostc nomics Ke"Co(huaroeogsno:niecranteipvhe.ropaalttheircatifoocnis, mbaiilnaltyerianl,theg.ratduebui1i, with round ALCThoiOlTsHtEfeRi.rndFiIRnnOgfFi01CctOorLrart1eisSopGnoUsnSdSsintWtoIhTeHnOeSIcTrnoCpPesRrMysHtOoiLbtOvGieIorCmv,atFiIoNnDINnGoSs. O1. - ALL OTHER ANIMALS TN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PT02 -0222+ 439 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT ASRYTSICTLEEM:: TRa-t7,7581 month, Oral Gavage SPONSOR 3M Corporate Toxicology ADNOISEMALGRHEOAUDIPNG: DAD4T,A mid-low dose PAGE + 10s26-/022s2s DPaAtTeHOL. NO.:: 10262-2320-H0E3 Pathbata System V5.1b NAONMIBMEARL SME/XF 6623 u 6651Mu 66 TE 66kEF 70 DSTEAFTIENEODFANNDECRFOIPNSAYL K0o x00 K0o 0x0 Kxo0 k0o 0Ko K0o x0 x0 TDEASYTS DFAIYRSTUNADNEDR TLEASSTT DNAETCEROPOSFY PR PrePasyy 2295 1188--NNOoVv--0022 1166--DDEECC--0022 1166--DDEECC--0022 2259 1188--NNoOvV--0022 1166--DDEECC--0022 1166--DDEECC--0022 2288 11h8N-Noovv-0020 1166--DDEECC-0022 1166%-DDRECC--0022 2255 1188--NNOoVv--0022 1166--DDEECC--0022 1166--DDEECC--0022 29 18-NOV-02 16-DEC-02 16-DEC-02 PT02 -0222+ 440 PIANTDHIOVLIODGUYALRAENPDOMRATL DATA TTEESSTT ASRYTSICTLEEM:: TR1a-t7,7581 month, Oral Gavage SPONSOR 3u Corporate Toxicology TDEOXSTE OGFRGORUOSPS:ANDD4,MImCiRdO-SlCoOwPICdosFeINDINGS eAGE 1052-10/25282 DPaAtTeHOL. NO.: 01262-2320-H0E3 Pathbata System V5.1b ALE * SDTAAYTSEONATTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 61 + NECRORSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS Li"vMeirc:rogranuloma, focal/multifocal (inflammatory foci), grade 2 ALLwitOhTHEnRecrPoRtOiTcOChOeLpaTtIoScSyUtEeSs.WITHOUT PATHOLOGIC FINDINGS. + SDATYASTEOANTTNEECSROTPS:Y: KO 29 + ANIMAL NO. : 64 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS LI-vMEiRc:rogranuloma, focal/multifocal (inflammatory foci), grade 2 -M+ixesdingcleellceilnlfilntercartoisoins, in the portal area, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PTO2 -0222+ 441 NeaDmIiVoILDoOcAyLRAEpNoTRATL DATA S1Tr6eo3sn7tsaoSnnYtSiTcEsM::{SR7Wa1t7,C5o8r1pomornatrhe, ToOrmailcotGoagvsage DToEsTE GOFroGuROSS AND4,MICmRiOdS-CiOoPnICdosFeINDINGS ence erosezs-022se0 Poeaarmceihobra.taoNo.s:yt st0e2n2n 2VS.11%5 seis + sSaaicssonarTeNeercRoPsY: KO 2s mun vo. + necropsy Fons sLrav0ne1mi: Margins changed, partly, transparent. NOGO1THEoRnNcEeCR.OPSY OBSERVATIONS NOTED + uxcroscoprc FINDINGS LOaNvMoeI:mCiRcOrSoCsOcPoIpEicFINfDiInNdGiSngNOcToErDr:esponding to necropsy observation no. 01. - ALL OTHER ANIWALS T DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PTO2 -0222+ 442 PATHOLOGY REPORT Study-No.: PT02-0222 T-7758 PathData-No. 90222 prepared by: DR. BERNDT HEIN Pathologist PT02 -0222% 443 SUMMARY Mortality: There were no unscheduled deaths during the courseofthe 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 ocurred at an incidence and severity historically seen at the testing facility for rats of their age and strain. Therefore, they were not considered related to treatment. MATERIAL AND METHODS PT02 -0222+ 444 GROUP DESIGN FOR PATHOLOGIC EVALUATION: Group No.* Animal-No.: male Animal-No.: female Dose (mg/kg) C1/06 Control 7175 81-85 0 D5/07 Low Dose 76-80 86-90 03 the dose groups DT to D4 (15--60 ~ 240 3 mgikg) Incl a control group are reported in no. 02222) ADMINISTRATION OF THE TEST ARTICLE `The test article was orally administrated by means ofa pharyngeal tube, 28 administrations for four weeks. NECROPSY AND HISTOPATHOLOGY All animals were killed by exsanguination (dissectionofthe 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: Hsetaermt,, mleundgusll(aincol.blbornognacthai)), asnpdintarlachceoar,dli(vcere,rvkiicdaln)e,yst,esstpelse,ene,pbirdaiidnym(icse,rebprrousmt,atcee,resbeemlilnuaml, vesicles, ovaries, uterus, urinary bladder, stomach, small (jejunum) and large intestine (colon), adrenals, thymus, bone marrow (stemum), 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. PTO2 =-0222+ 445 DATA COMPILATION TPhreoTaonximKaalsdtaetnagrasunwdellTeasstitnhge nFeaccirloiptsy,y deanttaerweedreinrteocotrhdeedPiAnTPHrDovAaTnAtisc,odmupruitnegrthseyssetcetmionanadt 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 syste. 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 lesionsofdifferent severity werescoredas follows: grade 1/2 orgrade 1/3 grade 1/4 or grade 2/3 or grade 2/4 grade 1/5 or grade 2/5 or grade 3/4 or grade 3/5 grade 4/5 =grad2e = grade 3 = grade 4 = grade 5 Allincidence tables were created by the PATHDATA computer system. RESULTS PT02 =0222% 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 administrationofthe test compound in all animals investigated. Sporadic changes in formofdilatation and cellular infiltration could be observes in the uterus of animal no. 89 (group DS/07). Single control animals (group C1/06) exhibited rubular dilatation in the Kidney (no. 71), or cellular infiltrations in the lungs (no. 83) or glandular stomach (no. 75) For further details see also NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS, TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS, and TEXT OF GROSS AND MICROSCOPIC FINDINGS. CONCLUSIONS PTO2 -0222% 447 -- 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 tfarceialtimtyentf.or rats of their age and strain. Therefore, they were not considered related to 4Sig-- nature A/F) (Dr. B. Hein) VPeritnecriipnaalryInPvaetshtoilgoagtiosrt _ END OF REPORT SECTION oxsuosoor savor PT02 =-0222+ 448 me srodulornt] 4 fuaneis Heli oy PTO2 -0222+ 449 eammoroo savor mee: #103w02w2 TTEesrt aSYnSttaiMci:i Srovson 1 1Ra7t7,581 month, 5M Corperated TOroatlicogiavoasgye FoeaamtaihooLra.tasoNo".s:ysT3t0e3e22Ve5H.sE1p STATHHENT OF COMPLIANCE The undereiT aned hR ereby dA eclares thatI I this R study wn es pea rfor, med bi (Study Pathologist) [p-- sate: AE 1) 23 PT02 -0222+ 450 eamHoLoGY REPORT STTeoeosswttsoaSnnYtSiTcEiMs |: | R13a7t7,C5o8r3pomronatthe,s TOroaxlicagtaovnayge EXPLANATION OF CODES AND SYHROLS ence seryoztomze: DPEaaamceihopra.taoNos.yst3T0ee2n7s2UsS.if1ee0 CODES AND SWBOLS USED AT ANRAL LEVEL: K W PeC TnTrenreminaianlime seacrifice group CODES AND SWEOLS USED AT ORGAN LEVEL: I+ : kITC OtiazMtunoloSegivimecimnieenxdea,dminnFaoitripioanntgnsoniotbpsriorcoeeqsuFtiirneddings noted (OFT only) ` 2 Galy one of `paired Groans exanined/prasent Cops AND SWHEOLS USED AT FINDING LEVEL: GRRE 2 = tight / few / mall PT02 =-0222% 451 PSAUTMHMOALROYGTYABRLEEPSORT PAGE R P102R -0222 TEST ARTICLE : T-7758 STPEOSNTSOSRYSTEM:+ R3a4t,Cor1pomornatthe,d TOroaxlicoglaovgayge PATHOL. NO.: 90222 HE DaPtaethData Sy:st1e6m-3V0S-.013b NSTOAMTBUESR OATF ANENCIRMOAPLSSY:WITKHO MICROSCOPIC FINDINGS BY ORGAN/GROUZ/SEX SDEOXSE GROUP:cow a1 or NO.ANIMALS: 5 5 mo 05 F 55 K-IDDNiElYaStion:Twbular + 01s 5= 5= 5= LCoInngtserstit.infiltrat.:cs- s 1 s- s G"LMAiNxDeUdLARcelSlT.iOnMfiAltCrHat:: 51 5- 5= 5= T- EbRilSatation P E -st - 5 - PMN cell.infiltrat. : - - - 1 pTO2 -0222+ 452 IeaNmDwIoVLIoDcUtALsApNoTRATL DATA eace Cero-s 0227 STTrEeoSsuTsoaSnnYtSiTcEsM: {|1S1Ri75Cao8+rtmpoonr,taht,e TOroaxlicogtaovgayge oaPFaarmtsihobra.taoNo.srypst3e0rn:22v5eH.E10 DT0hSSEEGROFOUPINDTV3IOCULN SMiIxCtRhOSCgOrPoEwS FINDINGS Anta Nowe omo.2 m0"3 HO wo.7s FROsTwKO. EKOs.a FROssKOs pD e n CLI L LT L L I L ation: tubular on L ersticR .meittrac. . ao LL LL TL L Se Ts eon reneesnr lL LL RR to 1010 Tetaede os eroe nDd S apLo a ed Solider... oa TT LL LL TL ee LLL LLL LL many eres eres nessae ese s pessoas posEToT sses eas emere seen ene Tene Ss EE ot gs 440 1101 prs ss PT02 =-0222% 453 PATHOLOGY REPORT INDIVIDUAL ANIMAL DATA eAcE c10e2-02212 TTEESSTT ASRYTSITCELME:: TR-7a 1518tmon, th, Oral gavage SPONSOR 31 Corporated Toxicology DPaAtTeHOL. NO.:1960-23202-H0E3 Pathbata System Vs.1b TDAOBSLEEGORF OIUNDPIV:IDUClA,L MICROSCOPIC Sixth group FINDINGS ANIMAL NUMBER : MKO71 MKO72 MKO73 MKO74 MKO75 FKO81 FKO52 FKO83 FKO83 EKO6s ARDREL NAL B CORTEX - A a ee L e HO aL ARG ATL LL RRR Baa TL Sadun RL La TT bib CR BRR PT02 =-0222% 454 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTeEeSrT mSrYiScTiEsM:+ nRaot,se1 month, Oral gavage sponsor : 3 Coxporated Toxicology TDAOBSLEEOGFRIONUDIPV:IDUDAS,LMSiecvReenstchorgircouFp INS eace sPwr02a-02n22 abamtel. No.: 91062-20201W-E03 PathDacao System VS.1b ANAL NwezR+ MO76 MK71 MKD78 MKO79 MK80 EKO86 FXO81 EK88 EKO89 EKO90 BR EART TTITTIT TTITITITITTTITTITTTTTTTT RTT RL Con Ga RR Ren ELA ah LT SRSA RAR BRAG ee SEG eT CoRR RRR OA SAAR EG AR RTL RRL Sona EL MLL PT02 =-0222+ 455 PIANTDHIOVLIODGUYALRAENPTORMTAL DATA PAGE sP1e02-02212 ETESSTT ASRYTSICTLEEM::TR-77a518tmon, th, Oral gavage SPONSOR 3u Corporated Toxicology DaPtATsHOL. No.:: 91062-2021-H0E3 PathData System V5.1b TDAOBSLEEGORFOIUNDPI:VIDUDSA,L MICROSCOPIC FINDINGS Seventh group ANIMAL NUMBER : MKO76 MKO77 MKO78 MKO79 MKO80 FKO86 FKO87 FKO88 EKO89 FKO90 THYRROIODGLRANSDLA ee eee eee RAR Baa TL CRE RL Gas hI --DiPlMNactealtli.oinnfiltrat. Lo + 5 aos DD PT02 -0222+ 456 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT SARYTSICTLEEM:: TR-at7,7581 month, Oral gavage SPONSOR 3u Corporated Toxicology ADNOISMEALGRHEOAUDIPNG: DATA Cl, Sixth group PAGE cPre02-02212 DPaATeHOL. NO.: 19062-2320-H0E3 Pathbata System V5.1b NANUIMMBAELR MS/EXF SDTEAFTIENEDOFANNDECRFOIPNSAYL TDEAYSST DFAIYRSTUNADNEDR TLEASSTT NDAETCEROPOSFY EE TPRPPEPPIONY 273mou KKoo KKoO 2299 2288--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 5uMM KKoo KKoO 2299 2288--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 ET FEPF Re PEPEPRTPPS 8832 FFEE 8845 oFFE KKoO KKOo KKoo KKoo 2295 2288--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 2299 2268--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 PTO2 -0222+ 457 eIaNDmIoVLIODGUYALRAEPNOTRATL DATA STTrEeoSsnTtsoaSnnytsiTceiNs |{: SR7ua7t7,C5o8r1pomornatthe,s OTroaxlicogtaovnayge T50H5T% OGFRoGvrFoss A+NDC1,MICSRiOxtShCOPgIrCoupFINDINGS ence Froaz-0w222 oPTaaamtcrehobna.taNoousry| st3le0en2s2sV2uS.u=o1sb wis + sSevasmsonanTewescrRoRST: KO 2s - mma vo. : 7" + uecropsY FrpnGs NO NECROPSY OBSERVATIONS NOTED. + wicRoscopic FrvomNGs AcLNoLuvbeOuTslH:EaRr, dPiROlTaOtCiOoLn', TmIuSlStUiEfSocWaIlT,HObUiTlaPtAeTrHaOlL,OGIgCradFeIND2INGS. + sSthaesteonaTmeneecrRoRsY: KO 2s Aw vo. ws + Necropsy FrDINGS NO NECROPSY OBSERVATIONS NOTED. + wicRoscopic FromiGs G"uMaipxoeLdaRcelslTuowlAaCrH:infiltration, in the submucosal area, grade 2 EAORnAlTyINRonOeTDofGLApNaDiSr:ed organs examined/present 32 OPER, PROTOCOL TISSUSS WITHOUT PATHOLOGIC FINDINGS. PT02 -0222% 458 PIANTDHIOVLIODGUYALRAENPOIRMTAL DATA TTEESSTT ASRYTSICTLEEM:: R1a-t7,7581 month, Oral gavage SPONSOR : 3% Corporated Toxicology TDEOXSTE OGFRGORUOSPS:ANCDl,MICSRiOxtShCOPgIrCoupFINDINGS * SDTAAYSTEOANTTNEECSROTPS:Y: KO 29 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS PAORnAlTyHYRonOeIDofGLApNaDiSr:ed organs examined/present NO MICROSCOPIC FINDINGS NOTED. PAGE. sPo102o-02n22 DAPATTEHOL. NO.:: 19062-2021-H0E3 PathData System V5.1b FEvALE + ANDMAL NO. : 5 * SDTAAYTSEONAT1N8ECSROTPS:Y: KO 29 + ANIMAL NO. : 83 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS Lo-NIGnSt:erstitial infiltration (mononuclear)/ pneumonia, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. PT02 -0222+ 459 PIANTDHIOVLIODGUYALRAENPIORMTAL DATA EESSTT ASRYTSITCELME:: TR-at7,7581 month, Oral gavage SPONSOR 3M Corporated Toxicology TDEOXSTE OGFRGORUOSPS:ANDCl,MISCiRxOtShCOPgIrCoupFINDINGS * SDATYASTEOANTTNEECSROTPS:Y: KO 29 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS THOYnRlOyIDoGnLeANoDf: paired organs examined/present PAORnAlTyHYRoOnIeDofGLApNaDiSr:ed organs examined/present NO MICROSCOPIC FINDINGS NOTED. PAGE soP11022/-02212 DaPtATsHOL. NO.:: 19062-2321-H0E3 PathData System S.1b FEMALE + ANDMAL NO. 8s - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS - PT02 =-0222+ 460 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA 1T5ESSTT SARYTSICTLEEM:: TR-at7,7581 month, Oral gavage SPONSOR 3m Corporated Toxicology ADNOISMEALGRHEOAUDIPNG: DDAST,A Seventh group PAGE : 1012-022127 DPaArTHOL. NO.: 91062-2321-H0E3 Pathbata System V5.1b NAONMIBMEARL MSE/XF SDTEAFTIENEDOFANNDECRFOIPNSAYL 7787Mu 00 K0o 7809 nuu KKOO 00 eg 888 KKOO KKOo 809 ooFF KKoo KKOO TDEASYTS DFAIYRSTUNDAENRD TLEASSTT NDAETCEROPOSFY Ee PEF PTY P RPPPTIEIN 2299 2288--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 2299 2288--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 2299 2288--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 2299 2286--JJAANN--0033 2255--FFEEBB--0033 2255--FFEEBB--0033 PT02 -0222+ 461 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT ASRYTSICTLEEM:: TRa-t1,7581 month, Oral gavage SPONSOR : 34 Corporated Toxicology TDEOXSTE OGFRGORUOSPS:ANDDS,MICSReOvSenCtOhPICgroFuIpNDINGS + DSATYASTEOANTTNEECSROTPS:Y: KO 29 + NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS PAoRnAlTyHYRonOeIDoGfLApNaDiSr:ed organs examined/present NO MICROSCOPIC FINDINGS NOTED. ence F1T02V-0222 DPAATTEH.OL. No.:: 91062-2021-H0E3 Pathbata System V5.1b MALE + ANDMRL NO. 7% * DSATYASTEOANTTNEECSROTPS:Y: KO 29 + ANDMAL NO. : 7 * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS PAoRnAlTyHYoRnOeIDoGfLApNaDiSr:ed organs examined/present NO MICROSCOPIC FINDINGS NOTED. PT02 =-0222+ 462 PIANTDHIOVLIODGUYALRAENPIOMRATL DATA TTEESSTT ASRYTSICTLEEM:: TRa-t7,7581 month, Oral gavage SPONSOR 3m Corporated Toxicology TDEOXSTE OGFRGORUOSPS:ANDD5,MISCeRvOeSnCtOhPICgroFuIpNDINGS + SDATYASTEONATTNEECSROTPS:Y: KO 29 + NECROBSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. + MICROSCOPIC FINDINGS PAORnAlTyHYRonOeIDoGfLApNaDiSr:ed organs examined/present NO MICROSCOPIC FINDINGS NOTED. AGE Pr012s-022127 DPaAtTHeOL. No.:} 91062-2020L-HE0.3 Pathbata System V5.1b MALE + ANIMAL NO. 80 PTO2 -0222+ 463 eIaNTDiIoVLIoDGUYALRAENRTOHRATL DATA STTr5eoSsuTtsoSarYnStTiEcMs |1 R1a7t7,581 month, oral gavage {SW Corporated Tovictosy T20S5T% GOFROGVREOSS A+ND05,MICSReOvSenCtOhPICgroFuIpNDINGS ence eroase-022a2 oPFaaarTtishopLa.caoo.s:y{stl3e0en22n2vt5A.Eo1 eewe + ssaomsnanmNesrcRoRSY:ot KO 2a + mma vo. os + necropsy Frwomics NO NECROPSY OBSERVATIONS NOTED. + ucroscopc Fronis urIoeinrlfuaistl:attriaotni,ongwriatdhe s2olymorphauclear cells, endometrial, grade 2 AL OTHER. PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS. + SsatiasteowanTeweecrRopsT:oh KO 29 + nna vo. : 0 + necropsy FrioiGs NO NECROPSY OBSERVATIONS NOTED. + wrcroscoptc nomics NEoAORnMAIlTEyRRYOoRBnOCeIODPoIGfCL,ApNaFDrISsN:eDdINGoSrgaNnOsTEDe:xamined/present PT02 IPNADTIHVOILDOUGAYLRAENPTOMRATL DATA TEST 18ST SARYTSICTLEEM:: 1R-at7,7581 month, Oral gavage SPONSOR 34 Corporated Toxicology DTOESXET GOFRGORUOSPS:ANDDS,MICSReOvSenCtOhPICgroFuIpNDINGS -0222+ 464 PAGE + PT0y2-0n222 DaPArTeHOL. NO.: 19062-2321-HE0.3 Pathbata System V5.1b FEMALE - ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS =