report, bsl bioservice study no. 112936 page 2 of 110

Report, BSL BIOSERVICE Study No. 112936 page 2 of 110 Version: Final

1. Contents

page

1. Contents ....................................................................................................................................... 2

2. List of Tables and Figures .......................................................................................................... 4 2.1. List of Tables ................................................................................................................................................... 4

3. Preface .......................................................................................................................................... 6 3.1. Abbreviations .................................................................................................................................................. 6 3.2. General ........................................................................................................................................................... 8 3.3. Project Staff .................................................................................................................................................... 8 3.4. Schedule .......................................................................................................................................................... 8

4. Project Staff Signatures ............................................................................................................ 10

5. Quality Assurance ..................................................................................................................... 11 5.1. Guidelines ..................................................................................................................................................... 11 5.2. Archiving ....................................................................................................................................................... 11

6. Summary .................................................................................................................................... 12 6.1. Summary Results ........................................................................................................................................... 12 6.2. Conclusion .................................................................................................................................................... 12

7. Introduction ............................................................................................................................... 13 7.1. Justification for the Selection of the Test System .......................................................................................... 13 7.2. Justification for the Selection of the Test Method ......................................................................................... 13

8. Materials and Methods ............................................................................................................. 14 8.1. Characterisation of the Test Item .................................................................................................................. 14 8.2. Characterisation of the Vehicle .................................................................................................................... 14 8.3. Preparation of the Test Item Formulations ................................................................................................... 14 8.4. Dose Formulation Analysis ........................................................................................................................... 14 8.5. Test System .................................................................................................................................................... 14 8.5.1. Housing and Feeding Conditions ............................................................................................................ 15 8.6. Number and Sex of Animals .......................................................................................................................... 15 8.7. Preparation of the Animal ............................................................................................................................. 15 8.8. Administration of Doses ................................................................................................................................ 15 8.9. Dosage .......................................................................................................................................................... 16 8.10. Body Weight and Food Consumption ........................................................................................................... 16 8.11. Clinical Observation ..................................................................................................................................... 16 8.12. Haematology ................................................................................................................................................. 16 8.13. Clinical Biochemistry .................................................................................................................................... 17 8.14. Pathology ...................................................................................................................................................... 17 8.15. Organ Weight ................................................................................................................................................ 18 8.16. Histopathology .............................................................................................................................................. 18

9. Results ........................................................................................................................................ 19 9.1. Mortality ....................................................................................................................................................... 19 9.2. Clinical Observation ..................................................................................................................................... 19 9.3. Body Weight and Body Weight Change ........................................................................................................ 19 9.4. Food Consumption ........................................................................................................................................ 19 9.5. Haematology ................................................................................................................................................. 19 9.6. Clinical Biochemistry .................................................................................................................................... 19 9.7. Gross Pathology ............................................................................................................................................ 20 9.8. Organ Weight ................................................................................................................................................ 20


9.9. Histopathology .............................................................................................................................................. 20

10. Conclusion ................................................................................................................................. 21

11. Distribution of the Report ........................................................................................................ 22

12. References .................................................................................................................................. 23 12.1. Internal BSL BIOSERVICE SOPs ................................................................................................................. 23 12.2. Literature and Guidelines ............................................................................................................................. 23

13. Appendix .................................................................................................................................... 24 13.1. Appendix 1: Summary, Mean and Individual Tables .................................................................................... 24 13.2. Appendix 2: Histopathology Report .............................................................................................................. 74


2. 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


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


3. Preface

3.1. Abbreviations

ALAT alanine aminotransferase

Alb albumin

ANOVA Analysis of Variance

AP alkaline phosphatase

Art. Artikel (article)

ASAT aspartate-aminotransferase

BGBl. Bundesgesetzblatt (Federal Law Gazette)

bw body weight

C control

CFR Code of Federal Regulations

Che cholinesterase

Chol cholesterol

Crea creatinine

Dipl.-Biol. Diplom Biologe (Biology Diploma)

e.g. exempli gratia (for example)

EC European Commission

EDTA ethylen diamine tertraacetic acid

Ery erythrocytes

GLP Good Laboratory Practice

GmbH Gesellschaft mit beschränkter Haftung (company with limited liability)

H&E hematoxylin & eosin

Hb haemoglobin

Hct haematocrit

HD high dose

IVC individually ventilated cages

K potassium

LD low dose

Leu leukocytes

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Lym lymphocytes

MD medium dose

Na sodium

Nr. Nummer (number)

OECD Organisation for Economic Cooperation and Development

PLT platelet count

QA Quality Assurance

QAU Quality Assurance Unit

RBC red blood cell count

SOP Standard Operating Procedures

SPF specific-pathogen free

TP total protein

WBC white blood cells

WI Wistar


3.2. General Sponsor: Vires5 bvba

Bredabaan 926 2990 Wuustwezel Belgium

Study Monitor: Mr Remco Schade

Test Facility: BSL BIOSERVICE Scientific Laboratories GmbH Behringstraße 6/8 82152 Planegg Germany

BSL BIOSERVICE Study No.: 112936

Test Item: Vires5

Title: 14-Day Dose Range Finding Oral Toxicity Study in Wistar Rats with Vires5

3.3. Project Staff Study Director: Dr. Philip Allingham

Management: Dr. Wolfram Riedel Dr. Angela Lutterbach

Head of Quality Assurance Unit: Dipl.-Biol. Uwe Hamann

Test Site 1: KALEIDIS- Consultancy in Histopathology (Histopathology) 6 rue du Gers

68300 Saint-Louis France

Principal Investigator: Dr. Gabriele Pohlmeyer-Esch

Test Site 2: Propath UK Ltd (Tissue Processing) Willow Court, Netherwood Road Hereford HR2 6JU

Great Britain

Principal Investigator: 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


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


5. 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].

5.1. 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.


6. 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 Vires5.

6.2. 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).


7. 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.

7.2. Justification for the Selection of the Test Method No validated in vitro method is available for assessing systemic toxicity after repeated exposure.


8. 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.: 23105

Physical State at RT: Liquid

Density: 1.002 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.

8.3. 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.

8.4. Dose Formulation Analysis

A dose formulation analysis was not performed in this study.

8.5. Test System Species/strain: healthy Wistar rats, Crl: WI(Han) (Full Barrier)

Source: Charles River, 97633 Sulzfeld, Germany

Sex: male and female; the female animals were non-pregnant and nulliparous.


Age at the first administration: 8-9 weeks old

Body weight at the beginning of the study: males: 232 - 250 g; females: 158 - 181 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.

8.5.1. 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. 040311)

- 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.

8.7. 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.

8.8. 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.


8.9. 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]

Animal No.

M F

1 C 0 1-3 13-15

2 LD 30 4-6 16-18

3 MD 300 7-9 19-21

4 HD 1000 10-12 22-24

C = control, LD = low dose, MD = medium dose, HD = high dose

8.10. 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.

8.11. 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.

8.12. 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.


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) 1012/L

platelet count (PLT) ADVIA®120 (Siemens) 109/L

white blood cells (WBC) ADVIA®120 (Siemens) 109/L

8.13. 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

8.14. 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.


All animals found moribund and/or intercurrently sacrificed were subjected to a gross necropsy.

8.15. 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 Tissue/Organ

liver ovaries

kidneys uterus with cervix (females)

adrenals thymus

testes spleen

epididymides heart

Prostate and seminal vesicles with coagulating gland (as a whole)

brain

8.16. 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 GLP-certified 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, 68300 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 e-mail and sent a pathology phase report to the study director upon the completion of the study.


9. Results

9.1. Mortality

For a summary see Table 5.

There was no test item related mortality in this study.

9.2. 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.

9.4. 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.

9.5. 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.

9.6. Clinical Biochemistry For group means see Tables 16 and 17; for individual data see Tables 36 and 37.


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.

9.7. 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.

9.8. 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.

9.9. Histopathology

Histopathological findings noted in the organs evaluated were very few and none of them was considered to be test item-related.


10. 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).


11. Distribution of the Report

1 original (paper): Sponsor

1 copy (paper): BSL BIOSERVICE

1 copy (electronic): Sponsor


12. References

12.1. Internal BSL BIOSERVICE SOPs

Standard Operating Procedures (SOP), No. 11-4-3

12.2. 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. 0017 - 0036

[2] Richtlinie 93/42/EWG des Rates vom 14. Juni 1993 über Medizinprodukte, Amtsblatt Nr. L 169 vom 12/07/1993 S. 0001 - 0043

[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)

http://de.wikipedia.org/wiki/Bundesgesetzblatt_(Deutschland)�


13. Appendix

13.1. Appendix 1: Summary, Mean and Individual Tables

Table 5: Mortality Table - Summary

Dose Group Animals

Male Female

C 0/3 0/3

LD 0/3 0/3

MD 0/3 0/3

HD 0/3 0/3


Table 6: Clinical Observations - Males - Summary

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 3 3 3 3

Nasal discharge ‐ 1 ‐ ‐

Clinical Finding C LD MD HD


Slight piloerection ‐ ‐ ‐ 2


Table 8: Mean Body Weight (g) - Males

C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose

Table 9: Mean Body Weight (g) - Females


1 4 8 11 14Mean 247.33 269.33 289.37 298.23 308.97

SD 5.03 2.31 4.47 3.82 8.98

N 3 3 3 3 3

Mean 252.33 269.00 295.03 304.40 314.43

SD 4.51 7.00 7.77 6.63 9.21

N 3 3 3 3 3

% 102.02 99.88 101.96 102.07 101.77

Mean 245.33 267.00 286.57 296.27 306.23

SD 3.79 6.08 4.81 8.66 8.52

N 3 3 3 3 3

% 99.19 99.13 99.03 99.34 99.12

Mean 249.00 266.00 281.80 290.57 297.27

SD 6.24 7.21 6.43 4.95 5.22

N 3 3 3 3 3

% 100.67 98.76 97.39 97.43 96.21

Study Day

C

LD

MD

HD

Group

1 4 8 11 14Mean 169.57 174.33 181.00 178.47 185.20

SD 4.53 5.69 3.00 3.82 4.53

N 3 3 3 3 3

Mean 166.63 172.33 178.33 183.47 185.40

SD 5.15 13.58 13.58 11.38 10.72

N 3 3 3 3 3

% 98.27 98.85 98.53 102.80 100.11

Mean 165.13 172.33 175.67 176.20 180.30

SD 4.25 7.64 5.51 5.78 4.71

N 3 3 3 3 3

% 97.39 98.85 97.05 98.73 97.35

Mean 171.37 178.33 182.33 182.87 186.97

SD 1.14 3.51 2.52 6.45 7.07

N 3 3 3 3 3

% 101.06 102.29 100.74 102.47 100.95

Study Day

C

LD

MD

HD

Group


Table 10: Mean Body Weight Gain (g/week) - Males


Table 11: Mean Body Weight Gain (g/week) - Females


Group Day 1-4 Day 4-8 Day 8-11 Day 11-14 Day 1-14Mean 22.00 20.03 8.87 10.73 61.63

SD 3.46 3.10 4.86 5.26 8.22

N 3 3 3 3 3

Mean 16.67 26.03 9.37 10.03 62.10

SD 3.51 1.47 6.05 3.76 7.46

N 3 3 3 3 3

Mean 21.67 19.57 9.70 9.97 60.90

SD 2.31 1.60 4.46 2.03 5.38

N 3 3 3 3 3

Mean 17.00 15.80 8.77 6.70 48.27

SD 7.00 1.04 2.25 1.30 5.75

N 3 3 3 3 3

C

LD

MD

HD

Group Day 1-4 Day 4-8 Day 8-11 Day 11-14 Day 1-14Mean 4.77 6.67 -2.53 6.73 15.63

SD 2.77 5.69 5.19 6.63 4.02

N 3 3 3 3 3

Mean 5.70 6.00 5.13 1.93 18.77

SD 8.61 0.00 2.80 0.76 5.58

N 3 3 3 3 3

Mean 7.20 3.33 0.53 4.10 15.17

SD 3.64 2.31 0.93 4.09 3.66

N 3 3 3 3 3

Mean 6.97 4.00 0.53 4.10 15.60

SD 3.89 1.00 3.99 2.29 6.77

N 3 3 3 3 3

C

LD

MD

HD


Table 12: Mean Food Consumption (g/day) - Males


Table 13: Mean Food Consumption (g/day) - Females


Group Day 1-7 Day 7-14 Day 1-14Mean 22.90 26.22 24.56

SD 1.12 1.63 1.37

N 3 3 3

Mean 23.68 27.15 25.41

SD 0.38 0.88 0.45

N 3 3 3

% 103.39 103.54 103.47

Mean 24.35 26.41 25.38

SD 1.43 2.39 1.91

N 3 3 3

% 106.32 100.74 103.34

Mean 22.55 25.23 23.89

SD 1.88 1.32 1.60

N 3 3 3

% 98.48 96.22 97.28

C

LD

MD

HD

Group Day 1-8 Day 8-14 Day 1-14Mean 13.57 15.20 14.38

SD 0.31 1.09 0.61

N 3 3 3

Mean 14.00 15.39 14.69

SD 1.06 1.30 1.18

N 3 3 3

% 103.12 101.25 102.14

Mean 13.48 15.38 14.43

SD 1.01 2.05 1.53

N 3 3 3

% 99.33 101.19 100.31

Mean 13.94 15.90 14.92

SD 0.30 0.62 0.45

N 3 3 3

% 102.74 104.61 103.72

C

LD

MD

HD


Table 14: Mean Haematology - Males


Table 15: Mean Haematology - Females


RBC HB HCT PLT WBCUnits 1012/L g/dL % 109/L 109/L

Mean 8.57 16.05 47.25 1095.50 6.45

SD 0.07 0.35 0.49 3.54 2.50

N 2 2 2 2 2

Mean 8.20 15.43 45.53 1098.00 7.02

SD 0.23 0.47 2.11 48.07 2.59

N 3 3 3 3 3

Mean 8.38 15.93 46.70 948.00 4.78

SD 0.33 0.32 1.25 139.34 0.14

N 3 3 3 3 3

Mean 9.30 16.75 49.80 1087.00 6.95

SD 0.02 0.35 1.41 39.60 0.15

N 2 2 2 2 2

C

LD

MD

HD

Group

RBC HB HCT PLT WBCUnits 1012/L g/dL % 109/L 109/L

Mean 8.02 14.67 43.57 915.33 3.15

SD 0.69 0.42 1.88 92.65 0.09

N 3 3 3 3 3

Mean 8.70 15.70 46.85 1042.50 2.54

SD 0.23 0.42 0.07 98.29 0.07

N 2 2 2 2 2

Mean 8.30 15.07 44.33 888.33 3.47

SD 0.16 0.47 0.55 48.95 0.35

N 3 3 3 3 3

Mean 8.35 15.07 45.33 903.00 3.14

SD 0.62 0.60 1.60 59.10 0.15

N 3 3 3 3 3

C

LD

MD

HD

Group


Table 16: Mean Clinical Biochemistry - Males


ASAT ALAT AP Crea TP Alb Urea Chol Na KUnits U/L U/L U/L µmol/L g/L g/L mmol/L mmol/L mmol/L mmol/L

Mean 35.30 20.93 247.5 31.96 60.10 34.43 8.18 0.96 150.0 4.04

SD 3.67 5.56 65.8 3.01 3.15 2.15 0.51 0.11 2.0 0.64

N 3 3 2 3 3 3 3 3 3 3

Mean 29.33 19.70 187.7 27.87 58.50 32.03 7.96 0.77 151.0 4.39

SD 4.30 1.31 40.5 1.71 1.21 0.84 0.37 0.03 0.0 0.41

N 3 3 3 3 3 3 3 3 3 3

Mean 30.40 20.53 188.0 28.16 58.13 33.43 7.56 0.85 151.0 3.77

SD 3.67 2.15 45.9 2.24 0.57 0.15 0.61 0.25 3.6 0.21

N 3 3 3 3 3 3 3 3 3 3

Mean 36.10 23.35 182.5 29.99 59.70 33.80 8.23 0.81 153.5 4.47

SD 1.27 1.20 20.5 1.41 0.28 0.00 0.09 0.17 0.7 0.30

N 2 2 2 2 2 2 2 2 2 2

C

LD

MD

HD

Group


Table 17: Mean Clinical Biochemistry - Females


ASAT ALAT AP Crea TP Alb Urea Chol Na KUnits U/L U/L U/L µmol/L g/L g/L mmol/L mmol/L mmol/L mmol/L

Mean 44.23 13.93 67.33 33.52 51.67 32.67 7.18 0.57 144.33 3.74

SD 3.50 1.59 21.13 1.68 1.40 1.15 0.17 0.05 0.58 0.56

N 3 3 3 3 3 3 3 3 3 3

Mean 37.97 14.50 68.00 31.77 53.53 33.70 6.19 0.53 145.67 3.91

SD 2.38 1.00 3.00 9.71 2.55 1.30 0.55 0.08 1.53 0.60

N 3 3 3 3 3 3 3 3 3 3

Mean 31.07 14.17 76.00 25.32 54.47 33.93 7.31 0.56 144.67 3.40

SD 1.10 1.98 21.00 3.86 2.40 0.76 1.24 0.06 2.52 0.35

N 3 3 3 3 3 3 3 3 3 3

Mean 37.87 14.57 73.67 34.02 55.07 33.43 8.10 0.59 145.00 3.49

SD 3.60 0.51 20.26 5.27 0.61 1.63 0.37 0.08 2.65 0.25

N 3 3 3 3 3 3 3 3 3 3

C

LD

MD

HD

Group


Table 18: Macroscopic Findings - Males - Summary

Day of sacrifice: 15


Table 19: Macroscopic Findings - Females - Summary

Day of sacrifice: 15


Finding C LD MD HD


Stomach discolored red ‐ 1 ‐ ‐

Epididymides yellow foci ‐ 1 ‐ 1

Brain Blood at surface ‐ ‐ ‐ 1

Adrenals Cyst ‐ ‐ 1 1

Organ

Finding C LD MD HD


Stomach Mucosa thickened 1 ‐ ‐ ‐

Lung discolored dark ‐ ‐ ‐ ‐

Duodenum discolored red ‐ ‐ ‐ ‐

Organ


Table 20: Absolute Mean Organ Weights (g) - Males


left right total left right total

Mean 287 2.046 8.653 0.909 1.135 1.143 2.278 0.0376 0.0364 0.0740 0.738

SD 4.9 0.103 0.074 0.047 0.014 0.017 0.031 0.0036 0.0040 0.0074 0.082N 3 3 3 3 3 3 3 3 3 3 3

Mean 293 1.933 8.754 1.042 1.097 1.156 2.253 0.0383 0.0369 0.0752 0.703

SD 7.1 0.111 0.208 0.063 0.062 0.076 0.136 0.0028 0.0045 0.0065 0.030

N 3 3 3 3 3 3 3 3 3 3 3% 101.9 94.5 101.2 114.7 96.6 101.1 98.9 102.0 101.3 101.6 95.1

Mean 285 2.024 8.523 1.028 1.183 1.247 2.431 0.0374 0.0319 0.0693 0.743

SD 10.1 0.071 0.728 0.080 0.110 0.116 0.218 0.0043 0.0049 0.0082 0.068

N 3 3 3 3 3 3 3 3 3 3 3% 99.1 99.0 98.5 113.2 104.2 109.1 106.7 99.5 87.6 93.7 100.6

Mean 280 2.021 10.226 0.927 1.184 1.163 2.348 0.0367 0.0366 0.0733 0.620

SD 4.0 0.107 2.682 0.036 0.084 0.031 0.111 0.0047 0.0049 0.0094 0.027

N 3 3 3 3 3 3 3 3 3 3 3

% 97.6 98.8 118.2 102.0 104.3 101.8 103.0 97.6 100.5 99.1 83.9

MD

HD

Group

C

LD

SpleenKidneys AdrenalsBody weight

Brain Liver Heart


Table 20: Absolute Mean Organ Weights (g) - Males (Continued)



Mean 0.636 1.719 1.708 3.427 0.450 0.477 0.927 1.747

SD 0.109 0.058 0.065 0.108 0.015 0.017 0.032 0.119N 3 3 3 3 3 3 3 3

Mean 0.545 1.716 1.675 3.390 0.439 0.439 0.878 1.539

SD 0.090 0.197 0.096 0.247 0.036 0.012 0.044 0.039

N 3 3 3 3 3 3 3 3% 85.7 99.8 98.0 98.9 97.7 92.0 94.8 88.1

Mean 0.560 1.709 1.720 3.429 0.449 0.451 0.901 1.532

SD 0.057 0.130 0.123 0.252 0.043 0.039 0.081 0.051

N 3 3 3 3 3 3 3 3% 88.0 99.4 100.7 100.1 99.9 94.6 97.2 87.7

Mean 0.541 1.636 1.674 3.310 0.469 0.484 0.953 1.866

SD 0.047 0.057 0.019 0.063 0.049 0.043 0.067 0.145

N 3 3 3 3 3 3 3 3

% 85.0 95.2 98.0 96.6 104.3 101.5 102.8 106.8

# = including coagulating glands

MD

HD

Group Epididymides

C

LD

Thymus Testes Prostate #


Table 21: Absolute Mean Organ Weights (g) - Females



Mean 173 1.781 4.920 0.612 0.726 0.732 1.457 0.0330 0.0373 0.0703

SD 1.5 0.026 0.212 0.022 0.043 0.052 0.095 0.0030 0.0064 0.0085N 3 3 3 3 3 3 3 3 3 3

Mean 171 1.815 5.410 0.573 0.701 0.752 1.453 0.0393 0.0361 0.0754

SD 6.2 0.026 1.237 0.064 0.016 0.024 0.010 0.0040 0.0022 0.0056

N 3 3 3 3 3 3 3 3 3 3% 99.0 101.9 110.0 93.6 96.6 102.8 99.7 119.1 96.9 107.3

Mean 170 1.809 4.886 0.613 0.698 0.763 1.461 0.0405 0.0376 0.0781

SD 5.1 0.022 0.627 0.020 0.137 0.113 0.250 0.0076 0.0055 0.0130

N 3 3 3 3 3 3 3 3 3 3% 98.6 101.6 99.3 100.2 96.3 104.2 100.3 122.6 100.9 111.1

Mean 174 1.771 5.259 0.637 0.761 0.773 1.533 0.0442 0.0387 0.0829

SD 5.3 0.097 0.215 0.068 0.047 0.021 0.061 0.0055 0.0029 0.0052

N 3 3 3 3 3 3 3 3 3 3

% 100.8 99.4 106.9 104.1 104.9 105.6 105.2 134.0 103.8 118.0

AdrenalsBody weight

Brain KidneyLiver Heart

MD

HD

C

LD

Group


Table 21: Absolute Mean Organ Weights (g) - Females (Continued)


left right total

Mean 0.466 0.327 0.0524 0.0487 0.1012 0.509

SD 0.033 0.023 0.0074 0.0101 0.0175 0.105N 3 3 3 3 3 3

Mean 0.436 0.332 0.0452 0.0418 0.0870 0.668

SD 0.058 0.056 0.0085 0.0023 0.0073 0.269

N 3 3 3 3 3 3% 93.4 101.6 86.3 85.7 86.0 131.3

Mean 0.466 0.326 0.0459 0.0500 0.0959 0.602

SD 0.046 0.066 0.0107 0.0047 0.0135 0.369

N 3 3 3 3 3 3% 99.9 99.7 87.5 102.5 94.8 118.2

Mean 0.474 0.339 0.0424 0.0511 0.0935 0.551

SD 0.048 0.051 0.0060 0.0022 0.0079 0.156

N 3 3 3 3 3 3

% 101.7 103.6 80.9 104.8 92.4 108.2

# = including cervix and oviduct

Uterus #Thymus OvariesSpleenGroup

C

LD

MD

HD


Table 22: Relative Mean Organ Weights to Brain Weight (%) - Males



Mean 423.81 44.45 55.60 55.99 111.60 1.837 1.778 3.614 36.29

SD 25.38 2.18 3.34 3.43 6.77 0.128 0.113 0.218 5.93

N 3 3 3 3 3 3 3 3 3

Mean 453.57 53.92 56.91 59.94 116.85 1.985 1.917 3.902 36.45

SD 16.77 0.68 5.24 5.04 10.20 0.121 0.301 0.413 2.95

N 3 3 3 3 3 3 3 3 3

% 107.0 121.3 102.3 107.0 104.7 108.1 107.9 108.0 100.4

Mean 421.61 50.93 58.55 61.64 120.19 1.851 1.576 3.427 36.71

SD 41.82 5.85 6.35 5.63 11.64 0.246 0.221 0.408 3.58

N 3 3 3 3 3 3 3 3 3

% 99.5 114.6 105.3 110.1 107.7 100.8 88.7 94.8 101.2

Mean 511.40 45.95 58.58 57.63 116.21 1.828 1.823 3.651 30.77

SD 162.20 2.48 1.78 1.58 1.67 0.336 0.332 0.660 3.02

N 3 3 3 3 3 3 3 3 3

% 120.7 103.4 105.4 102.9 104.1 99.5 102.6 101.0 84.8

LiverAdrenals

HD

Group

LD

MD

Spleen

C

HeartKidneys


Table 22: Relative Mean Organ Weights to Brain Weight (%) - Males (Continued)

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

Prostate #left right total left right total

Mean 31.28 84.25 83.70 167.95 22.01 23.33 45.34 85.56

SD 6.50 7.21 6.33 13.25 0.46 0.63 1.08 7.64

N 3 3 3 3 3 3 3 3

Mean 28.14 88.99 86.66 175.65 22.84 22.79 45.63 79.76

SD 3.39 11.32 1.67 12.94 3.05 1.97 4.90 2.73

N 3 3 3 3 3 3 3 3

% 90 106 104 105 104 98 101 93

Mean 27.63 84.44 85.00 169.44 22.24 22.36 44.60 75.76

SD 2.26 6.38 5.60 11.95 2.65 2.67 5.24 3.92

N 3 3 3 3 3 3 3 3

% 88 100 102 101 101 96 98 89

Mean 26.73 81.15 83.01 164.16 23.18 24.02 47.20 92.33

SD 0.98 5.84 5.43 10.93 1.40 2.73 3.01 4.74

N 3 3 3 3 3 3 3 3

% 85 96 99 98 105 103 104 108

# = including coagulating glands

MD

EpididymidesTestesGroup Thymus

C

LD

HD


Table 23: Relative Mean Organ Weights to Brain Weight (%) - Females


left right total left right totalMean 276.10 34.37 40.73 41.09 81.82 1.854 2.096 3.949

SD 8.10 1.65 2.52 3.10 5.62 0.186 0.391 0.531

N 3 3 3 3 3 3 3 3

Mean 298.81 31.57 38.63 41.44 80.07 2.167 1.991 4.158

SD 72.86 3.27 0.87 1.42 0.98 0.243 0.148 0.366

N 3 3 3 3 3 3 3 3

% 108.2 91.8 94.8 100.9 97.9 116.9 95.0 105.3

Mean 270.28 33.90 38.62 42.19 80.81 2.240 2.080 4.320

SD 37.46 0.83 7.77 6.53 14.26 0.445 0.327 0.768

N 3 3 3 3 3 3 3 3

% 97.9 98.6 94.8 102.7 98.8 120.8 99.3 109.4

Mean 297.45 36.14 43.11 43.70 86.81 2.496 2.195 4.691

SD 17.34 5.34 4.55 2.34 6.89 0.236 0.282 0.364

N 3 3 3 3 3 3 3 3

% 107.7 105.1 105.8 106.4 106.1 134.6 104.8 118.8

HD

Group

LD

MD

LiverAdrenals

C

HeartKidney


Table 23: Relative Mean Organ Weights to Brain Weight (%) - Females (Continued)


left right totalMean 26.18 18.37 2.946 2.738 5.685 28.53

SD 1.72 1.56 0.442 0.586 1.021 5.45

N 3 3 3 3 3 3

Mean 23.97 18.29 2.497 2.301 4.798 36.85

SD 2.84 2.85 0.501 0.098 0.458 14.84

N 3 3 3 3 3 3

% 91.6 99.6 84.8 84.0 84.4 129.2

Mean 25.77 18.04 2.540 2.764 5.304 33.33

SD 2.77 3.80 0.615 0.289 0.801 20.61

N 3 3 3 3 3 3

% 98.4 98.2 86.2 100.9 93.3 116.8

Mean 26.94 19.26 2.400 2.892 5.292 31.28

SD 4.14 3.82 0.356 0.252 0.559 9.69

N 3 3 3 3 3 3

% 102.9 104.9 81.5 105.6 93.1 109.6


HD

Group Uterus #

C

LD

MD

Spleen ThymusOvaries


Table 24: Relative Mean Organ Weights to Body Weight (%) - Males



Mean 0.712 3.012 0.316 0.395 0.398 0.793 0.0131 0.0127 0.0257 0.257

SD 0.031 0.063 0.019 0.012 0.013 0.024 0.0010 0.0012 0.0022 0.032N 3 3 3 3 3 3 3 3 3 3

Mean 0.661 2.993 0.356 0.375 0.396 0.771 0.013 0.013 0.0257 0.240

SD 0.047 0.133 0.028 0.029 0.035 0.064 0.00 0.00 0.0028 0.015

N 3 3 3 3 3 3 3 3 3 3% 92.8 99.4 113 95 99 97 100 100 100 93

Mean 0.712 2.991 0.361 0.415 0.438 0.853 0.0131 0.0112 0.0243 0.261

SD 0.048 0.177 0.020 0.027 0.035 0.059 0.0011 0.0017 0.0024 0.031

N 3 3 3 3 3 3 3 3 3 3% 100.0 99.3 114 105 110 108 100 89 95 102

Mean 0.721 3.641 0.331 0.423 0.415 0.838 0.0131 0.0131 0.0261 0.221

SD 0.044 0.908 0.011 0.031 0.016 0.044 0.0015 0.0016 0.0030 0.008

N 3 3 3 3 3 3 3 3 3 3

% 101.3 120.9 104.5 106.9 104.3 105.6 100.1 103.0 101.5 85.9

Spleen

C

LD

Liver HeartGroup Brain

MD

Kidneys

HD

Adrenals


Table 24: Relative Mean Organ Weights to Body Weight (%) - Males (Continued)

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

Prostate #left right total left right total

Mean 0.222 0.598 0.595 1.193 0.157 0.166 0.323 0.608

SD 0.041 0.028 0.033 0.057 0.005 0.006 0.012 0.034N 3 3 3 3 3 3 3 3

Mean 0.187 0.588 0.573 1.160 0.150 0.150 0.300 0.526

SD 0.035 0.080 0.044 0.113 0.014 0.004 0.017 0.023

N 3 3 3 3 3 3 3 3% 84.2 98.2 96.3 97.2 96.0 90.4 93.1 86.6

Mean 0.197 0.600 0.605 1.205 0.158 0.158 0.316 0.538

SD 0.028 0.039 0.041 0.080 0.010 0.009 0.017 0.013

N 3 3 3 3 3 3 3 3% 88.9 100.3 101.6 101.0 100.6 95.4 97.9 88.6

Mean 0.193 0.583 0.597 1.181 0.168 0.173 0.340 0.666

SD 0.019 0.013 0.008 0.005 0.0192 0.017 0.029 0.061

N 3 3 3 3 3 3 3 3

% 87.0 97.5 100.4 98.9 107.0 104.1 105.5 109.6

# = including seminal vesicles and coagulating glands

C

LD

Testes EpididymidesGroup Thymus

MD

HD


Table 25: Relative Mean Organ Weights to Body Weight (%) - Females

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


Mean 1.032 2.849 0.355 0.420 0.424 0.844 0.0191 0.0216 0.0407

SD 0.013 0.106 0.016 0.028 0.034 0.062 0.0017 0.0038 0.0050N 3 3 3 3 3 3 3 3 3

Mean 1.062 3.170 0.335 0.410 0.440 0.850 0.0230 0.0211 0.0442

SD 0.042 0.759 0.028 0.024 0.002 0.026 0.0029 0.0014 0.0042

N 3 3 3 3 3 3 3 3 3% 102.9 111.3 94.4 97.7 103.7 100.7 120.6 97.8 108.5

Mean 1.063 2.864 0.361 0.409 0.447 0.856 0.0237 0.0220 0.0458

SD 0.038 0.301 0.022 0.068 0.053 0.120 0.00 0.00 0.01

N 3 3 3 3 3 3 3 3 3% 103.0 100.5 101.7 97.2 105.4 101.3 124.2 102.1 112.4

Mean 1.018 3.026 0.367 0.438 0.444 0.882 0.0255 0.0223 0.0477

SD 0.059 0.205 0.050 0.039 0.024 0.061 0.0036 0.0021 0.0043

N 3 3 3 3 3 3 3 3 3

% 98.7 106.2 103.6 104.2 104.8 104.5 133.3 103.1 117.3

LD

Group Adrenals

C

Brain Liver Heart Kidney

MD

HD


Table 25: Relative Mean Organ Weights to Body Weight (%) - Females (Continued)


left right total

Mean 0.270 0.189 0.0304 0.0282 0.0586 0.295

SD 0.020 0.015 0.0042 0.0057 0.0098 0.059N 3 3 3 3 3 3

Mean 0.255 0.194 0.0264 0.0244 0.0509 0.395

SD 0.038 0.031 0.0047 0.0012 0.0035 0.169

N 3 3 3 3 3 3% 94.4 102.5 87.0 86.6 86.8 134.0

Mean 0.274 0.192 0.0268 0.0293 0.0562 0.356

SD 0.032 0.042 0.0055 0.0029 0.0067 0.227

N 3 3 3 3 3 3% 101.4 101.2 88.4 104.1 96.0 120.9

Mean 0.273 0.195 0.0245 0.0294 0.0539 0.319

SD 0.029 0.029 0.0041 0.0021 0.0061 0.098

N 3 3 3 3 3 3

% 101.0 102.8 80.6 104.2 92.0 108.1


Group

HD

Uterus #

C

LD

MD

ThymusSpleen Ovaries


Table 26: Individual Clinical Findings - Males

Dose group: C

Animal No. 1No clinical findings observed throughout the whole observation period



Dose group: LD





Dose group: MD



Animal No. 9Clinical finding Days

Nasal discharge 10

There were no further clinical findings on any other study day for this animal

Dose group:

Animal No. HD10

No clinical findings observed throughout the whole observation period

Animal No.

11

No clinical findings observed throughout the whole observation period



Table 27: Individual Clinical Findings - Females

Dose group: C




Dose group: LD





Dose group: MD




Dose group: HD



slight piloerection 15



Slight piloerection 15



Table 28: Individual Body Weight (g) - Males


1 4 8 11 141 242 268 285 296 301

2 248 268 290 303 319

3 252 272 293 297 307

4 252 272 297 300 306

5 257 274 302 312 324

6 248 261 287 301 314

7 247 270 288 302 314

8 241 260 281 286 297

9 248 271 291 301 308

10 247 272 287 295 301

11 244 258 275 286 291

12 256 268 284 291 299

HD

Group Animal No.

C

LD

MD

Study Day


Table 29: Individual Body Weight (g) - Females


1 4 8 11 1413 168 176 178 181 180

14 166 168 181 174 186

15 175 179 184 180 189

16 165 165 171 179 182

17 163 164 170 175 177

18 172 188 194 196 198

19 165 174 176 176 176

20 161 164 170 171 179

21 170 179 181 182 185

22 172 175 180 178 184

23 170 178 182 181 182

24 172 182 185 190 195

HD

Group Animal No.

C

LD

MD

Study Day


Table 30: Individual Body Weight Gain (g/week) - Males


Group Animal No. Day 1-4 Day 4-8 Day 8-11 Day 11-14 Day 1-141 26 17 11 6 59

2 20 22 12 16 71

3 20 21 3 10 55

4 20 25 3 6 54

5 17 28 10 12 67

6 13 26 15 13 66

7 23 18 14 12 67

8 19 21 5 11 56

9 23 20 10 8 60

10 25 15 9 6 54

11 14 17 11 6 47

12 12 16 7 8 43

C

LD

MD

HD


Table 31: Individual Body Weight Gain (g/week) - Females


Group Animal No. Day 1-4 Day 4-8 Day 8-11 Day 11-14 Day 1-1413 8 2 3 -1 12

14 2 13 -7 12 20

15 4 5 -4 9 15

16 0 6 8 3 17

17 2 6 5 2 15

18 16 6 2 1 25

19 9 2 -1 1 11

20 3 6 1 9 18

21 10 2 1 3 16

22 3 5 -2 6 11

23 8 4 -1 2 12

24 10 3 5 5 23

C

LD

MD

HD


Table 32: Individual Food Consumption (g/day) - Males


Day 1-7 Day 7-14 Day 1-141 22.17 24.87 23.52

2 24.19 28.03 26.11

3 22.34 25.76 24.05

4 24.10 26.73 25.41

5 23.56 28.16 25.86

6 23.37 26.56 24.96

7 25.81 28.81 27.31

8 22.96 24.04 23.50

9 24.27 26.39 25.33

10 24.49 26.60 25.54

11 20.73 23.96 22.34

12 22.44 25.13 23.79

Study Day

C

LD

MD

HD

Group Animal No.


Table 33: Individual Food Consumption (g/day) - Females


Table 34: Individual Haematology - Males


Day 1-8 Day 8-14 Day 1-1413 13.53 13.94 13.74

14 13.29 15.67 14.48

15 13.90 15.97 14.94

16 14.17 15.50 14.84

17 12.86 14.03 13.44

18 14.96 16.63 15.79

19 12.44 13.19 12.81

20 13.54 15.69 14.61

21 14.46 17.26 15.86

22 13.70 15.24 14.47

23 14.27 16.49 15.38

24 13.86 15.96 14.91

Study Day

C

LD

MD

HD

Group Animal No.

Animal No. RBC HB HCT PLT WBCUnits 1012/L g/dL % 109/L 109/L

1 8.52 15.8 46.9 1093 8.22

2 8.62 16.3 47.6 1098 4.68

34 8.46 15.8 46.8 1077 5.60

5 8.09 14.9 43.1 1064 5.44

6 8.05 15.6 46.7 1153 10.01

7 8.25 15.7 46.6 1105 4.63

8 8.13 15.8 45.5 839 4.90

9 8.75 16.3 48.0 900 4.80

1011 9.28 16.5 48.8 1059 6.84

12 9.31 17.0 50.8 1115 7.05

C

LD

MD

HD

Group


Table 35: Individual Haematology - Females


Animal No. RBC HB HCT PLT WBCUnits 1012/L g/dL % 109/L 109/L

13 8.36 14.8 44.6 811 3.26

14 7.22 14.2 41.4 947 3.12

15 8.47 15.0 44.7 988 3.08

1617 8.54 15.4 46.8 1112 2.59

18 8.86 16.0 46.9 973 2.49

19 8.48 15.6 44.9 869 3.15

20 8.19 14.7 44.3 852 3.42

21 8.23 14.9 43.8 944 3.84

22 8.60 15.0 45.4 864 3.21

23 7.64 14.5 43.7 874 2.97

24 8.81 15.7 46.9 971 3.24

C

LD

MD

HD

Group


Table 36: Individual Clinical Biochemistry - Males


Animal No. ASAT ALAT AP Crea TP ALBB Urea Chol Na KUnits U/L U/L U/L µmol/L g/L g/L mmol/L mmol/L mmol/L mmol/L1 34.5 19.0 294 30.9 63.2 35.2 7.83 1.08 152 4.22

2 39.3 27.2 n 35.4 60.2 36.1 7.95 0.87 150 3.33

3 32.1 16.6 201 29.7 56.9 32.0 8.76 0.94 148 4.56

4 24.4 19.5 186 29.2 58.3 31.5 8.38 0.78 151 4.65

5 31.3 18.5 229 28.4 57.4 31.6 7.85 0.74 151 4.59

6 32.3 21.1 148 26.0 59.8 33.0 7.66 0.80 151 3.92

7 34.6 18.7 216 26.3 58.6 33.3 7.90 0.67 152 4.00

8 28.8 20.0 135 30.7 58.3 33.4 7.92 0.75 147 3.74

9 27.8 22.9 213 27.5 57.5 33.6 6.85 1.13 154 3.58

1011 35.2 24.2 197 29.0 59.5 33.8 8.29 0.69 153 4.25

12 37.0 22.5 168 31.0 59.9 33.8 8.16 0.93 154 4.68

C

LD

MD

HD

Group


Table 37: Individual Clinical Biochemistry - Females


Animal No. ASAT ALAT AP Crea TP ALBB Urea Chol Na KUnits U/L U/L U/L µmol/L g/L g/L mmol/L mmol/L mmol/L mmol/L

13 44.1 14.9 43 31.6 51.6 32.7 7.12 0.52 144 4.39

14 47.8 14.8 78 34.6 53.1 33.8 7.38 0.58 144 3.38

15 40.8 12.1 81 34.4 50.3 31.5 7.05 0.62 145 3.45

16 36.8 13.5 65 43.0 56.1 34.4 6.65 0.61 144 4.60

17 36.4 15.5 68 26.9 53.5 34.5 6.34 0.46 147 3.59

18 40.7 14.5 71 25.5 51.0 32.2 5.58 0.53 146 3.53

19 30.2 13.8 52 25.2 51.7 33.1 8.73 0.62 142 3.10

20 30.7 12.4 91 29.3 56.0 34.1 6.43 0.54 147 3.31

21 32.3 16.3 85 21.5 55.7 34.6 6.76 0.51 145 3.79

22 41.4 14.7 90 40.0 54.4 31.6 7.96 0.60 143 3.31

23 34.2 15.0 51 31.9 55.6 34.7 8.52 0.66 144 3.39

24 38.0 14.0 80 30.1 55.2 34.0 7.81 0.51 148 3.77

C

LD

MD

HD

Group


Table 38: Individual Macroscopic Findings - Males


Group: C

Animal No. 1

No abnormalities were detected

Animal No. 2


Animal No. 3


Group: LD

Animal No. 4


Animal No. 5


Animal No. 6

Organ Finding

Epididymis yellow foci

Stomach discoloured dark

In the remaining organs/tissues no abnormalities were detected



Group: MD

Animal No. 7


Animal No. 8


Animal No. 9


Group: HD

Animal No. 10

Organ Finding

Brain Blood at surface

Animal No. 11

Organ Finding

Epididymis yellow foci

Animal No. 12

Organ Finding

Adrenal Cyst


Table 39: Individual Macroscopic Findings - Females


Group: C

Animal No. 13


Animal No. 14


Animal No. 15

Organ Finding

Stomach Mucosa thickened

Group: LD

Animal No. 16No abnormalities were detected

Animal No. 17


Animal No. 18



Group: MD

Animal No. 19


Animal No. 20


Animal No. 21


Group: HD

Animal No. 22


Animal No. 23


Animal No. 24



Table 40: Absolute Individual Organ Weights (g) - Males


left right total left right total1 285 1.929 8.74 0.87 1.14 1.15 2.30 0.035 0.032 0.067 0.83

2 293 2.121 8.62 0.89 1.12 1.12 2.24 0.042 0.040 0.082 0.66

3 284 2.087 8.60 0.96 1.14 1.15 2.30 0.036 0.037 0.073 0.73

4 285 2.022 8.97 1.10 1.13 1.23 2.36 0.042 0.039 0.081 0.72

5 299 1.968 8.74 1.05 1.03 1.07 2.10 0.036 0.032 0.068 0.67

6 294 1.808 8.55 0.98 1.13 1.17 2.30 0.037 0.040 0.077 0.72

7 290 2.043 9.25 1.01 1.29 1.38 2.67 0.041 0.037 0.079 0.67

8 273 2.085 7.80 0.96 1.07 1.18 2.25 0.033 0.031 0.063 0.80

9 291 1.945 8.51 1.12 1.19 1.19 2.38 0.038 0.028 0.066 0.76

10 284 1.906 13.31 0.93 1.12 1.13 2.24 0.042 0.042 0.084 0.65

11 276 2.038 8.49 0.89 1.16 1.17 2.33 0.035 0.033 0.067 0.61

12 281 2.118 8.87 0.96 1.28 1.19 2.47 0.033 0.035 0.069 0.60

SpleenBrainBody weight

Kidneys AdrenalsLiver HeartAnimal No.

C

LD

MD

HD

Group


Table 40: Absolute Individual Organ Weights (g) - Males (Continued)


left right total left right total1 0.71 1.78 1.73 3.51 0.43 0.46 0.89 1.78

2 0.51 1.67 1.63 3.31 0.46 0.48 0.94 1.84

3 0.69 1.70 1.76 3.46 0.46 0.49 0.95 1.61

4 0.65 1.88 1.77 3.66 0.44 0.43 0.87 1.58

5 0.51 1.50 1.67 3.17 0.40 0.44 0.84 1.54

6 0.48 1.77 1.58 3.35 0.48 0.45 0.93 1.50

7 0.52 1.86 1.86 3.72 0.48 0.46 0.94 1.59

8 0.63 1.63 1.67 3.30 0.40 0.41 0.81 1.49

9 0.53 1.64 1.63 3.27 0.47 0.48 0.95 1.52

10 0.49 1.67 1.69 3.37 0.41 0.48 0.89 1.71

11 0.55 1.57 1.67 3.24 0.50 0.53 1.03 1.99

12 0.58 1.66 1.66 3.32 0.50 0.44 0.94 1.90

ThymusTestes Epididymides

Prostate #Animal No.Group

C

LD

MD

HD


Table 41: Absolute Individual Organ Weights (g) - Females


left right total left right total13 171 1.759 4.70 0.64 0.76 0.78 1.54 0.032 0.043 0.075

14 173 1.811 5.12 0.60 0.74 0.74 1.48 0.030 0.030 0.060

15 174 1.775 4.95 0.60 0.68 0.67 1.35 0.036 0.039 0.075

16 169 1.786 6.84 0.51 0.70 0.74 1.44 0.043 0.038 0.082

17 166 1.837 4.62 0.57 0.72 0.73 1.45 0.039 0.034 0.073

18 178 1.821 4.77 0.64 0.69 0.78 1.46 0.036 0.036 0.071

19 169 1.834 4.33 0.63 0.68 0.73 1.41 0.032 0.032 0.065

20 166 1.801 4.77 0.62 0.57 0.67 1.24 0.042 0.037 0.079

21 176 1.793 5.56 0.59 0.84 0.89 1.73 0.047 0.043 0.091

22 172 1.868 5.45 0.63 0.76 0.79 1.55 0.050 0.037 0.087

23 170 1.675 5.31 0.71 0.81 0.78 1.59 0.043 0.042 0.085

24 180 1.770 5.02 0.57 0.72 0.75 1.47 0.040 0.038 0.077

BrainBody weight

AdrenalsLiver

KidneyHeartGroup Animal No.

C

LD

MD

HD


Table 41: Absolute Individual Organ Weights (g) - Females (Continued)


left right total13 0.48 0.35 0.052 0.046 0.097 0.41

14 0.49 0.31 0.045 0.041 0.086 0.61

15 0.43 0.32 0.060 0.060 0.120 0.51

16 0.38 0.27 0.053 0.039 0.092 0.79

17 0.50 0.36 0.036 0.043 0.079 0.86

18 0.43 0.37 0.047 0.044 0.091 0.36

19 0.43 0.26 0.039 0.045 0.083 0.35

20 0.52 0.40 0.041 0.053 0.094 1.03

21 0.46 0.32 0.058 0.052 0.110 0.43

22 0.42 0.28 0.047 0.051 0.098 0.59

23 0.52 0.38 0.045 0.053 0.099 0.68

24 0.48 0.36 0.036 0.049 0.084 0.38

Uterus #SpleenAnimal No. ThymusOvaries

MD

HD

C

Group

LD


Table 42: Relative Individual Organ Weights to Brain Weight (%) - Males



1 452.95 45.31 59.29 59.71 119.00 1.825 1.669 3.494 42.80

2 406.50 41.97 52.76 52.95 105.71 1.971 1.895 3.866 31.20

3 411.99 46.06 54.76 55.32 110.08 1.715 1.768 3.483 34.88

4 443.51 54.53 56.12 60.61 116.73 2.053 1.929 3.981 35.70

5 444.28 53.18 52.11 54.60 106.71 1.845 1.611 3.456 33.94

6 472.93 54.06 62.49 64.62 127.11 2.057 2.212 4.269 39.69

7 453.02 49.28 63.13 67.60 130.72 2.017 1.831 3.847 32.63

8 374.14 46.08 51.30 56.40 107.70 1.569 1.463 3.032 38.20

9 437.69 57.42 61.23 60.93 122.16 1.969 1.434 3.403 39.32

10 698.69 48.63 58.58 59.20 117.78 2.209 2.204 4.413 34.08

11 416.54 43.73 56.81 57.64 114.45 1.698 1.595 3.292 30.05

12 418.97 45.48 60.36 56.04 116.41 1.577 1.671 3.248 28.17

MD

HD

Adrenals

C

LD

SpleenHeartKidneys

Group Animal No. Liver


Table 42: Relative Individual Organ Weights to Brain Weight (%) - Males (Continued)

C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose; * = including coagulating glands


2 24.10 78.80 77.08 155.88 21.51 22.62 44.13 86.94

3 33.00 81.54 84.31 165.86 22.09 23.57 45.65 77.33

4 32.04 93.11 87.72 180.82 21.71 21.18 42.89 77.94

5 26.02 76.19 84.74 160.92 20.52 22.20 42.72 78.43

6 26.35 97.68 87.52 185.20 26.30 24.99 51.29 82.90

7 25.50 90.98 91.10 182.08 23.53 22.64 46.17 77.65

8 30.00 78.23 80.10 158.33 19.20 19.55 38.75 71.25

9 27.40 84.10 83.82 167.92 24.00 24.88 48.88 78.37

10 25.60 87.83 88.88 176.71 21.67 25.23 46.90 89.63

11 27.23 77.07 82.02 159.09 24.42 25.94 50.36 97.80

12 27.37 78.54 78.14 156.69 23.46 20.89 44.35 89.55

#= including seminal vesicles and coagulating gland

MD

HD

C

Prostate #Group Animal No.Testes Epididymides

LD

Thymus


Table 43: Relative Individual Organ Weights to Brain Weight (%) - Females



13 267.04 36.25 43.19 44.18 87.37 1.842 2.422 4.265

14 282.67 33.12 40.86 41.09 81.96 1.674 1.663 3.336

15 278.58 33.75 38.15 37.99 76.14 2.045 2.203 4.247

16 382.72 28.75 39.21 41.64 80.85 2.430 2.150 4.580

17 251.61 30.80 39.04 39.93 78.98 2.123 1.856 3.979

18 262.10 35.15 37.64 42.76 80.39 1.950 1.966 3.916

19 235.85 34.25 37.14 39.90 77.04 1.756 1.761 3.517

20 264.82 34.49 31.70 37.11 68.80 2.332 2.066 4.398

21 310.17 32.94 47.02 49.55 96.58 2.632 2.414 5.046

22 291.46 33.95 40.47 42.31 82.78 2.687 1.959 4.646

23 316.98 42.23 48.36 46.41 94.77 2.568 2.508 5.076

24 283.89 32.24 40.49 42.40 82.88 2.232 2.119 4.352

HD

MD

C

LD

Kidney AdrenalsGroup Liver HeartAnimal No.


Table 43: Relative Individual Organ Weights to Brain Weight (%) - Females


left right total13 27.14 20.08 2.951 2.587 5.538 23.03

14 27.20 17.02 2.502 2.242 4.745 33.92

15 24.19 18.01 3.386 3.386 6.771 28.64

16 21.29 15.04 2.950 2.195 5.145 44.19

17 26.95 19.46 1.960 2.319 4.279 46.59

18 23.69 20.36 2.581 2.389 4.970 19.78

19 23.17 14.42 2.110 2.432 4.542 18.88

20 28.68 21.99 2.266 2.965 5.231 56.94

21 25.45 17.71 3.245 2.894 6.139 24.18

22 22.60 15.06 2.494 2.730 5.224 31.78

23 30.86 22.51 2.699 3.183 5.882 40.70

24 27.37 20.21 2.006 2.763 4.770 21.35

# including Cervix and Oviduct

HD

Uterus #

C

LD

MD

Group Animal No. ThymusOvaries

Spleen


Table 44: Relative Individual Organ Weights to Body Weight (%) - Males



1 0.677 3.066 0.307 0.401 0.404 0.805 0.0124 0.0113 0.0236 0.290

2 0.724 2.942 0.304 0.382 0.383 0.765 0.0143 0.0137 0.0280 0.226

3 0.735 3.028 0.339 0.402 0.407 0.809 0.0126 0.0130 0.0256 0.256

4 0.709 3.146 0.387 0.398 0.430 0.828 0.0146 0.0137 0.0282 0.253

5 0.658 2.924 0.350 0.343 0.359 0.702 0.0121 0.0106 0.0227 0.223

6 0.615 2.909 0.332 0.384 0.397 0.782 0.0127 0.0136 0.0263 0.244

7 0.704 3.191 0.347 0.445 0.476 0.921 0.0142 0.0129 0.0271 0.230

8 0.764 2.857 0.352 0.392 0.431 0.822 0.0120 0.0112 0.0232 0.292

9 0.668 2.926 0.384 0.409 0.407 0.817 0.0132 0.0096 0.0227 0.263

10 0.671 4.688 0.326 0.393 0.397 0.790 0.0148 0.0148 0.0296 0.229

11 0.738 3.076 0.323 0.419 0.426 0.845 0.0125 0.0118 0.0243 0.222

12 0.754 3.158 0.343 0.455 0.422 0.877 0.0119 0.0126 0.0245 0.212

SpleenLiver HeartAdrenals

LD

HD

Kidneys

C

Group Animal No. Brain

MD


Table 44: Relative Individual Organ Weights to Body Weight (%) - Males (Continued)

C = Control; LD = Low Dose; MD = Medium Dose; HD = High Dose; * = including seminal vesicles and coagulating gland


2 0.174 0.570 0.558 1.128 0.156 0.164 0.319 0.629

3 0.243 0.599 0.620 1.219 0.162 0.173 0.336 0.568

4 0.227 0.661 0.622 1.283 0.154 0.150 0.304 0.553

5 0.171 0.501 0.558 1.059 0.135 0.146 0.281 0.516

6 0.162 0.601 0.538 1.139 0.162 0.154 0.315 0.510

7 0.180 0.641 0.642 1.283 0.166 0.160 0.325 0.547

8 0.229 0.597 0.612 1.209 0.147 0.149 0.296 0.544

9 0.183 0.562 0.560 1.123 0.160 0.166 0.327 0.524

10 0.172 0.589 0.596 1.186 0.145 0.169 0.315 0.601

11 0.201 0.569 0.606 1.175 0.180 0.192 0.372 0.722

12 0.206 0.592 0.589 1.181 0.177 0.157 0.334 0.675

# = including seminal vesicles and coagulating gland

HD

Testes EpididymidesGroup Animal No. Thymus

C

LD

MD

Prostate #


Table 45: Relative Individual Organ Weights to Body Weight (%) - Females



13 1.028 2.746 0.373 0.444 0.454 0.899 0.0189 0.0249 0.0439

14 1.047 2.958 0.347 0.428 0.430 0.858 0.0175 0.0174 0.0349

15 1.020 2.842 0.344 0.389 0.388 0.777 0.0209 0.0225 0.0433

16 1.057 4.045 0.304 0.414 0.440 0.854 0.0257 0.0227 0.0484

17 1.107 2.784 0.341 0.432 0.442 0.874 0.0235 0.0205 0.0440

18 1.023 2.681 0.360 0.385 0.437 0.822 0.0199 0.0201 0.0401

19 1.085 2.559 0.372 0.403 0.433 0.836 0.0191 0.0191 0.0382

20 1.085 2.873 0.374 0.344 0.403 0.746 0.0253 0.0224 0.0477

21 1.019 3.161 0.336 0.479 0.505 0.984 0.0268 0.0246 0.0514

22 1.086 3.166 0.369 0.440 0.460 0.899 0.0292 0.0213 0.0505

23 0.985 3.122 0.416 0.476 0.457 0.934 0.0253 0.0247 0.0500

24 0.983 2.791 0.317 0.398 0.417 0.815 0.0219 0.0208 0.0428

Brain LiverGroup Animal No.Kidney

Heart

MD

HD

C

LD

Adrenals


Table 45: Relative Individual Organ Weights to Body Weight (%) - Females (Continued)


left right total13 0.279 0.206 0.0304 0.0266 0.0570 0.237

14 0.285 0.178 0.0262 0.0235 0.0497 0.355

15 0.247 0.184 0.0345 0.0345 0.0691 0.292

16 0.225 0.159 0.0312 0.0232 0.0544 0.467

17 0.298 0.215 0.0217 0.0257 0.0473 0.516

18 0.242 0.208 0.0264 0.0244 0.0508 0.202

19 0.251 0.156 0.0229 0.0264 0.0493 0.205

20 0.311 0.239 0.0246 0.0322 0.0567 0.618

21 0.259 0.180 0.0331 0.0295 0.0626 0.246

22 0.246 0.164 0.0271 0.0297 0.0567 0.345

23 0.304 0.222 0.0266 0.0314 0.0579 0.401

24 0.269 0.199 0.0197 0.0272 0.0469 0.210

MD

HD

Uterus #ThymusOvaries

Group Animal No. Spleen

C

LD


13.2. Appendix 2: Histopathology Report

report, bsl bioservice study no. 112936 page 2 of 110

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