Report, BSL BIOSERVICE Study No page 2 of 110 Version: Final List of Tables Preface... 6

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2 Report, BSL BIOSERVICE Study No page 2 of Contents 1. Contents List of Tables and Figures List of Tables Preface Abbreviations General Project Staff Schedule Project Staff Signatures Quality Assurance Guidelines Archiving Summary Summary Results Conclusion Introduction Justification for the Selection of the Test System Justification for the Selection of the Test Method Materials and Methods Characterisation of the Test Item Characterisation of the Vehicle Preparation of the Test Item Formulations Dose Formulation Analysis Test System Housing and Feeding Conditions Number and Sex of Animals Preparation of the Animal Administration of Doses Dosage Body Weight and Food Consumption Clinical Observation Haematology Clinical Biochemistry Pathology Organ Weight Histopathology Results Mortality Clinical Observation Body Weight and Body Weight Change Food Consumption Haematology Clinical Biochemistry Gross Pathology Organ Weight page

3 Report, BSL BIOSERVICE Study No page 3 of Histopathology Conclusion Distribution of the Report References Internal BSL BIOSERVICE SOPs Literature and Guidelines Appendix Appendix 1: Summary, Mean and Individual Tables Appendix 2: Histopathology Report... 74

4 Report, BSL BIOSERVICE Study No page 4 of List of Tables and Figures 2.1. List of Tables page Table 1: Group and Animal Identification 16 Table 2: Haematology 17 Table 3: Clinical Biochemistry 17 Table 4: Organs to be weighed at Necropsy 18 Table 5: Mortality Table - Summary 24 Table 6: Clinical Observations - Males - Summary 25 Table 7: Clinical Observations - Females - Summary 25 Table 8: Mean Body Weight (g) - Males 26 Table 9: Mean Body Weight (g) - Females 26 Table 10: Mean Body Weight Gain (g/week) - Males 27 Table 11: Mean Body Weight Gain (g/week) - Females 27 Table 12: Mean Food Consumption (g/day) - Males 28 Table 13: Mean Food Consumption (g/day) - Females 28 Table 14: Mean Haematology - Males 29 Table 15: Mean Haematology - Females 29 Table 16: Mean Clinical Biochemistry - Males 30 Table 17: Mean Clinical Biochemistry - Females 31 Table 18: Macroscopic Findings - Males - Summary 32 Table 19: Macroscopic Findings - Females - Summary 32 Table 20: Absolute Mean Organ Weights (g) - Males 33 Table 21: Absolute Mean Organ Weights (g) - Females 35 Table 22: Relative Mean Organ Weights to Brain Weight (%) - Males 37 Table 23: Relative Mean Organ Weights to Brain Weight (%) - Females 39 Table 24: Relative Mean Organ Weights to Body Weight (%) - Males 41 Table 25: Relative Mean Organ Weights to Body Weight (%) - Females 43 Table 26: Individual Clinical Findings - Males 45 Table 27: Individual Clinical Findings - Females 47 Table 28: Individual Body Weight (g) - Males 49 Table 29: Individual Body Weight (g) - Females 50 Table 30: Individual Body Weight Gain (g/week) - Males 51 Table 31: Individual Body Weight Gain (g/week) - Females 52

5 Report, BSL BIOSERVICE Study No page 5 of 110 Table 32: Individual Food Consumption (g/day) - Males 53 Table 33: Individual Food Consumption (g/day) - Females 54 Table 34: Individual Haematology - Males 54 Table 35: Individual Haematology - Females 55 Table 36: Individual Clinical Biochemistry - Males 56 Table 37: Individual Clinical Biochemistry - Females 57 Table 38: Individual Macroscopic Findings - Males 58 Table 39: Individual Macroscopic Findings - Females 60 Table 40: Absolute Individual Organ Weights (g) - Males 62 Table 41: Absolute Individual Organ Weights (g) - Females 64 Table 42: Relative Individual Organ Weights to Brain Weight (%) - Males 66 Table 43: Relative Individual Organ Weights to Brain Weight (%) - Females 68 Table 44: Relative Individual Organ Weights to Body Weight (%) - Males 70 Table 45: Relative Individual Organ Weights to Body Weight (%) - Females 72

6 Report, BSL BIOSERVICE Study No page 6 of Preface 3.1. Abbreviations ALAT Alb ANOVA AP Art. ASAT BGBl. bw C CFR Che Chol Crea Dipl.-Biol. e.g. EC EDTA Ery GLP GmbH H&E Hb Hct HD IVC K LD Leu alanine aminotransferase albumin Analysis of Variance alkaline phosphatase Artikel (article) aspartate-aminotransferase Bundesgesetzblatt (Federal Law Gazette) body weight control Code of Federal Regulations cholinesterase cholesterol creatinine Diplom Biologe (Biology Diploma) exempli gratia (for example) European Commission ethylen diamine tertraacetic acid erythrocytes Good Laboratory Practice Gesellschaft mit beschränkter Haftung (company with limited liability) hematoxylin & eosin haemoglobin haematocrit high dose individually ventilated cages potassium low dose leukocytes

7 Report, BSL BIOSERVICE Study No page 7 of 110 Lym MD Na Nr. OECD PLT QA QAU RBC SOP SPF TP WBC WI lymphocytes medium dose sodium Nummer (number) Organisation for Economic Cooperation and Development platelet count Quality Assurance Quality Assurance Unit red blood cell count Standard Operating Procedures specific-pathogen free total protein white blood cells Wistar

8 Report, BSL BIOSERVICE Study No page 8 of General Sponsor: Study Monitor: Test Facility: Vires5 bvba Bredabaan Wuustwezel Belgium Mr Remco Schade BSL BIOSERVICE Scientific Laboratories GmbH Behringstraße 6/ Planegg Germany BSL BIOSERVICE Study No.: Test Item: Vires5 Title: 14-Day Dose Range Finding Oral Toxicity Study in Wistar Rats with Vires Project Staff Study Director: Management: Head of Quality Assurance Unit: Test Site 1: (Histopathology) Principal Investigator: Test Site 2: (Tissue Processing) Principal Investigator: Dr. Philip Allingham Dr. Wolfram Riedel Dr. Angela Lutterbach Dipl.-Biol. Uwe Hamann KALEIDIS- Consultancy in Histopathology 6 rue du Gers Saint-Louis France Dr. Gabriele Pohlmeyer-Esch Propath UK Ltd Willow Court, Netherwood Road Hereford HR2 6JU Great Britain Mrs Elizabeth Richards 3.4. Schedule Arrival of the Test Item: 20 June 2011 Date of Draft Study Plan: 28 June 2011 Date of Final Study Plan: 29 June 2011 Start of Experiment: 06 July 2011 End of Experiment: 21 July 2011 Start of Delegated Phase (Histopathology): 25 August 2011 End of Delegated Phase (Histopathology): 25 August 2011

9 Report, BSL BIOSERVICE Study No page 9 of 110 Date of Draft Phase Report (Histopathology): 30 August 2011 Date of Final Phase Report (Histopathology): 22 September 2011 Date of Draft Report (BSL): 29 August 2011 Date of Final Report (BSL): 26 September 2011

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11 Report, BSL BIOSERVICE Study No page 11 of Quality Assurance This study was performed in conformity with internal quality assurance regulations, on the basis of GLP regulations, but was not audited by the quality assurance unit. Therefore, it does not have a GLP status. The test facility BSL BIOSERVICE Scientific Laboratories GmbH is certified according to the Principles of Good Laboratory Practice and accredited according to 90/385/EWG [1], 93/42/EWG [2] and DIN EN ISO/IEC 17025:2000 [3] Guidelines This study followed the procedures indicated by internal BSL BIOSERVICE SOPs and the following internationally accepted guidelines and recommendations: First Addendum to OECD Guidelines for Testing of Chemicals, Section 4, No. 407, Repeated Dose 28-Day Oral Toxicity Study in Rodents, adopted 03 October, 2008 [4]. Commission Directive 2001/59/EC 06 August 2001 [5] Commission Regulation (EC) No. 440/2008, L 142, Annex Part B, May 30, 2008 [6] OECD Series on principles of Good Laboratory Practice and compliance monitoring Document No 13 ENV/JM/MONO (2002) 9 [7] 5.2. Archiving All original data generated during the conduct of the study (raw data, copy of report) will be stored in the scientific archives of BSL BIOSERVICE Scientific Laboratories GmbH for 12 years after issue of the report. The remaining test item will be discarded three months after the release of the report.

12 Report, BSL BIOSERVICE Study No page 12 of Summary 6.1. Summary Results The aim of this study was to assess possible health hazards of the test item Vires5 which could arise from repeated exposure via oral administration to rats over a period of 14 days and also to provide a basis for the selection of dose levels for a 28- day repeated dose oral toxicity study. The test item was administered orally in graduated doses to 3 groups of male and female Wistar rats, Crl: WI(Han) (Full Barrier) by oral gavage using a gavaging canula. Each group comprised 3 males and 3 females. One group received the vehicle water which served as control. The application volume was 5 ml/kg body weight. The animals were treated with the test item 7 days per week for a period of 14 days. For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured. All surviving animals were sacrificed on day 15 and were subjected to a detailed gross necropsy. All animals found dead, moribund or intercurrently sacrificed were subjected to a gross necropsy. The wet weight of the organs was taken from all terminally sacrificed animals as soon as possible. Haematological and clinical biochemistry examinations were made on blood samples obtained from animals. A histopathological evaluation was carried out on all animals of all groups which were sacrificed at the end of the treatment period. There was no test item-related mortality and no effect of Vires5 on the health condition of the animals was noted. No findings were recorded for body weight development, food consumption, haematology, and clinical biochemistry parameters analyzed. Macroscopic findings were incidental and not related to the test item. Slight differences in spleen and thymus weight are not assumed to be test item related. No histopathological findings were noted that could be related to Vires Conclusion On the basis of the present study, a 14-day Repeated dose oral toxicity study with Vires5 in male and female rats, with dose levels of 30, 300 and 1000 mg/kg/day the following conclusions can be made. None of the dose levels used in this study was associated with any sign of toxicity. Therefore the limit dose of 1000 mg/kg bw can be recommended to be used in the high dose group of higher tier studies (e.g. 28-day oral repeated dose toxicity study).

13 Report, BSL BIOSERVICE Study No page 13 of Introduction 7.1. Justification for the Selection of the Test System This test is performed on the rat. Although several mammalian species may be used, the rat is the preferred rodent species. This study provides information on the possible health hazards which could arise from repeated exposure via oral administration to rats over a period of 14 days. As a dose range finding study, it should provide a basis for the selection of dose levels to be used in a 28-day repeated dose oral (gavage) toxicity study. The test item is administered daily in graduated doses to 3 groups of test animals, one dose level per group for a treatment period of 14 days. During the treatment period, the animals are observed each day for signs of toxicity. Animals which die or are humanely sacrificed in a condition of impending or predictable death are subjected to necropsy. At the conclusion of the test, the surviving animals are sacrificed and subjected to necropsy Justification for the Selection of the Test Method No validated in vitro method is available for assessing systemic toxicity after repeated exposure.

14 Report, BSL BIOSERVICE Study No page 14 of Materials and Methods 8.1. Characterisation of the Test Item The test item and the information concerning the test item were provided by the sponsor. All data related to the test item are the responsibility of the sponsor and have not been verified by the test facility. Name: Vires5 Product: Enhanced Redox Water Batch No.: Physical State at RT: Liquid Density: kg/l (4 C) Colour: Colourless Date of production: 31 March 2011 Expiry Date: No expiry date is available Storage Conditions: 2-8 C Safety Precautions: Eye protection was recommended 8.2. Characterisation of the Vehicle The test item was suspended in aqua ad injectionem (sterile water). The test item formulation was prepared freshly on each administration day before the administration procedure Preparation of the Test Item Formulations The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle (aqua ad injectionem) was added to give the appropriate final concentration of the test item. Afterwards, the test sample was thoroughly mixed. The vehicle was selected as suggested by the sponsor and on the basis of the test item s characteristics Dose Formulation Analysis A dose formulation analysis was not performed in this study Test System Species/strain: Source: Sex: healthy Wistar rats, Crl: WI(Han) (Full Barrier) Charles River, Sulzfeld, Germany male and female; the female animals were non-pregnant and nulliparous.

15 Report, BSL BIOSERVICE Study No page 15 of 110 Age at the first administration: Body weight at the beginning of the study: 8-9 weeks old males: g; females: g The animals were derived from a controlled full-barrier maintained breeding system (SPF). According to Art. 9.2, No. 7 of the German Act on Animal Welfare [8] the animals are bred for experimental purposes Housing and Feeding Conditions - Full barrier in an air-conditioned room - Temperature: 22 ± 3 C - Relative humidity: 55 ± 10% - Artificial light, sequence being 12 hours light, 12 hours dark - Air change: 10 x / hour - Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1018) - Free access to tap water, sulphur acidified to a ph of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals) - The animals were housed individually in IVC cages, type III H, polysulphone cages on Altromin saw fiber bedding (lot no ) - Certificates of food, water and bedding are filed at BSL BIOSERVICE. - Adequate acclimatisation period (at least five days) 8.6. Number and Sex of Animals 12 males and 12 female animals were used for the study. It included 1 control (C) and 3 dose groups (LD, MD, HD), each group containing 3 males and 3 females Preparation of the Animal Prior to the start of the treatment period a detailed clinical observation outside the home cage was made. Animals showing pathological signs before the first administration were excluded from the study. Supplementary animals from the same delivery were provided in exchange. Before the first administration all animals used for the study were weighed and assigned to the experimental groups with achieving a most homogenous variation in body weight throughout the groups of males and females Administration of Doses The animals were treated with the test item or vehicle on 7 days per week for a period of 14 days. The test item formulation or vehicle was administered at a single dose to the animals by oral gavage. For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured.

16 Report, BSL BIOSERVICE Study No page 16 of Dosage In consultation with the sponsor the following doses (Table 1) were selected for the 3 dose groups (LD, MD, HD) and 1 control group (C): Table 1: Group and Animal Identification Group No. Group Name Dose [mg/kg bw] M Animal No. F 1 C LD MD HD C = control, LD = low dose, MD = medium dose, HD = high dose Body Weight and Food Consumption The body weight was recorded once before assignment to the experimental groups and on study days 1, 4, 8, 11 and 14 during the treatment period as well as on the day of necropsy. Food consumption was measured on study days 1, 8 and 14 for each animal Clinical Observation Animals were observed for clinical signs during the entire treatment period of 14 days. General clinical observations were made at least once a day, approximately at the same time each day and considering the peak period of anticipated effects after dosing. The health condition of the animals was recorded. At least once daily all animals were observed for morbidity and mortality Haematology To investigate major toxic effects on blood cells, the following haematological examinations (Table 2) were made. After overnight fasting of the animals, blood from the abdominal aorta was collected in EDTA-coated tubes prior to or as part of the sacrifice of the animals.

17 Report, BSL BIOSERVICE Study No page 17 of 110 Table 2: Haematology Parameter Instrument Units haematocrit value (HCT) ADVIA 120 (Siemens) % haemoglobin content (Hb) ADVIA 120 (Siemens) g/dl red blood cell count (RBC) ADVIA 120 (Siemens) /L platelet count (PLT) ADVIA 120 (Siemens) 10 9 /L white blood cells (WBC) ADVIA 120 (Siemens) 10 9 /L Clinical Biochemistry To investigate major toxic effects, the following clinical biochemistry examinations (Table 3) were made. After overnight fasting of the animals, blood from the abdominal aorta was collected in serum separator tubes prior to or as part of the sacrifice of the animals. Table 3: Clinical Biochemistry Parameter Instrument Units alanine aminotransferase (ALAT) Synchron Cx 5 Beckman U/L aspartate-aminotransferase (ASAT) Synchron Cx 5 Beckman U/L alkaline phosphatase (AP) Synchron Cx 5 Beckman U/L creatinine (Crea) Synchron Cx 5 Beckman µmol/l total protein (TP) Synchron Cx 5 Beckman g/l albumin (Alb) Synchron Cx 5 Beckman g/l urea Synchron Cx 5 Beckman mmol/l total cholesterol (Chol) Synchron Cx 5 Beckman mmol/l sodium (Na) Synchron Cx 5 Beckman mmol/l potassium (K) Synchron Cx 5 Beckman mmol/l Pathology On study day 15, all surviving animals of the study were subjected to a detailed gross necropsy which included careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents. All macroscopic findings were recorded and organs showing gross abnormalities were preserved in neutral buffered formalin.

18 Report, BSL BIOSERVICE Study No page 18 of 110 All animals found moribund and/or intercurrently sacrificed were subjected to a gross necropsy Organ Weight The wet weight of the following organs (Table 4) was taken from all sacrificed animals as soon as possible. Paired organs were weighed separately. Table 4: Organs to be weighed at Necropsy Tissue/Organ liver kidneys adrenals testes epididymides Prostate and seminal vesicles with coagulating gland (as a whole) Tissue/Organ ovaries uterus with cervix (females) thymus spleen heart brain Histopathology A histopathological evaluation of stomach as well as small (duodenum, jejunum, ileum) and large (caecum, colon) intestine (after the preparation of paraffin sections and haematoxylin-eosin staining) was carried out on all animals of all groups. The histological processing of tissues to microscope slides was performed at the GLPcertified contract laboratory Propath UK Ltd, Willow Court, Netherwood Road, Hereford HR2 6JU, Great Britain (test site for tissue processing). The histopathological evaluation were performed at the GLP-certified contract laboratory KALEIDIS Consultancy in Histopathology (test site for histopathology), 6 rue du Gers, Saint-Louis, France. Blocking, embedding, cutting, H&E staining and scientific slide evaluation were performed according to the corresponding SOP s of the test sites. The principal histopathological investigator provided the histopathology results to the study director by and sent a pathology phase report to the study director upon the completion of the study.

19 Report, BSL BIOSERVICE Study No page 19 of Results 9.1. Mortality For a summary see Table 5. There was no test item related mortality in this study Clinical Observation For a summary see Table 6; for a detailed description of the individual findings see Tables 26 and 27. On the day of necropsy piloerection was noted in 2 female animals of the high dose group. This was, however, not associated with any other pathological signs. None of the male animals of this group was affected. Thus this slight finding is not assumed to be related to the test item. With the exception of transient nasal discharge in one animal of the mid dose group, which is not assumed to be test item related, there were no clinical findings in this study 9.3. Body Weight and Body Weight Change For group means see Tables 8, 9, 10 and 11; for individual data see Tables 28, 29, 30 and 31. Vires5 did not have any effect on body weight development in this study. Throughout the treatment period body weights of male and female animals of all groups were in the normal range of variation for this strain and age. There were no considerable differences in body weight between any of the dose groups and the control group Food Consumption For group means see Tables 12 and 13; for individual data see Tables 32 and 33. Vires5 did not affect food consumption in this study. There were no biologically relevant differences in food intake between any of the dose groups and the control group Haematology For group means see Tables 14 and 15; for individual data see Tables 34 and 35. All haematological parameters analyzed in this study were in the normal range of biological variation for this strain. There were no considerable differences, neither in red cell parameters (RBC, haematocrit, haemoglobine) nor in white blood cells or platelets when comparing dose groups to control group Clinical Biochemistry For group means see Tables 16 and 17; for individual data see Tables 36 and 37.

20 Report, BSL BIOSERVICE Study No page 20 of 110 All clinical pathology parameters analyzed at the end of the treatment period were within the normal range of variation for this strain. There were no considerable differences between dose groups and control group Gross Pathology For a summary see Tables 18 and 19; for a detailed description of the individual findings see Tables 38 and 39. After 14 days of oral treatment with Vires5 only one or few mild findings were noted that are assumed to be incidental and not related to the test item. One male animal of the low dose group had a discolored red stomach, which was not associated with any histopathological findings in this organ. On the epididymides of two male animals (one from the low dose group and one from the high dose group), yellow foci were found a common background finding in this strain. One male animal of the high dose group had blood on the surface of the brain and 2 male animals (one of the medium dose group and one of the high dose group) had a cyst on the adrenals. These single mild findings are not assumed to be related to the test item. One female control animal of the low dose group had a thickened mucosa in the stomach, which was not associated with any histopathological findings in this organ Organ Weight For group means see Tables 20 to 25; for individual data see Tables 40 to 45. The absolute and relative spleen weight of the spleens of the male animals of the high dose group was slightly lower than in controls. As this slight difference in spleen weight was not observed in female animals and due to the low number of animals, this is not assumed to be related to the test item. A tendency towards a lower thymus weight was also observed in Vire5 treated male animals of this study, however, not dose-dependently. Due to the slight degree, the low number of animals and the fact that female animals were not affected, a relation to the test item is doubtful. Besides, there were no considerable differences in organ weights of Vires5 treated animals when compared to controls Histopathology Histopathological findings noted in the organs evaluated were very few and none of them was considered to be test item-related.

21 Report, BSL BIOSERVICE Study No page 21 of Conclusion On the basis of the present study, a 14-day Repeated dose oral toxicity study with Vires5 in male and female rats, with dose levels of 30, 300 and 1000 mg/kg/day the following conclusions can be made. None of the dose levels used in this study was associated with any sign of toxicity. Therefore the limit dose of 1000 mg/kg bw can be recommended to be used in the high dose group of higher tier studies (e.g. 28-day oral repeated dose toxicity study).

22 Report, BSL BIOSERVICE Study No page 22 of Distribution of the Report 1 original (paper): Sponsor 1 copy (paper): BSL BIOSERVICE 1 copy (electronic): Sponsor

23 Report, BSL BIOSERVICE Study No page 23 of References Internal BSL BIOSERVICE SOPs Standard Operating Procedures (SOP), No Literature and Guidelines [1] Richtlinie 90/385/EWG des Rates vom 20. Juni 1990 zur Angleichung der Rechtsvorschriften der Mitgliedstaaten über aktive implantierbare medizinische Geräte, Amtsblatt Nr. L 189 vom 20/07/1990 S [2] Richtlinie 93/42/EWG des Rates vom 14. Juni 1993 über Medizinprodukte, Amtsblatt Nr. L 169 vom 12/07/1993 S [3] DIN EN ISO/IEC 17025: 2005: Allgemeine Anforderungen an die Kompetenz von Prüf- und Kalibrierlaboratorien, DIN Deutsches Institut für Normung e.v., Berlin, August 2005 [4] First Addendum to OECD Guidelines for Testing of Chemicals, Section 4, No. 407, Repeated Dose 28-Day Oral Toxicity Study in Rodents, adopted 03 October, 2008 [5] Commission Directive 2001/59/EC adapting to technical progress for the 28th time Council Directive 67/548/EC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances, 06 August 2001 (Official Journal of the European Communities no. L 225/1, 21 August 2001) [6] Commission Regulation (EC) No 440/2008, L 142, Annex Part B of 30 May 2008 laying down test methods pursuant to Regulation (EC) No. 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) [7] OECD Series on principles of Good Laboratory Practice and compliance monitoring Document No 13 ENV/JM/MONO (2002) 9 [8] German Animal Welfare Act, Art. 9.2, No. 7 (Deutsches Tierschutzgesetz, 24. Juli 1972 (BGBl. I S. 1277), Inkrafttreten der letzten Änderung: 22. Juli 2009, (Art. 2 ÄndG vom 15. Juli 2009)

24 Report, BSL BIOSERVICE Study No page 24 of Appendix Appendix 1: Summary, Mean and Individual Tables Table 5: Mortality Table - Summary Dose Group Male Animals Female C 0/3 0/3 LD 0/3 0/3 MD 0/3 0/3 HD 0/3 0/3

25 Report, BSL BIOSERVICE Study No page 25 of 110 Table 6: Clinical Observations - Males - Summary Clinical Finding C LD MD HD Total number of animals examined Nasal discharge 1 C = Control, LD = Low Dose, MD = Medium Dose, HD = High Dose Table 7: Clinical Observations - Females - Summary Clinical Finding C LD MD HD Total number of animals examined Slight piloerection 2 C = Control, LD = Low Dose, MD = Medium Dose, HD = High Dose

26 Report, BSL BIOSERVICE Study No page 26 of 110 Table 8: Mean Body Weight (g) - Males Group Study Day Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose Table 9: Mean Body Weight (g) - Females Group Study Day Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

27 Report, BSL BIOSERVICE Study No page 27 of 110 Table 10: Mean Body Weight Gain (g/week) - Males Group Day 1-4 Day 4-8 Day 8-11 Day Day 1-14 Mean C SD N Mean LD SD N Mean MD SD N Mean HD SD N C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose Table 11: Mean Body Weight Gain (g/week) - Females Group Day 1-4 Day 4-8 Day 8-11 Day Day 1-14 Mean C SD N Mean LD SD N Mean MD SD N Mean HD SD N C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

28 Report, BSL BIOSERVICE Study No page 28 of 110 Table 12: Mean Food Consumption (g/day) - Males Group Day 1-7 Day 7-14 Day 1-14 Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose Table 13: Mean Food Consumption (g/day) - Females Group Day 1-8 Day 8-14 Day 1-14 Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

29 Report, BSL BIOSERVICE Study No page 29 of 110 Table 14: Mean Haematology - Males Group RBC HB HCT PLT WBC Units /L g/dl % 10 9 /L 10 9 /L Mean C SD N Mean LD SD N Mean MD SD N Mean HD SD N C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose Table 15: Mean Haematology - Females Group RBC HB HCT PLT WBC Units /L g/dl % 10 9 /L 10 9 /L Mean C SD N Mean LD SD N Mean MD SD N Mean HD SD N C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

30 Report, BSL BIOSERVICE Study No page 30 of 110 Table 16: Mean Clinical Biochemistry - Males Group ASAT ALAT AP Crea TP Alb Urea Chol Na K Units U/L U/L U/L µmol/l g/l g/l mmol/l mmol/l mmol/l mmol/l Mean C SD N Mean LD SD N Mean MD SD N Mean HD SD N C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

31 Report, BSL BIOSERVICE Study No page 31 of 110 Table 17: Mean Clinical Biochemistry - Females Group ASAT ALAT AP Crea TP Alb Urea Chol Na K Units U/L U/L U/L µmol/l g/l g/l mmol/l mmol/l mmol/l mmol/l Mean C SD N Mean LD SD N Mean MD SD N Mean HD SD N C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

32 Report, BSL BIOSERVICE Study No page 32 of 110 Table 18: Macroscopic Findings - Males - Summary Day of sacrifice: 15 Organ Finding C LD MD HD Total number of animals examined Stomach discolored red 1 Epididymides yellow foci 1 1 Brain Blood at surface 1 Adrenals Cyst 1 1 C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose Table 19: Macroscopic Findings - Females - Summary Day of sacrifice: 15 Organ Finding C LD MD HD Total number of animals examined Stomach Mucosa thickened 1 Lung discolored dark Duodenum discolored red C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

33 Report, BSL BIOSERVICE Study No page 33 of 110 Table 20: Absolute Mean Organ Weights (g) - Males Group Body Brain Liver Heart Kidneys Adrenals Spleen weight left right total left right total Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

34 Report, BSL BIOSERVICE Study No page 34 of 110 Table 20: Absolute Mean Organ Weights (g) - Males (Continued) Group Thymus Testes Epididymides Prostate # left right total left right total Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % # = including coagulating glands C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

35 Report, BSL BIOSERVICE Study No page 35 of 110 Table 21: Absolute Mean Organ Weights (g) - Females Group C LD MD HD Body weight Brain Liver Heart Kidney Adrenals left right total left right total Mean SD N Mean SD N % Mean SD N % Mean SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

36 Report, BSL BIOSERVICE Study No page 36 of 110 Table 21: Absolute Mean Organ Weights (g) - Females (Continued) Group Spleen Thymus Ovaries Uterus # left right total Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % # = including cervix and oviduct C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

37 Report, BSL BIOSERVICE Study No page 37 of 110 Table 22: Relative Mean Organ Weights to Brain Weight (%) - Males Group Liver Heart Kidneys Adrenals left right total left right total Spleen Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

38 Report, BSL BIOSERVICE Study No page 38 of 110 Table 22: Relative Mean Organ Weights to Brain Weight (%) - Males (Continued) Group C LD MD HD # = including coagulating glands Thymus Testes Epididymides Prostate # left right total left right total Mean SD N Mean SD N % Mean SD N % Mean SD N % Asterisks indicate statistically significant differences to control group C, with* p<0.05, ** p<0.01 and *** p<0.001 C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose; * = including coagulating glands

39 Report, BSL BIOSERVICE Study No page 39 of 110 Table 23: Relative Mean Organ Weights to Brain Weight (%) - Females Group Liver Heart Kidney Adrenals left right total left right total Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

40 Report, BSL BIOSERVICE Study No page 40 of 110 Table 23: Relative Mean Organ Weights to Brain Weight (%) - Females (Continued) Group Spleen Thymus Ovaries left right total Uterus # Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % # = including cervix and oviduct C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

41 Report, BSL BIOSERVICE Study No page 41 of 110 Table 24: Relative Mean Organ Weights to Body Weight (%) - Males Group Brain Liver Heart Kidneys Adrenals Spleen left right total left right total Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

42 Report, BSL BIOSERVICE Study No page 42 of 110 Table 24: Relative Mean Organ Weights to Body Weight (%) - Males (Continued) Group C LD MD Thymus Testes Epididymides left right total left right total Prostate # Mean SD N Mean SD N % Mean SD N % Mean HD SD N % # = including seminal vesicles and coagulating glands Asterisks indicate statistically significant differences to control group C, with* p<0.05, ** p<0.01 and *** p<0.001 C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose; * = including seminal vesicles and coagulating glands

43 Report, BSL BIOSERVICE Study No page 43 of 110 Table 25: Relative Mean Organ Weights to Body Weight (%) - Females Group C LD MD HD Brain Liver Heart Kidney Adrenals left right total left right total Mean SD N Mean SD N % Mean SD N % Mean SD N % Asterisks indicate statistically significant differences to control group C, with* p<0.05, ** p<0.01 and *** p<0.001 C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

44 Report, BSL BIOSERVICE Study No page 44 of 110 Table 25: Relative Mean Organ Weights to Body Weight (%) - Females (Continued) Group Spleen Thymus Ovaries Uterus # left right total Mean C SD N Mean LD SD N % Mean MD SD N % Mean HD SD N % # = including cervix and oviduct C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

45 Report, BSL BIOSERVICE Study No page 45 of 110 Table 26: Individual Clinical Findings - Males Dose group: C Animal No. 1 No clinical findings observed throughout the whole observation period Animal No. 2 No clinical findings observed throughout the whole observation period Animal No. 3 No clinical findings observed throughout the whole observation period Dose group: LD Animal No. 4 No clinical findings observed throughout the whole observation period Animal No. 5 No clinical findings observed throughout the whole observation period Animal No. 6 No clinical findings observed throughout the whole observation period

46 Report, BSL BIOSERVICE Study No page 46 of 110 Dose group: MD Animal No. 7 No clinical findings observed throughout the whole observation period Animal No. 8 No clinical findings observed throughout the whole observation period Animal No. 9 Clinical finding Days Nasal discharge 10 There were no further clinical findings on any other study day for this animal Dose group: Animal No. HD 10 No clinical findings observed throughout the whole observation period Animal No. 11 No clinical findings observed throughout the whole observation period Animal No. 12 No clinical findings observed throughout the whole observation period

47 Report, BSL BIOSERVICE Study No page 47 of 110 Table 27: Individual Clinical Findings - Females Dose group: C Animal No. 13 No clinical findings observed throughout the whole observation period Animal No. 14 No clinical findings observed throughout the whole observation period Animal No. 15 No clinical findings observed throughout the whole observation period Dose group: LD Animal No. 16 No clinical findings observed throughout the whole observation period Animal No. 17 No clinical findings observed throughout the whole observation period Animal No. 18 No clinical findings observed throughout the whole observation period

48 Report, BSL BIOSERVICE Study No page 48 of 110 Dose group: MD Animal No. 19 No clinical findings observed throughout the whole observation period Animal No. 20 No clinical findings observed throughout the whole observation period Animal No. 21 No clinical findings observed throughout the whole observation period Dose group: HD Animal No. 22 No clinical findings observed throughout the whole observation period Animal No. 23 Clinical finding Days slight piloerection 15 There were no further clinical findings on any other study day for this animal Animal No. 24 Clinical finding Days Slight piloerection 15 There were no further clinical findings on any other study day for this animal

49 Report, BSL BIOSERVICE Study No page 49 of 110 Table 28: Individual Body Weight (g) - Males Group C LD MD HD Animal No. Study Day C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

50 Report, BSL BIOSERVICE Study No page 50 of 110 Table 29: Individual Body Weight (g) - Females Group Animal No. Study Day C LD MD HD C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

51 Report, BSL BIOSERVICE Study No page 51 of 110 Table 30: Individual Body Weight Gain (g/week) - Males Group Animal No. Day 1-4 Day 4-8 Day 8-11 Day Day C LD MD HD C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

52 Report, BSL BIOSERVICE Study No page 52 of 110 Table 31: Individual Body Weight Gain (g/week) - Females Group Animal No. Day 1-4 Day 4-8 Day 8-11 Day Day C LD MD HD C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose