# FINAL REPORT

Study Title 

# COMBINED 28 - DAY REPEATED DOSE TO XICITY STUDY WITH TH E REPRODUCTION/DEVELOP MENTAL TOXICITY SCRE ENING TEST OF 1 - PROPANESULFONIC ACID , 2 - HYDROXY - 3 - (2 - PROPEN - 1 - YLOXY) - , SODIUM SALT (1:1) IN RATS BY ORAL GAVA GE

Author F.M. van Otterdijk, M.Sc. Test Facility WIL Research Europe B.V. Hambakenwetering 7 5231 DD 's - Hertogenbosch The Netherlands Laboratory Project Identification Project 500682 Substance 204240/A

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### 1. CONTENTS 1. CONTENTS ...................................................................................................................................... 2 2. STATEMENT OF GLP COMPLIANCE ............................................................................................. 4 3. QUALITY ASSURANCE STATEMENT ............................................................................................ 5 4. SUMMARY ........................................................................................................................................ 7 5. INTRODUCTION .............................................................................................................................. 9 5.1. Preface ..................................................................................................................................... 9 5.2. Study plan ................................................................................................................................ 9 5.3. Aims of study .......................................................................................................................... 10 5.4. Guidelines .............................................................................................................................. 10 5.5. Storage and retention of records and materials ..................................................................... 10 6. MATERIALS AND METHODS ........................................................................................................ 11 6.1. Test substance ....................................................................................................................... 11 6.1.1. Test substance information ........................................................................................ 11 6.1.2. Study specific test substance information .................................................................. 11 6.1.3. Test substance formulation ........................................................................................ 11 6.1.4. Chemical analysis of dose preparations .................................................................... 12 6.2. Test system ............................................................................................................................ 12 6.3. Allocation ................................................................................................................................ 13 6.4. Animal husbandry .................................................................................................................. 13 6.5. Treatment ............................................................................................................................... 14 6.5.1. Parental animals ......................................................................................................... 14 6.5.2. Pups ........................................................................................................................... 14 6.6. Observations .......................................................................................................................... 14 6.6.1. Parental animals ......................................................................................................... 14 6.6. 2. Pups ........................................................................................................................... 15 6.7. Clinical laboratory investigations ............................................................................................ 16 6.7.1. Haematology .............................................................................................................. 16 6.7.2. Clinical biochemistry ................................................................................................... 17 6.8. Pathology ............................................................................................................................... 17 6.8.1. Necropsy parental animals ......................................................................................... 17 6.8.2. Necropsy pups ........................................................................................................... 19 6.8.3. Organ weights ............................................................................................................ 19 6.8.4. Histotechnology .......................................................................................................... 19 6.8.5. Histopathology ............................................................................................................ 19 6.9. Electronic data capture .......................................................................................................... 20 6.10. Interpretation .......................................................................................................................... 20 6.10.1. Calculations ................................................................................................................ 20 6.10.2. Statistical analyses ..................................................................................................... 21 6.11. List of deviations .................................................................................................................... 21 6.11.1. List of protocol deviations ........................................................................................... 21 6.11.2. List of standard operating procedure deviations ........................................................ 21 7. RESULTS ....................................................................................................................................... 22 7.1. Analysis of dose preparations ................................................................................................ 22 7.2. Observations parental animals .............................................................................................. 22 7.2.1. Mortality ...................................................................................................................... 22 7.2.2. Clinical signs .............................................................................................................. 22 7.2.3. Functional observations ............................................................................................. 22 7.2.4. Body weights .............................................................................................................. 22 7.2.5. Food consumption ...................................................................................................... 23 7.2. 6. Haematology .............................................................................................................. 23 7.2.7. Clinical biochemistry ................................................................................................... 23 7.2.8. Macroscopic examination ........................................................................................... 23 7.2.9. Organ weights ............................................................................................................ 24 7.2.10. Microscopic examination ............................................................................................ 24 7.3. Reproduction/developmental data ......................................................................................... 24 7.3.1. Reproduction data ...................................................................................................... 24 7.3.2. Developmental data ................................................................................................... 25 8. DISCUSSION AND CONCLUSION ................................................................................................ 26

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### 9. REFERENCES ............................................................................................................................... 27 APPENDICES APPENDIX 1 SUMMARY TABLES APPENDIX 2 INDIVIDUAL TABLES APPENDIX 3 CERTIFICATE OF ANALYSIS APPENDIX 4 FORMULATION ANALYSIS APPENDIX 5 HISTOPATHOLOGY REPORT

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### 4. SUMMARY Title Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of COPS_1 or CS-AHPS in rats by oral gavage. Guidelines The study was based on the following guidelines: 1) OECD 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, March 1996. 2) OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000. 3) OECD 421, Reproduction/Developmental Toxicity Screening Test, July 1995. 4) OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test, July 2000. 5) EC No 440/2008 B.7: "Repeated Dose (28 days) Toxicity (oral)", May 2008. 6) OECD 407, Repeated Dose 28-day Oral Toxicity Study in Rodents, October 2008. 7) OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000. Study outline After acclimatization, four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 100 , 300 and 1000 mg/kg (corresponding to 41, 123 and 409 mg active ingredient/kg, respectively). Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 42 -48 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum , and during at least 4 days of lactation. Evaluated parameters The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (end of treatme nt ) , body weight and food consumption ( at least at weekly intervals), clinical pathology (end of treatment), macroscopy at termination, organ weights and histopathology on a selection of tissues, and reproduction/developmental parameters, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy). Formulations were analyzed once to assess accuracy and homogeneity. Results/discussion Accuracy and homogeneity of formulations were demonstrated by analyses. Parental results: No toxicologically relevant findings were observed up to the highest dose level tested (1000 mg/kg). Several effects considered to be secondary to a small litter size or absence of litters were noted for females at 300 and 1000 mg/kg in motor activity, body weight gain, food consumption, clinical biochemistry parameters, organ weights and microscopic examinations. No direct treatment-related changes were noted in any of the parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). Reproductive results: At 1000 mg/kg, none of the females were found pregnant, and at 300 mg/kg only two females were found pregnant (based on presence of implantation sites) and showed a reduced number of corpora lutea and implantation sites . At 100 mg/kg, nine females were found pregnant (one of these based on pres ence of implantation sites). One female was found not pregnant, and one female had a total litter loss (her single pup died on Day 5 of lactation). Two females showed a reduced number of corpora lutea and implantation sites, while other pregnant females of this dose group showed a normal number of corpora lutea and implantation sites. As these findings at 100 mg/kg were in line with the affected reproduction noted at 300 and 1000 mg/kg, a possible treatment related effect could not be excluded.

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### Mating index and precoital time were normal up to the highest dose level tested (1000 mg/kg). Developmental results: No developmental toxicity was observed at 100 mg/kg in any of the developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy). Developmental effects could not be assessed at 300 and 1000 mg/kg as no pups were born. In conclusion, treatment with COPS_1 or CS-AHPS by oral gavage in male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg revealed no parental toxicity up to 1000 mg/kg. Reproduction toxicity was observed at all dose levels. No developmental toxicity was observed at 100 mg/kg. However, developmental toxicity could not be assessed at 300 and 1000 mg/kg since no pups were born. Based on these results, the following No Observed Adverse Effect Levels (NOAEL) were derived: Parental NOAEL: at least 1000 mg/kg (409 mg active ingredient/kg) Reproduction NOAEL: could not be determined (below 100 mg/kg (41 mg active ingredient/kg )) Developmental NOAEL: at least 100 mg/kg (41 mg active ingredient/kg)

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### 5. INTRODUCTION Two project numbers were used to collect online data (project 500682 and 501107). All data was reported under Project 500682. 5.1. Preface Sponsor Society of Chemical Manufacturers and Affiliates 1850 M Street, NW Suite 700 WASHINGTON, DC 20036 , USA Study Monitor Dr. C. T. Helmes Study Director F.M. van Otterdijk, M.Sc. WIL Research Europe B.V. Hambakenwetering 7 5231 DD 's - Hertogenbosch The Netherlands Tel: +31 73 640 6700 Fax: +31 73 640 6799 Email: francois.van.otterdijk @wilresearch.com Coordinating Biotechnician M. Nijhoff ( WIL Research Europe B.V.) Clinical Pathology Dr. M. Stitzinger ( WIL Research Europe B.V.) Analytical Chemistry Ir. M.J.C. Brekelmans (Principal Scientist, WIL Research Europe B.V.) Histotechnology W. Verhoef ( WIL Research Europe B.V.) Necropsy Ing T.A. Mijnders ( WIL Research Europe B.V.) Histopathology E.J.M. Lambregts, DVM (Principal Scientist, WIL Research Europe B.V.) Quality Assurance C. J. Mitchell, B.Sc. ( WIL Research Europe B.V.) Email: christine.mitchell@wilresearch.com Test F acility Management H.H. Emmen, M.Sc. ( WIL Research Europe B.V.) Email: harry.emmen@wilresearch.com Test Facility WIL Research Europe B.V. Hambakenwetering 7 5231 DD ‘s - Hertogenbosch The Netherlands 5.2. Study plan Experimental starting date 25 January 2013 (allocation) Start treatment 29 January 2013 Start mating 12 February 2013 Blood sampling 27 February 2013 (selected males) 12 , 14 and 15 March 201 3 (selected females) Delivery of litters 06 - 10 and 12 March 201 3 Necropsy 27 February 2013 (males) 12 - 15 and 18 M arch 201 3 (females and/or pups) Experimental completion date 18 M arch 201 3 (end of in - life phase)

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### 5.3. Aims of study The purpose of this study w as to evaluate the potential toxic effects of the test substance when administered to rats for a minimum of 28 days and to evaluate the potential of the test substance to affect male and female reproductive performance such as gonadal function, mating behaviour, conception, parturition and early postnatal development. Parental, reproduction (up to and including implantation) and developmental (from implantation onwards) No Observed Adverse Effect Levels (NOAELs) were evaluated. This study should provide part of a rational basis for toxicological risk assessment in man. 5.4. Guidelines Th e protocol was reviewed and agreed by the Laboratory Animal Welfare Officer and the Ethical Committee (DEC 10 - 81 ) as required by the Dutch Act on Animal Experimentation (February 1997). The study procedures described in this report we re in compliance with the following guidelines: 1) Organisation of Economic Co-operation and Development (OECD) Guidelines for Testing of Chemicals, Guideline 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, March 1996. 2) The United States Environmental Protection Agency (EPA) Health Effects Test Guidelines, OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, July 2000. In addition, the procedures described in this report essentially conform to the following guidelines: 3) OECD Guidelines for Testing of Chemicals, Guideline 421, Reproduction/Developmental Toxicity Screening Test, July 1995. 4) The United States EPA Health Effects Test Guidelines, OPPTS 870.3550, Reproduction/Developmental Toxicity Screening Test, July 2000. 5) Commission regulation (EC) No 440/2008 Part B: Methods for the Determination of Toxicity and other Health Effects; B.7: "Repeated Dose (28 days) Toxicity (oral)". Official Journal of the European Union No. L142, May 2008. 6) OECD Guidelines for Testing of Chemicals, Guideline 407 , Repeated Dose 28-day Oral Toxicity Study in Rodents, October 2008. 7) The United States EPA Health Effects Test Guidelines, OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000. 5.5. Storage and retention of records and materials Records and materials pertaining to the study, including protocol, raw data, specimens (except specimens requiring refrigeration or freezing) and the final report are retained in the WIL Research Europe archives for a period of at least 2 years after finalization of the report. After this period, the sponsor will be contacted to determine how the records and materials should be handled. WIL Research Europe will retain information concerning decisions made. Those specimens requiring refrigeration or freezing will be retained by WIL Research Europe for as long as the quality of the specimens permits evaluation but no longer than three months after finalization of the report. WIL Research Europe will retain a test substance sample until the expiry date, but no longer than 10 years after finalization of the report. After this period the sample will be destroyed.

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### 6. MATERIALS AND METHODS 6.1. Test substance 6.1.1. Test substance information Identification 1 - Propanesulfonic acid, 2 - hydroxy - 3 - (2 - propen - 1 - yloxy) - , sodium salt (1:1) Synonyms COPS_1 or CS - AHPS Structure Molecular formula C 6 

### H 11 

### NaO 5 

### S Molecular weight 218.22 Description Clear colourless liquid Batch 12E1101 Purity/Composition Sodium - 1 - allyloxy - 2 - hydroxypropane sulphonate 3 - allyl - 1,2 - propanediol Water CAS Number Percent 52556 - 42 - 0 38.64 123 - 34 - 2 2.26 7732 - 18 - 5 59.1 Test substance storage At room temperature in the dark Stability under storage conditions Stable Expiry date 13 August 2013 See also Certificate of Analysis (APPENDIX 3) . 6.1.2. Study specific test substance information Puri ty/composition correction factor required No Hygroscopic No Volatile No Specific Gravity / Density 1.17 pH 7 at concentration of 40.9% Stability in vehicle:  Water 1 year Solubility in vehicle:  Water 1 - 45% 6.1.3. Test substance formulation Vehicle Water (Elix, Millipore S.A.S., Molsheim, France). Rationale for vehicle Based on trial formulations performed at WIL Research Europe and on information provided by the sponsor. Method of formulation Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment w as made for specific gravity of the test substance . No correction was made for the puri ty/composition of the test substance. Storage conditions At ambient temperature.

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### 6.1.4. Chemical analysis of dose preparations Analyses were conducted on a single occasion after the in-life phase (no validated analytical method was available during the in-life phase) according to a validated method (Project 500674). Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). The accuracy of preparation was considered acceptable if the mean measured concentrations were 90 -110% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. 6.2. Test system Test system Rat: Crl:WI(Han) (outbred, SPF-Quality). Nulliparous and non-pregnant females and untreated animals were used at initiation of the study. Rationale This species and strain of rat has been recognized as appropriate for general and reproduction toxicity studies. WIL Research Europe B.V. has general and reproduction/developmental historical data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants. Source F 0 

### Charles River Deutschland, Sulzfeld, Germany. Age at start F 0 

### -treatment Approximately 11 weeks. Number of F 0 

### -animals 40 females and 40 males. Acclimatization F 0 

### At least 5 days prior to start of treatment. Health inspection F 0 

### Upon receipt of the animals. Randomization F 0 

### Prior to commencement of treatment, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the sex mean. Identification F 0 

### Earmark and tattoo. Mating procedures Following a minimum of 14 days of exposure for the males and females, one female w as cohabitated with one male of the same treatment group, avoiding sibling mating. Detection of mating w as confirmed by evidence of sperm in the vaginal lavage or by the appearance of an intravaginal copulatory plug. This day w as designated Day 0 post-coitum. Once mating occurred, the males and females were separated. Parturition The females were allowed to litter normally. Day 1 of lactation wa s defined as the day when a litter wa s found completed (i.e. membranes and placentas cleaned up, nest build up and/or feeding of pups started). Females that were littering were left undisturbed. Number of pups 19 6 pups. Identification of pups On Day 1 of lactation, all pups were individually identified by means of subcutaneous injection of Indian ink.

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### 6.3. Allocation Group Dose level 1



### mg/kg Dose level Number of animals Animal numbers

mg/kg mg active

ingredient 2 

### /kg Males Females Males Females 1 0 0 0 10 10 01 - 10 41 - 50 2 100 100 41 10 10 11 - 20 51 - 60 3 300 300 123 10 10 21 - 30 61 - 70 4 1000 1000 409 10 10 31 - 40 71 - 80 1 Dose levels were based on information supplied by the sponsor. 2 The purity of 40.9% was based on all components, except water. 

### The following 5 animals/sex/group we re selected for functional observations, locomotor activity, clinical pathology, macroscopic examination (full list), organ weights (full list) and histopathology (see also respective paragraphs): Group Animal numbers

Males Females 1 

### 1 01 - 05 41, 43, 44, 48, 50 2 11 - 15 51, 54, 55, 57, 60 3 21 - 25 61, 62, 63, 64, 65 4 31 - 35 73, 76, 78, 79, 80 1 With live pups only for Groups 1 and 2, and randomly selected (as no litters with live pups) for Groups 3 and 4. 

### 6.4. Animal husbandry Room number A0.09 (A0.23 for motor activity measurements). Conditions Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study. Accommodation

Pre-mating Animals were housed in groups of 5 animals/sex/cage in Macrolon plastic

cages (MIV type, height 18 cm). Mating Females were caged together with males on a one- to - one -basis in

Macrolon plastic cages (MIII type, height 18 cm). Post-mating Males were housed in their home cage (Macrolon plastic cages, MIV type,

height 18 cm) with a maximum of 5 animals/cage. Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm). Lactation Pups were kept with the dam until termination in Macrolon plastic cages

(MIII type, height 18 cm). During locomotor activity monitoring of the dams the pups were kept warm in their home cage using bottles filled with warm water. In order to avoid hypothermia of pups, pups were not left without their dam or a bottle filled with warm water for longer than 30-40 minutes. General Sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil,

France) and paper as cage-enrichment/nesting material (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom) were supplied. During locomotor activity monitoring, animals were housed individually in a Hi -temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20. 3 cm) without cage-enrichment or bedding material, food and water. Diet Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany). Water Free access to tap-water.

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### Diet, water, bedding and cage-enrichment/nesting material evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study. 6.5. Treatment 6.5.1. Parental animals Method Oral gavage, using a plastic feeding tube. Formulations were placed on a magnetic stirrer during dosing. Dose volume 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight. Frequency Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose. Exposure period Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to the day prior to scheduled necropsy. Females were exposed for 42 -48 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necrops y) . Female no s. 41, 43 (Group 1), 53 and 54 (Group 2) were not dosed during littering. 6.5.2. Pups Pups were not dosed directly but could have potentially be exposed to the test substance in utero, via maternal milk or from exposure to maternal urine/faeces. 6.6. Observations 6.6.1. Parental animals Mortality / Viability At least twice daily. The time of death was recorded as precisely as possible. Clinical signs Daily from treatment onwards up to the day prior to necropsy, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals during the treatment period this w as also performed outside the home cage in a standard arena. Clinical observations (clinical signs and arena) were conducted after dosing at no specific time point, but within a similar time period after dosing for the respective animals. The time of onset, grade and duration of any observed sign w as recorded. Signs were graded for severity and the maximum grade w as predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) w as scored. In the data tables, the scored grades were reported, as well as the percentage of animals affected in summary tables.

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### Functional Observations The following tests were performed on the selected 5 animals/sex/group:

- hearing ability *

- pupillary reflex *

- static righting reflex *

- grip strength * * score 0 = normal/present, score 1 = abnormal/absent

- locomotor activity (recording period: 1-hour under normal laboratory light conditions, using a computerized monitoring system, Kinder Scientific LLC, Poway, USA). Total movements and ambulations are reported. Ambulations represent movements characterized by a relocation of the entire body position like walking, whereas total movements represent all movements made by the animals, including ambulations but also smaller or more fine movements like grooming, weaving or movements of the head. The selected males were tested during Week 4 of treatment. T he selected Group 1 and 2 females were tested towards the end of the scheduled lactation period (from lactation Day 4 onwards), and the selected Group 3 and 4 females were tested at the scheduled end of the post-coitum period (none of the Group 3 and 4 females delivered offspring) . These test were performed after observation for clinical signs (incl. arena observation, if applicable) at no specific time point, but within a similar time period after dosing for the respective animals. Body weights Males and females were weighed on the first day of exposure and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on Days 1 and 4. Food consumption Weekly, except for males and females which we re housed together for mating and for females without evidence of mating. Food consumption of mated females w as measured on Days 0, 4, 7, 11, 14, 17 and 20 postcoitum and on Days 1 and 4 of lactation. Water consumption Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected. General reproduction data Male number paired with, mating date, confirmation of pregnancy, and delivery day were recorded. Pregnant females were examined to detect signs of difficult or prolonged parturition, and cage debris of pregnant females was examined to detect signs of abortion or premature birth. Any deficiencies in maternal care (such as inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups or apparently inadequate lactation or feeding) were examined. 6.6.2. Pups Each litter w as examined to determine the following, if practically possible: Mortality / Viability The numbers of live and dead pups on Day 1 of lactation and daily thereafter were determined. If possible, defects or cause of death were evaluated. Clinical signs At least once daily, detailed clinical observations were made for all animals.

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### Body weights Live pups were weighed on Days 1 and 4 of lactation. Sex Sex w as determined for all pups on Days 1 and 4 of lactation. 6.7. Clinical laboratory investigations Blood samples were collected at the end of the treatment period on the day of scheduled necropsy from the selected 5 animals/sex/group under anaesthesia using isoflurane (Abbott B.V., Hoofddorp, The Netherlands) between 7.00 and 10.30 a.m. The animals were deprived of food overnight (with a maximum of 24 hours) before blood sampling, but water was available. Blood samples were drawn from the retro-orbital sinus and collected into tubes prepared with K 3 

### -EDTA for haematological parameters (0.5 mL), with citrate for clotting tests (0.45 mL) and tubes treated with Li-heparin (0.5 mL) for clinical biochemistry parameters. An additional blood sample (0.25 mL) w as collected into serum tubes for determination of bile acids (tubes: Greiner BioOne GmbH, Kremsmünster, Austria). 6.7.1. Haematology The following haematology parameters were determined in blood prepared with K 3 

### -EDTA as an anticoagulant, using the ADVIA ® 120 Hematology System (Siemens Healthcare Diagnostics B.V., Breda, The Netherlands): Parameter (Abbreviation) Unit White blood cells (WBC) 10 9 

### /L Differential leucocyte count: Neutrophils %WBC Lymphocytes %WBC Monocytes %WBC Eosinophils %WBC Basophils %WBC Red blood cells 10 12 

### /L Reticulocytes %RBC Red blood cell distribution width (RDW) % Haemoglobin mmol/L Haematocrit L/L Mean corpuscular volume (MCV) fL Mean corpuscular haemoglobin (MCH) fmol Mean corpuscular haemoglobin concentration (MCHC) mmol/L Platelets 10 9 

### /L The following clotting parameters were determined in plasma prepared with citrate as anti-coagulant, using the STA Compact ® ( Diagnostica Stago S.A.S., Asnières, France): Parameter (Abbreviation) Unit Prothrombin Time (PT) s Activated Partial Thromboplastin Time (APTT) s

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### 6.7.2. Clinical biochemistry The following clinical biochemistry parameters were determined using the AU400 ® Chemistry System ( Beckman Coulter Nederland B.V., Woerden, The Netherlands). All parameters were determined in plasma, except for bile acids which were determined in seru m: Parameter (Abbreviation) Unit Alanine aminotransferase (ALAT) U/L Aspartate aminotransferase (ASAT) U/L Alkaline Phosphatase (ALP) U/L Total protein g/L Albumin g/L Total globulin g/L Calculation [protein - albumin] Albumin/Globulin ratio (Alb/Gl ratio) Calculation [albumin/globulin] Total Bilirubin μmol/L Bile acids μmol/L Urea mmol/L Creatinine μmol/L Glucose mmol/L Cholesterol mmol/L Sodium mmol/L Potassium mmol/L Chloride mmol/L Calcium mmol/L Inorganic Phosphate (Inorg. Phos) mmol/L 6.8. Pathology 6.8.1. Necropsy parental animals All males and the selected 5 females/group were deprived of food overnight (with a maximum of 24 hours) prior to planned necropsy, but water was provided. Non-selected females were not deprived of food. Animals were deeply anaesthetized using isoflurane (Abbott B.V., Hoofddorp, The Netherlands) and subsequently exsanguinated. Necropsy was conducted on the following days: Condition Day of necropsy Females which deliver ed Lactation Days 5 - 7. Females which fail ed to deliver (nos. 42, 52, 59, 6 1 - 80 ) Post - coitum Days 25 - 27 (females with evidence of mating) Female with total litter loss (no. 53 ) Within 24 hours of litter loss. Males Following completion of the mating period (a minimum of 28 days of dose administration). All animals were subjected to macroscopic examination of the cranial, thoracic and abdominal tissues and organs, with special attention being paid to the reproductive organs. Descriptions of all macroscopic abnormalities were recorded. The numbers of former implantation sites and corpora lutea were recorded for all paired females.

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### Samples of the following tissues and organs were collected and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution, Klinipath, Duiven, The Netherlands). Selected 5 animals/sex/group: Identification marks: not processed Ovaries Adrenal glands (Pancreas) (Aorta) Peyer's patches [ jejunum, ileum ] if detectable Brain - cerebellum, mid - brain, cortex Pituitary gland Caecum Preputial gland Cervix Prostate gland Clitoral gland Rectum Colon (Salivary glands - mandibular, sublingual) Coagulation gland Sciatic nerve Duodenum Seminal vesicles Epididymides 1 

### Skeletal muscle Eyes (with optic nerve (if detectable) and Harderian gland) 1 

### (Skin) Spinal cord - cervical, midthoracic, lumbar Female mammary gland area Spleen Femur including joint Sternum with bone marrow Heart Stomach Ileum Testes 1 

### Jejunum Thymus Kidneys Thyroid including parathyroid if detectable (Lacrimal gland, exorbital) (Tongue) (Larynx) Trachea Liver Urinary bladder Lung, infused with formalin Uterus Lymph nodes - mandibular, mesenteric Vagina (Nasopharynx) All gross lesions ( E sophagus) All remaining animals, females which fail ed to deliver 2 

### and females with total litter loss 3 

### : Cervix Preputial gland Clitoral gland Prostate gland Coagulation gland Seminal vesicles Epididymides 1 

### Testes 1 

### Mammary gland area 3 

### Uterus Ovaries Vagina Identification marks: not processed All gross lesions 1 

### Fixed in modified Davidson's solution (prepared at WIL Research Europe using Formaldehyde 37- 40%, Ethanol, Acetic acid (glacial) (all Merck, Darmstadt, Germany) and Milli-Ro water (Millipore Corporation, Bedford, USA)) and transferred to formalin after fixation for at least 24 hours. 2 

### In case no macroscopically visible implantation sites we re present, nongravid uteri were stained using the Salewski technique (Ref. 1) in order to detect any former implantation sites (Salewski staining prepared at WIL Research Europe using Ammoniumsulfide-solution 20% (Merck, Darmstadt, Germany) and Milli-Ro water (Millipore Corporation, Bedford, USA)). 3 

### The mammary gland area wa s required for female no. 53 with total litter loss in which the pup had no milk visible in the stomach. Tissues/organs mentioned in parentheses were not examined by the pathologist, since no signs of toxicity were noted at macroscopi c examination.

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### 6.8.2. Necropsy pups Pups surviving to planned termination were killed by decapitation on Days 5-7 of lactation. All pups were sexed and descriptions of all external abnormalities were recorded. The stomach of pups not surviving to the scheduled necropsy date were examined for the presence of milk. If possible, defects or cause of death were evaluated. 6.8.3. Organ weights Terminal body weight w as recorded from all males and the selected 5 females/sex/group. The following organ weights were recorded from the following animals on the scheduled day of necropsy: Selected 5 animals/sex/group: Adrenal glands Spleen Brain Testes Epididymides Thymus Heart Uterus (including cervix) Kidneys Prostate 1 

### Liver Seminal vesicles including coagulating glands 1 

### Ovaries Thyroid including parathyroid 1 1 weighed when fixed for at least 24 hours. 

### All remaining males: Epididymides Testes 6.8.4. Histotechnology All organ and tissue samples, as defined under Histopathology (following section), were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin (Klinipath, Duiven, The Netherlands). From the selected 5 males of the control and high dose group and all males suspected to be infertile additional slides of the testes were prepared to examine staging of spermatogenesis. The testes were processed, sectioned at 3-4 micrometers, and stained with PAS/haematoxylin (Klinipath, Duiven, The Netherlands). 6.8.5. Histopathology The following slides were examined by a pathologist:

- The preserved organs and tissues of the selected 5 animals/sex of Groups 1 and 4.

- The additional slides of the testes of the selected 5 males of Groups 1 and 4 and all males suspected to be infertile to examine staging of spermatogenesis.

- All gross lesions of all animals (all dose groups).

- The spleen of the selected 5 fe males of Groups 2 and 3, based on (possible) treatment-related changes in this organ in Group 4 females.

- The reproductive organs 1 

### of all males that failed to sire and all females that failed to deliver healthy pups: Group Female / Male nos. Reason 1 42 / 02 No offspring 2 52 / 12

53 / 13 59 / 19 No offspring

Total litter loss No offspring 3 61 - 70 / 21 - 30 All no offspring 4 71 - 80 / 31 - 40 All no offspring 1 Reproductive organs included the cervix, clitoral gland, coagulation gland, epididymides, ovaries, preputial gland, prostate gland, seminal vesicles, testes, uterus, and vagina.

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### All abnormalities were described and included in the report. An attempt was made to correlate gross observations with microscopic findings. A peer review on the histopathology data was performed by a second pathologist. 6.9. Electronic data capture Observations/measurements in the study were recorded electronically using the following programs:



## - REES Centron Environmental Monitoring system version SQL 2.0 (REES Scientific, Trenton, NJ, USA).

- TOXDATA version 8.0 (WIL Research Europe B.V., ‘s -Hertogenbosch, The Netherlands): Mortality / Clinical signs / Body weights / Food consumption / Reproduction parameters / Observations pups / Organ weights.

- ADVIA ® 120 Hematology SystemVersion V.3.1.8.0.MS (Siemens Healthcare Diagnostics B.V., Breda, The Netherlands): Haematology.

- STA Compact ®

version 107.07 (Diagnostica Stago S.A.S., Asnières, France): Clotting parameters.

- AU400 ® Chemistry System version 8.2A (Beckman Coulter Nederland B.V., Woerden, The Netherlands): Clinical biochemistry.

- Motor Monitor version 08356-14 (Kinder Scientific LLC, Poway, USA): Motor activity measurement.

- Pathdata version 6.2D (Pathology Data Systems, Basel, Switzerland): Histopathology.

- Empower version 7.00 (Waters, Milford, MA, USA) : Analytical chemistry. T wo project numbers were used to collect online data (all data was reported under Project 500682 ). Project number Online data 501107 Parental animals: mortality, clinical signs, functional observations (except motor

activity), body weights and food consumption pre - mating period, body weights mating period, food consumption mating period (males only), clinical laboratory investigations, macroscopic findings and organ weights 500682 All other data 6.10. Interpretation 6.10.1. Calculations For each group, the following calculations were performed: M ating index (%) Number of females mated x 100 Number of females paired Fertility index (%) Number of pregnant females x 100 Number of females paired Conception index (%) Number of pregnant females x 100 Number of females mated Gestation index (%) Number of females bearing live pups x 100 Number of pregnant females Duration of gestation Number of days between confirmation of mating and the beginning of parturition Percentage live males at First Litter Check Number of live male pups at First Litter Check x 100 Number of live pups at First Litter Check

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### Percentage live females at First Litter Check Number of live female pups at First Litter Check x 100 Number of live pups at First Litter Check Percentage of postnatal loss Number of dead pups before planned necropsy x 100 Number of live pups at First Litter Check Viability index Number of live pups before planned necropsy x 100 Number of pups born alive 6.10.2. Statistical analyses The following statistical methods were used to analyze the data:

 If the variables could be assumed to follow a normal distribution, the Dunnett-test (Ref. 2; manyto -one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.

 The Steel-test (Ref. 3; many- to -one rank test) was applied if the data could not be assumed to follow a normal distribution.

 The Fisher Exact-test (Ref. 4) was applied to frequency data.

 The Kruskal-Wallis nonparametric ANOVA test (Ref. 5) was applied to motor activity data to determine intergroup differences. In case intergroup differences were seen, the Wilcoxon test (Ref. 6) was applied to compare the treated groups to the control group. All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values. 6.11. List of deviations 6.11.1. List of protocol deviations 1 . Temporary d eviations from the minimum level of daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations. 2. N o clinical observations were registered in the computer for all pup s of litter 58 (Group 2 ) on Day 4 of lactation. Evaluation: Sufficient observations were conducted for adequate assessment of the study results . Moreover, these pups were weighed on Day 4 of lactation and therefore no major signs would have been missed. 3. The cervix from female no. 66, the vagina f rom female no. 65, and the coagulating glands from male nos. 23 and 35 were not available for histopathology. Evaluation: Sufficient data was available for evaluation. 4. Pup 11 from litter 54 was fixed in 10% buffered formalin . Evaluation: This pup was fixed due to an abnormal posture of the left hind leg, and w a s not further processed. This fixation does not affect interpretation of the study outcome. The study integrity was not adversely affected by the deviations. 6.11.2. List of standard operating procedure deviations Any deviations from standard operating procedures were evaluated and filed in the study file. There were no deviations from standard operating procedures that affected the integrity of the study.

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### 7. RESULTS 7.1. Analysis of dose preparations The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%). No test substance was detected in the Group 1 formulations . The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%). For further details, see APPENDIX 4. 7.2. Observations parental animals For further detail on summary data, see APPENDIX 1 and on individual data, see APPENDIX 2. Note to clinical signs tables : For males, “Repro period” represents the mating phase. For females, “Repro period” represents the mating, post coitum and lactation phase. 7.2.1. Mortality No mortality occurred during the study period. One female (no. 53) at 100 mg/kg was sacrificed before scheduled necropsy due to total litter loss on Day 5 of lactation. 7.2.2. Clinical signs No clinical signs of toxicity were noted during the observation period. For one female at 300 mg/kg (no. 61) blood coming out of the vagina was recorded on the scheduled day of necropsy. This was considered to be related to the observation of a large fetus at necropsy of this same animal, and no such finding was noted for any of the other females. The incidence of alopecia and scabs occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological relevance. 7.2.3. Functional observations Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all animals tested. No toxicologically relevant changes in motor activity were noted. Fo r motor activity, all groups showed a similar habituation profile with high activity in the first interval that decreased over the duration of the test period. The higher motor activity of females at 300 and 1000 mg/kg (statistically significant at 1000 mg/kg) was considered due to these females not having delivered offspring. This variation was therefore considered to be of no toxicological relevance. 7.2.4. Body weights No toxicologically relevant changes in body weights and body weight gain were noted. The lower body weight gain of the two females at 300 mg/kg found pregnant (based on implantation sites) and two females (nos. 53 and 59) at 100 mg/kg during the end of the post-coitum period was considered to be due to a small litter size or absence of litters, and was therefore not considered toxicologically relevant. The pregnant females at 100 mg/kg showed a normal body weight gain during the complete study period.

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### No data on body weight gain during lactation was obtained at 300 and 1000 mg/kg as no litters were born in these groups. 7.2.5. Food consumption No toxicologically relevant changes in food consumption before or after correction for body weight was noted. The lower food intake of the two females at 300 mg/kg found pregnant based on implantation sites (but no offspring) and two females (nos. 53 and 59) at 100 mg/kg during the end of the post-coitum period (and for female no. 53 also during lactation) was considered to be due to a small litter size or absence of litters, and was therefore not considered toxicologically relevant. 7.2.6. Haematology No toxicologically relevant changes were noted in haematological parameters. The lower reticulocyte counts at 300 and 1000 mg/kg were considered to be due to the pregnancy status (small litter size or absence of litters), and to be within the physiological range of non-pregnant females . The higher relative neutrophil counts with concurrently lower relative lymphocyte counts for on e female (no. 80) at 1000 mg/kg was considered to be a secondary non-specific response to stress , and similar changes in other animals of the same group were absent. The statistically significantly higher activated partial thromboplastin time (APTT) for females at 300 mg/kg occurred in the absence of a dose-related tren d. The higher reticulocyte, red cell distribution width (RDW) and/or mean corpuscular volume (MCV) values shown by two females at 100 mg/kg (nos. 54 and 60) were not seen for other animals of this dose group. These changes were therefore considered to be of no toxicological relevance. 7.2.7. Clinical biochemistry No toxicologically relevant changes were noted in clinical biochemistry parameters. All statistically significant changes in clinical biochemistry parameters in males at 100 and 300 mg/kgwere considered to be of no toxicological significance as they occurred in the absence of a doserelated trend and remained within the range considered normal for rats of this age and strain. These changes consisted of higher total bilirubin, creatinine, bile acid and sodium levels and lower cholesterol levels. The statistically significantly changes for females at 300 and 1000 mg/kg were considered to have occurred due to the pregnancy status of these females (small litter size or absence of litters), and means remained within the range of values expected for non-pregnant females of a similar age and same strain. These changes consisted of a lower alanine aminotransferase activity level (ALAT), higher albumin, sodium and chloride level, and lower urea level. The lower sodium level of females at 100 mg/kg remained within the range considered normal for rats of this age and strain . These changes were therefore considered to be of no toxicological relevance. 7.2.8. Macroscopic examination Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a direct result of treatment. T he large fetus noted in utero of female no. 61 at 300 mg/kg was considered due to it being the only fetus growing larger than normal compared to fetuses from a larger litter. This was therefore considered to be an indirect effect of treatment. The incidence of other necropsy findings among control and treated animals was within the background range of findings that are encountered among rats of this age and strain, and did not show a dose-related incidence trend. No toxicological relevance was therefore ascribed to these findings.

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### 7.2.9. Organ weights No toxicologically relevant changes were noted in organ weights and organ to body weight ratios. The statistically significant lower liver weight, and higher thymus and ovary weight of females at 300 and 1000 mg/kg were considere d to be due to their pregnancy status (small litter size or absence of litters). The statistically significantly higher thyroid to body weight ratio of females at 1000 mg/kg remained within the range considered normal for rats of this age and strain, and occurred in the absence of correlating treatment-related histopathology findings. These changes were therefore not considered toxicologically relevant. 7.2.10. Microscopic examination No toxicologically relevant microscopic findings were noted. The microscopic findings for one female treated at 1000 mg/kg (no. 80) were regarded to be related to a gavage accident, because of the single incidence and the recorded disruption of the normal glandular stomach architecture. The remainder of microscopic findings recorded were within the normal range of background pathology encountered in Wistar (Han) rats of this age. No histological correlation could be made for the lack of offspring. All females showed a normal reproductive cycle. For the males, no abnormalities were seen in the reproductive organs which could account for their infertility. Furthermore, the spermatogenic staging profiles were normal for all examined males. For further details, see APPENDIX 5. 7.3. Reproduction/developmental data For further detail on summary data, see APPENDIX 1 and on individual data, see APPENDIX 2. 7.3.1. Reproduction data Reproduction parameters were affected at all dose levels. At 1000 mg/kg, no ne of the females were found pregnant . At 300 mg/kg, only two females were found pregnant based on presence of implantation sites, resulting in a reduced fertility and conception index. The two pregnant females showed a reduced number of corpora lutea and /or implantation sites. At 100 mg/kg, nine females were found pregnant. One of these females (no. 59) was found pregnant based on presence of implantation sites. One female (no. 52) was found not pregnant, and one female (no. 53) had a total litter loss (her single pup died on Day 5 of lactation). Female no. 53 and 59 showed a reduced number of corpora lutea and implantation sites. Other pregnant females of this dose group showed a normal number of corpora lutea and implantation sites. Mating index and precoital time were unaffected by treatment up to 1000 mg/kg.

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### 7.3.2. Developmental data No toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed at 100 mg/kg. At 300 and 1000 mg/kg no pups were delivered, and hence developmental effects could not be assessed for these dose levels. Mortality One pup of the control group was missing (most likely cannibalised) on Day 2 of lactation, three pups at 100 mg/kg were found dead at first litter check, and one pup at 100 mg/kg was found dead on Day 5 of lactation. No toxicological relevance was attributed to these dead/missing pups since the mortality incidences remained within the range considered normal for pups of this age. Observations The one pup of litter 53 at 100 mg/kg that was found dead on Day 5 of lactation showed a lean appearance from first litter check onwards and absence of milk in the stomach from Day 2 onwards. In addition, this pup showed a slight weight loss over Days 1-4 of lactation. At this single occurrence, it was not considered toxicologically significant. Incidental findings consisted of a wound, scabbing, absence of milk in the stomach, blue spot, and abnormal posture of the hindleg. The pups that were found dead at first litter check showed severe autolysis. The nature and incidence of these findings remained within the range considered normal for pups of this age, and were therefore considered to be of no toxicological relevance. Absence of milk in the stomach was noted for one litter (no. 41) of the control group. This finding for these control pups surviving to the scheduled necropsy is likely secondary to the time when the actual necropsies were performed, and not considered toxicologically relevant.

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### 8. DISCUSSION AND CONCLUSION COPS_1 or CS-AHPS was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 100 , 300 and 1000 mg/kg. Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 29 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum , and at least 4 days of lactation (for 42 -48 days). Formulation analysis showed that the formulations were prepared accurately and homogenously. Parental results: No toxicologically relevant findings were observed up to the highest dose level tested (1000 mg/kg). Several effects considered to be secondary to a small litter size or absence of litters were noted for females at 300 and 1000 mg/kg in motor activity, body weight gain, food consumption, clinical biochemistry parameters, organ weights and microscopic examinations. No direct treatment-related changes were noted in any of the parental parameters investigated in this study (i.e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). Reproductive results: At 1000 mg/kg, none of the females were found pregnant, and at 300 mg/kg only two females were found pregnant (based on presence of implantation sites) and showed a reduced number of corpora lutea and implantation sites . At 100 mg/kg, nine females were found pregnant (one of these based on pres ence of implantation sites). One female was found not pregnant, and one female had a total litter loss (her single pup died on Day 5 of lactation). Two females showed a reduced number of corpora lutea and implantation sites, while other pregnant females of this dose group showed a normal number of corpora lutea and implantation sites. As these findings at 100 mg/kg were in line with the affected reproduction noted at 300 and 1000 mg/kg, a possible treatment related effect could not be excluded. Mating index and precoital time were normal up to the highest dose level tested (1000 mg/kg). Developmental results: No developmental toxicity was observed at 100 mg/kg in any of the developmental parameters investigated in this study (i.e. gestation index and duration, parturition, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight and macroscopy). Developmental effects could not be assessed at 300 and 1000 mg/kg as no pups were born. In conclusion, treatment with COPS_1 or CS-AHPS by oral gavage in male and female Wistar Han rats at dose levels of 100 , 300 and 1000 mg/kg revealed no pa rental toxicity up to 1000 mg/kg. Reproduction toxicity was observed at all dose levels. No developmental toxicity was observed at 100 mg/kg. However, developmental toxicity could not be assessed at 300 and 1000 mg/kg since no pups were born. Based on these results, the following No Observed Adverse Effect Levels (NOAEL) were derived: Parental NOAEL: at least 1000 mg/kg (409 mg active ingredient/kg) Reproduction NOAEL: could not be determined (below 100 mg/kg (41 mg active ingredient/ kg )) Developmental NOAEL: at least 100 mg/kg (41 mg active ingredient/kg)

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### 9. REFERENCES Ref. 1 Salewski, E. Färbemethode zum makroskopischen Nachweis von Implantationsstellen

am Uterus der Ratte. [Staining method for a macroscopic test for implantation sites in the uterus of the rat]. Naunyn - Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie, 247, 367 (1964). Ref. 2 Dunnett C.W., A Multiple Comparison Procedure for Comparing Several Treatments

with a Control, J. Amer. Stat. Assoc. 50, 1096-1121 (1955). Ref. 3 Miller R.G., Simultaneous Statistical Inference, Springer Verlag, New York (1981). Ref. 4 Fisher R.A., Statistical Methods for Research Workers, Oliver and Boyd, Edinburgh

(1950). Ref. 5 Kruskal W.H. and Wallis W.A.. Use of ranks in one-criterion variance analysis. Journal

of the American Statistical Association 47 (260): 583-621, December (1952). Ref. 6 Wilcoxon, F. Individual comparisons by ranking methods. Biometrics , 1 , 80 -83 (1945).

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APPENDIX 1

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### APPENDIX 1 SUMMARY TABLES23May13 12h42

.: Observation performed, sign not present %: Percent of affected animals (0=less than 5%, 1=between 5% and 15%,..., A=more than 95%) G: Median value of the highest individual daily grades COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.1 CLINICAL SIGNS SUMMARY MALES PRE MATING MATING PERIOD SIGN (MAX. GRADE) (LOCATION) WEEK: DAY: 1

1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 1 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 4 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 ' GROUP 1 (CONTROL) Skin / fur . Alopecia (3) G: . . . . . . . . . 11111 111111111111111 . %: . . . . . . . . . 11111 111111111111111 . GROUP 2 (100 MG/KG) Skin / fur . Scabs (3) G: . . . . . . . . . . . . . . . . . . . . . . . . 11111 . (Neck) %: . . . . . . . . . . . . . . . . . . . . . . . . 11111 . GROUP 3 (300 MG/KG) No clinical signs noted . GROUP 4 (1000 MG/KG) No clinical signs noted . FEMALES PRE MATING MATING PERIOD SIGN (MAX. GRADE) (LOCATION) WEEK: DAY: 1

1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 1 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 4 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 ' GROUP 1 (CONTROL) No clinical signs noted . GROUP 2 (100 MG/KG) No clinical signs noted . GROUP 3 (300 MG/KG) No clinical signs noted . GROUP 4 (1000 MG/KG) No clinical signs noted . REPRO PERIOD

REPRO PERIOD23May13 12h42

+/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.2 FUNCTIONAL OBSERVATIONS SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' AT WEEK 4 HEARING MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. PUPIL L MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. PUPIL R MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. STATIC R MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. GRIP MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3 #

300 MG/KG GROUP 4 #

1000 MG/KG ' AT LACTATION HEARING MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. PUPIL L MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. PUPIL R MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. STATIC R MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

. GRIP MEDIAN 0 0 0 0 . SCORE 0/1 N 5 5 5 5 .

.

# End of post-coitum period for Group 3 and 4 femalesCOPS_1 or CS-AHPS Project 500682

APPENDIX 1 1.3 MOTOR ACTIVITY TEST SUMMARY MALES AT WEEK 4 GROUP 1 CONTROL Total Movements MEAN 1 4680 5290 4200 4127 ST.DEV 1077 2088 1163 1366 N 5 5 5 5 Ambulations MEAN 1 792 964 876 815 ST.DEV 151 381 198 249 N 5 5 5 5

*/** Wilcoxon test significant at 5% (*) or 1% (**) level 1 Group mean of all intervals combined 2 Mean counts per interval. GROUP 2 100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG



### 0 200 400 600 800 1000 1200 1400

1 2 3 4 5 6 7 8 9 10 11 12Counts



### Interval (5 min) 

## Total Movements Males 2 

### Group 1 Group 2 Group 3 Group 4



### 0 50 100 150 200 250 300 350

1 2 3 4 5 6 7 8 9 10 11 12Counts



### Interval (5 min) 

## Ambulations Males 2 

### Group 1 Group 2 Group 3 Group 4COPS_1 or CS-AHPS Project 500682

APPENDIX 1 1.3 MOTOR ACTIVITY TEST SUMMARY FEMALES LACTATION GROUP 1 CONTROL MEAN 1 3775 4488 5578 6663 * ST.DEV 1196 1212 1140 1646 N 5 5 5 5 Ambulations MEAN 1 762 1086 1235 1537 ST.DEV 354 408 333 332 N 5 5 5 5

*/** Wilcoxon test significant at 5% (*) or 1% (**) level 1 Group mean of all intervals combined 2 Mean counts per interval. Total Movements GROUP 2 100 MG/KG GROUP 3 #

300 MG/KG GROUP 4 #

1000 MG/KG



### 0 200 400 600 800 1000 1200 1400 1600

1 2 3 4 5 6 7 8 9 10 11 12Counts



### Interval (5 min) 

## Total Movements Females 2 

### Group 1 Group 2 Group 3 Group 4



### 0 50 100 150 200 250 300 350 400 450

1 2 3 4 5 6 7 8 9 10 11 12Counts



### Interval (5 min) 

## Ambulations Females 2 

### Group 1 Group 2 Group 3 Group 4

# End of post-coitum period for Group 3 and 4 females23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 4 BODY WEIGHTS (GRAM) SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAY 1 MEAN 324 320 320 322 . WEEK 1 ST.DEV 5.6 8.1 6.4 12.3 . N 10 10 10 10 .

. DAY 8 MEAN 343 335 335 341 . WEEK 2 ST.DEV 8.9 11.8 9.6 15.6 . N 10 10 10 10 .

. MATING PERIOD DAY 1 MEAN 361 352 356 358 . WEEK 1 ST.DEV 10.7 12.2 13.2 17.4 . N 10 10 10 10 .

. DAY 8 MEAN 371 365 365 366 . WEEK 2 ST.DEV 12.0 12.3 16.9 16.2 . N 10 10 10 10 .

. DAY 15 MEAN 385 383 381 383 . WEEK 3 ST.DEV 14.6 15.2 21.9 19.0 . N 10 10 10 10 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 4 BODY WEIGHTS (GRAM) SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAY 1 MEAN 207 205 201 204 . WEEK 1 ST.DEV 6.3 6.8 7.6 5.8 . N 10 10 10 10 .

. DAY 8 MEAN 217 216 213 211 . WEEK 2 ST.DEV 10.0 6.1 7.6 7.1 . N 10 10 10 10 .

. MATING PERIOD DAY 1 MEAN 226 223 221 222 . WEEK 1 ST.DEV 10.3 6.5 8.4 5.4 . N 10 10 10 10 .

.23May13 14h14

Explanations for excluded data are listed in the tables of the individual values */** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 4 BODY WEIGHTS (GRAM) SUMMARY FEMALES F0-GENERATION GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG ' POST COITUM DAY 0 MEAN 225 222 223 . ST.DEV. 9.6 5.8 0.0 . N 9 9 2 .

. DAY 4 MEAN 239 236 238 . ST.DEV. 9.6 8.2 0.7 . N 9 9 2 .

. DAY 7 MEAN 247 244 249 . ST.DEV. 12.0 8.2 2.1 . N 9 9 2 .

. DAY 11 MEAN 263 260 255 . ST.DEV. 12.5 12.1 1.4 . N 9 9 2 .

. DAY 14 MEAN 275 270 252 . ST.DEV. 13.3 11.9 2.8 . N 9 9 2 .

. DAY 17 MEAN 299 292 252 ** . ST.DEV. 12.0 22.8 6.4 . N 9 9 2 .

. DAY 20 MEAN 336 320 257 ** . ST.DEV. 12.7 37.6 16.3 . N 9 9 2 .

. LACTATION DAY 1 MEAN 260 258 --- . ST.DEV. 13.0 10.0 --- . N 9 8 0 .

. DAY 4 MEAN 274 273 --- . ST.DEV. 11.5 16.3 --- . N 9 8 0 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 5 BODY WEIGHT GAIN (%) SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAY 1 MEAN 0 0 0 0 . WEEK 1 ST.DEV 0.0 0.0 0.0 0.0 . N 10 10 10 10 .

. DAY 8 MEAN 6 5 5 6 . WEEK 2 ST.DEV 1.3 2.0 1.5 2.1 . N 10 10 10 10 .

. MATING PERIOD DAY 1 MEAN 11 10 11 11 . WEEK 1 ST.DEV 2.0 2.7 2.5 2.4 . N 10 10 10 10 .

. DAY 8 MEAN 15 14 14 14 . WEEK 2 ST.DEV 2.7 2.5 3.8 2.0 . N 10 10 10 10 .

. DAY 15 MEAN 19 20 19 19 . WEEK 3 ST.DEV 3.1 2.9 5.1 2.6 . N 10 10 10 10 .

. FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAY 1 MEAN 0 0 0 0 . WEEK 1 ST.DEV 0.0 0.0 0.0 0.0 . N 10 10 10 10 .

. DAY 8 MEAN 5 5 6 3 . WEEK 2 ST.DEV 2.7 2.5 4.2 1.8 . N 10 10 10 10 .

. MATING PERIOD DAY 1 MEAN 9 9 10 9 . WEEK 1 ST.DEV 3.6 4.4 4.2 2.9 . N 10 10 10 10 .

.23May13 14h14

Explanations for excluded data are listed in the tables of the individual values */** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 6 BODY WEIGHT GAIN (%) SUMMARY FEMALES F0-GENERATION GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG ' POST COITUM DAY 0 MEAN 0 0 0 . ST.DEV. 0.0 0.0 0.0 . N 9 9 2 .

. DAY 4 MEAN 6 6 7 . ST.DEV. 1.5 2.0 0.3 . N 9 9 2 .

. DAY 7 MEAN 10 10 11 . ST.DEV. 1.8 1.6 1.0 . N 9 9 2 .

. DAY 11 MEAN 17 17 14 . ST.DEV. 2.1 3.1 0.6 . N 9 9 2 .

. DAY 14 MEAN 22 21 13 ** . ST.DEV. 2.2 3.0 1.3 . N 9 9 2 .

. DAY 17 MEAN 33 31 13 ** . ST.DEV. 2.7 8.0 2.9 . N 9 9 2 .

. DAY 20 MEAN 50 44 15 ** . ST.DEV. 4.6 15.3 7.3 . N 9 9 2 .

. LACTATION DAY 1 MEAN 0 0 --- . ST.DEV. 0.0 0.0 --- . N 9 8 0 .

. DAY 4 MEAN 5 6 --- . ST.DEV. 2.5 3.4 --- . N 9 8 0 .

.23May13 12h42

COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 6 FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAYS 1-8 MEAN 24 24 23 24 . WEEKS 1-2 ST.DEV 0.6 0.5 0.2 0.2 . N (CAGE) 2 2 2 2 .

. DAYS 8-15 MEAN 24 24 23 23 . WEEKS 2-3 ST.DEV 0.2 0.2 0.4 0.6 . N (CAGE) 2 2 2 2 .

. MEAN OF MEANS . OVER PRE MATI... MEAN 24 24 23 24 . MATING PERIOD DAYS 1-8 MEAN 25 26 25 25 . WEEKS 1-2 ST.DEV 0.1 0.1 0.3 0.2 . N (CAGE) 2 2 2 2 .

. DAYS 8-15 MEAN 24 25 24 24 . WEEKS 2-3 ST.DEV 0.7 0.2 0.1 0.6 . N (CAGE) 2 2 2 2 .

. MEAN OF MEANS . OVER MATING P... MEAN 24 25 25 25 . FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAYS 1-8 MEAN 17 17 17 17 . WEEKS 1-2 ST.DEV 0.4 0.5 0.1 0.3 . N (CAGE) 2 2 2 2 .

. DAYS 8-15 MEAN 17 17 17 18 . WEEKS 2-3 ST.DEV 0.1 0.5 0.1 0.6 . N (CAGE) 2 2 2 2 .

. MEAN OF MEANS . OVER PRE MATI... MEAN 17 17 17 18 .23May13 14h14

Explanations for excluded data are listed in the tables of the individual values */** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 6 FOOD CONSUMPTION (G/ANIMAL/DAY) SUMMARY FEMALES F0-GENERATION GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG ' POST COITUM DAYS 0-4 MEAN 18 18 18 . ST.DEV. 1.7 1.5 1.1 . N 9 9 2 .

. DAYS 4-7 MEAN 20 20 20 . ST.DEV. 1.9 1.6 1.2 . N 9 9 2 .

. DAYS 7-11 MEAN 21 20 20 . ST.DEV. 1.9 1.6 0.5 . N 9 9 2 .

. DAYS 11-14 MEAN 23 22 20 . ST.DEV. 2.9 1.8 1.2 . N 9 9 2 .

. DAYS 14-17 MEAN 23 23 16 ** . ST.DEV. 1.7 2.8 0.5 . N 9 9 2 .

. DAYS 17-20 MEAN 25 23 18 * . ST.DEV. 1.6 4.4 3.5 . N 9 9 2 .

.

. MEAN OF MEANS 22 21 19 . LACTATION DAYS 1-4 MEAN 32 32 . ST.DEV. 2.8 7.7 . N 9 8 .

.23May13 12h42

COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 7 RELATIVE FOOD CONSUMPTION (G/KG BODY WEIGHT/DAY) SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAYS 1-8 MEAN 70 71 70 70 . WEEKS 1-2 ST.DEV 1.2 1.7 0.8 0.7 . N (CAGE) 2 2 2 2 .

. DAYS 8-15 MEAN 69 71 70 69 . WEEKS 2-3 ST.DEV 0.2 0.5 1.4 2.0 . N (CAGE) 2 2 2 2 .

. MEAN OF MEANS . OVER PRE MATI... MEAN 70 71 70 70 . MATING PERIOD DAYS 1-8 MEAN 68 70 69 69 . WEEKS 1-2 ST.DEV 0.6 0.2 0.4 0.3 . N (CAGE) 2 2 2 2 .

. DAYS 8-15 MEAN 61 65 63 64 . WEEKS 2-3 ST.DEV 1.4 0.2 0.2 1.0 . N (CAGE) 2 2 2 2 .

. MEAN OF MEANS . OVER MATING P... MEAN 65 67 66 66 . FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' PRE MATING DAYS 1-8 MEAN 80 80 80 82 . WEEKS 1-2 ST.DEV 1.0 1.3 1.7 0.3 . N (CAGE) 2 2 2 2 .

. DAYS 8-15 MEAN 80 79 79 84 . WEEKS 2-3 ST.DEV 0.8 1.1 1.5 4.4 . N (CAGE) 2 2 2 2 .

. MEAN OF MEANS . OVER PRE MATI... MEAN 80 79 79 83 .23May13 14h14

Explanations for excluded data are listed in the tables of the individual values */** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 7 RELATIVE FOOD CONSUMPTION (G/KG BODY WEIGHT/DAY) SUMMARY FEMALES F0-GENERATION GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG ' POST COITUM DAYS 0-4 MEAN 75 75 76 . ST.DEV. 5.4 4.6 4.7 . N 9 9 2 .

. DAYS 4-7 MEAN 81 83 78 . ST.DEV. 5.0 4.9 4.1 . N 9 9 2 .

. DAYS 7-11 MEAN 79 78 78 . ST.DEV. 4.3 3.7 2.5 . N 9 9 2 .

. DAYS 11-14 MEAN 83 83 80 . ST.DEV. 6.7 5.2 5.6 . N 9 9 2 .

. DAYS 14-17 MEAN 78 79 62 ** . ST.DEV. 3.5 5.7 0.3 . N 9 9 2 .

. DAYS 17-20 MEAN 74 73 71 . ST.DEV. 3.3 8.2 9.3 . N 9 9 2 .

.

. MEAN OF MEANS 78 78 74 . LACTATION DAYS 1-4 MEAN 116 115 . ST.DEV. 10.7 24.1 . N 9 8 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level +/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 8 HAEMATOLOGY SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT WBC MEAN 9.1 7.3 8.2 7.9 . 10E9/L ST.DEV 2.3 0.8 1.1 2.0 . N 4 5 4 5 .

. Neutrophils MEAN 15.4 15.6 17.5 13.2 . %WBC ST.DEV 2.8 4.0 6.2 2.9 . N 4 5 4 5 .

. Lymphocytes MEAN 81.1 81.1 78.9 83.5 . %WBC ST.DEV 3.0 4.7 6.6 3.4 . N 4 5 4 5 .

. Monocytes MEAN 1.7 2.0 2.0 1.7 . %WBC ST.DEV 0.1 1.0 0.5 0.7 . N 4 5 4 5 .

. Eosinophils MEAN 1.7 1.2 1.5 1.4 . %WBC ST.DEV 0.7 0.2 0.2 0.3 . N 4 5 4 5 .

. Basophils MEAN 0.2 0.2 0.2 0.2 . %WBC ST.DEV 0.1 0.1 0.1 0.0 . N 4 5 4 5 .

. Red blood cells MEAN 8.88 8.71 8.48 8.39 . 10E12/L ST.DEV 0.21 0.54 0.68 0.63 . N 4 5 4 5 .

. Reticulocytes MEAN 2.4 2.6 2.7 2.4 . %RBC ST.DEV 0.3 0.2 0.4 0.4 . N 4 5 4 5 .

. RDW MEAN 12.4 13.0 13.5 12.7 . % ST.DEV 0.7 0.9 1.9 0.7 . N 4 5 4 5 .

. Haemoglobin MEAN 10.2 10.1 10.1 9.7 . mmol/L ST.DEV 0.3 0.5 0.4 0.4 . N 4 5 4 5 .

. Haematocrit MEAN 0.477 0.473 0.466 0.439 . L/L ST.DEV 0.012 0.027 0.022 0.029 . N 4 5 4 5 .

. MCV MEAN 53.8 54.3 55.1 52.4 . fL ST.DEV 1.3 1.0 1.9 1.5 . N 4 5 4 5 .

. MCH MEAN 1.15 1.16 1.20 1.16 . fmol ST.DEV 0.05 0.05 0.05 0.05 . N 4 5 4 5 .

. MCHC MEAN 21.37 21.33 21.73 22.06 . mmol/L ST.DEV 0.55 0.71 0.20 0.54 . N 4 5 4 5 .

. Platelets MEAN 919 842 964 813 . 10E9/L ST.DEV 70 74 48 135 . N 4 5 4 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level +/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 8 HAEMATOLOGY SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT PT MEAN 16.4 16.2 16.4 16.0 . s ST.DEV 0.5 0.4 0.7 0.4 . N 5 5 4 5 .

. APTT MEAN 16.3 15.1 16.5 15.3 . s ST.DEV 2.7 2.2 3.2 4.0 . N 5 5 4 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level +/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 8 HAEMATOLOGY SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT WBC MEAN 4.6 5.2 5.3 6.8 . 10E9/L ST.DEV 1.0 1.5 1.3 2.8 . N 5 5 5 5 .

. Neutrophils MEAN 20.8 25.8 15.6 23.0 . %WBC ST.DEV 3.3 5.1 6.7 32.7 . N 5 5 5 5 .

. Lymphocytes MEAN 75.4 70.8 79.9 72.5 . %WBC ST.DEV 3.4 5.4 7.4 33.7 . N 5 5 5 5 .

. Monocytes MEAN 2.0 1.7 2.4 2.4 . %WBC ST.DEV 0.8 0.2 1.4 1.1 . N 5 5 5 5 .

. Eosinophils MEAN 1.7 1.6 2.0 1.9 . %WBC ST.DEV 0.6 0.5 0.7 0.9 . N 5 5 5 5 .

. Basophils MEAN 0.1 0.1 0.1 0.1 . %WBC ST.DEV 0.0 0.0 0.0 0.0 . N 5 5 5 5 .

. Red blood cells MEAN 7.86 7.27 7.56 8.52 . 10E12/L ST.DEV 0.47 0.54 1.29 0.49 . N 5 5 5 5 .

. Reticulocytes MEAN 5.1 6.8 3.0 1.7 + . %RBC ST.DEV 1.6 3.1 2.8 0.3 . N 5 5 5 5 .

. RDW MEAN 13.9 18.9 12.2 13.6 . % ST.DEV 1.3 5.9 2.3 5.6 . N 5 5 5 5 .

. Haemoglobin MEAN 9.2 9.1 9.0 9.8 . mmol/L ST.DEV 0.4 0.5 1.6 0.2 . N 5 5 5 5 .

. Haematocrit MEAN 0.435 0.424 0.413 0.458 . L/L ST.DEV 0.012 0.016 0.069 0.016 . N 5 5 5 5 .

. MCV MEAN 55.4 58.5 54.7 53.7 . fL ST.DEV 2.2 3.4 1.1 2.0 . N 5 5 5 5 .

. MCH MEAN 1.17 1.26 1.19 1.15 . fmol ST.DEV 0.04 0.07 0.04 0.06 . N 5 5 5 5 .

. MCHC MEAN 21.18 21.50 21.72 21.45 . mmol/L ST.DEV 0.27 0.77 0.42 0.45 . N 5 5 5 5 .

. Platelets MEAN 1080 1079 928 1046 . 10E9/L ST.DEV 169 225 227 180 . N 5 5 5 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level +/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 8 HAEMATOLOGY SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT PT MEAN 16.6 16.0 17.0 16.5 . s ST.DEV 0.3 0.7 0.5 0.4 . N 5 5 5 5 .

. APTT MEAN 12.2 13.2 14.9 * 13.5 . s ST.DEV 1.4 0.4 1.9 1.7 . N 5 5 5 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 9 CLINICAL BIOCHEMISTRY SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT ALAT MEAN 42.6 45.2 40.1 38.1 . U/L ST.DEV 4.7 8.1 5.9 6.5 . N 5 5 5 5 .

. ASAT MEAN 79.5 80.2 77.2 75.6 . U/L ST.DEV 3.8 8.7 16.0 7.9 . N 5 5 5 5 .

. ALP MEAN 131 137 117 128 . U/L ST.DEV 29 37 13 29 . N 5 5 5 5 .

. Total protein MEAN 65.7 64.5 66.1 65.5 . g/L ST.DEV 1.7 3.2 2.5 1.5 . N 5 5 5 5 .

. Albumin MEAN 33.4 32.9 34.1 33.1 . g/L ST.DEV 0.8 0.9 0.5 0.5 . N 5 5 5 5 .

. Total bilirubin MEAN 2.4 2.3 2.9 * 2.1 . umol/L ST.DEV 0.2 0.3 0.4 0.2 . N 5 5 5 5 .

. Urea MEAN 6.2 6.9 6.1 6.4 . mmol/L ST.DEV 0.5 1.0 1.0 1.0 . N 5 5 5 5 .

. Creatinine MEAN 39.5 43.1 * 41.2 40.8 . umol/L ST.DEV 1.3 2.6 2.9 1.4 . N 5 5 5 5 .

. Glucose MEAN 8.93 9.64 8.54 9.72 . mmol/L ST.DEV 0.94 0.98 1.61 1.58 . N 5 5 5 5 .

. Cholesterol MEAN 2.19 1.80 * 1.68 ** 1.84 . mmol/L ST.DEV 0.17 0.23 0.21 0.27 . N 5 5 5 5 .

. Bile Acids MEAN 12.0 20.1 24.9 ** 16.5 . umol/L ST.DEV 3.6 8.5 7.0 2.7 . N 5 5 5 5 .

. Sodium MEAN 142.8 143.6 146.8 * 142.8 . mmol/L ST.DEV 0.7 1.5 4.5 1.1 . N 5 5 5 5 .

. Potassium MEAN 4.07 3.89 4.34 4.21 . mmol/L ST.DEV 0.22 0.07 0.28 0.20 . N 5 5 5 5 .

. Chloride MEAN 102 102 106 103 . mmol/L ST.DEV 2 2 4 2 . N 5 5 5 5 .

. Calcium MEAN 2.61 2.55 2.62 2.58 . mmol/L ST.DEV 0.07 0.04 0.06 0.04 . N 5 5 5 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 9 CLINICAL BIOCHEMISTRY SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT Inorg.Phos MEAN 2.01 1.93 1.83 1.90 . mmol/L ST.DEV 0.16 0.20 0.11 0.18 . N 5 5 5 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 9 CLINICAL BIOCHEMISTRY SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT ALAT MEAN 58.6 60.9 27.5 ** 37.4 * . U/L ST.DEV 19.1 4.8 5.9 7.0 . N 5 5 5 5 .

. ASAT MEAN 86.7 88.2 67.7 80.8 . U/L ST.DEV 14.1 21.7 7.1 5.7 . N 5 5 5 5 .

. ALP MEAN 103 94 55 51 . U/L ST.DEV 57 55 14 6 . N 5 5 5 5 .

. Total protein MEAN 64.2 64.2 68.8 66.3 . g/L ST.DEV 2.3 3.4 1.8 4.2 . N 5 5 5 5 .

. Albumin MEAN 32.8 32.8 37.1 ** 34.8 . g/L ST.DEV 1.4 1.4 0.8 3.0 . N 5 5 5 5 .

. Total bilirubin MEAN 2.1 1.9 2.8 2.5 . umol/L ST.DEV 0.2 0.2 1.0 0.3 . N 5 5 5 5 .

. Urea MEAN 8.6 8.0 6.1 ** 6.7 * . mmol/L ST.DEV 1.7 0.9 0.8 0.8 . N 5 5 5 5 .

. Creatinine MEAN 42.3 43.6 44.9 41.6 . umol/L ST.DEV 1.0 3.7 3.0 2.6 . N 5 5 5 5 .

. Glucose MEAN 7.85 7.38 8.25 7.28 . mmol/L ST.DEV 0.75 0.87 0.62 0.77 . N 5 5 5 5 .

. Cholesterol MEAN 1.67 1.84 1.47 1.21 . mmol/L ST.DEV 0.27 0.46 0.42 0.28 . N 5 5 5 5 .

. Bile Acids MEAN 26.6 27.1 14.7 20.2 . umol/L ST.DEV 12.6 14.4 8.4 5.7 . N 5 5 5 5 .

. Sodium MEAN 140.5 138.8 * 141.1 142.3 * . mmol/L ST.DEV 0.7 1.6 0.7 0.6 . N 5 5 5 5 .

. Potassium MEAN 3.88 3.91 3.84 3.79 . mmol/L ST.DEV 0.34 0.43 0.16 0.19 . N 5 5 5 5 .

. Chloride MEAN 99 97 103 * 104 ** . mmol/L ST.DEV 3 2 1 2 . N 5 5 5 5 .

. Calcium MEAN 2.64 2.57 2.68 2.66 . mmol/L ST.DEV 0.09 0.10 0.09 0.10 . N 5 5 5 5 .

.23May13 12h42

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 9 CLINICAL BIOCHEMISTRY SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT Inorg.Phos MEAN 1.97 2.02 1.71 1.79 . mmol/L ST.DEV 0.54 0.17 0.11 0.08 . N 5 5 5 5 .

.04Jun13 08h02

# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.1 0 MACROSCOPIC FINDINGS SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT Animals examined 10 10 10 10 . Animals without findings 9 8 9 7 .

. Animals affected 1 2 1 3 .

. Liver . Diaphragmatic hernia 0 0 0 1 . Kidneys . Pelvic dilation 0 1 0 1 . Testes . Reduced in size 0 0 0 1 . Epididymides . Nodule(s) 0 2 1 0 . Reduced in size 0 0 0 1 . Thymus . Focus/foci 1 0 0 0 . Mandibular lymph n . Enlarged 0 0 0 1 . Skin . Scab formation 0 1 0 0 . FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' INTERCURRENT DEATH Animals examined 1 . Animals affected 1 .

. General observations . Total litter loss 1 . END OF TREATMENT Animals examined 10 9 10 10 . Animals without findings 9 6 9 8 .

. Animals affected 1 3 1 2 .

. Duodenum . Thickened 1 1 0 0 . Jejunum . Thickened 1 1 0 0 . Kidneys . Pelvic dilation 0 1 0 0 . Discolouration 0 1 0 0 . Uterus . Right horn: large fetus. 0 0 1 0 . Contents: 0 0 1 0 . Clitoral glands . Focus/foci 0 1 0 0 . Discolouration 0 0 0 1 . Adrenal glands . Enlarged 0 1 0 1 . Discolouration 0 1 0 0 . Spleen . Enlarged 0 1 0 0 . Thymus . Discolouration 0 0 0 1 .04Jun13 08h02

# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.1 0 MACROSCOPIC FINDINGS SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT Mesenteric lymph n . Enlarged 0 0 0 1 . Mandibular lymph n . Discolouration 0 0 0 1 .04Jun13 08h02

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.11 ORGAN WEIGHTS (GRAM) SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT BODY W. MEAN 361 358 356 359 . (GRAM) ST.DEV 13 16 20 19 . N 10 10 10 10 .

. BRAIN MEAN 2.06 2.06 1.98 2.05 . (GRAM) ST.DEV 0.08 0.07 0.08 0.04 . N 5 5 5 5 .

. HEART MEAN 1.044 1.039 1.070 1.057 . (GRAM) ST.DEV 0.118 0.052 0.051 0.078 . N 5 5 5 5 .

. LIVER MEAN 8.68 8.42 8.38 9.06 . (GRAM) ST.DEV 0.24 0.69 1.01 0.41 . N 5 5 5 5 .

. THYROIDS MEAN 0.027 0.028 0.030 0.024 . (GRAM) ST.DEV 0.007 0.004 0.010 0.007 . N 5 5 5 5 .

. THYMUS MEAN 0.314 0.327 0.379 0.353 . (GRAM) ST.DEV 0.040 0.068 0.032 0.055 . N 5 5 5 5 .

. KIDNEYS MEAN 2.32 2.42 2.30 2.60 . (GRAM) ST.DEV 0.15 0.09 0.24 0.35 . N 5 5 5 5 .

. ADRENALS MEAN 0.064 0.061 0.063 0.064 . (GRAM) ST.DEV 0.007 0.006 0.011 0.004 . N 5 5 5 5 .

. SPLEEN MEAN 0.628 0.652 0.708 0.640 . (GRAM) ST.DEV 0.078 0.097 0.223 0.133 . N 5 5 5 5 .

. TESTES MEAN 3.63 3.66 3.67 3.35 . (GRAM) ST.DEV 0.29 0.28 0.24 0.29 . N 10 10 10 10 .

. PROSTATE MEAN 0.565 0.588 0.648 0.638 . (GRAM) ST.DEV 0.182 0.060 0.127 0.133 . N 5 5 5 5 .

. EPIDIDYMIDES MEAN 1.168 1.215 1.203 1.140 . (GRAM) ST.DEV 0.057 0.166 0.092 0.097 . N 10 10 10 10 .

. SEMINAL VES MEAN 1.382 1.410 1.306 1.543 . (GRAM) ST.DEV 0.091 0.238 0.070 0.091 . N 5 5 5 5 .

.04Jun13 08h02

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.11 ORGAN/BODY WEIGHT RATIOS (%) SUMMARY MALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT BODY W. MEAN 361 358 356 359 . (GRAM) ST.DEV 13 16 20 19 . N 10 10 10 10 .

. BRAIN MEAN 0.57 0.58 0.56 0.57 . (%) ST.DEV 0.03 0.04 0.04 0.03 . N 5 5 5 5 .

. HEART MEAN 0.289 0.293 0.303 0.292 . (%) ST.DEV 0.034 0.014 0.018 0.015 . N 5 5 5 5 .

. LIVER MEAN 2.40 2.37 2.37 2.50 . (%) ST.DEV 0.06 0.11 0.22 0.07 . N 5 5 5 5 .

. THYROIDS MEAN 0.007 0.008 0.009 0.007 . (%) ST.DEV 0.002 0.001 0.003 0.002 . N 5 5 5 5 .

. THYMUS MEAN 0.087 0.092 0.107 0.098 . (%) ST.DEV 0.010 0.018 0.004 0.019 . N 5 5 5 5 .

. KIDNEYS MEAN 0.64 0.68 0.65 0.72 . (%) ST.DEV 0.04 0.04 0.04 0.07 . N 5 5 5 5 .

. ADRENALS MEAN 0.018 0.017 0.018 0.018 . (%) ST.DEV 0.002 0.002 0.003 0.002 . N 5 5 5 5 .

. SPLEEN MEAN 0.174 0.184 0.198 0.176 . (%) ST.DEV 0.019 0.023 0.048 0.033 . N 5 5 5 5 .

. TESTES MEAN 1.01 1.02 1.03 0.93 . (%) ST.DEV 0.09 0.07 0.09 0.08 . N 10 10 10 10 .

. PROSTATE MEAN 0.157 0.167 0.182 0.176 . (%) ST.DEV 0.053 0.024 0.026 0.032 . N 5 5 5 5 .

. EPIDIDYMIDES MEAN 0.324 0.340 0.339 0.318 . (%) ST.DEV 0.024 0.040 0.035 0.026 . N 10 10 10 10 .

. SEMINAL VES MEAN 0.383 0.399 0.370 0.426 . (%) ST.DEV 0.028 0.074 0.023 0.021 . N 5 5 5 5 .

.04Jun13 08h02

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.11 ORGAN WEIGHTS (GRAM) SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT BODY W. MEAN 241 242 236 225 . (GRAM) ST.DEV 14 7 11 5 . N 5 5 5 5 .

. BRAIN MEAN 1.98 1.89 1.93 1.95 . (GRAM) ST.DEV 0.06 0.02 0.06 0.09 . N 5 5 5 5 .

. HEART MEAN 0.744 0.754 0.742 0.719 . (GRAM) ST.DEV 0.086 0.041 0.028 0.065 . N 5 5 5 5 .

. LIVER MEAN 7.57 7.96 6.33 ** 5.61 ** . (GRAM) ST.DEV 0.77 0.39 0.62 0.33 . N 5 5 5 5 .

. THYROIDS MEAN 0.018 0.021 0.021 0.022 . (GRAM) ST.DEV 0.003 0.002 0.002 0.003 . N 5 5 5 5 .

. THYMUS MEAN 0.188 0.256 0.360 ** 0.311 ** . (GRAM) ST.DEV 0.027 0.078 0.054 0.051 . N 5 5 5 5 .

. KIDNEYS MEAN 1.70 1.66 1.64 1.67 . (GRAM) ST.DEV 0.06 0.17 0.08 0.14 . N 5 5 5 5 .

. ADRENALS MEAN 0.078 0.073 0.072 0.069 . (GRAM) ST.DEV 0.006 0.011 0.010 0.008 . N 5 5 5 5 .

. SPLEEN MEAN 0.466 0.583 0.490 0.407 . (GRAM) ST.DEV 0.085 0.143 0.098 0.033 . N 5 5 5 5 .

. OVARIES MEAN 0.113 0.115 0.152 * 0.146 * . (GRAM) ST.DEV 0.015 0.007 0.025 0.024 . N 5 5 5 5 .

. UTERUS MEAN 0.547 0.593 0.613 0.470 . (GRAM) ST.DEV 0.084 0.109 0.147 0.109 . N 5 5 4 5 .

.04Jun13 08h02

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.11 ORGAN/BODY WEIGHT RATIOS (%) SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' END OF TREATMENT BODY W. MEAN 241 242 236 225 . (GRAM) ST.DEV 14 7 11 5 . N 5 5 5 5 .

. BRAIN MEAN 0.82 0.78 0.82 0.87 . (%) ST.DEV 0.05 0.02 0.05 0.03 . N 5 5 5 5 .

. HEART MEAN 0.308 0.311 0.314 0.320 . (%) ST.DEV 0.019 0.016 0.015 0.033 . N 5 5 5 5 .

. LIVER MEAN 3.15 3.28 2.68 * 2.50 ** . (%) ST.DEV 0.37 0.10 0.19 0.14 . N 5 5 5 5 .

. THYROIDS MEAN 0.008 0.009 0.009 0.010 * . (%) ST.DEV 0.001 0.001 0.001 0.001 . N 5 5 5 5 .

. THYMUS MEAN 0.078 0.105 0.152 ** 0.138 ** . (%) ST.DEV 0.013 0.032 0.022 0.023 . N 5 5 5 5 .

. KIDNEYS MEAN 0.71 0.68 0.70 0.74 . (%) ST.DEV 0.03 0.08 0.05 0.06 . N 5 5 5 5 .

. ADRENALS MEAN 0.033 0.030 0.030 0.030 . (%) ST.DEV 0.002 0.004 0.005 0.003 . N 5 5 5 5 .

. SPLEEN MEAN 0.194 0.240 0.206 0.181 . (%) ST.DEV 0.038 0.056 0.033 0.014 . N 5 5 5 5 .

. OVARIES MEAN 0.047 0.047 0.064 * 0.065 * . (%) ST.DEV 0.008 0.003 0.012 0.012 . N 5 5 5 5 .

. UTERUS MEAN 0.229 0.244 0.264 0.209 . (%) ST.DEV 0.044 0.039 0.059 0.049 . N 5 5 4 5 .

.COPS_1 or CS-AHPS Project 500682

APPENDIX 1 1.12 REPRODUCTION DATA SUMMARY GROUP 1 GROUP 2 GROUP 3 GROUP 4 CONTROL 100 MG/KG 300 MG/KG 1000 MG/KG Females paired 10 10 10 10 Females mated 10 10 10 10 Females pregnant 9 9 2 0 Females with implantation sites only 0 1 2 0 Females with living pups on Day 1 9 8 0 0 Mating index (%) 100.0 100.0 100.0 100.0 (Females mated / Females paired) * 100 Fertility index (%) 90.0 90.0 20.0 0.0 (Pregnant females / Females paired) * 100 Conception index (%) 90.0 90.0 20.0 0.0 (Pregnant females / Females mated) * 100 Gestation index (%) 100.0 88.9 0.0 not applicable (Females with living pups on Day 1 / Pregnant females) * 10023May13 14h14

+/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 13 PRECOITAL TIME F0-GENERATION - POST COITUM DAY OF THE PAIRING PERIOD GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' NUMBER OF FEMALES MATED 1 4 2 2 4 . 2 1 3 2 - . 3 2 4 3 4 . 4 2 1 3 2 . 6 1 - - - . . MEDIAN PRECOITAL TIME 3 3 3 3 . MEAN PRECOITAL TIME 2.6 2.4 2.7 2.4 . N 10 10 10 10 .23May13 12h42

+/++ Steel-test significant at 5% (+) or 1% (++) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1.1 4 CORPORA LUTEA AND IMPLANTATION SITES SUMMARY FEMALES GROUP 1 CONTROL GROUP 2

100 MG/KG GROUP 3

300 MG/KG GROUP 4

1000 MG/KG ' NECROPSY Corpora Lutea MEAN 14.7 11.4 11.0 --- . ST.DEV 1.9 5.8 12.7 --- . N 9 9 2 0 .

. Implantations MEAN 12.9 10.4 1.5 --- . ST.DEV 2.5 5.5 0.7 --- . N 9 9 2 0 .

.23May13 14h14

# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level +/++ Steel-test significant at 5% (+) or 1% (++) level Viability index = (Number of alive pups before planned necropsy / Number of pups born alive) *100 COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 15 DEVELOPMENTAL DATA F0-GENERATION - LACTATION GROUP 1 CONTROL GROUP 2

100 MG/KG '

. LITTERS . TOTAL 9 8 .

. DURATION OF GESTATION . MEAN (+) 21.4 21.6 . ST.DEV. 0.5 0.7 . N 9 8 .

. DEAD PUPS AT FIRST LITTER CHECK . LITTERS AFFECTED (#) 0 1 . TOTAL 0 3 . MEAN (+) 0.0 0.4 . ST.DEV. 0.0 1.1 . N 9 8 .

. LIVING PUPS AT FIRST LITTER CHECK . % OF MALES / FEMALES (#) 57 / 43 48 / 52 . TOTAL 110 83 . MEAN (+) 12.2 10.4 . ST.DEV. 2.4 4.3 . N 9 8 .

. POSTNATAL LOSS . % OF LIVING PUPS 0.9 1.2 . LITTERS AFFECTED (#) 1 1 . TOTAL (#) 1 1 . MEAN (+) 0.1 0.1 . ST.DEV. 0.3 0.4 . N 9 8 .

. VIABILITY INDEX (#) 99.1 98.8 .23May13 14h14

*/** Dunnett-test based on pooled variance significant at 5% (*) or 1% (**) level COPS_1 or CS-AHPS Project 500682 APPENDIX 1 1. 16 BODY WEIGHTS OF PUPS (GRAM) F0-GENERATION - LACTATION DAY SEX GROUP 1 CONTROL GROUP 2

100 MG/KG ' 1 M MEAN 6.5 6.4 . ST.DEV. 0.7 0.7 . N 9 8 .

. F MEAN 6.2 6.3 .

ST.DEV. 0.7 0.7 . N 9 7 .

. M+F MEAN 6.4 6.3 .

ST.DEV. 0.7 0.7 . N 9 8 .

. 4 M MEAN 9.7 9.4 . ST.DEV. 1.1 2.1 . N 9 8 .

. F MEAN 9.4 9.7 .

ST.DEV. 1.0 1.3 . N 9 7 .

. M+F MEAN 9.6 9.3 .

ST.DEV. 1.1 2.0 . N 9 8 .

.

### COPS_1 or CS-AHPS Project 500682

APPENDIX 2

- Page 1 - 

### APPENDIX 2 INDIVIDUAL TABLES24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.1 MORTALITY DATA MALES ANIMAL SCHEDULED

SACRIFICE OTHER TREATMENT FROM TO ' GROUP 1 (CONTROL) 1 27FEB13 29JAN13 26FEB13 . 2 27FEB13 29JAN13 26FEB13 . 3 27FEB13 29JAN13 26FEB13 . 4 27FEB13 29JAN13 26FEB13 . 5 27FEB13 29JAN13 26FEB13 . 6 27FEB13 29JAN13 26FEB13 . 7 27FEB13 29JAN13 26FEB13 . 8 27FEB13 29JAN13 26FEB13 . 9 27FEB13 29JAN13 26FEB13 . 10 27FEB13 29JAN13 26FEB13 . GROUP 2 (100 MG/KG) 11 27FEB13 29JAN13 26FEB13 . 12 27FEB13 29JAN13 26FEB13 . 13 27FEB13 29JAN13 26FEB13 . 14 27FEB13 29JAN13 26FEB13 . 15 27FEB13 29JAN13 26FEB13 . 16 27FEB13 29JAN13 26FEB13 . 17 27FEB13 29JAN13 26FEB13 . 18 27FEB13 29JAN13 26FEB13 . 19 27FEB13 29JAN13 26FEB13 . 20 27FEB13 29JAN13 26FEB13 . GROUP 3 (300 MG/KG) 21 27FEB13 29JAN13 26FEB13 . 22 27FEB13 29JAN13 26FEB13 . 23 27FEB13 29JAN13 26FEB13 . 24 27FEB13 29JAN13 26FEB13 . 25 27FEB13 29JAN13 26FEB13 . 26 27FEB13 29JAN13 26FEB13 . 27 27FEB13 29JAN13 26FEB13 . 28 27FEB13 29JAN13 26FEB13 . 29 27FEB13 29JAN13 26FEB13 . 30 27FEB13 29JAN13 26FEB13 . GROUP 4 (1000 MG/KG) 31 27FEB13 29JAN13 26FEB13 . 32 27FEB13 29JAN13 26FEB13 . 33 27FEB13 29JAN13 26FEB13 . 34 27FEB13 29JAN13 26FEB13 . 35 27FEB13 29JAN13 26FEB13 . 36 27FEB13 29JAN13 26FEB13 . 37 27FEB13 29JAN13 26FEB13 . 38 27FEB13 29JAN13 26FEB13 . 39 27FEB13 29JAN13 26FEB13 . 40 27FEB13 29JAN13 26FEB13 . FEMALES ANIMAL SCHEDULED

SACRIFICE OTHER TREATMENT FROM TO ' GROUP 1 (CONTROL) 41 12MAR13 29JAN13 11MAR13 . 42 13MAR13 29JAN13 12MAR13 . 43 15MAR13 29JAN13 14MAR13 . 44 12MAR13 29JAN13 11MAR13 . 45 18MAR13 29JAN13 17MAR13 . 46 15MAR13 29JAN13 14MAR13 . 47 15MAR13 29JAN13 14MAR13 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.1 MORTALITY DATA FEMALES ANIMAL SCHEDULED

SACRIFICE OTHER TREATMENT FROM TO ' GROUP 1 (CONTROL) 48 12MAR13 29JAN13 11MAR13 . 49 15MAR13 29JAN13 14MAR13 . 50 12MAR13 29JAN13 11MAR13 . GROUP 2 (100 MG/KG) 51 15MAR13 29JAN13 14MAR13 . 52 12MAR13 29JAN13 11MAR13 . 53 15MAR13 29JAN13 14MAR13 . 54 15MAR13 29JAN13 14MAR13 . 55 12MAR13 29JAN13 11MAR13 . 56 15MAR13 29JAN13 14MAR13 . 57 12MAR13 29JAN13 11MAR13 . 58 15MAR13 29JAN13 14MAR13 . 59 13MAR13 29JAN13 12MAR13 . 60 12MAR13 29JAN13 11MAR13 . GROUP 3 (300 MG/KG) 61 14MAR13 29JAN13 13MAR13 . 62 14MAR13 29JAN13 13MAR13 . 63 14MAR13 29JAN13 13MAR13 . 64 14MAR13 29JAN13 13MAR13 . 65 14MAR13 29JAN13 13MAR13 . 66 12MAR13 29JAN13 11MAR13 . 67 13MAR13 29JAN13 12MAR13 . 68 13MAR13 29JAN13 12MAR13 . 69 12MAR13 29JAN13 11MAR13 . 70 13MAR13 29JAN13 12MAR13 . GROUP 4 (1000 MG/KG) 71 12MAR13 29JAN13 11MAR13 . 72 13MAR13 29JAN13 12MAR13 . 73 14MAR13 29JAN13 13MAR13 . 74 12MAR13 29JAN13 11MAR13 . 75 12MAR13 29JAN13 11MAR13 . 76 14MAR13 29JAN13 13MAR13 . 77 12MAR13 29JAN13 11MAR13 . 78 14MAR13 29JAN13 13MAR13 . 79 14MAR13 29JAN13 13MAR13 . 80 14MAR13 29JAN13 13MAR13 .24May13 08h29

.: Observation performed, sign not present G: Highest daily grades COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.2 CLINICAL SIGNS MALES PRE MATING MATING PERIOD SIGN (MAX. GRADE) (LOCATION) WEEK: DAY: 1

1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 1 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 4 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 ' GROUP 1 (CONTROL) ANIMAL 1 . No clinical signs noted . ANIMAL 2 . No clinical signs noted . ANIMAL 3 . No clinical signs noted . ANIMAL 4 . No clinical signs noted . ANIMAL 5 . No clinical signs noted . ANIMAL 6 . No clinical signs noted . ANIMAL 7 . No clinical signs noted . ANIMAL 8 . No clinical signs noted . ANIMAL 9 . No clinical signs noted . ANIMAL 10 . Skin / fur . Alopecia (3) G: . . . . . . . . . 11111 111111111111111 . GROUP 2 (100 MG/KG) ANIMAL 11 . No clinical signs noted . ANIMAL 12 . No clinical signs noted . ANIMAL 13 . No clinical signs noted . ANIMAL 14 . No clinical signs noted . ANIMAL 15 . No clinical signs noted . ANIMAL 16 . Skin / fur . Scabs (3) G: . . . . . . . . . . . . . . . . . . . . . . . . 11111 . (Neck) . ANIMAL 17 . No clinical signs noted . ANIMAL 18 . No clinical signs noted . ANIMAL 19 . No clinical signs noted . ANIMAL 20 . No clinical signs noted . GROUP 3 (300 MG/KG) ANIMAL 21 . No clinical signs noted . ANIMAL 22 . No clinical signs noted . ANIMAL 23 . No clinical signs noted . ANIMAL 24 . No clinical signs noted . ANIMAL 25 . No clinical signs noted . ANIMAL 26 . No clinical signs noted . ANIMAL 27 . No clinical signs noted . REPRO PERIOD24May13 08h29

.: Observation performed, sign not present G: Highest daily grades COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.2 CLINICAL SIGNS MALES PRE MATING MATING PERIOD SIGN (MAX. GRADE) (LOCATION) WEEK: DAY: 1

1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 1 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 4 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 ' GROUP 3 (300 MG/KG) ANIMAL 28 . No clinical signs noted . ANIMAL 29 . No clinical signs noted . ANIMAL 30 . No clinical signs noted . GROUP 4 (1000 MG/KG) ANIMAL 31 . No clinical signs noted . ANIMAL 32 . No clinical signs noted . ANIMAL 33 . No clinical signs noted . ANIMAL 34 . No clinical signs noted . ANIMAL 35 . No clinical signs noted . ANIMAL 36 . No clinical signs noted . ANIMAL 37 . No clinical signs noted . ANIMAL 38 . No clinical signs noted . ANIMAL 39 . No clinical signs noted . ANIMAL 40 . No clinical signs noted . FEMALES PRE MATING MATING PERIOD SIGN (MAX. GRADE) (LOCATION) WEEK: DAY: 1

1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 1 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 4 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 ' GROUP 1 (CONTROL) ANIMAL 41 . No clinical signs noted . ANIMAL 42 . No clinical signs noted . ANIMAL 43 . No clinical signs noted . ANIMAL 44 . No clinical signs noted . ANIMAL 45 . No clinical signs noted . ANIMAL 46 . No clinical signs noted . ANIMAL 47 . No clinical signs noted . ANIMAL 48 . No clinical signs noted . ANIMAL 49 . No clinical signs noted . ANIMAL 50 . No clinical signs noted . GROUP 2 (100 MG/KG) ANIMAL 51 . No clinical signs noted . REPRO PERIOD

REPRO PERIOD24May13 08h29

.: Observation performed, sign not present G: Highest daily grades COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.2 CLINICAL SIGNS FEMALES PRE MATING MATING PERIOD SIGN (MAX. GRADE) (LOCATION) WEEK: DAY: 1

1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 1 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 . 7 4 1 . 2 . 3 . 4 . 5 . 6 . 7 . 1 . 2 . 3 . 4 . 5 . 6 ' GROUP 2 (100 MG/KG) ANIMAL 52 . No clinical signs noted . ANIMAL 53 . No clinical signs noted . ANIMAL 54 . No clinical signs noted . ANIMAL 55 . No clinical signs noted . ANIMAL 56 . No clinical signs noted . ANIMAL 57 . No clinical signs noted . ANIMAL 58 . No clinical signs noted . ANIMAL 59 . No clinical signs noted . ANIMAL 60 . No clinical signs noted . GROUP 3 (300 MG/KG) ANIMAL 61 . No clinical signs noted . ANIMAL 62 . No clinical signs noted . ANIMAL 63 . No clinical signs noted . ANIMAL 64 . No clinical signs noted . ANIMAL 65 . No clinical signs noted . ANIMAL 66 . No clinical signs noted . ANIMAL 67 . No clinical signs noted . ANIMAL 68 . No clinical signs noted . ANIMAL 69 . No clinical signs noted . ANIMAL 70 . No clinical signs noted . GROUP 4 (1000 MG/KG) ANIMAL 71 . No clinical signs noted . ANIMAL 72 . No clinical signs noted . ANIMAL 73 . No clinical signs noted . ANIMAL 74 . No clinical signs noted . ANIMAL 75 . No clinical signs noted . ANIMAL 76 . No clinical signs noted . ANIMAL 77 . No clinical signs noted . ANIMAL 78 . No clinical signs noted . ANIMAL 79 . No clinical signs noted . ANIMAL 80 . No clinical signs noted . REPRO PERIOD

Animal no. 61: on the day of scheduled necropsy it was recorded that blood came out of the vagina24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.3 FUNCTIONAL OBSERVATIONS MALES AT WEEK 4 ANIMAL HEARING

SCORE 0/1 PUPIL L

SCORE 0/1 PUPIL R

SCORE 0/1 STATIC R

SCORE 0/1 GRIP

SCORE 0/1 ' GROUP 1 (CONTROL) 1 0 0 0 0 0 . 2 0 0 0 0 0 . 3 0 0 0 0 0 . 4 0 0 0 0 0 . 5 0 0 0 0 0 . GROUP 2 (100 MG/KG) 11 0 0 0 0 0 . 12 0 0 0 0 0 . 13 0 0 0 0 0 . 14 0 0 0 0 0 . 15 0 0 0 0 0 . GROUP 3 (300 MG/KG) 21 0 0 0 0 0 . 22 0 0 0 0 0 . 23 0 0 0 0 0 . 24 0 0 0 0 0 . 25 0 0 0 0 0 . GROUP 4 (1000 MG/KG) 31 0 0 0 0 0 . 32 0 0 0 0 0 . 33 0 0 0 0 0 . 34 0 0 0 0 0 . 35 0 0 0 0 0 . FEMALES AT LACTATION # ANIMAL HEARING

SCORE 0/1 PUPIL L

SCORE 0/1 PUPIL R

SCORE 0/1 STATIC R

SCORE 0/1 GRIP

SCORE 0/1 ' GROUP 1 (CONTROL) 41 0 0 0 0 0 . 43 0 0 0 0 0 . 44 0 0 0 0 0 . 48 0 0 0 0 0 . 50 0 0 0 0 0 . GROUP 2 (100 MG/KG) 51 0 0 0 0 0 . 54 0 0 0 0 0 . 55 0 0 0 0 0 . 57 0 0 0 0 0 . 60 0 0 0 0 0 . GROUP 3 (300 MG/KG) # 61 0 0 0 0 0 . 62 0 0 0 0 0 . 63 0 0 0 0 0 . 64 0 0 0 0 0 . 65 0 0 0 0 0 . GROUP 4 (1000 MG/KG) # 73 0 0 0 0 0 . 76 0 0 0 0 0 . 78 0 0 0 0 0 . 79 0 0 0 0 0 . # End of post-coitum period for Group 3 and 4 females24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.3 FUNCTIONAL OBSERVATIONS FEMALES AT LACTATION # ANIMAL HEARING

SCORE 0/1 PUPIL L

SCORE 0/1 PUPIL R

SCORE 0/1 STATIC R

SCORE 0/1 GRIP

SCORE 0/1 ' GROUP 4 (1000 MG/KG) # 80 0 0 0 0 0 .

# End of post-coitum period for Group 3 and 4 femalesCOPS_1 or CS-AHPS Project 500682

APPENDIX 2 2.4 MOTOR ACTIVITY TEST - TOTAL MOVEMENTS MALES AT WEEK 4 1 2 3 4 5 6 7 8 9 10 11 12 Total 1 910 944 449 324 179 264 413 212 56 13 46 2 3812 2 1270 674 482 358 192 272 557 202 20 159 0 1 4187 3 907 664 340 354 613 259 480 76 2 41 0 22 3758 4 1135 762 758 420 114 410 166 145 345 344 366 543 5508 5 1102 1000 777 847 415 406 282 250 405 262 234 153 6133 11 985 657 409 443 400 478 173 594 290 142 268 273 5112 12 1707 1706 1150 412 886 179 505 464 448 634 4 7 8102 13 932 737 644 454 543 402 325 394 228 6 1 7 4673 14 725 481 282 366 142 115 8 181 6 51 27 16 2400 15 871 816 807 535 375 265 547 507 719 604 91 25 6162 21 1279 897 832 401 624 351 400 10 4 447 241 372 5858 22 1053 686 506 437 418 158 26 3 7 11 19 53 3377 23 828 609 470 186 325 321 25 224 390 75 5 55 3513 24 802 589 646 278 173 466 33 89 0 179 1 5 3261 25 1092 979 495 662 469 223 0 410 474 4 0 184 4992 31 1255 1142 789 516 688 313 547 90 352 302 0 42 6036 32 945 425 190 408 367 247 145 93 10 0 51 202 3083 33 1265 845 580 344 482 73 36 19 6 9 14 50 3723 34 724 506 443 377 159 260 58 243 1 7 0 9 2787 35 1355 743 763 628 115 246 521 160 25 83 303 63 5005 GROUP 4 (1000 MG/KG) GROUP 3 (300 MG/KG) ANIMAL Interval (5 min.) GROUP 1 (CONTROL)

GROUP 2 (100 MG/KG)COPS_1 or CS-AHPS Project 500682

APPENDIX 2 2.4 MOTOR ACTIVITY TEST - AMBULATIONS MALES AT WEEK 4 1 2 3 4 5 6 7 8 9 10 11 12 Total 1 154 191 102 35 4 64 92 5 1 0 0 0 648 2 226 106 51 60 2 34 100 14 0 59 0 0 652 3 147 179 57 49 203 63 95 16 0 0 0 0 809 4 204 104 127 46 0 85 29 12 73 36 32 92 840 5 171 181 128 143 58 60 61 54 18 53 49 35 1011 11 138 147 52 89 33 84 11 81 26 0 40 48 749 12 327 355 237 50 149 13 97 80 49 118 0 1 1476 13 264 189 144 105 127 94 56 65 7 0 0 0 1051 14 167 88 54 65 33 28 0 19 0 2 2 4 462 15 172 168 159 104 61 40 79 81 107 106 2 2 1081 21 338 194 170 29 132 68 98 0 0 97 4 88 1218 22 237 169 140 104 109 9 0 0 0 0 1 14 783 23 210 163 119 35 73 72 0 24 86 2 0 10 794 24 167 142 186 47 19 99 1 17 0 44 0 0 722 25 223 194 56 129 66 1 0 92 51 0 0 49 861 31 195 216 137 46 130 25 108 1 59 60 0 1 978 32 281 101 36 98 76 26 20 2 1 0 4 43 688 33 273 158 97 53 68 0 0 0 0 0 0 0 649 34 177 110 86 61 11 86 0 59 0 0 0 0 590 35 359 239 174 136 9 61 116 3 1 12 62 0 1172 GROUP 3 (300 MG/KG)

GROUP 4 (1000 MG/KG) ANIMAL Interval (5 min.) GROUP 1 (CONTROL)

GROUP 2 (100 MG/KG)COPS_1 or CS-AHPS Project 500682

APPENDIX 2 2.4 MOTOR ACTIVITY TEST - TOTAL MOVEMENTS FEMALES AT LACTATION #

1 2 3 4 5 6 7 8 9 10 11 12 Total 41 1173 498 231 9 10 52 28 154 205 29 0 3 2392 43 873 345 440 280 262 425 220 313 257 81 264 186 3946 44 934 705 500 823 575 334 483 218 6 423 276 340 5617 48 1192 715 221 236 192 0 4 438 450 152 156 11 3767 50 1002 562 408 208 3 69 59 103 349 288 103 0 3154 51 935 551 477 438 185 436 512 366 215 196 462 151 4924 54 1066 520 220 506 115 682 286 319 468 37 307 475 5001 55 859 572 748 442 449 263 291 477 252 158 343 123 4977 57 883 543 208 312 245 56 37 0 9 12 6 17 2328 60 1013 494 435 406 579 233 372 162 501 595 260 158 5208 61 1411 840 722 404 866 765 555 695 363 156 118 412 7307 62 1370 790 807 524 218 708 300 447 80 37 2 45 5328 63 932 757 690 440 842 421 622 155 0 61 222 247 5389 64 1196 755 665 248 476 244 234 266 13 16 18 1 4132 65 1459 984 666 476 923 467 150 5 9 334 259 0 5732 73 687 595 455 566 476 473 313 413 245 78 257 4 4562 76 931 613 826 910 801 487 444 1056 454 889 259 553 8223 78 1286 849 528 627 471 302 714 412 209 7 218 762 6385 79 1134 922 793 598 734 939 519 635 561 594 300 680 8409 80 1166 612 530 497 485 400 211 147 475 435 268 508 5734 GROUP 3 (300 MG/KG) #

GROUP 4 (1000 MG/KG) # ANIMAL Interval (5 min.) GROUP 1 (CONTROL)

GROUP 2 (100 MG/KG)

# End of post-coitum period for Group 3 and 4 femalesCOPS_1 or CS-AHPS Project 500682

APPENDIX 2 2.4 MOTOR ACTIVITY TEST - AMBULATIONS FEMALES AT LACTATION #

1 2 3 4 5 6 7 8 9 10 11 12 Total 41 195 59 22 0 0 1 0 24 35 3 0 0 339 43 288 65 146 36 41 152 75 85 69 10 77 12 1056 44 195 166 115 172 123 87 123 35 0 87 36 50 1189 48 251 115 8 48 29 0 0 54 83 34 52 1 675 50 247 103 82 0 0 0 0 4 53 47 14 0 550 51 313 160 105 115 48 136 122 97 58 36 140 43 1373 54 327 122 18 141 5 232 59 81 125 0 76 186 1372 55 279 129 168 97 83 52 78 84 31 15 78 18 1112 57 207 81 35 56 3 0 3 0 0 0 1 0 386 60 227 99 87 65 159 66 132 2 109 147 73 22 1188 61 396 230 195 81 198 156 73 140 61 2 0 68 1600 62 406 208 199 100 28 176 68 98 2 2 0 5 1292 63 233 216 195 85 207 84 145 2 0 0 30 74 1271 64 237 159 120 5 74 41 6 47 0 0 0 0 689 65 425 221 130 83 242 114 2 0 0 69 36 0 1322 73 210 135 99 142 75 99 37 85 8 4 63 0 957 76 198 125 153 184 132 77 44 237 60 263 24 98 1595 78 451 254 157 155 138 96 202 82 3 0 52 200 1790 79 316 295 140 105 111 208 52 110 88 110 29 108 1672 80 306 211 142 131 165 129 78 56 139 137 36 140 1670 GROUP 4 (1000 MG/KG) # ANIMAL Interval (5 min)

GROUP 2 (100 MG/KG)

GROUP 3 (300 MG/KG) # GROUP 1 (CONTROL)

# End of post-coitum period for Group 3 and 4 females24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 5 BODY WEIGHTS (GRAM) MALES PRE MATING MATING PERIOD DAYS WEEKS ANIMAL 1

1 8 2 1

1 8 2 15 3 22 4 29 5 36 6 ' GROUP 1 (CONTROL) 1 324 340 359 368 388 . 2 319 343 360 365 375 . 3 326 349 370 379 398 . 4 330 350 368 382 395 . 5 325 342 357 368 378 . 6 331 355 381 397 410 . 7 313 326 343 361 366 . 8 326 346 365 375 397 . 9 319 331 349 359 368 . 10 328 349 359 360 377 . GROUP 2 (100 MG/KG) 11 332 357 375 387 413 . 12 310 324 340 348 363 . 13 313 319 333 354 368 . 14 312 332 356 368 385 . 15 321 339 351 367 382 . 16 324 347 366 381 399 . 17 320 327 344 355 376 . 18 320 330 353 360 374 . 19 333 345 357 373 394 . 20 313 329 349 361 377 . GROUP 3 (300 MG/KG) 21 311 329 349 358 371 . 22 319 328 341 338 348 . 23 331 354 383 392 425 . 24 321 332 353 360 376 . 25 322 337 359 366 382 . 26 316 336 356 370 378 . 27 311 318 335 338 354 . 28 323 338 359 371 394 . 29 326 343 365 378 394 . 30 324 337 359 374 390 . GROUP 4 (1000 MG/KG) 31 323 345 359 366 385 . 32 302 322 338 348 362 . 33 337 357 375 384 402 . 34 330 350 368 377 400 . 35 311 329 349 361 376 . 36 325 357 373 378 393 . 37 307 315 327 338 347 . 38 325 334 351 364 379 . 39 319 340 355 358 374 . 40 339 360 383 390 408 . FEMALES PRE MATING MATING PERIOD DAYS WEEKS ANIMAL 1

1 8 2 1

1 8 2 15 3 22 4 29 5 36 6 ' GROUP 1 (CONTROL) 41 203 207 220 . 42 212 234 246 . 43 220 232 242 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 5 BODY WEIGHTS (GRAM) FEMALES PRE MATING MATING PERIOD DAYS WEEKS ANIMAL 1

1 8 2 1

1 8 2 15 3 22 4 29 5 36 6 ' GROUP 1 (CONTROL) 44 200 203 216 . 45 204 217 220 . 46 205 218 227 . 47 211 216 216 . 48 200 212 225 . 49 208 217 223 . 50 202 209 222 . GROUP 2 (100 MG/KG) 51 196 212 222 . 52 215 226 228 . 53 214 218 220 . 54 195 209 222 . 55 204 225 235 . 56 210 219 227 . 57 200 211 218 . 58 205 213 212 . 59 204 214 217 . 60 203 210 226 . GROUP 3 (300 MG/KG) 61 204 211 213 . 62 208 220 229 . 63 215 217 227 . 64 199 212 221 . 65 193 217 223 . 66 194 210 225 . 67 197 208 212 . 68 191 208 210 . 69 203 202 216 . 70 206 229 236 . GROUP 4 (1000 MG/KG) 71 202 208 221 . 72 206 215 223 . 73 202 212 216 . 74 199 203 221 . 75 192 200 218 . 76 206 215 224 . 77 205 216 232 . 78 204 205 217 . 79 208 209 218 . 80 214 224 230 .24May13 11h54

<NP> Non-pregnant COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.5 BODY WEIGHTS (GRAM) FEMALES F0-GENERATION

POST COITUM LACTATION DAYS ANIMAL 0 4 7 11 14 17 20 1 4 ' GROUP 1 (CONTROL) 41 215 229 235 253 261 283 317 249 267 . 42 <NP> 237 259 265 276 268 265 269 --- --- . 43 245 261 275 291 302 320 347 290 298 . 44 214 232 239 253 263 292 332 253 276 . 45 227 235 244 256 269 293 335 258 274 . 46 227 243 248 269 279 303 338 256 275 . 47 224 239 252 267 284 304 346 265 282 . 48 223 236 243 261 273 304 343 254 259 . 49 231 241 250 267 282 306 350 268 274 . 50 217 231 237 251 262 283 315 248 262 . GROUP 2 (100 MG/KG) 51 222 235 243 260 270 298 338 251 274 . 52 <NP> 226 241 245 239 237 244 238 --- --- . 53 215 226 233 245 254 260 274 246 245 . 54 221 243 246 261 276 299 338 262 282 . 55 230 246 252 276 283 313 342 272 283 . 56 232 247 257 276 286 317 351 271 295 . 57 216 227 234 252 263 292 337 253 269 . 58 224 230 242 255 267 293 323 248 254 . 59 218 230 240 246 252 249 239 --- --- . 60 223 240 252 272 276 304 335 258 279 . GROUP 3 (300 MG/KG) 61 223 238 247 256 254 256 268 --- --- . 62 <NP> 233 246 251 257 261 257 250 --- --- . 63 <NP> 226 245 255 265 269 268 251 --- --- . 64 <NP> 218 233 240 249 242 236 243 --- --- . 65 223 237 250 254 250 247 245 --- --- . 66 <NP> 221 240 243 248 238 237 241 --- --- . 67 <NP> 217 230 243 240 237 233 231 --- --- . 68 <NP> 215 228 230 236 230 225 229 --- --- . 69 <NP> 213 227 231 239 234 227 232 --- --- . 70 <NP> 233 247 255 266 254 249 251 --- --- . GROUP 4 (1000 MG/KG) 71 <NP> 225 241 247 256 250 248 245 --- --- . 72 <NP> 220 240 248 250 240 239 239 --- --- . 73 <NP> 219 228 237 245 237 232 237 --- --- . 74 <NP> 218 246 240 250 246 247 251 --- --- . 75 <NP> 213 228 231 236 237 233 229 --- --- . 76 <NP> 229 241 251 255 248 240 248 --- --- . 77 <NP> 228 250 255 268 265 261 258 --- --- . 78 <NP> 216 231 239 241 244 239 231 --- --- . 79 <NP> 216 231 244 253 246 238 239 --- --- . 80 <NP> 225 248 258 263 264 251 252 --- --- .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 6 BODY WEIGHT GAIN (%) MALES PRE MATING MATING PERIOD DAYS WEEKS ANIMAL 1

1 8 2 1

1 8 2 15 3 22 4 29 5 36 6 ' GROUP 1 (CONTROL) 1 0 5 11 14 20 . 2 0 8 13 14 18 . 3 0 7 13 16 22 . 4 0 6 12 16 20 . 5 0 5 10 13 16 . 6 0 7 15 20 24 . 7 0 4 10 15 17 . 8 0 6 12 15 22 . 9 0 4 9 13 15 . 10 0 6 9 10 15 . GROUP 2 (100 MG/KG) 11 0 8 13 17 24 . 12 0 5 10 12 17 . 13 0 2 6 13 18 . 14 0 6 14 18 23 . 15 0 6 9 14 19 . 16 0 7 13 18 23 . 17 0 2 8 11 18 . 18 0 3 10 13 17 . 19 0 4 7 12 18 . 20 0 5 12 15 20 . GROUP 3 (300 MG/KG) 21 0 6 12 15 19 . 22 0 3 7 6 9 . 23 0 7 16 18 28 . 24 0 3 10 12 17 . 25 0 5 11 14 19 . 26 0 6 13 17 20 . 27 0 2 8 9 14 . 28 0 5 11 15 22 . 29 0 5 12 16 21 . 30 0 4 11 15 20 . GROUP 4 (1000 MG/KG) 31 0 7 11 13 19 . 32 0 7 12 15 20 . 33 0 6 11 14 19 . 34 0 6 12 14 21 . 35 0 6 12 16 21 . 36 0 10 15 16 21 . 37 0 3 7 10 13 . 38 0 3 8 12 17 . 39 0 7 11 12 17 . 40 0 6 13 15 20 . FEMALES PRE MATING MATING PERIOD DAYS WEEKS ANIMAL 1

1 8 2 1

1 8 2 15 3 22 4 29 5 36 6 ' GROUP 1 (CONTROL) 41 0 2 8 . 42 0 10 16 . 43 0 5 10 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 6 BODY WEIGHT GAIN (%) FEMALES PRE MATING MATING PERIOD DAYS WEEKS ANIMAL 1

1 8 2 1

1 8 2 15 3 22 4 29 5 36 6 ' GROUP 1 (CONTROL) 44 0 2 8 . 45 0 6 8 . 46 0 6 11 . 47 0 2 2 . 48 0 6 13 . 49 0 4 7 . 50 0 3 10 . GROUP 2 (100 MG/KG) 51 0 8 13 . 52 0 5 6 . 53 0 2 3 . 54 0 7 14 . 55 0 10 15 . 56 0 4 8 . 57 0 6 9 . 58 0 4 3 . 59 0 5 6 . 60 0 3 11 . GROUP 3 (300 MG/KG) 61 0 3 4 . 62 0 6 10 . 63 0 1 6 . 64 0 7 11 . 65 0 12 16 . 66 0 8 16 . 67 0 6 8 . 68 0 9 10 . 69 0 0 6 . 70 0 11 15 . GROUP 4 (1000 MG/KG) 71 0 3 9 . 72 0 4 8 . 73 0 5 7 . 74 0 2 11 . 75 0 4 14 . 76 0 4 9 . 77 0 5 13 . 78 0 0 6 . 79 0 0 5 . 80 0 5 7 .24May13 11h54

<NP> Non-pregnant COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.6 BODY WEIGHT GAIN (%) FEMALES F0-GENERATION

POST COITUM LACTATION DAYS ANIMAL 0 4 7 11 14 17 20 1 4 ' GROUP 1 (CONTROL) 41 0 7 9 18 21 32 47 0 7 . 42 <NP> 0 9 12 16 13 12 14 --- --- . 43 0 7 12 19 23 31 42 0 3 . 44 0 8 12 18 23 36 55 0 9 . 45 0 4 7 13 19 29 48 0 6 . 46 0 7 9 19 23 33 49 0 7 . 47 0 7 13 19 27 36 54 0 6 . 48 0 6 9 17 22 36 54 0 2 . 49 0 4 8 16 22 32 52 0 2 . 50 0 6 9 16 21 30 45 0 6 . GROUP 2 (100 MG/KG) 51 0 6 9 17 22 34 52 0 9 . 52 <NP> 0 7 8 6 5 8 5 --- --- . 53 0 5 8 14 18 21 27 0 0 . 54 0 10 11 18 25 35 53 0 8 . 55 0 7 10 20 23 36 49 0 4 . 56 0 6 11 19 23 37 51 0 9 . 57 0 5 8 17 22 35 56 0 6 . 58 0 3 8 14 19 31 44 0 2 . 59 0 6 10 13 16 14 10 --- --- . 60 0 8 13 22 24 36 50 0 8 . GROUP 3 (300 MG/KG) 61 0 7 11 15 14 15 20 --- --- . 62 <NP> 0 6 8 10 12 10 7 --- --- . 63 <NP> 0 8 13 17 19 19 11 --- --- . 64 <NP> 0 7 10 14 11 8 11 --- --- . 65 0 6 12 14 12 11 10 --- --- . 66 <NP> 0 9 10 12 8 7 9 --- --- . 67 <NP> 0 6 12 11 9 7 6 --- --- . 68 <NP> 0 6 7 10 7 5 7 --- --- . 69 <NP> 0 7 8 12 10 7 9 --- --- . 70 <NP> 0 6 9 14 9 7 8 --- --- . GROUP 4 (1000 MG/KG) 71 <NP> 0 7 10 14 11 10 9 --- --- . 72 <NP> 0 9 13 14 9 9 9 --- --- . 73 <NP> 0 4 8 12 8 6 8 --- --- . 74 <NP> 0 13 10 15 13 13 15 --- --- . 75 <NP> 0 7 8 11 11 9 8 --- --- . 76 <NP> 0 5 10 11 8 5 8 --- --- . 77 <NP> 0 10 12 18 16 14 13 --- --- . 78 <NP> 0 7 11 12 13 11 7 --- --- . 79 <NP> 0 7 13 17 14 10 11 --- --- . 80 <NP> 0 10 15 17 17 12 12 --- --- .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 7 FOOD CONSUMPTION (G/ANIMAL/DAY) MALES PRE MATING MATING PERIOD DAYS WEEKS CAGE 1-8

1-2 8-15 2-3 1-8 1-2 8-15 2-3 ' GROUP 1 (CONTROL) 1 24 24 25 24 . 2 24 24 25 23 . GROUP 2 (100 MG/KG) 3 24 24 25 25 . 4 23 24 26 25 . GROUP 3 (300 MG/KG) 5 23 23 25 24 . 6 24 24 25 24 . GROUP 4 (1000 MG/KG) 7 24 24 25 25 . 8 24 23 25 24 . FEMALES PRE MATING MATING PERIOD DAYS WEEKS CAGE 1-8

1-2 8-15 2-3 1-8 1-2 8-15 2-3 ' GROUP 1 (CONTROL) 9 18 17 . 10 17 17 . GROUP 2 (100 MG/KG) 11 18 17 . 12 17 17 . GROUP 3 (300 MG/KG) 13 17 17 . 14 17 17 . GROUP 4 (1000 MG/KG) 15 17 18 . 16 18 17 .24May13 11h54

<NP> Non-pregnant COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.7 FOOD CONSUMPTION (G/ANIMAL/DAY) FEMALES F0-GENERATION

POST COITUM LACTATION DAYS ANIMAL 0-4 4-7 7-11 11-14 14-17 17-20 1-4 ' GROUP 1 (CONTROL) 41 16 18 19 20 20 23 36 . 42 <NP> 21 23 23 20 21 20 --- . 43 20 24 24 28 26 26 29 . 44 19 20 21 21 24 26 32 . 45 18 18 19 21 23 24 33 . 46 20 21 23 26 25 26 32 . 47 19 21 21 23 23 25 34 . 48 18 20 21 22 24 26 30 . 49 19 20 21 25 23 26 34 . 50 15 17 18 19 22 22 27 . GROUP 2 (100 MG/KG) 51 19 22 22 24 24 25 36 . 52 <NP> 18 19 17 16 17 15 --- . 53 16 17 18 20 20 21 15 . 54 20 22 21 25 27 28 37 . 55 19 21 23 23 26 26 31 . 56 19 21 21 24 24 24 40 . 57 16 19 19 20 21 25 34 . 58 17 20 19 23 23 23 28 . 59 16 19 19 21 19 13 --- . 60 19 22 22 21 24 25 32 . GROUP 3 (300 MG/KG) 61 17 19 20 19 16 21 --- . 62 <NP> 19 21 21 21 20 17 --- . 63 <NP> 19 22 21 22 19 13 --- . 64 <NP> 19 21 22 19 15 16 --- . 65 19 20 20 21 15 16 --- . 66 <NP> 17 19 20 13 16 16 --- . 67 <NP> 18 20 17 19 15 14 --- . 68 <NP> 18 17 19 15 17 17 --- . 69 <NP> 16 18 18 15 15 17 --- . 70 <NP> 20 23 24 19 18 18 --- . GROUP 4 (1000 MG/KG) 71 <NP> 18 21 21 20 17 15 --- . 72 <NP> 19 22 20 18 15 15 --- . 73 <NP> 16 19 20 17 16 17 --- . 74 <NP> 18 19 21 18 17 18 --- . 75 <NP> 19 21 22 --- 17 17 --- . 76 <NP> 18 18 20 16 15 17 --- . 77 <NP> 21 23 25 22 19 17 --- . 78 <NP> 20 21 20 21 17 15 --- . 79 <NP> 18 20 19 20 18 18 --- . 80 <NP> 21 24 24 23 18 16 --- .

* Food wet *24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 8 RELATIVE FOOD CONSUMPTION (G/KG BODY WEIGHT/DAY) MALES PRE MATING MATING PERIOD DAYS WEEKS CAGE 1-8

1-2 8-15 2-3 1-8 1-2 8-15 2-3 ' GROUP 1 (CONTROL) 1 71 70 68 62 . 2 69 69 68 60 . GROUP 2 (100 MG/KG) 3 72 70 70 64 . 4 69 71 70 65 . GROUP 3 (300 MG/KG) 5 69 69 69 63 . 6 70 71 69 63 . GROUP 4 (1000 MG/KG) 7 71 70 69 65 . 8 70 67 69 63 . FEMALES PRE MATING MATING PERIOD DAYS WEEKS CAGE 1-8

1-2 8-15 2-3 1-8 1-2 8-15 2-3 ' GROUP 1 (CONTROL) 9 81 79 . 10 79 80 . GROUP 2 (100 MG/KG) 11 81 79 . 12 79 78 . GROUP 3 (300 MG/KG) 13 79 78 . 14 81 80 . GROUP 4 (1000 MG/KG) 15 83 87 . 16 82 81 .24May13 11h54

<NP> Non-pregnant COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.8 RELATIVE FOOD CONSUMPTION (G/KG BODY WEIGHT/DAY) FEMALES F0-GENERATION

POST COITUM LACTATION DAYS ANIMAL 0-4 4-7 7-11 11-14 14-17 17-20 1-4 ' GROUP 1 (CONTROL) 41 70 78 75 77 72 72 134 . 42 <NP> 80 86 83 75 78 73 --- . 43 78 86 83 93 81 76 98 . 44 81 85 83 81 81 79 116 . 45 74 74 75 79 77 71 120 . 46 80 85 85 93 84 78 118 . 47 77 85 80 82 77 71 119 . 48 77 84 80 82 78 76 115 . 49 78 80 79 87 76 74 124 . 50 64 73 72 74 77 71 102 . GROUP 2 (100 MG/KG) 51 82 89 84 90 79 75 130 . 52 <NP> 75 79 70 68 70 64 --- . 53 72 74 73 77 76 78 60 . 54 82 89 80 89 91 84 130 . 55 76 82 82 81 84 77 108 . 56 75 82 75 84 75 68 136 . 57 72 80 74 76 73 73 125 . 58 72 81 75 85 78 71 112 . 59 70 81 78 85 75 54 --- . 60 77 87 82 77 79 75 116 . GROUP 3 (300 MG/KG) 61 72 76 76 76 63 77 --- . 62 <NP> 75 84 81 79 77 67 --- . 63 <NP> 76 85 80 82 72 53 --- . 64 <NP> 79 86 87 77 64 66 --- . 65 79 81 80 84 62 64 --- . 66 <NP> 70 78 79 56 66 66 --- . 67 <NP> 76 84 71 79 63 59 --- . 68 <NP> 79 75 78 65 74 74 --- . 69 <NP> 69 78 74 63 68 72 --- . 70 <NP> 81 92 88 75 74 70 --- . GROUP 4 (1000 MG/KG) 71 <NP> 75 86 82 79 67 61 --- . 72 <NP> 78 89 81 76 63 64 --- . 73 <NP> 68 79 83 73 70 70 --- . 74 <NP> 72 78 84 75 67 72 --- . 75 <NP> 83 91 92 --- 74 73 --- . 76 <NP> 74 73 77 65 63 69 --- . 77 <NP> 83 90 91 83 73 65 --- . 78 <NP> 84 89 84 87 71 65 --- . 79 <NP> 77 83 75 83 74 75 --- . 80 <NP> 84 94 89 88 73 63 --- .

* Food wet *24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 9 HAEMATOLOGY MALES END OF TREATMENT ANIMAL WBC

10E9/L Neutrophils

%WBC Lymphocytes

%WBC Monocytes

%WBC Eosinophils

%WBC GROUP 1 (CONTROL) 1 --- --- --- --- --- 2 10.3 11.5 85.3 1.7 1.3 3 11.8 17.4 79.7 1.5 1.1 4 7.0 17.3 78.4 1.6 2.7 5 7.3 15.2 81.0 1.8 1.8 GROUP 2 (100 MG/KG) 11 7.5 22.4 73.3 3.0 1.2 12 7.8 14.2 83.1 1.5 1.1 13 7.2 14.4 83.5 0.9 1.1 14 8.1 12.1 85.1 1.4 1.3 15 6.0 14.7 80.5 3.1 1.5 GROUP 3 (300 MG/KG) 21 9.5 14.0 82.8 1.3 1.7 22 --- --- --- --- --- 23 8.1 11.7 84.9 1.9 1.3 24 8.4 18.3 77.9 2.2 1.5 25 6.8 25.8 70.0 2.6 1.6 GROUP 4 (1000 MG/KG) 31 6.5 15.1 80.5 2.8 1.6 32 5.6 13.9 82.9 1.2 1.8 33 7.8 11.1 86.3 1.1 1.2 34 9.0 16.5 80.1 1.8 1.3 35 10.7 9.3 87.8 1.7 1.0 MALES END OF TREATMENT ANIMAL Basophils

%WBC Red blood cells

10E12/L Reticulocytes

%RBC RDW

% Haemoglobin

mmol/L GROUP 1 (CONTROL) 1 --- --- --- --- --- 2 0.2 8.99 2.6 12.5 9.8 3 0.2 8.80 2.8 11.7 10.1 4 0.1 9.09 2.1 12.0 10.5 5 0.2 8.62 2.2 13.4 10.4 GROUP 2 (100 MG/KG) 11 0.1 8.44 2.6 12.3 9.8 12 0.2 8.19 2.8 14.6 10.1 13 0.2 9.58 2.6 12.8 10.7 14 0.1 8.49 2.6 12.7 9.5 15 0.2 8.86 2.3 12.5 10.3 GROUP 3 (300 MG/KG) 21 0.2 9.33 2.1 12.0 10.6 22 --- --- --- --- --- 23 0.2 7.81 3.1 16.2 9.7 24 0.2 8.70 2.6 12.4 10.3 25 0.1 8.09 2.9 13.3 9.9 GROUP 4 (1000 MG/KG) 31 0.2 8.86 2.0 12.3 9.7 32 0.1 7.33 2.1 12.4 9.0 33 0.2 8.27 2.5 13.9 9.6 34 0.2 8.73 2.9 12.4 10.124May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 9 HAEMATOLOGY MALES END OF TREATMENT ANIMAL Basophils

%WBC Red blood cells

10E12/L Reticulocytes

%RBC RDW

% Haemoglobin

mmol/L GROUP 4 (1000 MG/KG) 35 0.2 8.75 2.4 12.6 9.9 MALES END OF TREATMENT ANIMAL Haematocrit

L/L MCV

fL MCH

fmol MCHC

mmol/L Platelets

10E9/L GROUP 1 (CONTROL) 1 --- --- --- --- --- 2 0.467 51.9 1.09 21.06 955 3 0.479 54.5 1.14 21.00 921 4 0.493 54.3 1.15 21.24 979 5 0.468 54.4 1.21 22.19 821 GROUP 2 (100 MG/KG) 11 0.465 55.1 1.16 21.04 890 12 0.448 54.7 1.24 22.60 816 13 0.512 53.4 1.12 20.90 921 14 0.452 53.2 1.12 21.10 729 15 0.489 55.2 1.16 21.02 854 GROUP 3 (300 MG/KG) 21 0.491 52.6 1.14 21.57 1001 22 --- --- --- --- --- 23 0.442 56.6 1.24 21.98 993 24 0.476 54.8 1.18 21.56 895 25 0.456 56.4 1.23 21.79 966 GROUP 4 (1000 MG/KG) 31 0.442 49.9 1.10 22.02 801 32 0.392 53.6 1.23 22.90 589 33 0.434 52.5 1.16 22.17 856 34 0.466 53.3 1.16 21.74 879 35 0.460 52.6 1.13 21.48 940 MALES END OF TREATMENT ANIMAL PT

s APTT

s ' GROUP 1 (CONTROL) 1 15.8 13.1 . 2 15.9 16.1 . 3 16.8 19.1 . 4 17.0 14.5 . 5 16.6 18.9 . GROUP 2 (100 MG/KG) 11 16.5 18.2 . 12 15.9 16.2 . 13 15.6 12.5 . 14 16.6 14.6 . 15 16.4 14.1 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 9 HAEMATOLOGY MALES END OF TREATMENT ANIMAL PT

s APTT

s ' GROUP 3 (300 MG/KG) 21 16.0 19.1 . 22 --- --- . 23 17.4 15.0 . 24 16.5 19.3 . 25 15.7 12.7 . GROUP 4 (1000 MG/KG) 31 16.2 11.6 . 32 15.6 19.3 . 33 16.6 18.7 . 34 15.6 10.7 . 35 16.2 16.2 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 9 HAEMATOLOGY FEMALES END OF TREATMENT ANIMAL WBC

10E9/L Neutrophils

%WBC Lymphocytes

%WBC Monocytes

%WBC Eosinophils

%WBC GROUP 1 (CONTROL) 41 6.0 23.4 72.8 2.4 1.3 43 3.4 20.4 73.8 3.1 2.5 44 4.6 24.5 72.8 1.2 1.3 48 4.9 16.3 80.7 1.5 1.3 50 4.1 19.4 76.8 1.7 2.1 GROUP 2 (100 MG/KG) 51 4.7 33.2 62.7 2.1 1.9 54 4.9 27.6 69.7 1.6 1.0 55 3.5 24.0 72.1 1.6 2.2 57 7.5 24.9 71.7 1.8 1.4 60 5.4 19.2 77.6 1.6 1.3 GROUP 3 (300 MG/KG) 61 4.2 27.6 67.4 2.8 2.0 62 6.2 13.1 84.1 1.6 1.1 63 3.5 13.7 78.7 4.6 3.0 64 6.3 12.2 84.0 1.6 2.1 65 6.2 11.6 85.3 1.3 1.6 GROUP 4 (1000 MG/KG) 73 5.8 11.4 82.1 2.9 3.4 76 8.0 8.7 88.4 1.6 1.1 78 4.8 8.4 87.8 2.1 1.5 79 4.3 5.2 91.7 1.3 1.8 80 11.1 81.3 12.6 4.1 1.9 FEMALES END OF TREATMENT ANIMAL Basophils

%WBC Red blood cells

10E12/L Reticulocytes

%RBC RDW

% Haemoglobin

mmol/L GROUP 1 (CONTROL) 41 0.1 7.98 7.2 15.8 9.1 43 0.1 8.34 3.2 12.4 9.7 44 0.2 7.23 5.9 14.3 8.7 48 0.1 8.23 3.9 14.0 9.4 50 0.1 7.52 5.4 13.2 9.3 GROUP 2 (100 MG/KG) 51 0.2 8.06 5.9 14.4 9.5 54 0.1 7.40 3.8 27.6 9.9 55 0.1 7.18 6.4 13.1 8.8 57 0.1 7.14 5.8 17.5 8.9 60 0.1 6.55 12.0 21.7 8.6 GROUP 3 (300 MG/KG) 61 0.1 5.32 8.1 15.5 6.2 62 0.1 8.31 1.7 10.4 10.1 63 0.1 8.19 1.3 10.1 9.7 64 0.1 8.38 2.2 11.5 9.6 65 0.1 7.58 1.9 13.7 9.4 GROUP 4 (1000 MG/KG) 73 0.1 8.76 2.1 10.7 9.8 76 0.1 8.98 1.8 11.7 9.7 78 0.2 8.56 1.8 11.3 9.8 79 0.1 8.63 1.7 10.6 10.124May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 9 HAEMATOLOGY FEMALES END OF TREATMENT ANIMAL Basophils

%WBC Red blood cells

10E12/L Reticulocytes

%RBC RDW

% Haemoglobin

mmol/L GROUP 4 (1000 MG/KG) 80 0.1 7.69 1.2 23.5 9.6 FEMALES END OF TREATMENT ANIMAL Haematocrit

L/L MCV

fL MCH

fmol MCHC

mmol/L Platelets

10E9/L GROUP 1 (CONTROL) 41 0.431 54.0 1.14 21.10 1346 43 0.450 54.0 1.16 21.46 911 44 0.418 57.9 1.20 20.78 1003 48 0.441 53.6 1.14 21.21 1001 50 0.434 57.7 1.23 21.37 1138 GROUP 2 (100 MG/KG) 51 0.442 54.8 1.17 21.41 773 54 0.439 59.3 1.34 22.55 1157 55 0.418 58.1 1.23 21.09 994 57 0.405 56.7 1.24 21.92 1084 60 0.418 63.8 1.31 20.54 1389 GROUP 3 (300 MG/KG) 61 0.293 55.0 1.16 21.14 640 62 0.461 55.5 1.22 21.97 960 63 0.448 54.7 1.19 21.72 756 64 0.443 52.9 1.14 21.55 1119 65 0.421 55.5 1.24 22.24 1166 GROUP 4 (1000 MG/KG) 73 0.462 52.7 1.12 21.32 888 76 0.462 51.4 1.08 21.00 988 78 0.455 53.1 1.14 21.46 1032 79 0.477 55.2 1.17 21.27 968 80 0.433 56.3 1.25 22.19 1354 FEMALES END OF TREATMENT ANIMAL PT

s APTT

s ' GROUP 1 (CONTROL) 41 16.4 12.5 . 43 16.2 12.2 . 44 16.9 10.5 . 48 16.7 11.3 . 50 17.0 14.3 . GROUP 2 (100 MG/KG) 51 15.0 12.7 . 54 15.8 13.7 . 55 16.3 13.1 . 57 16.3 13.4 . 60 16.7 13.0 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 9 HAEMATOLOGY FEMALES END OF TREATMENT ANIMAL PT

s APTT

s ' GROUP 3 (300 MG/KG) 61 17.8 17.8 . 62 16.7 13.0 . 63 16.9 15.5 . 64 16.9 14.0 . 65 16.7 14.0 . GROUP 4 (1000 MG/KG) 73 16.3 12.4 . 76 16.3 14.4 . 78 17.1 13.5 . 79 16.7 15.8 . 80 16.0 11.4 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 10 CLINICAL BIOCHEMISTRY MALES END OF TREATMENT ANIMAL ALAT

U/L ASAT

U/L ALP

U/L Total protein

g/L Albumin

g/L GROUP 1 (CONTROL) 1 47.6 85.9 134 67.8 34.5 2 45.5 78.4 115 64.6 33.2 3 35.3 78.1 93 63.8 32.4 4 43.1 78.9 140 67.0 33.4 5 41.7 76.0 172 65.1 33.5 GROUP 2 (100 MG/KG) 11 53.5 74.1 140 69.0 33.6 12 38.7 73.2 104 63.2 32.4 13 47.1 91.1 139 65.1 33.7 14 51.6 74.4 107 60.2 31.6 15 35.0 88.1 195 65.2 33.2 GROUP 3 (300 MG/KG) 21 37.6 76.5 139 67.0 33.5 22 42.0 104.1 104 65.3 34.4 23 33.4 68.9 115 65.6 33.8 24 49.2 62.5 110 69.8 34.8 25 38.1 74.2 115 62.9 34.0 GROUP 4 (1000 MG/KG) 31 40.8 78.6 120 68.0 33.9 32 47.2 85.9 163 64.1 33.2 33 34.7 74.3 147 64.5 33.1 34 37.8 75.4 119 65.7 33.0 35 30.0 64.0 89 65.4 32.4 MALES END OF TREATMENT ANIMAL Total bilirubin

umol/L Urea

mmol/L Creatinine

umol/L Glucose

mmol/L Cholesterol

mmol/L GROUP 1 (CONTROL) 1 2.5 5.8 38.2 7.47 2.28 2 2.7 6.0 40.8 9.57 2.36 3 2.3 7.1 40.8 9.37 1.91 4 2.3 6.1 39.5 8.50 2.19 5 2.2 6.0 38.2 9.72 2.22 GROUP 2 (100 MG/KG) 11 2.6 7.9 44.0 8.61 1.81 12 1.9 6.3 42.1 9.06 1.43 13 2.2 8.0 47.2 11.08 1.81 14 2.5 6.7 40.2 9.28 1.88 15 2.2 5.8 42.1 10.16 2.06 GROUP 3 (300 MG/KG) 21 2.8 5.2 40.2 8.36 1.98 22 3.5 6.1 44.7 6.82 1.40 23 3.0 7.0 41.4 7.24 1.60 24 2.4 7.2 42.7 10.66 1.74 25 2.9 5.0 36.9 9.61 1.66 GROUP 4 (1000 MG/KG) 31 2.5 6.5 38.9 8.30 1.59 32 2.0 8.0 42.7 9.08 1.57 33 2.1 5.7 40.8 10.08 1.92 34 2.2 5.9 41.4 8.84 2.2224May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 10 CLINICAL BIOCHEMISTRY MALES END OF TREATMENT ANIMAL Total bilirubin

umol/L Urea

mmol/L Creatinine

umol/L Glucose

mmol/L Cholesterol

mmol/L GROUP 4 (1000 MG/KG) 35 1.9 5.7 40.2 12.29 1.90 MALES END OF TREATMENT ANIMAL Bile Acids

umol/L Sodium

mmol/L Potassium

mmol/L Chloride

mmol/L Calcium

mmol/L GROUP 1 (CONTROL) 1 9.3 143.5 4.39 103 2.64 2 9.4 142.5 3.81 102 2.61 3 9.7 141.9 4.15 105 2.48 4 14.0 143.4 3.98 100 2.65 5 17.4 142.5 4.04 102 2.65 GROUP 2 (100 MG/KG) 11 33.1 141.5 3.96 102 2.58 12 19.6 145.4 3.81 101 2.51 13 22.0 144.4 3.83 101 2.51 14 10.7 142.9 3.86 104 2.60 15 14.9 143.8 3.97 104 2.53 GROUP 3 (300 MG/KG) 21 32.1 144.2 4.21 103 2.63 22 13.9 153.4 4.70 112 2.55 23 27.2 144.0 4.04 104 2.58 24 22.8 149.5 4.55 107 2.71 25 28.6 142.9 4.19 103 2.61 GROUP 4 (1000 MG/KG) 31 12.2 142.7 3.97 103 2.61 32 17.5 142.7 4.03 106 2.56 33 19.5 144.5 4.39 103 2.52 34 17.3 142.6 4.40 103 2.57 35 15.8 141.4 4.26 101 2.62 MALES END OF TREATMENT ANIMAL Inorg.Phos

mmol/L ' GROUP 1 (CONTROL) 1 1.99 . 2 1.82 . 3 2.04 . 4 2.26 . 5 1.95 . GROUP 2 (100 MG/KG) 11 2.23 . 12 1.82 . 13 1.87 . 14 1.71 . 15 2.04 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 10 CLINICAL BIOCHEMISTRY MALES END OF TREATMENT ANIMAL Inorg.Phos

mmol/L ' GROUP 3 (300 MG/KG) 21 1.80 . 22 1.98 . 23 1.91 . 24 1.72 . 25 1.73 . GROUP 4 (1000 MG/KG) 31 2.03 . 32 1.98 . 33 1.79 . 34 2.04 . 35 1.64 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 10 CLINICAL BIOCHEMISTRY FEMALES END OF TREATMENT ANIMAL ALAT

U/L ASAT

U/L ALP

U/L Total protein

g/L Albumin

g/L GROUP 1 (CONTROL) 41 52.0 82.5 172 65.8 34.0 43 45.8 80.5 51 62.8 31.8 44 91.2 109.4 156 67.2 34.7 48 58.8 71.9 56 64.0 32.1 50 45.0 89.4 81 61.3 31.5 GROUP 2 (100 MG/KG) 51 68.1 82.0 43 62.0 32.1 54 59.2 126.5 75 63.9 32.2 55 57.8 78.5 119 60.5 31.6 57 56.2 81.0 56 65.1 33.0 60 63.2 72.9 178 69.3 35.1 GROUP 3 (300 MG/KG) 61 20.8 70.9 64 66.4 36.1 62 35.5 75.9 57 68.3 36.5 63 28.8 68.6 42 68.6 37.1 64 29.8 66.5 39 71.3 38.1 65 22.8 56.7 73 69.2 37.8 GROUP 4 (1000 MG/KG) 73 35.7 77.4 59 64.0 33.9 76 32.0 76.4 55 69.9 36.5 78 37.3 76.2 45 68.3 35.8 79 49.3 86.2 48 69.4 37.7 80 32.8 87.9 49 60.0 29.9 FEMALES END OF TREATMENT ANIMAL Total bilirubin

umol/L Urea

mmol/L Creatinine

umol/L Glucose

mmol/L Cholesterol

mmol/L GROUP 1 (CONTROL) 41 2.0 9.1 40.6 7.50 2.10 43 2.2 6.4 42.3 6.71 1.44 44 2.0 11.0 43.5 8.52 1.44 48 2.0 7.9 42.5 8.09 1.62 50 2.4 8.7 42.5 8.43 1.73 GROUP 2 (100 MG/KG) 51 1.7 8.3 40.3 6.06 2.02 54 2.1 7.4 41.0 7.08 1.87 55 1.8 7.7 41.6 7.80 1.12 57 2.1 7.1 46.5 7.60 2.37 60 1.7 9.4 48.5 8.36 1.84 GROUP 3 (300 MG/KG) 61 1.4 7.2 48.8 7.22 2.06 62 2.8 5.2 41.6 8.40 1.75 63 4.2 5.8 46.2 8.24 1.04 64 2.9 6.7 42.2 8.48 1.30 65 2.5 5.7 45.5 8.89 1.21 GROUP 4 (1000 MG/KG) 73 2.7 6.8 42.9 7.40 1.21 76 2.8 6.2 42.2 7.96 1.59 78 2.5 5.6 37.0 7.05 1.37 79 2.1 7.4 42.9 7.93 0.9824May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 10 CLINICAL BIOCHEMISTRY FEMALES END OF TREATMENT ANIMAL Total bilirubin

umol/L Urea

mmol/L Creatinine

umol/L Glucose

mmol/L Cholesterol

mmol/L GROUP 4 (1000 MG/KG) 80 2.5 7.3 42.9 6.08 0.92 FEMALES END OF TREATMENT ANIMAL Bile Acids

umol/L Sodium

mmol/L Potassium

mmol/L Chloride

mmol/L Calcium

mmol/L GROUP 1 (CONTROL) 41 30.5 140.5 3.43 93 2.77 43 31.1 140.6 4.10 101 2.58 44 9.6 141.0 4.28 101 2.69 48 19.2 139.3 3.94 100 2.58 50 42.6 141.1 3.66 99 2.56 GROUP 2 (100 MG/KG) 51 19.3 139.2 4.13 97 2.46 54 51.9 140.7 3.20 96 2.51 55 25.1 139.4 4.12 101 2.52 57 24.3 138.4 3.84 95 2.67 60 15.0 136.4 4.26 97 2.68 GROUP 3 (300 MG/KG) 61 5.8 141.0 3.99 105 2.73 62 25.8 142.0 3.79 102 2.59 63 21.0 141.2 3.72 103 2.60 64 11.7 140.1 4.03 102 2.79 65 9.1 141.3 3.69 104 2.71 GROUP 4 (1000 MG/KG) 73 23.6 141.9 3.70 102 2.64 76 17.0 141.8 3.93 103 2.80 78 27.6 142.2 3.71 105 2.70 79 13.0 143.3 3.56 107 2.64 80 19.8 142.3 4.03 104 2.54 FEMALES END OF TREATMENT ANIMAL Inorg.Phos

mmol/L ' GROUP 1 (CONTROL) 41 2.90 . 43 1.88 . 44 1.54 . 48 1.67 . 50 1.86 . GROUP 2 (100 MG/KG) 51 2.06 . 54 1.94 . 55 2.07 . 57 2.25 . 60 1.80 .24May13 08h29

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2. 10 CLINICAL BIOCHEMISTRY FEMALES END OF TREATMENT ANIMAL Inorg.Phos

mmol/L ' GROUP 3 (300 MG/KG) 61 1.69 . 62 1.75 . 63 1.60 . 64 1.87 . 65 1.62 . GROUP 4 (1000 MG/KG) 73 1.87 . 76 1.83 . 78 1.80 . 79 1.65 . 80 1.79 .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.11 MACROSCOPIC FINDINGS MALES ALL NECROPSIES ANIMAL ORGAN FINDING DAY OF DEATH ' GROUP 1 (CONTROL) 1 No findings noted Scheduled sacrifice, 27Feb2013 . 2 Thymus Focus/foci, isolated, reddish. Scheduled sacrifice, 27Feb2013 . 3 No findings noted Scheduled sacrifice, 27Feb2013 . 4 No findings noted Scheduled sacrifice, 27Feb2013 . 5 No findings noted Scheduled sacrifice, 27Feb2013 . 6 No findings noted Scheduled sacrifice, 27Feb2013 . 7 No findings noted Scheduled sacrifice, 27Feb2013 . 8 No findings noted Scheduled sacrifice, 27Feb2013 . 9 No findings noted Scheduled sacrifice, 27Feb2013 . 10 No findings noted Scheduled sacrifice, 27Feb2013 . GROUP 2 (100 MG/KG) 11 No findings noted Scheduled sacrifice, 27Feb2013 . 12 No findings noted Scheduled sacrifice, 27Feb2013 . 13 Kidneys Right side: pelvic dilation. Scheduled sacrifice, 27Feb2013 .

Epididymides Right side, tail: nodule(s), d=2x2 mm, . yellowish, soft. . 14 No findings noted Scheduled sacrifice, 27Feb2013 . 15 No findings noted Scheduled sacrifice, 27Feb2013 . 16 Epididymides Left side, tail: nodule(s), d=11x6 mm, Scheduled sacrifice, 27Feb2013 . yellowish, soft. . Skin Back of the neck: scab formation. . 17 No findings noted Scheduled sacrifice, 27Feb2013 . 18 No findings noted Scheduled sacrifice, 27Feb2013 . 19 No findings noted Scheduled sacrifice, 27Feb2013 . 20 No findings noted Scheduled sacrifice, 27Feb2013 . GROUP 3 (300 MG/KG) 21 No findings noted Scheduled sacrifice, 27Feb2013 . 22 No findings noted Scheduled sacrifice, 27Feb2013 . 23 No findings noted Scheduled sacrifice, 27Feb2013 . 24 No findings noted Scheduled sacrifice, 27Feb2013 . 25 No findings noted Scheduled sacrifice, 27Feb2013 . 26 No findings noted Scheduled sacrifice, 27Feb2013 . 27 Epididymides Right side, tail: nodule(s), d=5x3 mm, Scheduled sacrifice, 27Feb2013 . yellowish, soft. . 28 No findings noted Scheduled sacrifice, 27Feb2013 . 29 No findings noted Scheduled sacrifice, 27Feb2013 . 30 No findings noted Scheduled sacrifice, 27Feb2013 . GROUP 4 (1000 MG/KG) 31 No findings noted Scheduled sacrifice, 27Feb2013 . 32 No findings noted Scheduled sacrifice, 27Feb2013 . 33 Kidneys Right side: pelvic dilation. Scheduled sacrifice, 27Feb2013 . 34 Liver Left median lobe: diaphragmatic hernia. Scheduled sacrifice, 27Feb2013 .

Mandibular lymph n Enlarged. . 35 No findings noted Scheduled sacrifice, 27Feb2013 . 36 No findings noted Scheduled sacrifice, 27Feb2013 . 37 No findings noted Scheduled sacrifice, 27Feb2013 . 38 Testes Left side: reduced in size. Scheduled sacrifice, 27Feb2013 .

Epididymides Left side: reduced in size. . 39 No findings noted Scheduled sacrifice, 27Feb2013 . 40 No findings noted Scheduled sacrifice, 27Feb2013 .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.11 MACROSCOPIC FINDINGS FEMALES ALL NECROPSIES ANIMAL ORGAN FINDING DAY OF DEATH ' GROUP 1 (CONTROL) 41 No findings noted Scheduled sacrifice, 12Mar2013 . 42 No findings noted Scheduled sacrifice, 13Mar2013 . 43 No findings noted Scheduled sacrifice, 15Mar2013 . 44 Duodenum Wall: thickened. Scheduled sacrifice, 12Mar2013 .

Jejunum Wall: thickened. . 45 No findings noted Scheduled sacrifice, 18Mar2013 . 46 No findings noted Scheduled sacrifice, 15Mar2013 . 47 No findings noted Scheduled sacrifice, 15Mar2013 . 48 No findings noted Scheduled sacrifice, 12Mar2013 . 49 No findings noted Scheduled sacrifice, 15Mar2013 . 50 No findings noted Scheduled sacrifice, 12Mar2013 . GROUP 2 (100 MG/KG) 51 No findings noted Scheduled sacrifice, 15Mar2013 . 52 No findings noted Scheduled sacrifice, 12Mar2013 . 53 General observations Total litter loss. Other, 15Mar2013 . 54 No findings noted Scheduled sacrifice, 15Mar2013 . 55 Clitoral glands Left side: focus/foci, many, reddish. Scheduled sacrifice, 12Mar2013 .

Adrenal glands Both sides: enlarged. . Both sides: discolouration, dark red. . 56 No findings noted Scheduled sacrifice, 15Mar2013 . 57 No findings noted Scheduled sacrifice, 12Mar2013 . 58 No findings noted Scheduled sacrifice, 15Mar2013 . 59 Kidneys Left side: pelvic dilation. Scheduled sacrifice, 13Mar2013 . 60 Duodenum Wall: thickened. Scheduled sacrifice, 12Mar2013 .

Jejunum Wall: thickened. . Kidneys Both sides: discolouration, . black-brown. . Spleen Enlarged. . GROUP 3 (300 MG/KG) 61 Uterus Right horn: large fetus. Scheduled sacrifice, 14Mar2013 . Right horn: contents: black, dark red. . 62 No findings noted Scheduled sacrifice, 14Mar2013 . 63 No findings noted Scheduled sacrifice, 14Mar2013 . 64 No findings noted Scheduled sacrifice, 14Mar2013 . 65 No findings noted Scheduled sacrifice, 14Mar2013 . 66 No findings noted Scheduled sacrifice, 12Mar2013 . 67 No findings noted Scheduled sacrifice, 13Mar2013 . 68 No findings noted Scheduled sacrifice, 13Mar2013 . 69 No findings noted Scheduled sacrifice, 12Mar2013 . 70 No findings noted Scheduled sacrifice, 13Mar2013 . GROUP 4 (1000 MG/KG) 71 No findings noted Scheduled sacrifice, 12Mar2013 . 72 No findings noted Scheduled sacrifice, 13Mar2013 . 73 No findings noted Scheduled sacrifice, 14Mar2013 . 74 No findings noted Scheduled sacrifice, 12Mar2013 . 75 No findings noted Scheduled sacrifice, 12Mar2013 . 76 No findings noted Scheduled sacrifice, 14Mar2013 . 77 No findings noted Scheduled sacrifice, 12Mar2013 . 78 No findings noted Scheduled sacrifice, 14Mar2013 . 79 Clitoral glands Right side: discolouration, tan. Scheduled sacrifice, 14Mar2013 .

Adrenal glands Both sides: enlarged. . 80 Thymus Discolouration, red-brown. Scheduled sacrifice, 14Mar2013 .

Mesenteric lymph n Enlarged. . Mandibular lymph n Both sides: discolouration, reddish. .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN WEIGHTS (GRAM) MALES END OF TREATMENT ANIMAL BODY W.

(GRAM) BRAIN

(GRAM) HEART

(GRAM) LIVER

(GRAM) THYROIDS

(GRAM) THYMUS

(GRAM) GROUP 1 (CONTROL) 1 365 2.11 0.956 8.45 0.024 0.318 2 353 1.97 0.980 8.42 0.027 0.297 3 368 2.10 1.178 8.96 0.019 0.379 4 368 1.98 0.940 8.85 0.038 0.302 5 352 2.14 1.166 8.75 0.026 0.272 6 385 --- --- --- --- --- 7 342 --- --- --- --- --- 8 373 --- --- --- --- --- 9 350 --- --- --- --- --- 10 351 --- --- --- --- --- GROUP 2 (100 MG/KG) 11 384 2.08 1.109 9.58 0.034 0.348 12 338 2.03 1.060 8.12 0.023 0.254 13 339 2.13 1.015 8.20 0.028 0.344 14 359 1.95 1.042 8.41 0.030 0.421 15 353 2.13 0.970 7.78 0.027 0.268 16 381 --- --- --- --- --- 17 351 --- --- --- --- --- 18 351 --- --- --- --- --- 19 368 --- --- --- --- --- 20 351 --- --- --- --- --- GROUP 3 (300 MG/KG) 21 346 1.93 1.026 7.86 0.033 0.371 22 320 1.92 1.042 7.09 0.043 0.348 23 394 1.97 1.119 8.87 0.030 0.430 24 354 1.99 1.131 9.75 0.016 0.388 25 354 2.11 1.030 8.36 0.027 0.357 26 354 --- --- --- --- --- 27 335 --- --- --- --- --- 28 369 --- --- --- --- --- 29 369 --- --- --- --- --- 30 364 --- --- --- --- --- GROUP 4 (1000 MG/KG) 31 364 1.99 1.003 9.41 0.015 0.357 32 341 2.04 1.009 8.39 0.032 0.373 33 382 2.06 1.091 9.24 0.030 0.266 34 373 2.10 1.180 9.31 0.025 0.351 35 351 2.07 1.004 8.94 0.020 0.416 36 370 --- --- --- --- --- 37 324 --- --- --- --- --- 38 351 --- --- --- --- --- 39 348 --- --- --- --- --- 40 383 --- --- --- --- --- MALES END OF TREATMENT ANIMAL KIDNEYS

(GRAM) ADRENALS

(GRAM) SPLEEN

(GRAM) TESTES

(GRAM) PROSTATE

(GRAM) EPIDIDYMIDES

(GRAM) GROUP 1 (CONTROL) 1 2.11 0.071 0.597 3.45 0.648 1.087 2 2.27 0.070 0.640 4.04 0.848 1.173 3 2.36 0.066 0.736 4.09 0.457 1.122 4 2.51 0.059 0.645 3.34 0.452 1.134 5 2.37 0.056 0.522 3.89 0.419 1.22004Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN WEIGHTS (GRAM) MALES END OF TREATMENT ANIMAL KIDNEYS

(GRAM) ADRENALS

(GRAM) SPLEEN

(GRAM) TESTES

(GRAM) PROSTATE

(GRAM) EPIDIDYMIDES

(GRAM) GROUP 1 (CONTROL) 6 --- --- --- 3.56 --- 1.181 7 --- --- --- 3.54 --- 1.288 8 --- --- --- 3.71 --- 1.158 9 --- --- --- 3.25 --- 1.124 10 --- --- --- 3.48 --- 1.190 GROUP 2 (100 MG/KG) 11 2.39 0.067 0.715 3.62 0.539 1.123 12 2.46 0.055 0.547 3.72 0.618 1.185 13 2.34 0.062 0.657 3.48 0.634 1.163 14 2.35 0.055 0.776 3.45 0.508 1.120 15 2.54 0.068 0.567 3.82 0.641 1.306 16 --- --- --- 4.32 --- 1.623 17 --- --- --- 3.44 --- 1.143 18 --- --- --- 3.32 --- 1.105 19 --- --- --- 3.78 --- 1.326 20 --- --- --- 3.61 --- 1.060 GROUP 3 (300 MG/KG) 21 2.34 0.082 0.575 3.52 0.623 1.107 22 1.92 0.058 0.537 3.73 0.460 1.252 23 2.51 0.058 1.047 4.01 0.782 1.266 24 2.52 0.057 0.824 3.74 0.747 1.159 25 2.23 0.062 0.557 3.95 0.627 1.265 26 --- --- --- 3.38 --- 1.034 27 --- --- --- 3.95 --- 1.333 28 --- --- --- 3.37 --- 1.229 29 --- --- --- 3.42 --- 1.127 30 --- --- --- 3.66 --- 1.261 GROUP 4 (1000 MG/KG) 31 2.61 0.062 0.683 3.02 0.648 1.053 32 2.05 0.066 0.403 3.10 0.555 1.043 33 3.02 0.059 0.715 3.70 0.844 1.354 34 2.66 0.063 0.705 3.38 0.494 1.131 35 2.65 0.069 0.696 3.06 0.648 1.207 36 --- --- --- 3.77 --- 1.194 37 --- --- --- 3.28 --- 1.173 38 --- --- --- 3.70 --- 1.047 39 --- --- --- 3.08 --- 1.080 40 --- --- --- 3.37 --- 1.116 MALES END OF TREATMENT ANIMAL SEMINAL VES

(GRAM) ' GROUP 1 (CONTROL) 1 1.226 . 2 1.451 . 3 1.429 . 4 1.423 . 5 1.381 . 6 --- . 7 --- . 8 --- . 9 --- . 10 --- .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN WEIGHTS (GRAM) MALES END OF TREATMENT ANIMAL SEMINAL VES

(GRAM) ' GROUP 2 (100 MG/KG) 11 1.350 . 12 1.704 . 13 1.061 . 14 1.401 . 15 1.534 . 16 --- . 17 --- . 18 --- . 19 --- . 20 --- . GROUP 3 (300 MG/KG) 21 1.331 . 22 1.225 . 23 1.346 . 24 1.240 . 25 1.387 . 26 --- . 27 --- . 28 --- . 29 --- . 30 --- . GROUP 4 (1000 MG/KG) 31 1.603 . 32 1.459 . 33 1.663 . 34 1.455 . 35 1.534 . 36 --- . 37 --- . 38 --- . 39 --- . 40 --- .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN/BODY WEIGHT RATIOS (%) MALES END OF TREATMENT ANIMAL BODY W.

(GRAM) BRAIN

(%) HEART

(%) LIVER

(%) THYROIDS

(%) THYMUS

(%) GROUP 1 (CONTROL) 1 365 0.58 0.262 2.31 0.007 0.087 2 353 0.56 0.278 2.38 0.008 0.084 3 368 0.57 0.320 2.43 0.005 0.103 4 368 0.54 0.255 2.41 0.010 0.082 5 352 0.61 0.331 2.49 0.007 0.077 6 385 --- --- --- --- --- 7 342 --- --- --- --- --- 8 373 --- --- --- --- --- 9 350 --- --- --- --- --- 10 351 --- --- --- --- --- GROUP 2 (100 MG/KG) 11 384 0.54 0.289 2.49 0.009 0.091 12 338 0.60 0.314 2.40 0.007 0.075 13 339 0.63 0.299 2.42 0.008 0.101 14 359 0.54 0.290 2.34 0.008 0.117 15 353 0.60 0.275 2.20 0.008 0.076 16 381 --- --- --- --- --- 17 351 --- --- --- --- --- 18 351 --- --- --- --- --- 19 368 --- --- --- --- --- 20 351 --- --- --- --- --- GROUP 3 (300 MG/KG) 21 346 0.56 0.297 2.27 0.010 0.107 22 320 0.60 0.326 2.21 0.013 0.109 23 394 0.50 0.284 2.25 0.008 0.109 24 354 0.56 0.319 2.76 0.005 0.110 25 354 0.60 0.291 2.36 0.008 0.101 26 354 --- --- --- --- --- 27 335 --- --- --- --- --- 28 369 --- --- --- --- --- 29 369 --- --- --- --- --- 30 364 --- --- --- --- --- GROUP 4 (1000 MG/KG) 31 364 0.55 0.276 2.59 0.004 0.098 32 341 0.60 0.296 2.46 0.009 0.109 33 382 0.54 0.286 2.42 0.008 0.070 34 373 0.56 0.316 2.50 0.007 0.094 35 351 0.59 0.286 2.55 0.006 0.119 36 370 --- --- --- --- --- 37 324 --- --- --- --- --- 38 351 --- --- --- --- --- 39 348 --- --- --- --- --- 40 383 --- --- --- --- --- MALES END OF TREATMENT ANIMAL KIDNEYS

(%) ADRENALS

(%) SPLEEN

(%) TESTES

(%) PROSTATE

(%) EPIDIDYMIDES

(%) GROUP 1 (CONTROL) 1 0.58 0.019 0.164 0.94 0.178 0.298 2 0.64 0.020 0.181 1.14 0.240 0.332 3 0.64 0.018 0.200 1.11 0.124 0.305 4 0.68 0.016 0.175 0.91 0.123 0.308 5 0.67 0.016 0.148 1.10 0.119 0.34704Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN/BODY WEIGHT RATIOS (%) MALES END OF TREATMENT ANIMAL KIDNEYS

(%) ADRENALS

(%) SPLEEN

(%) TESTES

(%) PROSTATE

(%) EPIDIDYMIDES

(%) GROUP 1 (CONTROL) 6 --- --- --- 0.92 --- 0.307 7 --- --- --- 1.03 --- 0.377 8 --- --- --- 0.99 --- 0.310 9 --- --- --- 0.93 --- 0.321 10 --- --- --- 0.99 --- 0.339 GROUP 2 (100 MG/KG) 11 0.62 0.017 0.186 0.94 0.140 0.292 12 0.73 0.016 0.162 1.10 0.183 0.351 13 0.69 0.018 0.194 1.03 0.187 0.343 14 0.65 0.015 0.216 0.96 0.142 0.312 15 0.72 0.019 0.161 1.08 0.182 0.370 16 --- --- --- 1.13 --- 0.426 17 --- --- --- 0.98 --- 0.326 18 --- --- --- 0.95 --- 0.315 19 --- --- --- 1.03 --- 0.360 20 --- --- --- 1.03 --- 0.302 GROUP 3 (300 MG/KG) 21 0.68 0.024 0.166 1.02 0.180 0.320 22 0.60 0.018 0.168 1.16 0.144 0.391 23 0.64 0.015 0.266 1.02 0.198 0.321 24 0.71 0.016 0.233 1.06 0.211 0.327 25 0.63 0.018 0.157 1.12 0.177 0.357 26 --- --- --- 0.96 --- 0.292 27 --- --- --- 1.18 --- 0.398 28 --- --- --- 0.91 --- 0.333 29 --- --- --- 0.93 --- 0.305 30 --- --- --- 1.01 --- 0.346 GROUP 4 (1000 MG/KG) 31 0.72 0.017 0.188 0.83 0.178 0.289 32 0.60 0.019 0.118 0.91 0.163 0.306 33 0.79 0.015 0.187 0.97 0.221 0.354 34 0.71 0.017 0.189 0.90 0.132 0.303 35 0.75 0.020 0.198 0.87 0.185 0.344 36 --- --- --- 1.02 --- 0.323 37 --- --- --- 1.01 --- 0.362 38 --- --- --- 1.05 --- 0.298 39 --- --- --- 0.88 --- 0.310 40 --- --- --- 0.88 --- 0.291 MALES END OF TREATMENT ANIMAL SEMINAL VES

(%) ' GROUP 1 (CONTROL) 1 0.336 . 2 0.411 . 3 0.388 . 4 0.387 . 5 0.392 . 6 --- . 7 --- . 8 --- . 9 --- . 10 --- .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN/BODY WEIGHT RATIOS (%) MALES END OF TREATMENT ANIMAL SEMINAL VES

(%) ' GROUP 2 (100 MG/KG) 11 0.352 . 12 0.504 . 13 0.313 . 14 0.390 . 15 0.435 . 16 --- . 17 --- . 18 --- . 19 --- . 20 --- . GROUP 3 (300 MG/KG) 21 0.385 . 22 0.383 . 23 0.342 . 24 0.350 . 25 0.392 . 26 --- . 27 --- . 28 --- . 29 --- . 30 --- . GROUP 4 (1000 MG/KG) 31 0.440 . 32 0.428 . 33 0.435 . 34 0.390 . 35 0.437 . 36 --- . 37 --- . 38 --- . 39 --- . 40 --- .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN WEIGHTS (GRAM) FEMALES END OF TREATMENT ANIMAL BODY W.

(GRAM) BRAIN

(GRAM) HEART

(GRAM) LIVER

(GRAM) THYROIDS

(GRAM) THYMUS

(GRAM) GROUP 1 (CONTROL) 41 239 2.01 0.740 7.89 0.019 0.150 42 --- --- --- --- --- --- 43 264 1.99 0.881 7.05 0.023 0.198 44 238 1.95 0.753 8.65 0.020 0.195 45 --- --- --- --- --- --- 46 --- --- --- --- --- --- 47 --- --- --- --- --- --- 48 234 1.90 0.691 7.62 0.015 0.174 49 --- --- --- --- --- --- 50 229 2.05 0.654 6.65 0.015 0.222 GROUP 2 (100 MG/KG) 51 236 1.88 0.765 7.85 0.022 0.151 52 --- --- --- --- --- --- 53 --- --- --- --- --- --- 54 234 1.88 0.716 7.46 0.020 0.332 55 252 1.93 0.759 8.25 0.025 0.336 56 --- --- --- --- --- --- 57 244 1.88 0.716 7.79 0.020 0.225 58 --- --- --- --- --- --- 59 --- --- --- --- --- --- 60 246 1.90 0.816 8.43 0.020 0.235 GROUP 3 (300 MG/KG) 61 255 1.94 0.755 7.33 0.019 0.393 62 233 1.87 0.722 6.09 0.021 0.378 63 237 1.88 0.744 5.70 0.021 0.317 64 226 2.03 0.708 6.45 0.023 0.292 65 231 1.95 0.780 6.08 0.023 0.420 66 --- --- --- --- --- --- 67 --- --- --- --- --- --- 68 --- --- --- --- --- --- 69 --- --- --- --- --- --- 70 --- --- --- --- --- --- GROUP 4 (1000 MG/KG) 71 --- --- --- --- --- --- 72 --- --- --- --- --- --- 73 219 1.86 0.720 5.44 0.025 0.380 74 --- --- --- --- --- --- 75 --- --- --- --- --- --- 76 233 2.03 0.629 5.55 0.023 0.335 77 --- --- --- --- --- --- 78 222 1.85 0.779 5.28 0.021 0.253 79 224 2.00 0.686 5.67 0.021 0.313 80 226 2.01 0.783 6.15 0.018 0.272 FEMALES END OF TREATMENT ANIMAL KIDNEYS

(GRAM) ADRENALS

(GRAM) SPLEEN

(GRAM) OVARIES

(GRAM) UTERUS

(GRAM) ' GROUP 1 (CONTROL) 41 1.78 0.080 0.584 0.134 0.582 . 42 --- --- --- --- --- . 43 1.73 0.086 0.415 0.103 0.399 . 44 1.69 0.077 0.504 0.096 0.602 . 45 --- --- --- --- --- .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN WEIGHTS (GRAM) FEMALES END OF TREATMENT ANIMAL KIDNEYS

(GRAM) ADRENALS

(GRAM) SPLEEN

(GRAM) OVARIES

(GRAM) UTERUS

(GRAM) ' GROUP 1 (CONTROL) 46 --- --- --- --- --- . 47 --- --- --- --- --- . 48 1.68 0.080 0.361 0.109 0.567 . 49 --- --- --- --- --- . 50 1.61 0.069 0.464 0.123 0.587 . GROUP 2 (100 MG/KG) 51 1.81 0.078 0.570 0.113 0.555 . 52 --- --- --- --- --- . 53 --- --- --- --- --- . 54 1.79 0.074 0.492 0.117 0.419 . 55 1.74 0.088 0.584 0.125 0.672 . 56 --- --- --- --- --- . 57 1.47 0.061 0.450 0.114 0.651 . 58 --- --- --- --- --- . 59 --- --- --- --- --- . 60 1.47 0.065 0.820 0.106 0.669 . GROUP 3 (300 MG/KG) 61 1.64 0.070 0.640 0.149 --- . 62 1.54 0.088 0.535 0.155 0.715 . 63 1.62 0.059 0.413 0.111 0.762 . 64 1.76 0.069 0.450 0.172 0.472 . 65 1.65 0.073 0.410 0.171 0.501 . 66 --- --- --- --- --- . 67 --- --- --- --- --- . 68 --- --- --- --- --- . 69 --- --- --- --- --- . 70 --- --- --- --- --- . GROUP 4 (1000 MG/KG) 71 --- --- --- --- --- . 72 --- --- --- --- --- . 73 1.44 0.065 0.397 0.163 0.409 . 74 --- --- --- --- --- . 75 --- --- --- --- --- . 76 1.61 0.077 0.410 0.105 0.506 . 77 --- --- --- --- --- . 78 1.74 0.058 0.362 0.158 0.639 . 79 1.76 0.068 0.413 0.144 0.354 . 80 1.78 0.075 0.454 0.161 0.443 .

 Uterus weight was determined including fetus (13.874 gram) *04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN/BODY WEIGHT RATIOS (%) FEMALES END OF TREATMENT ANIMAL BODY W.

(GRAM) BRAIN

(%) HEART

(%) LIVER

(%) THYROIDS

(%) THYMUS

(%) GROUP 1 (CONTROL) 41 239 0.84 0.310 3.30 0.008 0.063 42 --- --- --- --- --- --- 43 264 0.75 0.334 2.67 0.009 0.075 44 238 0.82 0.316 3.63 0.008 0.082 45 --- --- --- --- --- --- 46 --- --- --- --- --- --- 47 --- --- --- --- --- --- 48 234 0.81 0.295 3.26 0.006 0.074 49 --- --- --- --- --- --- 50 229 0.90 0.286 2.90 0.007 0.097 GROUP 2 (100 MG/KG) 51 236 0.80 0.324 3.33 0.009 0.064 52 --- --- --- --- --- --- 53 --- --- --- --- --- --- 54 234 0.80 0.306 3.19 0.009 0.142 55 252 0.77 0.301 3.27 0.010 0.133 56 --- --- --- --- --- --- 57 244 0.77 0.293 3.19 0.008 0.092 58 --- --- --- --- --- --- 59 --- --- --- --- --- --- 60 246 0.77 0.332 3.43 0.008 0.096 GROUP 3 (300 MG/KG) 61 255 0.76 0.296 2.88 0.007 0.154 62 233 0.80 0.310 2.61 0.009 0.162 63 237 0.79 0.314 2.41 0.009 0.134 64 226 0.90 0.313 2.85 0.010 0.129 65 231 0.85 0.338 2.63 0.010 0.182 66 --- --- --- --- --- --- 67 --- --- --- --- --- --- 68 --- --- --- --- --- --- 69 --- --- --- --- --- --- 70 --- --- --- --- --- --- GROUP 4 (1000 MG/KG) 71 --- --- --- --- --- --- 72 --- --- --- --- --- --- 73 219 0.85 0.329 2.48 0.011 0.174 74 --- --- --- --- --- --- 75 --- --- --- --- --- --- 76 233 0.87 0.270 2.38 0.010 0.144 77 --- --- --- --- --- --- 78 222 0.83 0.351 2.38 0.009 0.114 79 224 0.89 0.306 2.53 0.009 0.140 80 226 0.89 0.346 2.72 0.008 0.120 FEMALES END OF TREATMENT ANIMAL KIDNEYS

(%) ADRENALS

(%) SPLEEN

(%) OVARIES

(%) UTERUS

(%) ' GROUP 1 (CONTROL) 41 0.74 0.033 0.244 0.056 0.244 . 42 --- --- --- --- --- . 43 0.66 0.033 0.157 0.039 0.151 . 44 0.71 0.032 0.212 0.040 0.253 . 45 --- --- --- --- --- .04Jun13 08h06

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.12 ORGAN/BODY WEIGHT RATIOS (%) FEMALES END OF TREATMENT ANIMAL KIDNEYS

(%) ADRENALS

(%) SPLEEN

(%) OVARIES

(%) UTERUS

(%) ' GROUP 1 (CONTROL) 46 --- --- --- --- --- . 47 --- --- --- --- --- . 48 0.72 0.034 0.154 0.047 0.242 . 49 --- --- --- --- --- . 50 0.70 0.030 0.203 0.054 0.256 . GROUP 2 (100 MG/KG) 51 0.77 0.033 0.242 0.048 0.235 . 52 --- --- --- --- --- . 53 --- --- --- --- --- . 54 0.77 0.032 0.210 0.050 0.179 . 55 0.69 0.035 0.232 0.050 0.267 . 56 --- --- --- --- --- . 57 0.60 0.025 0.184 0.047 0.267 . 58 --- --- --- --- --- . 59 --- --- --- --- --- . 60 0.60 0.026 0.333 0.043 0.272 . GROUP 3 (300 MG/KG) 61 0.64 0.027 0.251 0.058 --- . 62 0.66 0.038 0.230 0.067 0.307 . 63 0.68 0.025 0.174 0.047 0.322 . 64 0.78 0.031 0.199 0.076 0.209 . 65 0.72 0.032 0.177 0.074 0.217 . 66 --- --- --- --- --- . 67 --- --- --- --- --- . 68 --- --- --- --- --- . 69 --- --- --- --- --- . 70 --- --- --- --- --- . GROUP 4 (1000 MG/KG) 71 --- --- --- --- --- . 72 --- --- --- --- --- . 73 0.66 0.030 0.181 0.074 0.187 . 74 --- --- --- --- --- . 75 --- --- --- --- --- . 76 0.69 0.033 0.176 0.045 0.217 . 77 --- --- --- --- --- . 78 0.78 0.026 0.163 0.071 0.288 . 79 0.79 0.030 0.184 0.064 0.158 . 80 0.79 0.033 0.201 0.071 0.196 . *

 Uterus weight was determined including fetus (13.874 gram)24May13 11h54

<NP> Non-pregnant COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.13 GENERAL REPRODUCTION DATA F0-GENERATION - POST COITUM FEMALE NUMBER MALE

NUMBER MATING

DATE PREGNANT SCHEDULE DELIVERY RECORDED NECROPSY

DATE ' GROUP 1 (CONTROL) 41 1 13FEB2013 YES BREEDING 07MAR2013 12MAR2013 . 42 <NP> 2 14FEB2013 NO --- --- 13MAR2013 . 43 3 15FEB2013 YES BREEDING 09MAR2013 15MAR2013 . 44 4 13FEB2013 YES BREEDING 06MAR2013 12MAR2013 . 45 5 18FEB2013 YES BREEDING 12MAR2013 18MAR2013 . 46 6 15FEB2013 YES BREEDING 08MAR2013 15MAR2013 . 47 7 16FEB2013 YES BREEDING 09MAR2013 15MAR2013 . 48 8 13FEB2013 YES BREEDING 06MAR2013 12MAR2013 . 49 9 16FEB2013 YES BREEDING 09MAR2013 15MAR2013 . 50 10 13FEB2013 YES BREEDING 07MAR2013 12MAR2013 . GROUP 2 (100 MG/KG) 51 11 15FEB2013 YES BREEDING 08MAR2013 15MAR2013 . 52 <NP> 12 13FEB2013 NO --- --- 12MAR2013 . 53 13 15FEB2013 YES BREEDING 10MAR2013 15MAR2013 . 54 14 14FEB2013 YES BREEDING 08MAR2013 15MAR2013 . 55 15 14FEB2013 YES BREEDING 07MAR2013 12MAR2013 . 56 16 15FEB2013 YES BREEDING 09MAR2013 15MAR2013 . 57 17 14FEB2013 YES BREEDING 07MAR2013 12MAR2013 . 58 18 16FEB2013 YES BREEDING 09MAR2013 15MAR2013 . 59 19 15FEB2013 YES --- --- 13MAR2013 . 60 20 13FEB2013 YES BREEDING 07MAR2013 12MAR2013 . GROUP 3 (300 MG/KG) 61 21 16FEB2013 YES --- --- 14MAR2013 . 62 <NP> 22 16FEB2013 NO --- --- 14MAR2013 . 63 <NP> 23 15FEB2013 NO --- --- 14MAR2013 . 64 <NP> 24 15FEB2013 NO --- --- 14MAR2013 . 65 25 15FEB2013 YES --- --- 14MAR2013 . 66 <NP> 26 13FEB2013 NO --- --- 12MAR2013 . 67 <NP> 27 16FEB2013 NO --- --- 13MAR2013 . 68 <NP> 28 14FEB2013 NO --- --- 13MAR2013 . 69 <NP> 29 13FEB2013 NO --- --- 12MAR2013 . 70 <NP> 30 14FEB2013 NO --- --- 13MAR2013 . GROUP 4 (1000 MG/KG) 71 <NP> 31 13FEB2013 NO --- --- 12MAR2013 . 72 <NP> 32 15FEB2013 NO --- --- 13MAR2013 . 73 <NP> 33 16FEB2013 NO --- --- 14MAR2013 . 74 <NP> 34 13FEB2013 NO --- --- 12MAR2013 . 75 <NP> 35 13FEB2013 NO --- --- 12MAR2013 . 76 <NP> 36 16FEB2013 NO --- --- 14MAR2013 . 77 <NP> 37 13FEB2013 NO --- --- 12MAR2013 . 78 <NP> 38 15FEB2013 NO --- --- 14MAR2013 . 79 <NP> 39 15FEB2013 NO --- --- 14MAR2013 . 80 <NP> 40 15FEB2013 NO --- --- 14MAR2013 .

Female nos. 59, 61 and 65 had only implantation sites24May13 12h14

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.1 4 CORPORA LUTEA AND IMPLANTATION SITES FEMALES NECROPSY ANIMAL Corpora Lutea Implantations ' GROUP 1 (CONTROL) 41 14.0 12.0 . 42 --- --- . 43 14.0 8.0 . 44 18.0 15.0 . 45 16.0 13.0 . 46 14.0 14.0 . 47 15.0 14.0 . 48 16.0 16.0 . 49 14.0 14.0 . 50 11.0 10.0 . GROUP 2 (100 MG/KG) 51 15.0 15.0 . 52 --- --- . 53 1.0 1.0 . 54 12.0 12.0 . 55 14.0 10.0 . 56 14.0 14.0 . 57 15.0 14.0 . 58 17.0 14.0 . 59 2.0 1.0 . 60 13.0 13.0 . GROUP 3 (300 MG/KG) 61 20.0 1.0 . 62 --- --- . 63 --- --- . 64 --- --- . 65 2.0 2.0 . 66 --- --- . 67 --- --- . 68 --- --- . 69 --- --- . 70 --- --- . GROUP 4 (1000 MG/KG) 71 --- --- . 72 --- --- . 73 --- --- . 74 --- --- . 75 --- --- . 76 --- --- . 77 --- --- . 78 --- --- . 79 --- --- . 80 --- --- .

All non- pregnant females had 0 corpora lutea and 0 implantation sites, except for female no. 79 which had 19 corpora lutea and 0 implantation sites24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.15 DEVELOPMENTAL DATA PER LITTER FEMALES F0-GENERATION - LACTATION - FIRST LITTER CHECK - LITTER DURATION OF

GESTATION DEAD PUPS

M F LIVING PUPS

M F TOT. P.NATAL LOSS M F ' GROUP 1 (CONTROL) 41 22 0 0 8 4 12 0 0 . 43 22 0 0 4 3 7 0 0 . 44 21 0 0 7 7 14 1 0 . 45 22 0 0 7 5 12 0 0 . 46 21 0 0 9 4 13 0 0 . 47 21 0 0 6 7 13 0 0 . 48 21 0 0 7 8 15 0 0 . 49 21 0 0 11 3 14 0 0 . 50 22 0 0 4 6 10 0 0 . . TOTAL 0 0 63 47 110 1 0 . N 9 9 9 9 9 9 9 9 . MEAN 21.4 0.0 0.0 7.0 5.2 12.2 0.1 0.0 . ST.DEV. 0.5 0.0 0.0 2.2 1.9 2.4 0.3 0.0 . GROUP 2 (100 MG/KG) 51 21 0 0 7 8 15 0 0 . 53 23 0 0 1 0 1 1 0 . 54 22 0 0 5 6 11 0 0 . 55 21 0 0 3 7 10 0 0 . 56 22 0 0 6 5 11 0 0 . 57 21 0 0 5 9 14 0 0 . 58 21 0 0 9 3 12 0 0 . 60 22 2 1 4 5 9 0 0 . . TOTAL 2 1 40 43 83 1 0 . N 8 8 8 8 8 8 8 8 . MEAN 21.6 0.3 0.1 5.0 5.4 10.4 0.1 0.0 . ST.DEV. 0.7 0.7 0.4 2.4 2.9 4.3 0.4 0.0 .24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.16 BODY WEIGHTS OF PUPS PER LITTER (GRAM) F0-GENERATION - LACTATION LITTER SEX DAY 1 DAY 4 ' GROUP 1 (CONTROL) 41 M 7.1 10.5 .

F 6.7 9.8 . M+F 6.9 10.3 .

. 43 M 7.1 11.4 .

F 7.3 11.3 . M+F 7.2 11.4 .

. 44 M 5.7 8.3 .

F 5.6 8.2 . M+F 5.6 8.2 .

. 45 M 7.2 10.4 .

F 6.7 9.8 . M+F 7.0 10.2 .

. 46 M 5.8 8.6 .

F 5.7 8.7 . M+F 5.7 8.6 .

. 47 M 6.3 9.6 .

F 5.9 9.3 . M+F 6.1 9.4 .

. 48 M 6.1 8.8 .

F 5.8 8.5 . M+F 5.9 8.7 .

. 49 M 5.9 9.2 .

F 5.3 8.4 . M+F 5.7 9.1 .

. 50 M 7.4 10.8 .

F 7.0 10.4 . M+F 7.1 10.6 .

. GROUP 2 (100 MG/KG) 51 M 5.7 8.6 .

F 5.3 8.2 . M+F 5.5 8.4 .

. 53 M 5.4 5.1 .

M+F 5.4 5.1 .

. 54 M 7.1 11.0 .

F 7.2 11.2 . M+F 7.1 11.1 .

. 55 M 6.7 10.5 .

F 6.3 10.0 . M+F 6.4 10.2 .

. 56 M 7.4 11.5 .

F 6.9 11.1 . M+F 7.2 11.3 .

. 57 M 5.8 8.5 .

F 5.7 8.3 . M+F 5.7 8.4 .

.24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.16 BODY WEIGHTS OF PUPS PER LITTER (GRAM) F0-GENERATION - LACTATION LITTER SEX DAY 1 DAY 4 ' GROUP 2 (100 MG/KG) 58 M 6.0 9.1 .

F 5.7 8.9 . M+F 5.9 9.1 .

. 60 M 6.9 10.8 .

F 6.7 10.4 . M+F 6.8 10.6 .

.24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.17 BODY WEIGHTS OF PUPS (GRAM) F0-GENERATION - LACTATION LITTER PUP SEX DAY 1 DAY 4 ' GROUP 1 (CONTROL) 41 1 M 7.2 10.5 .

2 M 7.5 10.7 . 3 M 7.5 10.8 . 4 M 7.1 10.7 . 5 M 6.9 10.5 . 6 M 6.8 10.3 . 7 M 6.8 10.5 . 8 M 6.9 10.2 . 9 F 6.4 9.6 . 10 F 7.1 10.4 . 11 F 6.4 9.5 . 12 F 6.8 9.6 .

. 43 1 M 6.9 11.6 .

2 M 7.5 12.2 . 3 M 7.5 11.9 . 4 M 6.5 10.1 . 5 F 7.2 11.4 . 6 F 7.5 11.5 . 7 F 7.1 11.0 .

. 44 1 M 6.3 9.5 .

2 M 5.7 7.2 . 3 M 5.5 8.1 . 4 M 6.2 8.7 . 5 M 5.4 8.1 . 6 M 5.6 8.1 . 7 M 5.1 -- . 8 F 5.5 8.1 . 9 F 5.5 7.9 . 10 F 5.8 8.7 . 11 F 5.3 7.9 . 12 F 5.5 7.9 . 13 F 5.7 8.4 . 14 F 6.0 8.6 .

. 45 1 M 7.3 10.7 .

2 M 7.1 9.9 . 3 M 6.5 9.6 . 4 M 7.3 10.4 . 5 M 7.3 10.7 . 6 M 7.4 10.5 . 7 M 7.4 11.3 . 8 F 6.8 10.2 . 9 F 6.6 9.8 . 10 F 7.3 10.4 . 11 F 6.3 8.9 . 12 F 6.8 9.5 .

. 46 1 M 3.9 5.8 .

2 M 5.7 8.4 . 3 M 5.6 8.2 . 4 M 5.8 8.8 . 5 M 6.2 9.4 . 6 M 6.3 9.6 . 7 M 6.2 9.2 . 8 M 5.9 8.7 . 9 M 6.1 9.3 . 10 F 6.2 9.5 . 11 F 5.7 8.6 . 12 F 5.4 8.4 . 13 F 5.4 8.4 .24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.17 BODY WEIGHTS OF PUPS (GRAM) F0-GENERATION - LACTATION LITTER PUP SEX DAY 1 DAY 4 ' GROUP 1 (CONTROL)

. 47 1 M 6.1 9.9 .

2 M 6.7 10.4 . 3 M 6.1 9.1 . 4 M 6.6 9.6 . 5 F 6.3 10.4 . 6 M 6.0 9.0 . 7 M 6.1 9.5 . 8 F 5.7 8.8 . 9 F 6.1 9.9 . 10 F 5.5 8.7 . 11 F 5.7 9.3 . 12 F 5.8 8.7 . 13 F 6.2 9.6 .

. 48 1 M 6.1 9.4 .

2 M 5.7 8.1 . 3 M 6.5 8.9 . 4 M 6.4 9.0 . 5 M 6.4 9.3 . 6 M 5.4 8.1 . 7 M 6.0 9.0 . 8 F 6.1 8.6 . 9 F 5.8 8.5 . 10 F 5.5 7.7 . 11 F 5.9 8.8 . 12 F 5.8 8.7 . 13 F 5.9 8.7 . 14 F 6.0 8.6 . 15 F 5.7 8.6 .

. 49 1 M 5.9 9.9 .

2 M 5.7 8.5 . 3 M 5.6 9.0 . 4 M 5.6 8.8 . 5 M 6.5 10.5 . 6 M 6.3 9.8 . 7 M 5.7 9.2 . 8 M 6.3 9.7 . 9 M 5.5 8.7 . 10 M 5.8 9.0 . 11 M 5.6 8.3 . 12 F 5.3 8.5 . 13 F 5.3 8.6 . 14 F 5.4 8.2 .

. 50 1 M 7.1 10.2 .

2 M 7.1 10.5 . 3 M 7.8 11.6 . 4 M 7.4 11.0 . 5 F 7.2 10.5 . 6 F 7.3 10.7 . 7 F 6.2 9.7 . 8 F 6.7 10.2 . 9 F 7.5 10.7 . 10 F 7.1 10.8 .

. GROUP 2 (100 MG/KG) 51 1 M 5.4 8.0 .

2 M 5.4 8.4 . 3 M 6.0 8.9 .24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.17 BODY WEIGHTS OF PUPS (GRAM) F0-GENERATION - LACTATION LITTER PUP SEX DAY 1 DAY 4 ' GROUP 2 (100 MG/KG)

4 M 5.5 8.5 . 5 M 5.6 8.7 . 6 M 6.5 8.9 . 7 M 5.9 9.0 . 8 F 4.7 7.1 . 9 F 5.7 9.0 . 10 F 5.3 8.6 . 11 F 5.7 8.8 . 12 F 5.1 7.9 . 13 F 5.3 8.0 . 14 F 5.3 7.8 . 15 F 5.3 8.1 .

. 53 1 M 5.4 5.1 .

. 54 1 M 7.1 11.0 .

2 M 6.7 10.9 . 3 M 7.3 10.8 . 4 M 7.7 12.2 . 5 M 6.5 10.2 . 6 F 7.1 10.8 . 7 F 7.8 12.1 . 8 F 7.2 11.2 . 9 F 7.0 10.9 . 10 F 7.1 11.2 . 11 F 6.9 10.8 .

. 55 1 M 6.6 10.6 .

2 M 7.2 11.2 . 3 M 6.3 9.8 . 4 F 6.1 10.0 . 5 F 6.4 10.0 . 6 F 6.4 10.2 . 7 F 6.0 9.6 . 8 F 6.4 10.2 . 9 F 6.3 9.7 . 10 F 6.6 10.5 .

. 56 1 M 7.7 12.1 .

2 M 7.5 11.3 . 3 M 7.2 11.3 . 4 M 7.5 12.0 . 5 M 7.1 11.4 . 6 M 7.3 11.1 . 7 F 6.8 10.7 . 8 F 7.1 11.6 . 9 F 6.6 11.0 . 10 F 6.7 11.0 . 11 F 7.2 11.4 .

. 57 1 M 6.1 8.9 .

2 M 5.7 8.9 . 3 M 6.2 8.6 . 4 M 5.9 8.7 . 5 M 5.1 7.6 . 6 F 5.8 8.8 . 7 F 5.8 8.6 . 8 F 5.6 8.5 . 9 F 6.0 8.4 . 10 F 5.4 7.6 . 11 F 5.5 8.2 . 12 F 5.6 7.9 .24May13 11h54

COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.17 BODY WEIGHTS OF PUPS (GRAM) F0-GENERATION - LACTATION LITTER PUP SEX DAY 1 DAY 4 ' GROUP 2 (100 MG/KG)

13 F 5.8 8.1 . 14 F 5.8 8.2 .

. 58 1 M 6.0 9.4 .

2 M 5.6 8.7 . 3 M 6.1 9.0 . 4 M 6.2 9.4 . 5 M 5.9 9.1 . 6 M 6.2 9.4 . 7 M 6.1 9.2 . 8 M 6.1 9.2 . 9 M 6.0 9.1 . 10 F 5.8 9.0 . 11 F 5.8 9.0 . 12 F 5.4 8.6 .

. 60 1 M 6.7 10.6 .

2 M 6.9 10.7 . 3 M 7.0 10.9 . 4 M 7.2 11.0 . 5 M -- -- . 6 M -- -- . 7 F 7.3 11.3 . 8 F 7.3 10.8 . 9 F 6.3 10.4 . 10 F 6.1 9.6 . 11 F 6.8 10.0 . 12 F -- -- .

.24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) LITTER 41 1 M DAY 5 Planned Necropsy FLC No findings . 07MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 2 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 3 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 4 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 5 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 6 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 7 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 8 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 9 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 10 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL)

11 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . 12 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No milk . LITTER 43 1 M DAY 6 Planned Necropsy FLC No findings . 09MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 Scabs back . DAY 5 Scabs back . LLC Scabs back . MACRO Scabs back . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC Wound hindleg right . DAY 2 Wound hindleg right . DAY 3 No findings . DAY 4 Scabs hindleg right . DAY 5 Scabs hindleg right . LLC Scabs hindleg right . MACRO Scabs hindleg right . 5 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 Scabs flank right . DAY 5 Scabs flank right . LLC Scabs flank right . MACRO Scabs flank right . 7 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) MACRO No findings . LITTER 44 1 M DAY 6 Planned Necropsy FLC No findings . 06MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 5 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 M DAY 2 Missing FLC No findings . 8 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 10 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 12 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 13 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 14 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 45 1 M DAY 6 Planned Necropsy FLC No findings . 12MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) MACRO No findings .

5 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 8 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 10 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 12 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 46 1 M DAY 7 Planned Necropsy FLC No milk . 08MAR2013 DAY 2 No findings . DAY 3 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 2 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 3 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 4 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 5 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 6 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 7 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 8 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) MACRO No findings .

9 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 10 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 11 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 12 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 13 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . LITTER 47 1 M DAY 6 Planned Necropsy FLC No findings . 09MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 5 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 8 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 10 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 12 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 13 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 48 1 M DAY 6 Planned Necropsy FLC No findings . 06MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 5 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) MACRO No findings .

8 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 10 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 12 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 13 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 14 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 15 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 49 1 M DAY 6 Planned Necropsy FLC No findings . 09MAR2013 DAY 2 No findings . DAY 3 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 5 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 8 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL)

10 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 12 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 13 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 14 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 50 1 M DAY 5 Planned Necropsy FLC No findings . 07MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 2 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 3 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 4 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 5 F DAY 5 Planned Necropsy FLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 1 (CONTROL) DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 6 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 7 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 8 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 9 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 10 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . GROUP 2 (100 MG/KG) LITTER 51 1 M DAY 7 Planned Necropsy FLC Blue spot left hindfoot . 08MAR2013 DAY 2 Blue spot left hindfoot . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 2 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 3 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) MACRO No findings .

4 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 5 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 6 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 7 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 8 F DAY 7 Planned Necropsy FLC Blue spot snout . DAY 2 Blue spot snout . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 9 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 10 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 11 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 12 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 13 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 14 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 15 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . LITTER 53 1 M DAY 5 Spontaneous death FLC Lean . 10MAR2013 DAY 2 Lean, no milk . DAY 3 Lean, no milk . DAY 4 Lean, no milk . LLC Lean, no milk . MACRO Lean, no milk . LITTER 54 1 M DAY 7 Planned Necropsy FLC No findings . 08MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 2 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 3 M DAY 7 Planned Necropsy FLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 4 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 5 M DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 6 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 7 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 8 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 9 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC No findings . MACRO No findings . 10 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 6 No findings . LLC No findings . MACRO No findings . 11 F DAY 7 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . DAY 6 No findings . LLC Abnormal posture hindleg left . MACRO Abnormal posture hindleg left . LITTER 55 1 M DAY 5 Planned Necropsy FLC No findings . 07MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 2 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 3 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 4 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 5 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 6 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 7 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 8 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 9 F DAY 5 Planned Necropsy FLC No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 10 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . LITTER 56 1 M DAY 6 Planned Necropsy FLC No findings . 09MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 5 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG)

8 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 10 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 57 1 M DAY 5 Planned Necropsy FLC No findings . 07MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 2 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 3 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 4 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 5 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 6 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 7 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 8 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 9 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 10 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 11 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 12 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 13 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 14 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . LITTER 58 1 M DAY 6 Planned Necropsy FLC No findings . 09MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 2 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 3 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 4 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 5 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 6 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 7 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 8 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 9 M DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 10 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 11 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . 12 F DAY 6 Planned Necropsy FLC No findings . DAY 2 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) DAY 3 No findings . DAY 5 No findings . LLC No findings . MACRO No findings . LITTER 60 1 M DAY 5 Planned Necropsy FLC No findings . 07MAR2013 DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 2 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 3 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 4 M DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 5 M DAY 1 Dead at FLC FLC Dead . MACRO Severe autolysis, no milk . 6 M DAY 1 Dead at FLC FLC Dead . MACRO Severe autolysis, no milk . 7 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 8 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 9 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 10 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings . LLC No findings . MACRO No findings . 11 F DAY 5 Planned Necropsy FLC No findings . DAY 2 No findings . DAY 3 No findings . DAY 4 No findings .24May13 11h54

LLC - LAST LITTER CHECK, MACRO - MACROSCOPIC FINDINGS FLC - FIRST LITTER CHECK, DAY P.P. - CLINICAL SIGNS , COPS_1 or CS-AHPS Project 500682 APPENDIX 2 2.18 MORTALITY, CLINICAL SIGNS AND MACROSCOPY OF PUPS FEMALES F0-GENERATION - LACTATION LITTER DELIVERY PUP END OF P.P. PHASE FINDINGS ' GROUP 2 (100 MG/KG) LLC No findings . MACRO No findings . 12 F DAY 1 Dead at FLC FLC Dead . MACRO Severe autolysis, no milk .COPS_1 or CS -AHPS Project 500682

APPENDIX 2 2.19 KEY TO MISSING VALUES AND REMARKS CLINICAL LABORATORY INVESTIGATIONS End of Treatment Haematology: Animal(s): 22 --- = Citrate sample clotted 1, 22 --- = EDTA sample clotted Clinical Biochemistr y: No remarks

### COPS_1 or CS -AHPS Project 500682

APPENDIX 3

- Page 1 - 

### APPENDIX 3 CERTIFICATE OF ANALYSIS

### COPS_1 or CS-AHPS Project 500682

APPENDIX 3

- Page 2 -

### COPS_1 or CS-AHPS Project 500682

APPENDIX 4

- Page 1 - 

### APPENDIX 4 FORMULATION ANALYS IS

### COPS_1 or CS - AHPS Project 500682

- Page 2 - 1. CONTENTS 1. CONTENTS ................................................................................................ ...................................... 2 2. REPORT APPROVAL ...................................................................................................................... 3 3. SUMMARY ................................................................................................ ........................................ 4 4. INTRODUCTION .............................................................................................................................. 5 4.1. Preface ................................................................................................ ...................................... 5 4.2. Aim of the study ........................................................................................................................ 5 5. MATERIALS AND METHOD S .......................................................................................................... 5 5.1. Reagents ................................................................................................ ................................... 5 5.2. Samples ................................................................................................ .................................... 5 5.3. Analytical method ...................................................................................................................... 6 5.3.1. Analytical conditions ....................................................................................................... 6 5.3.2. Preparation of solutions .................................................................................................. 6 5.3.3. Sample injections ............................................................................................................ 6 5.4. Electronic data capture ............................................................................................................. 6 5.5. Formulas ................................................................................................ ................................... 7 5.6. Specifications ............................................................................................................................ 7 6. RESULTS ................................................................................................ ......................................... 8 6.1. Calibration curves ..................................................................................................................... 8 6.2. Samples ................................................................................................ .................................... 8 6.2.1. Procedural recovery samples ......................................................................................... 8 6.2.2. Test samples ................................................................................................................... 8 TABLES Table 1 Procedural recovery samples .............................................................................................. 9 Table 2 Accuracy and homogeneity test ........................................................................................... 9

### COPS_1 or CS - AHPS Project 500682

- Page 4 - 3. SUMMARY The purpose of this part of the study was to determine the accuracy of preparation and homogeneity of the test substance in formulations. Accuracy of preparation The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 90 % and 11 0 %). No test substance was detected in the Group 1 formulations . Homogeneity The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%).

### COPS_1 or CS - AHPS Project 500682

- Page 5 - 4. INTRODUCTION 4.1. Preface Study plan analytical phase Start : 15 M ay 201 3 Completion : 17 M ay 201 3 4.2. Aim of the study The purpose of the analytical phase was to determine the accuracy of preparation and homogeneity of the test substance in formulations. 5. MATERIALS AND METHOD S 5.1. Reagents Water Tap water purified by a Milli - Q water purification system (Millipore, Bedford, MA, USA) Di - Sodium hydrogenphosphate dihydrate Merck, Darmstadt, Germany ( Na 2 

### HPO 4 

### · 2H 2 

### O) Sodium dihydrogenphosphate dihydrate Merck (NaH 2 

### PO 4 

### · 2H 2 

### O) Sodium nitrate Merc k (NaNO 3 

### ) All reagents were of analytical grade, unless specified otherwise. 5.2. Samples Accuracy and homogeneity were determined for formulations prepared after the in - life phase. These formulations were prepared similarly as those used during the in - life phase. Duplicate samples (approximately 500 mg), which were taken from the formulations using a pip ette, were accurately weighed into volumetric flasks of 25 ml. For determination of accuracy, samples were taken at middle position (50% height) or at top, middle and bottom position (90%, 50% and 10% height). The samples taken at 90%, 50% and 10% height w ere also used for the determination of the homogeneity of the formulations. The volumetric flasks were filled up to the mark with water . The solutions were further diluted to obtain an end solution of water and concentrations within the calibration range .

### COPS_1 or CS - AHPS Project 500682

- Page 6 - 5.3. Analytical method 5.3.1. Analytical conditions Quantitative analysis was based on the analytical method validated for the test substance in project 500674 . Instrument Alliance Separation Module 2695 (Waters, Milford, MA, USA) Detector Refractive Index Detector 2414 (Waters) Column Stationary phase Synergi Hydro - RP 80A Dimensions 250 mm × 4.6 mm i.d., dp =4 μm Brand Phenomenex, Torrance, CA , USA Column temperature 40°C ± 1°C Injection volume 50 μl Mobile phase water containing 0.05M Na 2 

### HPO 4 

### , 0.05M NaH 2 

### PO 4 

### and 0.05M NaNO 3 

### Flow 1 ml/min RI detection Temperature 30°C Sensitivity 4 Time constant 1 seconds 5.3.2. Preparation of solutions Stock and spiking solutions Stock and spiking solutions of the test substance were prepared in water at concentrations of 5621 and 5662 mg/l. Calibration solutions Calibration solutions in the concentration range of 80 – 1200 mg/l were prepared from two stock solutions. The end solution of the calibration solutions was mobile phase . Procedural recovery samples Approximately 500 mg blank vehicle was spiked with the test substance at a target concentration of 20 or 200 mg/g. The accuracy samples were treated similarly as the test samples (see paragraph 5.2 ‘Samples’). 5.3.3. Sample injections Calibration solutions were injected in duplicate. Test samples and procedural recovery samples were analysed by single injection. 5.4. Electronic data capture System control, data acquisition and data processing were performed using the following programme: - Empower version 7.00 (Waters, Milford, MA, USA). Temperature, relative humidity and/or atmospheric pressure during sample storage and/or performance of the studies was monitored continuously using the following programme: - REES Centron Environmental Monitoring system version SQL 2.0 (REES Scientific, Trenton, NJ,

USA) .

### COPS_1 or CS - AHPS Project 500682

- Page 7 - 5.5. Formulas Response (R) Peak area test substance [units] Calibration curve 

### b C a R N 

### += where: C N 

### = nominal concentration [mg/l] a = slope [units × l/mg] b = intercept [units] Analysed concentration (C A 

### ) 

### [mg/g] w d V a b) (R C A 

### × × − = where: w = weight sample [mg] V = volume volumetric flask [ml] d = dilution factor Recovery 

### [%] 100 C C N

A 

### × where: C N 

### = nominal concentration [mg/g] Accuracy 

### [%] 100 C C T

A 

### × where: C T 

### = target concentration [mg/g] 5.6. Specifications Preparation of formulations was considered acceptable if the mean accuracy was in the range 90 - 11 0 % of the target concentration and if the coefficient of variation was ≤ 10%.

### COPS_1 or CS - AHPS Project 500682

- Page 8 - 6. RESULTS 6.1. Calibration curves A calibration curve was constructed using five concentrations. For each concentration, two responses were used. Linear regression analysis was performed using the least squares method with a 1/concentration 2 

### weighting factor. The coefficient of correlation (r) was > 0.99. 6.2. Samples 6.2.1. Procedural recovery samples The results of the procedural recovery samples are given in Table 1 . The mean recoveries of the procedural recovery samples fell within the criterion of 90 -1 10 % . It demonstrated that the analytical method was adequate for the determination of the test substance in the test samples. 6.2.2. Test samples The results of the test samples are given in Table 2 . Accuracy of preparation In the Group 1 formulation s , no test substance was detected. The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 90 % and 11 0 %). Homogeneity The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%).

### COPS_1 or CS - AHPS Project 500682

- Page 9 - TABLES Table 1 Procedural recovery samples Date of preparation Date of analysis Target concentration [mg/g] Nominal concentration [mg/g] Analysed concentration [mg/g] Recovery [%] Mean recovery (coefficient of

variation) [%] 16 - May - 2013 16 - May - 2013 20 21.3 22.0 104 102 22.3 22.7 102 (1.5) 21.5 21.5 100 21.0 21.7 103 20.4 20.6 101 16 - May - 2013 16 - May - 2013 200 207 211 102 102 203 206 102 (0.93) 205 209 102 215 219 102 201 209 104 Table 2 Accuracy and homogeneity test Group Date of analysis Sample position Concentration [mg/g] Accuracy [%] Homogeneity (coefficient of

variation) [%] Target Analysed Individual Mean 1 16 - May - 2013 50% height 0.00 n.d. n.a. 0.00 n.d. n.a. 2 16 - May - 2013 90% height 20.0 20.2 101 101 0.40 20.0 20.2 101 50% height 20.0 20.2 101 20.0 20.4 102 10% height 20.0 20.2 101 20.0 20.4 102 3 16 - May - 2013 5 0% height 60.0 61.0 102 102 60.0 61.3 102 4 16 - May - 2013 90% height 200 198 99 101 1.2 200 203 101 50% height 200 202 101 200 203 101 10% height 200 205 102 200 204 102 n.d. Not detected. n.a. Not applicable.

### COPS_1 or CS-AHPS Project 500682

APPENDIX 5

- Page 1 - 

### APPENDIX 5 HISTOPATHOLOGY REPORT

### PATHOLOGY REPORT PAGE : 2/ 88 TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF CONTENTS

————————————————————————————————————————————————————————————————————————— PAGE : AUTHENTICATION 3 PRINCIPAL SECTION SUMMARY 4 METHODS 5 RESULTS 8 CONCLUSIONS 10 EXPLANATION OF CODES AND SYMBOLS 11 SUMMARY TABLES NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings 12 INDIVIDUAL ANIMAL DATA TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) 20 ANIMAL HEADING DATA DOSE GROUP 01 36 TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP 01 37 ANIMAL HEADING DATA DOSE GROUP 02 48 TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP 02 49 ANIMAL HEADING DATA DOSE GROUP 03 58 TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP 03 59 ANIMAL HEADING DATA DOSE GROUP 04 71 TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP 04 72

### PATHOLOGY REPORT PAGE : 4/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— SUMMARY

————————————————————————————————————————————————————————————————————————— Pathomorphologic examination was performed on 80 Wistar(Han) rats (40 males, 40 females) which had been subjected to a combined 28-day dose toxicity study and reproduction/developmental toxicity screening test with test item COPS_1 or CS - AHPS . The rats were assigned to four dose groups, each containing 10 males and 10 females. The test item was administered once daily by gavage at doses of 100, 300 and 1000 mg/kg (dose Groups 2, 3 and 4 respectively). The rats of the control Group 1 received the vehicle water (Elix) alone. The males and females were exposed from 2 weeks prior to mating, during mating, and up to the day prior to necropsy for at least 28 days. All rats were necropsied. Histopathologic examination was performed on an extensive list of organs and tissues from 5 selected males and females of Group 1 and Group 4 , spleen of the selected females of Groups 2 and 3, as well as all organs with macroscopic findings from all rats. In addition, the reproductive organs of animals that failed to sire or deliver healthy pups were examined. Additional slides of the testes were made of the selected males of Groups 1 and 4 and males suspected infertile and stained with PAS/haematoxylin to assess spermatogenesis. One Group 2 female (no.53) was sacrificed due to total litter loss. No cause for the total litter loss could be established from the sections examined. All remaining rats survived their scheduled study period. There were no direct test item - related macroscopic findings . There were no direct test item - related microscopic findings . There was an in creased incidence of pairs with out healthy offspring in rats treated at 100 mg/kg (3/10), 300 mg/kg (10/10) and 1000 mg/kg (10/10). However, no microscopic correlation could be made for this. Non pregnant females showed a normal reproductive cycle and spermatogenic staging profiles were normal for all males examined. The administration of COPS_1 or CS- AHPS by once daily gavage to Wistar (Han) rats at doses up to 1000 mg/kg for at least a total of 28 days of dosing did not cause any direct test item - related microscopic findings.

### PATHOLOGY REPORT PAGE : 5/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 3 1308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— METHODS

————————————————————————————————————————————————————————————————————————— Study Design Group Dose level

mg/kg b.w./day Number of

animals Animal numbers Selected animals Males Females Males Females Males Females 1 0 10 10 01 - 10 41 - 50 01 - 05 41,43,44,48,50 2 100 10 10 11 - 20 51 - 60 11 - 15 51,54,55,57,60 3 300 10 10 21 - 30 61 - 70 21 - 25 61,62,63,64,65 4 1000 10 10 31 - 40 71 - 80 31 - 35 73,76,78,79,80 Administration of the Test Item The males and females were ex posed from 2 weeks prior to mating, during mating, and up to the day prior to necropsy for at least 28 days. The test item COPS_1 or CS- AHPS was administered once daily by gavage at doses of 100, 300 or 1000 mg/kg to dose Groups 2, 3 and 4 respectively. Th e rats of the control Group 1 received the vehicle, water (Elix), alone. Necropsy and Histopathology At the end of the assigned study period all animals were killed by exsanguination under iso - flurane anaesthesia. Males were killed after the mating period, females were killed on Lactation Day 5 or shortly thereafter , within 24 hours of total litter loss (female no. 53) or on post - coitum Days 25 - 27. Complete necropsies were performed on all animals/sex/group at necropsy and all macroscopic abnormalities were recorded. From each Group, five males and five females were selected (see Study Design). From the 5 selected animals/sex/group the terminal body weight and the weights of the adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus and uterus (including cervix) were recorded at necropsy. Weights of prostate, seminal vesicles including coagulating glands and thyroid including parathyroid were recorded after fixation for at least 24 hours. From all remaining males the terminal body weight and the weight of testes and epididymides were recorded. Body and organ weights are reported in the main toxicology report .

### PATHOLOGY REPORT PAGE : 6/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— METHODS

————————————————————————————————————————————————————————————————————————— Representative tissue samples of the following organs from the 5 selected males and females of each Group were preserved: Adrenal glands(2), [aorta], bone - sternum(1) and femur including joint(1), bone ma rrow - sternum(1), brain (cerebellum, mid -brain, cortex)(3), clitoral gland (2), epididymides (2), [esophagus], eyes(2)[with optic nerve and Harderian glands], heart(1), kidneys(2), [lacrimal glands - exorbital], large intestine(3): caecum, colon and rectum, [larynx], liver(2), lungs(2), lymph nodes - mandibular(2) and mesenteric(1), [nasopharynx], ovaries (2), [pancreas], pituitary gland(1), preputial glands (2), prostate gland (1), [salivary glands- mandibular and sublingual], sciatic nerve(1), seminal vesicles (2) wi th coagulating gland (2), skeletal muscle(1), [skin], small intestine(3): duodenum, jejunum and ileum with Peyer's patches, spinal cord(3) - cervical, midthoracic and lumbar, spleen(1), stomach(1), testes (2), thymus(1), thyroid glands(2) with parathyroid glan ds(2), [tongue], trachea(1), urinary bladder(1), uterus (3), uterine cervix (1), vagina (1) and all gross lesions. From the remaining animals, the reproductive organs (listed in bold, including the mammary gland area (1 ) for female no.53) and all gross lesions were preserved. Testes, epididymides and eyes with optic nerves and Harderian glands were initially fixed in Modified Davidson's solution. All other organ samples were fixed in 4% phosphate buffered neutral formaldehyde solution (10% formalin). Foll owing fixation, organs (except those listed in brackets) from 5 selected males and females of Group 1 (0 mg/kg) and Group 4 (1000 mg/kg), and all organs with macroscopic findings from all rats were trimmed, processed and embedded in paraffin wax. Sections were cut at a thickness of 2-4 micrometers and stained with hematoxylin and eosin. Numbers of sections made are given in parentheses. Extra sections of testes cut at a thickness of 3-4 micrometers stained by the PAS method from the selected males of Groups 1 and 4 were prepared for spermatogenesis staging. Additional sections were prepared from the reproductive organs ( listed in bold) of rats that failed to sire or deliver healthy pups, including extra sections of the testes for spermatogenesis staging.

### PATHOLOGY REPORT PAGE : 7/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or C S — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— METHODS

————————————————————————————————————————————————————————————————————————— Following examination of the above tissues, extra sections of the spleen of the selected females of Group 2 and Group 3 were prepared to examine possible treatment - related effects. All sections were examined by light microscopy in the period 10 May - 23 May 2013. Data Compilation The animal data and macroscopic findings were electronically trans ferred from the necropsy raw data files of Toxdata system® into the computer system PathData© where the microscopic findings were recorded by the undersigned pathologist using on -line input under pathology number: 31308LAA. The incidence of microscopic findings is presented in tabular form: “ Incidence table - All microscopic findings ” . The microscopic findings are also presented in tabular form under “ Table of individual microscopic findings (AOFT = Animal Organ Finding Table) ” . All macroscopic and microscopic findings are given for each animal in text form under " Text of Gross and Microscopic Findings" . All tables are created by computer. Histopathological changes were described according to distribution, severity and morphological character. Severity scores were assigned as follows: Grade "1": Minimal / very few / very small. Grade "2": Slight / few / small. Grade "3": Moderate / moderate number / moderate size. Grade "4": Marked / many / large. Grade "5 ": Massive / extensive number / extensive size . Grade "p": Finding present, grading not scored. In the case of findings in bilaterally affected paired organs, the severity score of the worst affected organ was recorded and a comm ent was made listing the severity score in the contralateral organ. Peer Review Microscopic findings were subjected to a review by J.F.M. Lensen, PhD (Dutch CRP/TP Certified Toxicologic Pathologist, WIL Research Europe B.V.) whereby the reviewer and study pathologist reached consensus.

### PATHOLOGY REPORT PAGE : 8/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— RESULTS

————————————————————————————————————————————————————————————————————————— Mortality One female treated at 100 mg/kg (no. 53) was sacrificed due to total litter loss. No cause for this could be established from the sections examined. All other animals survived to the end of the scheduled study period. Macroscopic findings There were no direct test item - related macroscopic finding s. An indirect test i tem - related macroscopic finding was recorded in 1/10 female s (no. 61) treated at 300 mg/kg, consisting of right uterine horn containing a n enlarged dead fetus and black dark contents. This was considered to be a secondary effect due t o alterations of the reproductive performance (see reproductive performance ). The remaining recorded macroscopic findings were considered to be spontaneous in nature and did not distinguish treated animals from the controls. Microscopic findings There were no direct test item - related microscopic findings. F indings of note: There were findings of note for one female treated at 1000 mg/kg (no. 80). Findings consisted of slight focal ulceration with necrosis of the glandular stomach (adjacent to the limi ting ridge), slight multifocal myofiber degeneration and inflammation of the heart , slight lymphoid atrophy and histiocytosis of the spleen , moderate histiocytosis and lymphatic ectasia of the mesenteric lymph node and up to slight interstitial and pelvic inflammation of the kidney . Because of the single incidence and the recorded disruption of the normal glandular stomach architecture, these findings are regarded to be related to a gavage accident rather than a direct test item - related toxicity. Recorded differences in hematopoietic foci and hemosiderin pigment in the female spleen and glandular development of the female mammary gland are caused by differences in physiologic status (pregnant or not). These findings in the female spleen and mammary gland and the remainder of microscopic findings recorded, were within the normal range of background pathology encountered in Wistar (Han) rats of this age.

### PATHOLOGY REPORT PAGE : 9/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— RESULTS

——————————————————— —————————————————————————————————————————————————————— R eproductive performance There was an increased incidence of pairs without healthy offspring in rats treated at 100 mg/kg (3/10), 300 mg/kg (10/10) and 1000 mg/kg (10/10) compared to 1/10 pairs treated at 0 mg/kg. Evidence of pregnancy was noted in the reproductive organs of female no.61, treated at 100 mg/kg. Findings consisted of an early implantation site and hemorrhagic contents in one uterine horn (microscopic correlate of black, dark red conte nts ). At necropsy there was also a large fetus noted in one uterine horn. For the remaining females, no histological correlation could be made for the lack of offspring. These females showed a normal reproductive cycle. For the males, no abnormalities were seen in the reproductive organs which could account for their infertility. Further more, the spermatogenic staging profiles were normal for all examined males.

### PATHOLOGY REPORT PAGE : 10/ 88

PRINCIPAL SECTION TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— CONCLUSIONS

————————

————————————————————————————————————————————————————————————————— The administration of COPS_1 or CS- AHPS by once daily gavage to Wistar (Han) rats at doses up to 1000 mg/kg for at least a total of 28 days of dosing did not cause any direct test item - related microscopic findings.

### PATHOLOGY REPORT PAGE : 11/ 88 TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— EXPLANATION OF CODES AND SYMBOLS

————————————————————————————————————————————————————————————————————————— CODES AND SYMBOLS USED AT ANIMAL LEVEL:

———————————————————————————————————————— M = Male animal F = Female animal K0 = Terminal sacrifice group + = Intercurrent death/sacrificed moribund +3 = Other, total litter loss CODES AND SYMBOLS USED AT ORGAN LEVEL:

——————————————————————————————————————— G = Gross observation checked off histologically * = Comment in text of individual animal data 0 = Tissue not present for histologic examination ' = Histologic examination not required + = Organ examined, findings present

— = Organ examined, no pathologic findings noted (AOFT only) ( = Only one of paired organs examined/present CODES AND SYMBOLS USED AT FINDING LEVEL:

————————————————————————————————————————— GRADE 1 = Minimal / very few / very small GRADE 2 = Slight / few / small GRADE 3 = Moderate / moderate number / moderate size GRADE 4 = Marked / many / large P = Finding present, severity not scored ( = Finding unilateral in paired organs * = Comment in text of individual animal data

### PATHOLOGY REPORT PAGE : 12/ 88

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————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

——————————

——————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— HEART : 5 — — 5

— Inflamm. lymphocytic: 1 — — —

————————————————————————————————————————————————————————————————————————— LUNG : 5 — — 5

— Mineraliz., vascular: 2 — — 3

— Alv. macrophages : — — — 3

— Inflamm. infiltrate : 1 — — 4

— Alveolar inflamm. : 2 — — 4

————————————————————————————————————————————————————————————————————————— THYMUS : 5 — — 5

— Congestion : 1 — — —

— Epithelial hyperpl. : 1 — — 2

————————————————————————————————————————————————————————————————————————— TRACHEA : 5 — — 5

— Inflamm., lymphocyt.: — — — 1

————————————————————————————————————————————————————————————————————————— THYROID GLAND : 5 — — 5

— Hyperpl./hypertrophy: 2 — — 1

————————————————————————————————————————————————————————————————————————— PARATHYROID GLANDS : 5 — — 5

————————————————————————————————————————————————————————————————————————— STOMACH : 5 — — 4

— Dilated gastric pits: 1 — — —

— Hyperpl.lim.ridge : 1 — — —

————————————————————————————————————————————————————————————————————————— DUODENUM : 5 — — 4

————————————————————————————————————————————————————————————————————————— JEJUNUM : 5 — — 4

————————————————————————————————————————————————————————————————————————— ILEUM : 5 — — 4

————————————————————————————————————————————————————————————————————————— PEYER'S PATCHES : 5 — — 4

————————————————————————————————————————————————————————————————————————— CECUM : 5 — — 5

— Inflammation, : 1 — — 1

————————————————————————————————————————————————————————————————————————— COLON : 5 — — 5

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 13/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— RECTUM : 5 — — 5

————————————————————————————————————————————————————————————————————————— LIVER : 5 — — 5

— Hepatodiaphr. nodule: — — — 1

— Inflamm. cell foci : 5 — — 4

— Apoptos/s.cell necro: 2 — — —

————————————————————————————————————————————————————————————————————————— SPLEEN : 5 — — 5

— Hemopoietic foci : 2 — — 3

— Hemosiderin pigment : 2 — — 2

— Lymphoid hyperplasia: — — — 1

————————————————————————————————————————————————————————————————————————— MESENT. LYMPH NODE : 5 — — 5

— Increas.lymphoid : — — — 1

————————————

————————————————————————————————————————————————————————————— MANDIB.LYMPH NODES : 5 — — 5

— Con./erythrophag. : 1 — — —

— Lymphoid hyperplasia: — — — 1

————————————————————————————————————————————————————————————————————————— KIDNEYS : 5 1 — 5

— Pelvic dilation : — 1 —

1

— Hyaline cast(s) : 1 — — —

— Dilatation, tubular : 1 — — —

— Hyperpl. urothel. : — — — 1

— Erosion, urothelium : — — — 1

— Hyaline droplets : 2 1 — 3

— Inflamm., interstit.: — — — 1

— Basophilia, tubular : 3 1 — 4

————————————————————————————————————————————————————————————————————————— URINARY BLADDER : 5 — — 5

————————————————————————————————————————————————————————————————————————— ADRENAL GLANDS : 5 — — 5

— Vacuolation, z.fas. : 1 — — —

————————————————————————————————————————————————————————————————————————— BRAIN : 5 — — 5

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 14/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— PITUITARY GLAND : 5 — — 5

— Cyst(s) : — — — 1

————————————————————————————————————————————————————————————————————————— SCIATIC NERVE : 5 — — 5

— Dilated myelin sh. : 1 — — —

————————————————————————————————————————————————————————————————————————— EPIDIDYMIDES : 5 4 10 10

— Sperm granuloma : — 2 1 —

— Semin. cell debris : — — — 2

— Macro noted : — — — 1

— Inflamm. lymphocytic: 1 — — —

————————————————————————————————————————————————————————————————————————— TESTES : 5 3 10 10

— Sperm. giant cells : — — — 1

— Seminiferous atrophy: 1 — — 3

— Vacuolation, sem. ep: — — — 1

————————————————————————————————————————————————————————————————————————— TESTES, PAS STAGING : 5 3 10 10

— All stages present, : 5 3 10 10

————————————————————————————————————————————————————————————————————————— PROSTATE GLAND : 5 3 10 10

— Inflamm. lymphocytic: 2 — 3 3

————————————————————————————————————————————————————————————————————————— SEMINAL VESICLES : 5 3 10 10

————————————————————————————————————————————————————————————————————————— COAGULATING GLANDS : 5 3 10 10

— Inflamm. lymphocytic: — — 1 —

————————————————————————————————————————————————————————————————————————— PREPUTIAL GLANDS : 5 3 10 10

— Inflamm. lymphocytic: 1 — 1 1

— Dilated duct : — — — 2

————————————————————————————————————————————————————————————————————————— SKELETAL MUSCLE : 5 — — 5

— Myofiber degeneratio: 1 — — 2

— Inflamm. lymphocytic: 1 — — 1

————————————————————————————————————————————————————————————————————————— EYES : 5 — — 5

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 15/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : MALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

—————————————————————————————————————————————————————————————————————— ——— BONE, STERNUM : 5 — — 5

————————————————————————————————————————————————————————————————————————— BONE MARROW — STERN. : 5 — — 5

————————————————————————————————————————————————————————————————————————— SPINAL CORD — CERV. : 5 — — 5

————————————————————————————————————————————————————————————————————————— SPINAL CORD — THOR. : 5 — — 5

————————————————————————————————————————————————————————————————————————— SPINAL CORD — LUMBAR : 5 — — 5

————————————————————————————————————————————————————————————————————————— FEMUR : 5 — — 5

————————————————————————————————————————————————————————————————————————— FEMOROTIBIAL JOINT : 5 — — 5

————————————————————————————————————————————————————————————————————————— SKIN/SUBCUTIS : — 1 — —

— Epidermal hyperplas.: — 1 — —

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 16/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— GENERAL OBSERVATIONS : — 1 — —

— Macro noted : — 1 — —

————————————————————————————————————————————————————————————————————————— HEART : 5 — — 5

— Inflamm. mononuclear: — — — 1

— Myofiber degenerat. : — — — 1

————————————————————————————————————————————————————————————————————————— LUNG : 5 — — 5

— Mineraliz., vascular: 2 — — 1

— Alv. macrophages : 2 — — 1

— Inflamm. infiltrate : 1 — — 3

— Alveolar inflamm. : 1 — — 1

————————————————————————————————————————————————————————————————————————— THYMUS : 5 — — 5

— Congestion : — — — 1

— Pigmented macroph. : — — — 1

— Cystic medullar.duct: 1 — — —

— Lymphocytolysis : — — — 1

— Lymphoid atrophy : 1 — — —

— Epithelial hyperpl. : 2 — — —

————————————————————————————————————————————————————————————————————————— TRACHEA : 5 — — 5

————————————————————————————————————————————————————————————————————————— THYROID GLAND : 5 — — 5

— Ectopic thymus : 1 — — —

— Dilated follicles : — — — 1

————————————————————————————————————————————————————————————————————————— PARATHYROID GLANDS : 5 — — 5

————————————————————————————————————————————————————————————————————————— STOMACH : 5 — — 5

— Erosion, glandular : — — — 1

— Pigmented macroph. : — — — 1

— Hyperpl.lim.ridge : — — — 1

— Inflamm., lim.ridge : — — — 1

————————————————————————————————————————————————————————————————————————— DUODENUM : 5 1 — 5

— Hypertrophy, hyperpl: 1 1 — —

———— —————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 17/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— JEJUNUM : 5 1 — 5

— Hypertrophy, hyperpl: 1 — — —

————————————————————————————————————————————————————————————————————————— ILEUM : 5 — — 5

— Lymphangectasia, : — — — 1

————————————————————————————————————————————————————————————————————————— PEYER'S PATCHES : 5 — — 5

————————————————————————————————————————————————————————————————————————— CECUM : 5 — — 5

————————————————————————————————————————————————————————————————————————— COLON : 5 — — 5

————————————————————————————————————————————————————————————————————————— RECTUM : 5 — — 5

————————————————————————————————————————————————————————————————————————— LIVER : 5 — — 5

— Hemopoietic cells : 1 — — —

— Inflamm. cell foci : 3 — — 5

————————————————————————————————————————————————————————————————————————— SPLEEN : 5 5 5 5

— Hemopoietic foci : 5 5 3 —

— Hemosiderin pigment : 5 5 5 5

— Lymphoid atrophy : — — — 1

— Histiocytosis, : — — — 1

————————————————————————————————————————————————————————————————————————— MESENT. LYMPH NODE : 5 — — 5

— Lymphatic ectasia : — — — 1

— Histiocytosis, : — — — 1

— Plasmacytosis, : — — — 1

—————————————————————————————————————————————————————————————————————— ——— MANDIB.LYMPH NODES : 5 — — 5

— Con./erythrophag. : — — — 1

— Lymphoid hyperplasia: — — — 1

— Pigmented macroph. : — — — 1

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 18/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

————————————————————————————————————————————————————————————————————————— SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— KIDNEYS : 5 2 — 5

— Mineraliz., tubular : 3 — — 1

— Inflamm., interstit.: 2 — — 1

— Inflamm., pelvic : — — — 1

— Basophilia, tubular : 1 — — 1

— Congestion, : — 1 — —

————————————————————————————————————————————————————————————————————————— URINARY BLADDER : 5 — — 5

————————————————————————————————————————————————————————————————————————— ADRENAL GLANDS : 5 1 — 5

— Congestion : — 1 — —

— Vacuolation, z.glom.: 2 — — 1

————————————————————————————————————————————————————————————————————————— BRAIN : 5 — — 5

————————————————————————————————————————————————————————————————————————— PITUITARY GLAND : 5 — — 5

— Cyst(s) : 1 — — 1

———————————————————————————————————————————————————————————————————— ————— SCIATIC NERVE : 5 — — 5

————————————————————————————————————————————————————————————————————————— OVARIES : 6 3 10 10

— Cyst, oviduct : — — — 1

————————————————————————————————————————————————————————————————————————— UTERUS : 6 3 10 10

— Implantation site(s): 5 — 1 —

— Cyst(s) : 1 — — —

— Hemorrhagic contents: — — 1 —

————————————————————————————————————————————————————————————————————————— CERVIX : 6 3 9 10

————————————————————————————————————————————————————————————————————————— VAGINA : 6 3 9 10

— Mucification, epithe: 1 1 1 —

— Parturation debris : 5 1 — —

— Di/Metestrus epith. : 1 — 4 5

— Estrus epithelium : — 2 1 2

— Proestrus epithelium: — — 3 3

— Hemorrhagic contents: — — 1 —

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 19/ 88

SUMMARY TABLES TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— NUMBER OF ANIMALS WITH MICROSCOPIC FINDINGS BY ORGAN/GROUP/SEX STATUS AT NECROPSY: K0, INCL. DEATHS Incidence table — All microscopic findings

———————————————————————————————————————————————————————————————————————— — SEX : FEMALE DOSE GROUP: 01 02 03 04 NO.ANIMALS: 10 10 10 10

————————————————————————————————————————————————————————————————————————— CLITORAL GLANDS : 6 4 10 10

— Dilated duct : — 1 1 1

— Inflamm., granuloc. : — — 1 —

————————————————————————————————————————————————————————————————————————— F.MAMMARY GLAND AREA : 5 1 — 5

— Glandul. development: 5 1 — —

————————————————————————————————————————————————————————————————————————— SKELETAL MUSCLE : 5 — — 5

— Myofiber degeneratio: 1 — — —

————————————————————————————————————————————————————————————————————————— EYES : 5 — — 5

— Cornea proliferation: — — — 1

————————————————————————————————————————————————————————————————————————— BONE, STERNUM : 5 — — 5

————————————————————————————————————————————————————————————————————————— BONE MARROW — STERN. : 5 — — 5

— Myeloid hyperplasia : — — — 1

————————————————————————————————————————————————————————————————————————— SPINAL CORD — CERV. : 5 — — 5

————————————————————————————————————————————————————————————————————————— SPINAL CORD — THOR. : 5 — — 5

————————————————————————————————————————————————————————————————————————— SPINAL CORD — LUMBAR : 5 — — 5

————————————————————————————————————————————————————————————————————————— FEMUR : 5 — — 5

————————————————————————————————————————————————————————————————————————— FEMOROTIBIAL JOINT : 5 — — 5

————————

—————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 20/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, CONTROL

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— HEART + — — — — ' ' ' ' '

— Inflamm. lymphocytic 1. . . . .

......................................................................... LUNG + + + + + ' ' ' ' '

— Mineraliz., vascular 1. . 1. . .

— Inflamm. infiltrate . . . 1. .

— Alveolar inflamm. . 1. . . 1.

......................................................................... THYMUS + +G — — — ' ' ' ' '

— Congestion . P. . . .

— Epithelial hyperpl. 1. . . . .

......................................................................... TRACHEA — — — — — ' ' ' ' '

......................................................................... THYROID GLAND + — — + —

' ' ' ' '

— Hyperpl./hypertrophy 2. . . 1. .

......................................................................... PARATHYROID GLANDS — — — — — ' ' ' ' '

......................................................................... STOMACH — + —

+ —

' ' ' ' '

— Dilated gastric pits . . . 1. .

— Hyperpl.lim.ridge . 1. . . .

......................................................................... DUODENUM — — — — — ' ' ' ' '

......................................................................... JEJUNUM — — — — — ' ' ' ' '

......................................................................... ILEUM — — — — — ' ' ' ' '

......................................................................... PEYER'S PATCHES — — — — — ' ' ' ' '

......................................................................... CECUM — — + — —

' ' ' ' '

— Inflammation, . . 1. . .

......................................................................... COLON — — — — — ' ' ' ' '

......................................................................... RECTUM — — — — — ' ' ' ' '

.........................................................................

### PATHOLOGY REPORT PAGE : 21/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, CONTROL

————————————————

————————————————————————————————————————————————————————— ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— LIVER + + + + + ' ' ' ' '

— Inflamm. cell foci 1. 1. 1. 2. 1.

— Apoptos/s.cell necro . 1. . 1. .

......................................................................... SPLEEN + + + + — ' ' ' ' '

— Hemopoietic foci 1. 1. . . .

— Hemosiderin pigment . . 1. 1. .

......................................................................... MESENT. LYMPH NODE — — — — — ' ' ' ' '

......................................................................... MANDIB.LYMPH NODES — — + — —

' ' ' ' '

— Con./erythrophag. . . ( 2. . .

......................................................................... KIDNEYS + + + — + ' ' ' ' '

— Hyaline cast(s) . . . . 2.

— Dilatation, tubular . . . . 2.

— Hyaline droplets . . 1. . 2.

— Basophilia, tubular 1. 1. . . ( 1.

......................................................................... URINARY BLADDER — — — — — ' ' ' ' '

......................................................................... ADRENAL GLANDS — — + — —

' ' ' ' '

— Vacuolation, z.fas. . . 1. . .

......................................................................... BRAIN — — — — — ' ' ' ' '

......................................................................... PITUITARY GLAND — — — — — ' ' ' ' '

......................................................................... SCIATIC NERVE + — — — — ' ' ' ' '

— Dilated myelin sh. 1. . . . .

......................................................................... EPIDIDYMIDES + — — — — ' ' ' ' '

— Inflamm. lymphocytic ( 1. . . . .

......................................................................... TESTES — — — — + ' ' ' ' '

— Seminiferous atrophy . . . . ( 1.

......................................................................... TESTES, PAS STAGING + + + + + ' ' ' ' '

— All stages present, P. P. P. P. P.

.........................................................................

### PATHOLOGY REPORT PAGE : 22/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, CONTROL

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 1 2 3 4 5 6 7 8 9 10 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

—————————————————————————————————————————————————————————————————————— ——— PROSTATE GLAND + — — — + ' ' ' ' '

— Inflamm. lymphocytic 1. . . . 3.

......................................................................... SEMINAL VESICLES — — — — — ' ' ' ' '

......................................................................... COAGULATING GLANDS — — — — — ' ' ' ' '

......................................................................... PREPUTIAL GLANDS — + — — — ' ' ' ' '

— Inflamm. lymphocytic . ( 1. . . .

......................................................................... SKELETAL MUSCLE — + — — — ' ' ' ' '

— Myofiber degeneratio . 1. . . .

— Inflamm. lymphocytic . 1. . . .

......................................................................... EYES — — — — — ' ' ' ' '

......................................................................... BONE, STERNUM — — — — — ' ' ' ' '

......................................................................... BONE MARROW — STERN. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD — CERV. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD — THOR. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD — LUMBAR — — — — — ' ' ' ' '

......................................................................... FEMUR — — — — — ' ' ' ' '

......................................................................... FEMOROTIBIAL JOINT — — — — — ' ' ' ' '

.........................................................................

### PATHOLOGY REPORT PAGE : 23/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — D ay, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, CONTROL

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 41 42 43 44 45 46 47 48 49 50 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— HEART — ' — —

' ' ' — ' —

......................................................................... LUNG + ' + + ' ' ' + ' —

— Mineraliz., vascular 1. 1. . . .

— Alv. macrophages . 1. . 1. .

— Inflamm. infiltrate . . 1. . .

— Alveolar inflamm. 1. . . . .

......................................................................... THYMUS + ' + — ' ' ' + ' —

— Cystic medullar.duct 1. . . . .

— Lymphoid atrophy 1. . . . .

— Epithelial hyperpl. . 1. . 1. .

......................................................................... TRACHEA — ' — —

' ' ' — ' —

......................................................................... THYROID GLAND + ' — — ' ' ' — ' —

— Ectopic thymus ( P. . . . .

......................................................................... PARATHYROID GLANDS — ' — —

' ' ' — ' —

......................................................................... STOMACH — ' — —

' ' ' — ' —

......................................................................... DUODENUM — ' —

+G ' ' ' — ' —

— Hypertrophy, hyperpl . . 2. . .

......................................................................... JEJUNUM — ' —

+G ' ' ' — ' —

— Hypertrophy, hyperpl . . 1. . .

......................................................................... ILEUM — ' — —

' ' ' — ' —

......................................................................... PEYER'S PATCHES — ' — —

' ' ' — ' —

........................................................................ . CECUM — ' — —

' ' ' — ' —

......................................................................... COLON — ' — —

' ' ' — ' —

......................................................................... RECTUM — ' — —

' ' ' — ' —

.........................................................................

### PATHOLOGY REPORT PAGE : 24/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, CONTROL

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 41 42 43 44 45 46 47 48 49 50 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— LIVER + ' + + ' ' ' — ' +

— Hemopoietic cells . . 1. . .

— Inflamm. cell foci 1. 1. . . 1.

......................................................................... SPLEEN + ' + + ' ' ' + ' +

— Hemopoietic foci 3. 1. 2. 1. 1.

— Hemosiderin pigment 1. 2. 2. 1. 2.

......................................................................... MESENT. LYMPH NODE — ' — —

' ' ' — ' —

......................................................................... MANDIB.LYMPH NODES — ' — —

' ' ' — ' —

......................................................................... KIDNEYS — ' + —

' ' ' + ' +

— Mineraliz., tubular . ( 1. . ( 1. ( 1.

— Inflamm., interstit. . ( 1. . ( 1. .

— Basophilia, tubular . . . . 1.

......................................................................... URINARY BLADDER — ' — —

' ' ' — ' —

......................................................................... ADRENAL GLANDS — ' — —

' ' ' + ' +

— Vacuolation, z.glom. . . . 1. 1.

......................................................................... BRAIN — ' — —

' ' ' — ' —

......................................................................... PITUITARY GLAND — ' — —

' ' ' — ' +

— Cyst(s) . . . . 1.

......................................................................... SCIATIC NERVE — ' — —

' ' ' — ' —

......................................................................... OVARIES — — — — ' ' ' — ' —

......................................................................... UTERUS + — + + ' ' ' + ' +

— Implantation site(s) P. . P. P. P. P.

— Cyst(s) . . 1. . . .

......................................................................... CERVIX — — — — ' ' ' — ' —

.........................................................................

### PATHOLOGY REPORT PAGE : 25/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 01, CONTROL

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 41 42 43 44 45 46 47 48 49 50 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— VAGINA + + + + ' ' ' + ' +

— Mucification, epithe . . . 1. . .

— Parturation debris P. . P. P. P. P.

— Di/Metestrus epith. . P. . . . .

......................................................................... CLITORAL GLANDS — — — — ' ' ' — ' —

......................................................................... F.MAMMARY GLAND AREA + ' + + ' ' ' + ' +

— Glandul. development 3. 3. 3. 3. 3.

......................................................................... SKELETAL MUSCLE — ' + — ' ' ' — ' —

— Myofiber degeneratio . 1. . . .

......................................................................... EYES — ' — —

' ' ' — ' —

......................................................................... BONE, STERNUM — ' — —

' ' ' — ' —

......................................................................... BONE MARROW — STERN. — ' — —

' ' ' — ' —

......................................................................... SPINAL CORD — CERV. — ' — —

' ' ' — ' —

......................................................................... SPINAL CORD — THOR. — ' — —

' ' ' — ' —

......................................................................... SPINAL CORD — LUMBAR — ' — —

' ' ' — ' —

......................................................................... FEMUR — ' — —

' ' ' — ' —

......................................................................... FEMOROTIBIAL JOINT — ' — —

' ' ' — ' —

.........................................................................

### PATHOLOGY REPORT PAGE : 26/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

———————————————————————————————————————————————————————————————————————— — TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, 100 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 11 12 13 14 15 16 17 18 19 20 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

—————————————————————————————————————————————————————————————————— ——————— KIDNEYS ' ' +G ' ' ' ' ' ' '

— Pelvic dilation ( P.

— Hyaline droplets 1.

— Basophilia, tubular 1.

......................................................................... EPIDIDYMIDES ' — +G ' ' ( +G ' ' — '

— Sperm granuloma . ( 2. ( 4. .

......................................................................... TESTES ' — — ' ' ' ' ' — '

......................................................................... TESTES, PAS STAGING ' + + ' ' ' ' ' + '

— All stages present, P. P. P.

......................................................................... PROSTATE GLAND ' — — ' ' ' ' ' — '

......................................................................... SEMINAL VESICLES ' — — ' ' ' ' ' — '

......................................................................... COAGULATING GLANDS ' — — ' ' ' ' ' — '

......................................................................... PREPUTIAL GLANDS ' — — ' ' ' ' ' — '

......................................................................... SKIN/SUBCUTIS ' ' ' ' ' +G ' ' ' '

— Epidermal hyperplas. 1.

.........................................................................

### PATHOLOGY REPORT PAGE : 27/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

—————————————————————————————————————————————————————————————————————— ——— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 02, 100 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 51 52 53 54 55 56 57 58 59 60 FK0 FK0 FK0+ FK0 FK0 FK0 FK0 FK0 FK0 FK0

———————————————————————————————————————————————————————————————— ————————— GENERAL OBSERVATIONS ' ' +G ' ' ' ' ' ' '

— Macro noted P.

......................................................................... DUODENUM ' ' ' ' ' ' ' ' ' +G

— Hypertrophy, hyperpl 1.

......................................................................... JEJUNUM ' ' ' ' ' ' ' ' ' — G

......................................................................... SPLEEN + ' ' + + ' + ' ' +G

— Hemopoietic foci 2. 1. 1. 2. 3.

— Hemosiderin pigment 1. 1. 2. 1. 1.

......................................................................... KIDNEYS ' ' ' ' ' ' ' ' — G +G

— Congestion, . P.

......................................................................... ADRENAL GLANDS ' ' ' ' +G ' ' ' ' '

— Congestion 2.

......................................................................... OVARIES ' — — ' ' ' ' ' — '

......................................................................... UTERUS ' — — ' ' ' ' ' — '

......................................................................... CERVIX ' — — ' ' ' ' ' — '

......................................................................... VAGINA ' + + ' ' ' ' ' + '

— Mucification, epithe . 2. .

— Parturation debris . P. .

— Estrus epithelium P. . P.

......................................................................... CLITORAL GLANDS ' — — ' +G ' ' ' — '

— Dilated duct . . ( 2. .

......................................................................... F.MAMMARY GLAND AREA ' ' + ' ' ' ' ' ' '

— Glandul. development 3*

.........................................................................

### PATHOLOGY REPORT PAGE : 28/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, 300 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 21 22 23 24 25 26 27 28 29 30 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————

————————————————————————————————————————————————————————— EPIDIDYMIDES — — — — — — +G — — —

— Sperm granuloma . . . . . . ( 3. . . .

......................................................................... TESTES — — — — — — — — — —

......................................................................... TESTES, PAS STAGING + + + + + + + + + +

— All stages present, P. P. P. P. P. P. P. P. P. P.

......................................................................... PROSTATE GLAND + — — — + — — — + —

— Inflamm. lymphocytic 2. . . . 1. . . . 1. .

......................................................................... SEMINAL VESICLES — — — — — — — — — —

......................................................................... COAGULATING GLANDS — — ( — — — — — + — —

— Inflamm. lymphocytic . . . . . . . ( 1. . .

......................................................................... PREPUTIAL GLANDS — — — — — — — + — —

— Inflamm. lymphocytic . . . . . . . ( 1. . .

.........................................................................

### PATHOLOGY REPORT PAGE : 29/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 03, 300 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 61 62 63 64 65 66 67 68 69 70 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— SPLEEN + + + + + ' ' ' ' '

— Hemopoietic foci 2. . . 1. 1.

— Hemosiderin pigment 2. 3. 2. 2. 1.

......................................................................... OVARIES — — — — — — — — — —

......................................................................... UTERUS +G — — — — — — — — —

— Implantation site(s) P. . . . . . . . . .

— Hemorrhagic contents P. . . . . . . . . .

......................................................................... CERVIX — — — — — 0 — — — —

......................................................................... VAGINA + + + + 0 + + + + +

— Mucification, epithe 3. . . . . . . . . .

— Di/Metestrus epith. . . . P. . P. . . P. P.

— Estrus epithelium . P. . . . . . . . .

— Proestrus epithelium . . P. . . . P. P. . .

— Hemorrhagic contents P. . . . . . . . . .

......................................................................... CLITORAL GLANDS — + — —

+ — * — — — —

— Dilated duct . . . . ( 2. . . . . .

— Inflamm., granuloc. . ( 1. . . . . . . . .

.........................................................................

### PATHOLOGY REPORT PAGE : 30/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 1000 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 31 32 33 34 35 36 37 38 39 40 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— HEART — — — — — ' ' ' ' '

......................................................................... LUNG + + + + + ' ' ' ' '

— Mineraliz., vascular 1. . 1. 1. .

— Alv. macrophages 1. . 1. 1. .

— Inflamm. infiltrate . 1. 1. 1. 2.

— Alveolar inflamm. 1. 1. 1. . 1.

......................................................................... THYMUS + + — — — ' ' ' ' '

— Epithelial hyperpl. 1. 1. . . .

......................................................................... TRACHEA — — — + —

' ' ' ' '

— Inflamm., lymphocyt. . . . 1. .

......................................................................... THYROID GLAND — — — — + ' ' ' ' '

— Hyperpl./hypertrophy . . . . 1.

......................................................................... PARATHYROID GLANDS — — — — ( — ' ' ' ' '

......................................................................... STOMACH ' — — — — ' ' ' ' '

......................................................................... DUODENUM ' — — — — ' ' ' ' '

......................................................................... JEJUNUM ' — — — — ' ' ' ' '

......................................................................... ILEUM ' — — — — ' ' ' ' '

......................................................................... PEYER'S PATCHES ' — — — — ' ' ' ' '

......................................................................... CECUM + — — — — ' ' ' ' '

— Inflammation, 1. . . . .

......................................................................... COLON — — — — — ' ' ' ' '

......................................................................... RECTUM — — — — — ' ' ' ' '

......................................................................... LIVER + — + +G + ' ' ' ' '

— Hepatodiaphr. nodule . . . P. .

— Inflamm. cell foci 1. . 1. 2. 1.

.........................................................................

### PATHOLOGY REPORT PAGE : 31/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 1000 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 31 32 33 34 35 36 37 38 39 40 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— SPLEEN + + + + + ' ' ' ' '

— Hemopoietic foci 1. . 1. . 1.

— Hemosiderin pigment . 1. . 1. .

— Lymphoid hyperplasia . . . . 1.

......................................................................... MESENT. LYMPH NODE — — — + —

' ' ' ' '

— Increas.lymphoid . . . 1. .

......................................................................... MANDIB.LYMPH NODES — — — + —

' ' ' ' '

— Lymphoid hyperplasia . . . ( 2. .

......................................................................... KIDNEYS + + +G + + ' ' ' ' '

— Pelvic dilation . . ( P. . .

— Hyperpl. urothel. . . ( 2. . .

— Erosion, urothelium . . ( 1. . .

— Hyaline droplets 1. . 2. . 1.

— Inflamm., interstit. . ( 1. . . .

— Basophilia, tubular . ( 1. ( 1. ( 1. 1.

......................................................................... URINARY BLADDER — — — — — ' ' ' ' '

......................................................................... ADRENAL GLANDS — — — — — ' ' ' ' '

......................................................................... BRAIN — — — — — ' ' ' ' '

......................................................................... PITUITARY GLAND — — + — —

' ' ' ' '

— Cyst(s) . . 1. . .

......................................................................... SCIATIC NERVE — — — — — ' ' ' ' '

......................................................................... EPIDIDYMIDES — — — + — — — +G — —

— Semin. cell debris . . . 1. . . . ( 1. . .

— Macro noted . . . . . . . ( P. . .

......................................................................... TESTES — — — + + —

+ — G — —

— Sperm. giant cells . . . 1. . . . . . .

— Seminiferous atrophy . . . 2. 1. . ( 1. . . .

— Vacuolation, sem. ep . . . 2. . . . . . .

.........................................................................

### PATHOLOGY REPORT PAGE : 32/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 1000 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 31 32 33 34 35 36 37 38 39 40 M K0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0 MK0

————————————————————————————————————————————————————————————————————————— TESTES, PAS STAGING + + + + + + + + + +

— All stages present, P. P. P. P. P. P. P. P. P. P.

......................................................................... PROSTATE GLAND — — — + + — — — + —

— Inflamm. lymphocytic . . . 1. 1. . . . 1. .

......................................................................... SEMINAL VESICLES — — — — — — — — — —

......................................................................... COAGULATING GLANDS — — — — ( — — — — — —

......................................................................... PREPUTIAL GLANDS — — — + — — — — + +

— Inflamm. lymphocytic . . . 1. . . . . . .

— Dilated duct . . . . . . . . ( 1. ( 1.

......................................................................... SKELETAL MUSCLE — + + — — ' ' ' ' '

— Myofiber degeneratio . 1. 1. . .

— Inflamm. lymphocytic . . 1. . .

......................................................................... EYES — — — — — ' ' ' ' '

......................................................................... BONE, STERNUM — — — — — ' ' ' ' '

......................................................................... BONE MARROW — STERN. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD — CERV. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD — THOR. — — — — — ' ' ' ' '

......................................................................... SPINAL CORD — LUMBAR — — — — — ' ' ' ' '

......................................................................... FEMUR — — — — — ' ' ' ' '

......................................................................... FEMOROTIBIAL JOINT — — — — — ' ' ' ' '

.........................................................................

### PATHOLOGY REPORT PAGE : 33/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 1000 MG/KG

————————————————

————————————————————————————————————————————————————————— ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— HEART ' ' — ' ' —

' — —

+

— Inflamm. mononuclear . . . . 2.

— Myofiber degenerat. . . . . 2.

......................................................................... LUNG ' ' +* ' ' — ' + + +

— Mineraliz., vascular . . . . 1.

— Alv. macrophages 1. . . . .

— Inflamm. infiltrate 1. . 1. 1. .

— Alveolar inflamm. . . . . 1.

......................................................................... THYMUS ' ' — ' ' + ' — — +G

— Congestion . . . . P.

— Pigmented macroph. . . . . 1.

— Lymphocytolysis . 1. . . .

......................................................................... TRACHEA ' ' — ' ' —

' — — —

......................................................................... THYROID GLAND ' ' + ' ' — ' — — —

— Dilated follicles 1. . . . .

......................................................................... PARATHYROID GLANDS ' ' ( — ' ' —

' — —

( —

......................................................................... STOMACH ' ' + ' ' — ' — + +

— Erosion, glandular . . . . 2*

— Pigmented macroph. 1. . . . .

— Hyperpl.lim.ridge . . . 1. .

— Inflamm., lim.ridge . . . . 1.

......................................................................... DUODENUM ' ' — ' ' —

' — — —

......................................................................... JEJUNUM ' ' — ' ' —

' — — —

......................................................................... ILEUM ' ' + ' ' — ' — — —

— Lymphangectasia, 1. . . . .

......................................................................... PEYER'S PATCHES ' ' — ' ' —

' — — —

......................................................................... CECUM ' ' — ' ' —

' — — —

.........................................................................

### PATHOLOGY REPORT PAGE : 34/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 1000 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— COLON ' ' — ' ' —

' — — —

......................................................................... RECTUM ' ' — ' ' —

' — — —

......................................................................... LIVER ' ' + ' ' + ' + + +

— Inflamm. cell foci 1. 1. 1. 1. 1.

......................................................................... SPLEEN ' ' + ' ' + ' + + +

— Hemosiderin pigment 2. 3. 3. 4. 3.

— Lymphoid atrophy . . . . 2.

— Histiocytosis, . . . . 2.

......................................................................... MESENT. LYMPH NODE ' ' — ' ' —

' — —

+G

— Lymphatic ectasia . . . . 3.

— Histiocytosis, . . . . 3.

— Plasmacytosis, . . . . 2.

......................................................................... MANDIB.LYMPH NODES ' ' — ' ' + ' — — +G

— Con./erythrophag. . . . . 2.

— Lymphoid hyperplasia . 1. . . .

— Pigmented macroph. . . . . 2.

......................................................................... KIDNEYS ' ' + ' ' — ' — —

+

— Mineraliz., tubular ( 1. . . . .

— Inflamm., interstit. . . . . 2.

— Inflamm., pelvic . . . . 1.

— Basophilia, tubular . . . . 1.

......................................................................... URINARY BLADDER ' ' — ' ' —

' — — —

......................................................................... ADRENAL GLANDS ' ' — ' ' + ' — — G —

— Vacuolation, z.glom. . 1. . . .

......................................................................... BRAIN ' ' — ' ' —

' — — —

......................................................................... PITUITARY GLAND ' ' — ' ' —

' —

+ —

— Cyst(s) . . . 1. .

......................................................................... SCIATIC NERVE ' ' — ' ' —

' — — —

.........................................................................

### PATHOLOGY REPORT PAGE : 35/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TABLE OF INDIVIDUAL MICROSCOPIC FINDINGS (AOFT) DOSE GROUP : 04, 1000 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL NUMBER : 71 72 73 74 75 76 77 78 79 80 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0 FK0

————————————————————————————————————————————————————————————————————————— OVARIES — — — — + — — — — —

— Cyst, oviduct . . . . ( 2. . . . . .

......................................................................... UTERUS — — — — — — — — — —

......................................................................... CERVIX — — — — — — — — — —

......................................................................... VAGINA + + + + + + + + + +

— Di/Metestrus epith. P. . P. P. . P. . . P. .

— Estrus epithelium . P. . . . . P. . . .

— Proestrus epithelium . . . . P. . . P. . P.

......................................................................... CLITORAL GLANDS — — — — — — — — +G —

— Dilated duct . . . . . . . . ( 3. .

......................................................................... F.MAMMARY GLAND AREA ' ' — ' ' —

' — — — *

......................................................................... SKELETAL MUSCLE ' ' — ' ' —

' — — —

......................................................................... EYES ' ' — ' ' + ' — — —

— Cornea proliferation . ( 1. . . .

......................................................................... BONE, STERNUM ' ' — ' ' —

' — — —

......................................................................... BONE MARROW — STERN. ' ' — ' ' —

' — —

+

— Myeloid hyperplasia . . . . 2.

......................................................................... SPINAL CORD — CERV. ' ' — ' ' —

' — — —

......................................................................... SPINAL CORD — THOR. ' ' — ' ' —

' — — —

......................................................................... SPINAL CORD — LUMBAR ' ' — ' ' —

' — — —

......................................................................... FEMUR ' ' — ' ' —

' — — —

......................................................................... FEMOROTIBIAL JOINT ' ' — ' ' —

' — — —

.........................................................................

### PATHOLOGY REPORT PAGE : 36/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 01, CONTROL

————————————————————————————————————————————————————————————————————————— ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 1 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 2 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 3 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 4 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 5 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 6 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 7 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 8 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 9 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 10 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13

......................................................................... 41 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 42 F K0 K0 43 29 — JAN — 13 12 — MAR — 13 13 — MAR — 13 43 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 44 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 45 F K0 K0 48 29 — JAN — 13 17 — MAR — 13 18 — MAR — 13 46 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 47 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 48 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 49 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 50 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13

.........................................................................

### PATHOLOGY REPORT PAGE : 37/ 88

INDIVIDUAL ANIMAL DATA T OX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 1

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS HEART:

— Inflammation lymphocytic, focal, grade 1 LUNG:

— Mineralization, vascular, grade 1 T HYMUS:

— Epithelial hyperplasia, grade 1 THYROID GLANDS:

— Hyperplasia/hypertrophy, follicular diffuse, bilateral, grade 2 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1 KIDNEYS:

— Basophilia, tubular, corticomedullary, bilateral, grade 1 SCIATIC NERVE:

— Dilated myelin sheath, focal, bilateral, grade 1 EPIDIDYMIDES:

— Inflammation, lymphocytic, unilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 38/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LA A TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 2

......................................................................... * NECROPSY FINDINGS THYMUS: 01: FOCUS/FOCI, ISOLATED, REDDISH. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS LUNG:

— Alveolar inflammation, mononuclear, grade 1 THYMUS:

— Congestion This finding corresponds to necropsy observation no: 01. STOMACH:

— Hyperplasia limiting ridge, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1

— Apoptosis/single cell necrosis, hepatocellular, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1 KIDNEYS:

— Basophilia, tubular, corticomedullary, bilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral PREPUTIAL GLANDS (INGUINAL GLANDS):

— Inflammation lymphocytic, unilateral, grade 1 SKELETAL MUSCLE:

— Myofiber degeneration, grade 1

— Inflammation, lymphocytic, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 39/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 3

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Mineralization, vascular, grade 1 CECUM:

— Inflammation, lymphogranulocytic, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemosiderin pigment, grade 1 MANDIBULAR LYMPH NODES:

— Congestion/erythrophagocytosis, unilateral, grade 2 KIDNEYS:

— Hyaline droplets, bilateral, grade 1 ADRENAL GLANDS:

— Vacuolation, zona fasciculata, multifocal, bilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 40/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 4

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1 THYROID GLANDS:

— Hyperplasia/hypertrophy, follicular diffuse, bilateral, grade 1 STOMACH:

— Dilated gastric pits, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 2

— Apoptosis/single cell necrosis, hepatocellular, grade 1 SPLEEN:

— Hemosiderin pigment, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 41/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 5

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Alveolar inflammation, mononuclear, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 KIDNEYS:

— Hyaline cast(s), bilateral, grade 2

— Dilatation, tubular, focal, associated with hyaline cast, bilateral, grade 2

— Hyaline droplets, bilateral, grade 2

— Basophilia, tubular, corticomedullary, unilateral, grade 1 TESTES:

— Seminiferous tubular atrophy, focal, unilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 42/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

—————————————————— ——————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 41

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Mineralization, vascular, grade 1

— Alveolar inflammation, mononuclear, grade 1 THYMUS:

— Cystic medullary duct, grade 1

— Lymphoid atrophy (involution), grade 1 THYROID GLANDS:

— Ectopic thymus, unilateral LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 3

— Hemosiderin pigment, grade 1 UTERUS:

— Implantation site(s) VAGINA:

— Parturation debris FEMALE MAMMARY GLAND AREA:

— Glandular development, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 43/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 42

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Diestrus/Metestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 45 * ANIMAL NO. : 43

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Mineralization, vascular, grade 1

— Alveolar macrophage foci, grade 1 THYMUS:

— Epithelial hyperplasia, grade 1 LIVER:

— Inflammatory cell foci, mononuclear, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 2

### PATHOLOGY REPORT PAGE : 44/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 43

......................................................................... KIDNEYS:

— Mineralization, tubular, unilateral, grade 1

— Inflammation, interstitial lymphocytic, unilateral, grade 1 UTERUS:

— Implantation site(s)

— Cyst(s), grade 1 VAGINA:

— Parturation debris FEMALE MAMMARY GLAND AREA:

— Glandular development, grade 3 SKELETAL MUSCLE:

— Myofiber degeneration, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 44

......................................................................... * NECROPSY FINDINGS DUODENUM: 01: WALL: THICKENED. JEJUNUM: 01: WALL: THICKENED. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS LUNG:

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1

### PATHOLOGY REPORT PAGE : 45/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 44

......................................................................... DUODENUM:

— Hypertophy/hyperplasia, duodenal villi, grade 2 This finding corresponds to necropsy observation no: 01. JEJUNUM:

— Hypertophy/hyperplasia, duodenal villi, grade 1 This finding corresponds to necropsy observation no: 01. LIVER:

— Hemopoietic cell foci, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 2

— Hemosiderin pigment, grade 2 UTERUS:

— Implantation site(s) VAGINA:

— Mucification, epithelium, grade 1

— Parturation debris FEMALE MAMMARY GLAND AREA:

— Glandular development, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 48

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED.

### PATHOLOGY REPORT PAGE : 46/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 48

......................................................................... * MICROSCOPIC FINDINGS LUNG:

— Alveolar macrophage foci, grade 1 THYMUS:

— Epithelial hyperplasia, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 1 KIDNEYS:

— Mineralization, tubular, unilateral, grade 1

— Inflammation, interstitial lymphocytic, unilateral, grade 1 ADRENAL GLANDS:

— Vacuolation, zona glomerulosa, bilateral, grade 1 UTERUS:

— Implantation site(s) VAGINA:

— Parturation debris FEMALE MAMMARY GLAND AREA:

— Glandular development, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 50

......................................................................... * NECROPSY FINDING S NO NECROPSY OBSERVATIONS NOTED.

### PATHOLOGY REPORT PAGE : 47/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 01, CONTROL FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 50

......................................................................... * MICROSCOPIC FINDINGS LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 2 KIDNEYS:

— Mineralization, tubular, unilateral, grade 1

— Basophilia, tubular, corticomedullary, bilateral, grade 1 ADRENAL GLANDS:

— Vacuolation, zona glomerulosa, bilateral, grade 1 PITUITARY GLAND:

— Cyst(s), pars intermedia, grade 1 UTERUS:

— Implantation site(s) VAGINA:

— Parturation debris FEMALE MAMMARY GLAND AREA:

— Glandular development, grade 3 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

— ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS —

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 48/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — A HPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

———————————————————————————————————————————————————————————————— ————————— ANIMAL HEADING DATA DOSE GROUP : 02, 100 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 11 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 12 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 13 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 14 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 15 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 16 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 17 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 18 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 19 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 20 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13

......................................................................... 51 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 52 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 53 F K0 +3 45 29 — J AN — 13 14 — MAR — 13 15 — MAR — 13 54 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 55 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 56 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 57 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 58 F K0 K0 45 29 — JAN — 13 14 — MAR — 13 15 — MAR — 13 59 F K0 K0 43 29 — JAN — 13 12 — MAR — 13 13 — MAR — 13 60 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13

.........................................................................

### PATHOLOGY REPORT PAGE : 49/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 12

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

——— —————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 13

......................................................................... * NECROPSY FINDINGS KIDNEYS: 01: RIGHT SIDE: PELVIC DILATION. EPIDIDYMIDES: 01: RIGHT SIDE, TAIL: NODULE(S), D=2X2 MM, YELLOWISH, SOFT. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS:

— Pelvic dilation, unilateral This finding corresponds to necropsy observation no: 01.

— Hyaline droplets, bilateral, grade 1

— Basophilia, tubular, corticomedullary, bilateral, grade 1

### PATHOLOGY REPORT PAGE : 50/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 13

......................................................................... EPIDIDYMIDES:

— Sperm granuloma, tail, unilateral, grade 2 This finding corresponds to necropsy observation no: 01. TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 16

......................................................................... * NECROPSY FINDINGS EPIDIDYMIDES: 01: LEFT SIDE, TAIL: NODULE(S), D=11X6 MM, YELLOWISH, SOFT. SKIN/SUBCUTIS: 01: BACK OF THE NECK: SCAB FORMATION. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS EPIDIDYMIDES: Only one of paired organs examined/present

— Sperm granuloma, tail, unilateral, grade 4 This finding corresponds to necropsy observation no: 01. SKIN/SUBCUTIS:

— Epidermal hyperplasia, with exudative inflammation, focal, grade 1 This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 51/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

———————————————————————————————————————————————————————————————— ————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 19

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 52/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 45 * ANIMAL NO. : 51

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 2

— Hemosiderin pigment, grade 1

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 52

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Estrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 53/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0/+3 DAYS ON TEST : 45 * ANIMAL NO. : 53

......................................................................... * NECROPSY FINDINGS GENERAL OBSERVATIONS: 01: TOTAL LITTER LOSS. NO OTHER NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS GENERAL OBSERVATIONS:

— Macro noted This finding corresponds to necropsy observation no: 01. VAGINA:

— Mucification, epithelium, grade 2

— Parturation debris FEMALE MAMMARY GLAND AREA:

— Glandular development, grade 3 low cuboidal and/or vacuolated epithelium. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 45 * ANIMAL NO. : 54

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED.

### PATHOLOGY REPORT PAGE : 54/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 54

......................................................................... * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 1

————————————

————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 55

......................................................................... * NECROPSY FINDINGS ADRENAL GLANDS: 01: BOTH SIDES: ENLARGED. 02: BOTH SIDES: DISCOLOURATION, DARK RED. CLITORAL GLANDS: 01: LEFT SIDE: FOCUS/FOCI, MANY, REDDISH. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 2 ADRENAL GLANDS:

— Congestion, bilateral, grade 2 This finding corresponds to necropsy observations nos: 01,02. CLITORAL GLANDS:

— Dilated duct, unilateral, grade 2 This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————— ———————

### PATHOLOGY REPORT PAGE : 55/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 57

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 2

— Hemosiderin pigment, grade 1

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 59

......................................................................... * NECROPSY FINDINGS KIDNEYS: 01: LEFT SIDE: PELVIC DILATION. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS KIDNEYS: No microscopic finding corresponding to necropsy observation no. 01. VAGINA:

— Estrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 56/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

———————————————

—————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG FEMALE

—————————

———————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 60

......................................................................... * NECROPSY FINDINGS DUODENUM: 01: WALL: THICKENED. JEJUNUM: 01: WALL: THICKENED. SPLEEN: 01: ENLARGED. KIDNEYS: 01: BOTH SIDES: DISCOLOURATION, BLACK — BROWN. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS DUODENUM:

— Hypertophy/hyperplasia, duodenal villi, grade 1 This finding corresponds to necropsy observation no: 01. JEJUNUM: Organ examined, no pathologic findings noted No microscopic finding corresponding to necropsy observation no. 01. SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 3 This finding corresponds to necropsy observation no: 01.

— Hemosiderin pigment, grade 1 KIDNEYS:

— Congestion, bilateral This finding corresponds to necropsy observation no: 01.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 57/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 02, 100 MG/KG FEMALE

—————————————————————————————————————————————————————————————————————————

— ALL OTHER ANIMALS IN DOSE GROUP WITHOUT PATHOLOGICAL FINDINGS —

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 58/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 03, 300 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 21 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 22 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 23 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 24 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 25 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 26 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 27 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 28 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 29 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 30 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13

......................................................................... 61 F K0 K0 44 29 — JAN — 13 1 3 — MAR — 13 14 — MAR — 13 62 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 63 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 64 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 65 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 66 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 67 F K0 K0 43 29 — JAN — 13 12 — MAR — 13 13 — MAR — 13 68 F K0 K0 43 29 — JAN — 13 12 — MAR — 13 13 — MAR — 13 69 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 70 F K0 K0 43 29 — JAN — 13 12 — MAR — 13 13 — MAR — 13

.........................................................................

### PATHOLOGY REPORT PAGE : 59/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

—————————————————————————————————————————————————————————————————————— ——— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 21

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 22

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 60/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — A HPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

———————————————————————————————————————————————————————————————— ————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 23

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral COAGULATING GLANDS (ANTERIOR PROSTATE): Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 24

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 61/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————— ———————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 25

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————— ———————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 26

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 62/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

——————————————————— —————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 27

......................................................................... * NECROPSY FINDINGS EPIDIDYMIDES: 01: RIGHT SIDE, TAIL: NODULE(S), D=5X3 MM, YELLOWISH, SOFT. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS EPIDIDYMIDES:

— Sperm granuloma, tail, unilateral, grade 3 This finding corresponds to necropsy observation no: 01. TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 28

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral COAGULATING GLANDS (ANTERIOR PROSTATE):

— Inflammation lymphocytic, unilateral, grade 1

### PATHOLOGY REPORT PAGE : 63/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 28

......................................................................... PREPUTIAL GLANDS (INGUINAL GLANDS):

— Inflammation lymphocytic, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————— ——— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 29

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 64/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

———————————————

—————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 30

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

———————————————————————————————————————————————————————————————— —————————

### PATHOLOGY REPORT PAGE : 65/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : C OPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 61

......................................................................... * NECROPSY FINDINGS UTERUS: 01: RIGHT HORN: CONTENTS: BLACK, DARK RED. 02: RIGHT HORN: LARGE FETUS. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 2

— Hemosiderin pigment, grade 2 UTERUS: No microscopic finding corresponding to necropsy observation no. 02.

— Implantation site(s), early, decidual zone

— Hemorrhagic contents This finding corresponds to necropsy observation no: 01. VAGINA:

— Mucification, epithelium, grade 3

— Hemorrhagic contents ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 66/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 62

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS SPLEEN:

— Hemosiderin pigment, grade 3 VAGINA:

— Estrus epithelium CLITORAL GLANDS:

— Inflammation, granulocytic, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

———————————————————————————————————————————————————————————————————— ————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 63

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS SPLEEN:

— Hemosiderin pigment, grade 2 VAGINA:

— Proestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 67/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 64

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 2 VAGINA:

— Diestrus/Metestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

——————————

——————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 65

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Hemosiderin pigment, grade 1 VAGINA: Tissue not present for histologic examination CLITORAL GLANDS:

— Dilated duct, unilateral, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 68/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 66

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS CERVIX: Tissue not present for histologic examination VAGINA:

— Diestrus/Metestrus epithelium CLITORAL GLANDS: slight lymphocytic infiltrate around urethra. ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 67

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Proestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 69/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 68

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Proestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 69

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Diestrus/Metestrus epithelium, late diestrus ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 70/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 03, 300 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 70

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Diestrus/Metestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 71/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— ANIMAL HEADING DATA DOSE GROUP : 04, 1000 MG/KG

————————————————————————————————————————————————————————————————————————— ANIMAL SEX DEFINED AND FINAL TEST FIRST AND LAST DATE OF NUMBER M/F STATE OF NECROPSY DAYS DAY UNDER TEST NECROPSY

......................................................................... 31 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 32 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 33 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 34 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 35 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 36 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 37 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 38 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 39 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13 40 M K0 K0 29 29 — JAN — 13 26 — FEB — 13 27 — FEB — 13

......................................................................... 71 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 72 F K0 K0 43 29 — JAN — 13 12 — MAR — 13 13 — MAR — 13 73 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 74 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 75 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 76 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 77 F K0 K0 42 29 — JAN — 13 11 — MAR — 13 12 — MAR — 13 78 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 79 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13 80 F K0 K0 44 29 — JAN — 13 13 — MAR — 13 14 — MAR — 13

.........................................................................

### PATHOLOGY REPORT PAGE : 72/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 31

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Mineralization, vascular, grade 1

— Alveolar macrophage foci, grade 1

— Alveolar inflammation, mononuclear, grade 1 THYMUS:

— Epithelial hyperplasia, grade 1 CECUM:

— Inflammation, lymphogranulocytic, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1 KIDNEYS:

— Hyaline droplets, bilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 73/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 32

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1

— Alveolar inflammation, mononuclear, grade 1 THYMUS:

— Epithelial hyperplasia, grade 1 SPLEEN:

— Hemosiderin pigment, grade 1 KIDNEYS:

— Inflammation, interstitial lymphocytic, unilateral, grade 1

— Basophilia, tubular, corticomedullary, unilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral SKELETAL MUSCLE:

— Myofiber degeneration, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 74/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————— ———————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 33

......................................................................... * NECROPSY FINDINGS KIDNEYS: 01: RIGHT SIDE: PELVIC DILATION. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS LUNG:

— Mineralization, vascular, grade 1

— Alveolar macrophage foci, grade 1

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1

— Alveolar inflammation, mononuclear, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1 KIDNEYS:

— Pelvic dilation, unilateral This finding corresponds to necropsy observation no: 01.

— Hyperplasia, pelvic urothelium, multifocal, unilateral, grade 2

— Erosion, urothelium, focal, unilateral, grade 1

— Hyaline droplets, bilateral, grade 2

— Basophilia, tubular, corticomedullary, unilateral, grade 1 PITUITARY GLAND:

— Cyst(s), pars intermedia, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral SKELETAL MUSCLE:

— Myofiber degeneration, grade 1

— Inflammation, lymphocytic, grade 1

### PATHOLOGY REPORT PAGE : 75/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 33

......................................................................... ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 34

......................................................................... * NECROPSY FINDINGS LIVER: 01: LEFT MEDIAN LOBE: DIAPHRAGMATIC HERNIA. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS LUNG:

— Mineralization, vascular, grade 1

— Alveolar macrophage foci, grade 1

— Inflammatory cell infiltrate, peri — vascular/bronchial, g rade 1 TRACHEA:

— Inflammation, lymphocytic, grade 1 LIVER:

— Hepatodiaphragmatic nodule This finding corresponds to necropsy observation no: 01.

— Inflammatory cell foci, mononuclear, grade 2 SPLEEN:

— Hemosiderin pigment, grade 1 MESENTERIC LYMPH NODE:

— Increased lymphoid tissue, grade 1 MANDIBULAR LYMPH NODES:

— Lymphoid hyperplasia, unilateral, grade 2

### PATHOLOGY REPORT PAGE : 76/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 34

......................................................................... KIDNEYS:

— Basophilia, tubular, corticomedullary, unilateral, grade 1 EPIDIDYMIDES:

— Seminiferous cell debris, bilateral, grade 1 TESTES:

— Spermatidic giant cells, bilateral, grade 1

— Seminiferous tubular atrophy, multifocal, bilateral, grade 2

— Vacuolation, seminiferous epithelium, increased, bilateral, grade 2 TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 1 PREPUTIAL GLANDS (INGUINAL GLANDS):

— Inflammation lymphocytic, bilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 35

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 2

— Alveolar inflammation, mixed, grade 1

### PATHOLOGY REPORT PAGE : 77/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————

————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

—— ——————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 35

......................................................................... THYROID GLANDS:

— Hyperplasia/hypertrophy, follicular diffuse, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present LIVER:

— Inflammatory cell foci, mononuclear, grade 1 SPLEEN:

— Hemopoietic foci, primarily erythropoiesis, grade 1

— Lymphoid hyperplasia, grade 1 KIDNEYS:

— Hyaline droplets, bilateral, grade 1

— Basophilia, tubular, corticomedullary, bilateral, grade 1 TESTES:

— Seminiferous tubular atrophy, multifocal, bilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 1 COAGULATING GLANDS (ANTERIOR PROSTATE): Only one of paired organs examined/present ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 36

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED.

### PATHOLOGY REPORT PAGE : 78/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 36

......................................................................... * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— A ll stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 37

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES:

— Seminiferous tubular atrophy, focal, unilateral, grade 1 TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 79/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO. : 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 38

......................................................................... * NECROPSY FINDINGS EPIDIDYMIDES: 01: LEFT SIDE: REDUCED IN SIZE. TESTES: 01: LEFT SIDE: REDUCED IN SIZE. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS EPIDIDYMIDES:

— Seminiferous cell debris, unilateral, grade 1

— Macro noted, reduced size but normal histology, unilateral This finding corresponds to necropsy observation no: 01. TESTES, PAS STAGING:

— All stages present, bilateral ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 39

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED.

### PATHOLOGY REPORT PAGE : 80/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

——— —————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG MALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 39

......................................................................... * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral PROSTATE GLAND:

— Inflammation lymphocytic, grade 1 PREPUTIAL GLANDS (INGUINAL GLANDS):

— Dilated duct, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 29 * ANIMAL NO. : 40

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS TESTES, PAS STAGING:

— All stages present, bilateral PREPUTIAL GLANDS (INGUINAL GLANDS):

— Dilated duct, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 81/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

——————————————

——————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————

————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 71

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Diestrus/Metestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 43 * ANIMAL NO. : 72

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Estrus epithelium, late ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————— ———

### PATHOLOGY REPORT PAGE : 82/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 73

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG: one lobe, insufficient inflated.

— Alveolar macrophage foci, with brown pigment, grade 1

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1 THYROID GLANDS:

— Dilated/cystic follicles, bilateral, grade 1 PARATHYROID GLANDS: Only one of paired organs examined/present STOMACH:

— Pigmented macrophages (brown), glandular mocosa, grade 1 ILEUM:

— Lymphangectasia, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemosiderin pigment, grade 2 KIDNEYS:

— Mineralization, tubular, unilateral, grade 1 VAGINA:

— Diestrus/Metestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————

—————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 83/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 74

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Diestrus/Metestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 75

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS OVARIES:

— Cyst, oviduct, unilateral, grade 2 VAGINA:

— Proestrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 84/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

———————————————————————————————————————————————————————————————————— ————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 76

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS THYMUS:

— Lymphocytolysis, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemosiderin pigment, grade 3 MANDIBULAR LYMPH NODES:

— Lymphoid hyperplasia, bilateral, grade 1 ADRENAL GLANDS:

— Vacuolation, zona glomerulosa, bilateral, grade 1 VAGINA:

— Diestrus/Metestrus epithelium, late diestrus EYES:

— Cornea proliferation, focal, unilateral, grade 1 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————

### PATHOLOGY REPORT PAGE : 85/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

——————————————

——————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————

————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 42 * ANIMAL NO. : 77

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS VAGINA:

— Estrus epithelium ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 78

......................................................................... * NECROPSY FINDINGS NO NECROPSY OBSERVATIONS NOTED. * MICROSCOPIC FINDINGS LUNG:

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemosiderin pigment, grade 3 VAGINA:

— Proestrus epithelium

### PATHOLOGY REPORT PAGE : 86/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 78

......................................................................... ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 79

......................................................................... * NECROPSY FINDINGS ADRENAL GLANDS: 01: BOTH SIDES: ENLARGED. CLITORAL GLANDS: 01: RIGHT SIDE: DISCOLOURATION, TAN. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS LUNG:

— Inflammatory cell infiltrate, peri — vascular/bronchial, grade 1 STOMACH:

— Hyperplasia limiting ridge, grade 1 LIVER:

— Inflammatory cell foci, lymphocytic, grade 1 SPLEEN:

— Hemosiderin pigment, grade 4 PITUITARY GLAND:

— Cyst(s), pars intermedia, grade 1 VAGINA:

— Diestrus/Metestrus epithelium, late diestrus CLITORAL GLANDS:

— Dilated duct, unilateral, grade 3 This finding corresponds to necropsy observation no: 01.

### PATHOLOGY REPORT PAGE : 87/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or CS — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— C ONT./FF. ANIMAL NO. : 79

......................................................................... ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

————————————————————————————————————————————————————————————————————————— * STATE AT NECROPSY: K0 DAYS ON TEST : 44 * ANIMAL NO. : 80

......................................................................... * NECROPSY FINDINGS THYMUS: 01: DISCOLOURATION, RED — BROWN. MESENTERIC LYMPH NODE: 01: ENLARGED. MANDIBULAR LYMPH NODES: 01: BOTH SIDES: DISCOLOURATION, REDDISH. NO OTHER NECROPSY OBSERVATIONS NOTED * MICROSCOPIC FINDINGS HEART:

— Inflamm. mononuclear, multifocal, grade 2

— Myofiber degeneration, multifocal, grade 2 LUNG:

— Mineralization, vascular, grade 1

— Alveolar inflammation, mixed, grade 1 THYMUS:

— Congestion This finding corresponds to necropsy observation no: 01.

— Pigmented macrophages, yellow — brown, grade 1 This finding corresponds to necropsy observation no: 01. PARATHYROID GLANDS: Only one of paired organs examined/present

### PATHOLOGY REPORT PAGE : 88/ 88

INDIVIDUAL ANIMAL DATA TOX : 500682

————————————————————————————————————————————————————————————————————————— TEST ITEM : COPS_1 or C S — AHPS PATHOL. NO.: 31308 LAA TEST SYSTEM : RAT, Combined 28 — Day, gavage DATE : 02 — JUL — 13 SPONSOR : SoCMA PathData©System V6.2d1

————————————————————————————————————————————————————————————————————————— TEXT OF GROSS AND MICROSCOPIC FINDINGS DOSE GROUP : 04, 1000 MG/KG FEMALE

————————————————————————————————————————————————————————————————————————— CONT./FF. ANIMAL NO. : 80

......................................................................... STOMACH:

— Erosion, glandular mucosa, focal, with necrosis, grade 2 Erosion located just behind limiting ridge.

— Inflammation, limiting ridge, lymphogranulocytic, grade 1 LIVER:

— Inflammatory cell foci, mononuclear, grade 1 SPLEEN:

— Hemosiderin pigment, grade 3

— Lymphoid atrophy, decreased marginal zone, grade 2

— Histiocytosis, red pulpa, grade 2 MESENTERIC LYMPH NODE:

— Lymphatic ectasia, grade 3 This finding corresponds to necropsy observation no: 01.

— Histiocytosis, grade 3

— Plasmacytosis, grade 2 MANDIBULAR LYMPH NODES:

— Congestion/erythrophagocytosis, bilateral, grade 2 This finding corresponds to necropsy observation no: 01.

— Pigmented macrophages, yellow — brown, bilateral, grade 2 KIDNEYS:

— Inflammation, interstitial lymphocytic, bilateral, grade 2

— Inflammation, pelvic, lymphogranulocytic, bilateral, grade 1

— Basophilia, tubular, corticomedullary, bilateral, grade 1 VAGINA:

— Proestrus epithelium, early FEMALE MAMMARY GLAND AREA: slight amount of macrophages with brown pigment present in lymph node. BONE MARROW — STERNAL:

— Myeloid hyperplasia, granuolopoiesis, grade 2 ALL OTHER PROTOCOL TISSUES WITHOUT PATHOLOGIC FINDINGS.

—————————————————————————————————————————————————————————————————————————