FINAL REPORT

Study Title

COMBINED 28-DAY REPEATED DOSE TOXICITY STUDY WITH THE 

REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST 

OF 1-PROPANESULFONIC ACID, 2-HYDROXY-3-(2-PROPEN-1-

YLOXY)-, SODIUM SALT (1:1) IN RATS BY ORAL GAVAGE

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 treatment), 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 

presence 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 Facility 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 2013 (selected females)

Delivery of litters 06-10 and 12 March 2013

Necropsy 27 February 2013 (males)

12-15 and 18 March 2013 (females and/or pups)

Experimental completion date 18 March 2013 (end of in-life phase)

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5.3. Aims of study 

The purpose of this study was 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 

The 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 were 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

O SO3

-

OH

Na+

Molecular formula C6H11NaO5S

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 

Purity/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 was made 

for specific gravity of the test substance. No correction was made for the 

purity/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 F0 Charles River Deutschland, Sulzfeld, Germany. 

Age at start F0-treatment Approximately 11 weeks. 

Number of F0-animals 40 females and 40 males. 

Acclimatization F0 At least 5 days prior to start of treatment. 

Health inspection F0 Upon receipt of the animals. 

Randomization F0 Prior to commencement of treatment, by computer-generated random 

algorithm according to body weight, with all animals within ± 20% of the 

sex mean. 

Identification F0 Earmark and tattoo. 

Mating procedures Following a minimum of 14 days of exposure for the males and females, 

one female was cohabitated with one male of the same treatment group, 

avoiding sibling mating. Detection of mating was confirmed by evidence 

of sperm in the vaginal lavage or by the appearance of an intravaginal 

copulatory plug. This day was 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 was 

defined as the day when a litter was 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 196 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 level1

mg/kg

Dose level Number of animals Animal numbers 

mg/kg mg active 

ingredient2/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 were 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 necropsy). Female nos. 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 was 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 was recorded. Signs were graded for severity and the maximum grade 

was 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) was 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. The 

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 were housed together for 

mating and for females without evidence of mating. Food consumption of 

mated females was 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 was 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 was 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 K3-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) was 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 K3-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) 109/L

Differential leucocyte count:

Neutrophils %WBC

Lymphocytes %WBC

Monocytes %WBC

Eosinophils %WBC

Basophils %WBC

Red blood cells 1012/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 109/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 serum:

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 delivered Lactation Days 5-7.

Females which failed to deliver

(nos. 42, 52, 59, 61 - 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. 

Final Report - Page 17 of 238-
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- Page 18 - 

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 1Skeletal 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

(Esophagus)

All remaining animals, females which failed to deliver2 and females with total litter loss3: 

Cervix Preputial gland

Clitoral gland Prostate gland

Coagulation gland Seminal vesicles

Epididymides 1Testes 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 were 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 was 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 macroscopic 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 was 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 Prostate1

Liver Seminal vesicles including coagulating glands1

Ovaries Thyroid including parathyroid1

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 females of Groups 2 and 3, based on (possible) treatment-related 

changes in this organ in Group 4 females. 

- The reproductive organs1 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. 

Two 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: 

Mating 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 deviations from the minimum level of daily mean relative humidity occurred.

Evaluation: Laboratory historical data do not indicate an effect of the deviations.

2. No clinical observations were registered in the computer for all pups 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 from 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 was 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. 

For 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 

one 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 trend. 

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/kg 

were 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. 

The 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 considered 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, none 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 

presence 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 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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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). 

Final Report - Page 27 of 238-
COPS_1 or CS-AHPS Project 500682 

APPENDIX 1 

- Page 1 - 

APPENDIX 1 SUMMARY TABLES 

Final Report - Page 28 of 238-
 23May13 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 PERIOD 

- Page 2 - Final Report - Page 29 of 238-
 23May13 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 .

.

- Page 3 -

# End of post-coitum period for Group 3 and 4 females 

Final Report - Page 30 of 238-
COPS_1 or CS-AHPS Project 500682

APPENDIX 1

1.3 MOTOR ACTIVITY TEST SUMMARY

MALES

AT WEEK 4

GROUP 1

CONTROL

Total Movements MEAN1 4680 5290 4200 4127

ST.DEV 1077 2088 1163 1366

N 5 5 5 5

Ambulations MEAN1 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 12

Counts

Interval (5 min)

Total Movements Males2

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 12

Counts

Interval (5 min)

Ambulations Males2

Group 1

Group 2

Group 3

Group 4

- Page 4 - Final Report - Page 31 of 238-
COPS_1 or CS-AHPS Project 500682

APPENDIX 1

1.3 MOTOR ACTIVITY TEST SUMMARY

FEMALES

LACTATION

GROUP 1

CONTROL

MEAN1

3775 4488 5578 6663 *

ST.DEV 1196 1212 1140 1646

N 5 5 5 5

Ambulations MEAN1 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 12

Counts

Interval (5 min)

Total Movements Females2

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 12

Counts

Interval (5 min)

Ambulations Females2

Group 1

Group 2

Group 3

Group 4

- Page 5 -

# End of post-coitum period for Group 3 and 4 females 

Final Report - Page 32 of 238-
 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

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 .

.

- Page 6 - Final Report - Page 33 of 238-
 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 .

.

- Page 7 - Final Report - Page 34 of 238-
 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 .

.

- Page 8 - Final Report - Page 35 of 238-
 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 .

.

- Page 9 - Final Report - Page 36 of 238-
 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 .

.

- Page 10 - Final Report - Page 37 of 238-
 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 .

- Page 11 - Final Report - Page 38 of 238-
 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 .

.

- Page 12 - Final Report - Page 39 of 238-
 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 .

- Page 13 - Final Report - Page 40 of 238-
 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 .

.

- Page 14 - Final Report - Page 41 of 238-
 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 .

.

- Page 15 - Final Report - Page 42 of 238-
 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 .

.

- Page 16 - Final Report - Page 43 of 238-
 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 .

.

- Page 17 - Final Report - Page 44 of 238-
 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 .

.

- Page 18 - Final Report - Page 45 of 238-
 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 .

.

- Page 19 - Final Report - Page 46 of 238-
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*/** 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 .

.

- Page 20 - Final Report - Page 47 of 238-
 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 .

.

- Page 21 - Final Report - Page 48 of 238-
 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 .

.

- Page 22 - Final Report - Page 49 of 238-
 04Jun13 08h02

# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level

COPS_1 or CS-AHPS Project 500682

APPENDIX 1

1.10 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 .

- Page 23 - Final Report - Page 50 of 238-
 04Jun13 08h02

# / ## Fisher's Exact test significant at 5% (#) or 1% (##) level

COPS_1 or CS-AHPS Project 500682

APPENDIX 1

1.10 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 .

- Page 24 - Final Report - Page 51 of 238-
 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 .

.

- Page 25 - Final Report - Page 52 of 238-
 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 .

.

- Page 26 - Final Report - Page 53 of 238-
 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 .

.

- Page 27 - Final Report - Page 54 of 238-
 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 .

.

- Page 28 - Final Report - Page 55 of 238-
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) * 100

- Page 29 - Final Report - Page 56 of 238-
 23May13 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 .

- Page 30 - Final Report - Page 57 of 238-
 23May13 12h42

+/++ Steel-test significant at 5% (+) or 1% (++) level

COPS_1 or CS-AHPS Project 500682

APPENDIX 1

1.14 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 .

.

- Page 31 - Final Report - Page 58 of 238-
 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 .

- Page 32 - Final Report - Page 59 of 238-
 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 .

.

- Page 33 - Final Report - Page 60 of 238-
COPS_1 or CS-AHPS Project 500682 

APPENDIX 2 

- Page 1 - 

APPENDIX 2 INDIVIDUAL TABLES 

Final Report - Page 61 of 238-
 24May13 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 .

- Page 2 - Final Report - Page 62 of 238-
 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 .

- Page 3 - Final Report - Page 63 of 238-
 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 .

- Page 4 -

REPRO PERIOD 

Final Report - Page 64 of 238-
 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 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 .

- Page 5 -

REPRO PERIOD 

REPRO PERIOD 

Final Report - Page 65 of 238-
 24May13 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 .

- Page 6 -

REPRO PERIOD 

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

Final Report - Page 66 of 238-
 24May13 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 .

- Page 7 -

# End of post-coitum period for Group 3 and 4 females 

Final Report - Page 67 of 238-
 24May13 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 .

- Page 8 -

# End of post-coitum period for Group 3 and 4 females 

Final Report - Page 68 of 238-
COPS_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)

- Page 9 - Final Report - Page 69 of 238-
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)

- Page 10 - Final Report - Page 70 of 238-
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)

- Page 11 -

# End of post-coitum period for Group 3 and 4 females 

Final Report - Page 71 of 238-
COPS_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)

- Page 12 -

# End of post-coitum period for Group 3 and 4 females 

Final Report - Page 72 of 238-
 24May13 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 .

- Page 13 - Final Report - Page 73 of 238-
 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 .

- Page 14 - Final Report - Page 74 of 238-
 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 --- --- .

- Page 15 - Final Report - Page 75 of 238-
 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 .

- Page 16 - Final Report - Page 76 of 238-
 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 .

- Page 17 - Final Report - Page 77 of 238-
 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 --- --- .

- Page 18 - Final Report - Page 78 of 238-
 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 .

- Page 19 - Final Report - Page 79 of 238-
 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 --- .

- Page 20 -

* Food wet 

* 

Final Report - Page 80 of 238-
 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 .

- Page 21 - Final Report - Page 81 of 238-
 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 --- .

- Page 22 -

* Food wet 

* 

Final Report - Page 82 of 238-
 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 10.1

- Page 23 - Final Report - Page 83 of 238-
 24May13 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 .

- Page 24 - Final Report - Page 84 of 238-
 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 .

- Page 25 - Final Report - Page 85 of 238-
 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 10.1

- Page 26 - Final Report - Page 86 of 238-
 24May13 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 .

- Page 27 - Final Report - Page 87 of 238-
 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 .

- Page 28 - Final Report - Page 88 of 238-
 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 2.22

- Page 29 - Final Report - Page 89 of 238-
 24May13 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 .

- Page 30 - Final Report - Page 90 of 238-
 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 .

- Page 31 - Final Report - Page 91 of 238-
 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 0.98

- Page 32 - Final Report - Page 92 of 238-
 24May13 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 .

- Page 33 - Final Report - Page 93 of 238-
 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 .

- Page 34 - Final Report - Page 94 of 238-
 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 .

- Page 35 - Final Report - Page 95 of 238-
 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. .

- Page 36 - Final Report - Page 96 of 238-
 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 1.220

- Page 37 - Final Report - Page 97 of 238-
 04Jun13 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 --- .

- Page 38 - Final Report - Page 98 of 238-
 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 --- .

- Page 39 - Final Report - Page 99 of 238-
 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 0.347

- Page 40 - Final Report - Page 100 of 238-
 04Jun13 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 --- .

- Page 41 - Final Report - Page 101 of 238-
 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 --- .

- Page 42 - Final Report - Page 102 of 238-
 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 --- --- --- --- --- .

- Page 43 - Final Report - Page 103 of 238-
 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 .

- Page 44 -


Uterus weight was determined including fetus (13.874 gram) 

* 

Final Report - Page 104 of 238-
 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 --- --- --- --- --- .

- Page 45 - Final Report - Page 105 of 238-
 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 .

- Page 46 -

* 




Final Report

Uterus weight was determined including fetus (13.874 gram) 

- Page 106 of 238-
 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 .

- Page 47 -

Female nos. 59, 61 and 65 had only implantation sites 

Final Report - Page 107 of 238-
 24May13 12h14

COPS_1 or CS-AHPS Project 500682

APPENDIX 2

2.14 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 --- --- .

- Page 48 -

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 sites 

Final Report - Page 108 of 238-
 24May13 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 .

- Page 49 - Final Report - Page 109 of 238-
 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 .

.

- Page 50 - Final Report - Page 110 of 238-
 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 .

.

- Page 51 - Final Report - Page 111 of 238-
 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 .

- Page 52 - Final Report - Page 112 of 238-
 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 .

- Page 53 - Final Report - Page 113 of 238-
 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 .

- Page 54 - Final Report - Page 114 of 238-
 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 -- -- .

.

- Page 55 - Final Report - Page 115 of 238-
 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 .

- Page 56 - Final Report - Page 116 of 238-
 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 .

- Page 57 - Final Report - Page 117 of 238-
 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 .

- Page 58 - Final Report - Page 118 of 238-
 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 .

- Page 59 - Final Report - Page 119 of 238-
 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 .

- Page 60 - Final Report - Page 120 of 238-
 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 .

- Page 61 - Final Report - Page 121 of 238-
 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 .

- Page 62 - Final Report - Page 122 of 238-
 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 .

- Page 63 - Final Report - Page 123 of 238-
 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 .

- Page 64 - Final Report - Page 124 of 238-
 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 .

- Page 65 - Final Report - Page 125 of 238-
 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 .

- Page 66 - Final Report - Page 126 of 238-
 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 .

- Page 67 - Final Report - Page 127 of 238-
 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 .

- Page 68 - Final Report - Page 128 of 238-
 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 .

- Page 69 - Final Report - Page 129 of 238-
 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 .

- Page 70 - Final Report - Page 130 of 238-
 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 .

- Page 71 - Final Report - Page 131 of 238-
 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 .

- Page 72 - Final Report - Page 132 of 238-
 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 .

- Page 73 - Final Report - Page 133 of 238-
 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 .

- Page 74 - Final Report - Page 134 of 238-
 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 .

- Page 75 - Final Report - Page 135 of 238-
 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 .

- Page 76 - Final Report - Page 136 of 238-
 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 .

- Page 77 - Final Report - Page 137 of 238-
 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 .

- Page 78 - Final Report - Page 138 of 238-
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 Biochemistry: No remarks

- Page 79 - Final Report - Page 139 of 238-
COPS_1 or CS-AHPS Project 500682 

APPENDIX 3 

- Page 1 - 

APPENDIX 3 CERTIFICATE OF ANALYSIS 

Final Report - Page 140 of 238-
COPS_1 or CS-AHPS Project 500682 

APPENDIX 3 

- Page 2 - 

Final Report - Page 141 of 238-
COPS_1 or CS-AHPS Project 500682 

APPENDIX 4 

- Page 1 - 

APPENDIX 4 FORMULATION ANALYSIS

Final Report - Page 142 of 238-
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 METHODS .......................................................................................................... 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

Final Report - Page 143 of 238-
- Page 144 of 238-
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 110%). 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%). 

Final Report - Page 145 of 238-
COPS_1 or CS-AHPS Project 500682

- Page 5 - 

4. INTRODUCTION

4.1. Preface

Study plan analytical phase Start : 15 May 2013

Completion : 17 May 2013

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 METHODS 

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

(Na2HPO4 · 2H2O)

Sodium dihydrogenphosphate dihydrate Merck

(NaH2PO4 · 2H2O)

Sodium nitrate Merck 

(NaNO3) 

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 pipette, 

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 were 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. 

Final Report - Page 146 of 238-
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 Na2HPO4, 0.05M NaH2PO4 and 

0.05M NaNO3

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).

Final Report - Page 147 of 238-
COPS_1 or CS-AHPS Project 500682

- Page 7 - 

5.5. Formulas

Response (R) Peak area test substance [units]

Calibration curve N += b C a R

where:

CN = nominal concentration [mg/l]

a = slope [units × l/mg]

b = intercept [units]

Analysed concentration (CA) [mg/g] 

w

d V

a

(R b) CA

× × − =

where:

w = weight sample [mg]

V = volume volumetric flask [ml]

d = dilution factor

Recovery [%] 100 C

C

N

A ×

where:

CN = nominal concentration [mg/g]

Accuracy [%] 100 C

C

T

A ×

where:

CT = target concentration [mg/g]

5.6. Specifications

Preparation of formulations was considered acceptable if the mean accuracy was in the range 

90-110% of the target concentration and if the coefficient of variation was ≤ 10%. 

Final Report - Page 148 of 238-
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/concentration2 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 90-110%. 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 formulations, 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 110%).

Homogeneity

The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%).

Final Report - Page 149 of 238-
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 50% 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.

Final Report - Page 150 of 238-
COPS_1 or CS-AHPS Project 500682 

APPENDIX 5 

- Page 1 - 

APPENDIX 5 HISTOPATHOLOGY REPORT 

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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

 

Final Report - Page 152 of 238-
- Page 153 of 238-
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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 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). 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.

Final Report - Page 154 of 238-
PATHOLOGY REPORT PAGE : 5/ 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 

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

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 exposed 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. 

The 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. 

Final Report - Page 155 of 238-
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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 marrow-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) with 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 

glands(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). 

Following 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. 

Final Report - Page 156 of 238-
PATHOLOGY REPORT PAGE : 7/ 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 

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

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 transferred 

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 comment 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.

Final Report - Page 157 of 238-
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 findings. 

An indirect test item-related macroscopic finding was recorded in 1/10 

females (no. 61) treated at 300 mg/kg, consisting of right uterine horn 

containing an enlarged dead fetus and black dark contents. This was 

considered to be a secondary effect due to 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.

Findings 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 limiting 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.

Final Report - Page 158 of 238-
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 

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

Reproductive 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 contents). 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. Furthermore, the 

spermatogenic staging profiles were normal for all examined males. 

Final Report - Page 159 of 238-
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.

Final Report - Page 160 of 238-
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 

Final Report - Page 161 of 238-
PATHOLOGY REPORT PAGE : 12/ 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 

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

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 

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

Final Report - Page 162 of 238-
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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 

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

Final Report - Page 163 of 238-
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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 

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

Final Report - Page 164 of 238-
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 — — 

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

Final Report - Page 165 of 238-
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 — — 

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

Final Report - Page 166 of 238-
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 

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

Final Report - Page 167 of 238-
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 — 

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

Final Report - Page 168 of 238-
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 

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

Final Report - Page 169 of 238-
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 — — — — — ' ' ' ' ' 

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

Final Report - Page 170 of 238-
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. 

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

Final Report - Page 171 of 238-
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 — — — — — ' ' ' ' ' 

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

Final Report - Page 172 of 238-
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—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 

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

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 — ' — — ' ' ' — ' — 

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

Final Report - Page 173 of 238-
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 — — — — ' ' ' — ' — 

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

Final Report - Page 174 of 238-
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 — ' — — ' ' ' — ' — 

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

Final Report - Page 175 of 238-
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. 

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

Final Report - Page 176 of 238-
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* 

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

Final Report - Page 177 of 238-
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. . . 

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

Final Report - Page 178 of 238-
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. . . . . . . . . 

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

Final Report - Page 179 of 238-
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. 

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

Final Report - Page 180 of 238-
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. . . . . . . 

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

Final Report - Page 181 of 238-
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 

 MK0 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 — — — — — ' ' ' ' ' 

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

Final Report - Page 182 of 238-
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 ' ' — ' ' — ' — — — 

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

Final Report - Page 183 of 238-
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 ' ' — ' ' — ' — — — 

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

Final Report - Page 184 of 238-
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 ' ' — ' ' — ' — — — 

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

Final Report - Page 185 of 238-
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

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

Final Report - Page 186 of 238-
PATHOLOGY REPORT PAGE : 37/ 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. : 1

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

* NECROPSY FINDINGS

 NO NECROPSY OBSERVATIONS NOTED.

* MICROSCOPIC FINDINGS

 HEART:

 —Inflammation lymphocytic, focal, grade 1 

 LUNG:

 —Mineralization, vascular, grade 1 

 THYMUS:

 —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.

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

Final Report - Page 187 of 238-
PATHOLOGY REPORT PAGE : 38/ 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. : 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.

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

Final Report - Page 188 of 238-
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.

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

Final Report - Page 189 of 238-
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.

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

Final Report - Page 190 of 238-
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.

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

Final Report - Page 191 of 238-
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.

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

Final Report - Page 192 of 238-
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 

Final Report - Page 193 of 238-
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 

Final Report - Page 194 of 238-
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.

Final Report - Page 195 of 238-
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 FINDINGS 

 NO NECROPSY OBSERVATIONS NOTED.

Final Report - Page 196 of 238-
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 —

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

Final Report - Page 197 of 238-
PATHOLOGY REPORT PAGE : 48/ 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 : 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—JAN—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

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

Final Report - Page 198 of 238-
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 

Final Report - Page 199 of 238-
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.

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

Final Report - Page 200 of 238-
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.

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

Final Report - Page 201 of 238-
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.

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

Final Report - Page 202 of 238-
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.

Final Report - Page 203 of 238-
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.

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

Final Report - Page 204 of 238-
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.

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

Final Report - Page 205 of 238-
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.

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

Final Report - Page 206 of 238-
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 —

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

Final Report - Page 207 of 238-
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 13—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

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

Final Report - Page 208 of 238-
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.

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

Final Report - Page 209 of 238-
PATHOLOGY REPORT PAGE : 60/ 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. : 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.

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

Final Report - Page 210 of 238-
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.

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

Final Report - Page 211 of 238-
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 

Final Report - Page 212 of 238-
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.

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

Final Report - Page 213 of 238-
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.

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

Final Report - Page 214 of 238-
PATHOLOGY REPORT PAGE : 65/ 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. : 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.

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

Final Report - Page 215 of 238-
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.

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

Final Report - Page 216 of 238-
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.

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

Final Report - Page 217 of 238-
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.

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

Final Report - Page 218 of 238-
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.

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

Final Report - Page 219 of 238-
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.

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

Final Report - Page 220 of 238-
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

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

Final Report - Page 221 of 238-
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.

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

Final Report - Page 222 of 238-
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.

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

Final Report - Page 223 of 238-
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 

Final Report - Page 224 of 238-
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,

 grade 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 

Final Report - Page 225 of 238-
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 

Final Report - Page 226 of 238-
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.

Final Report - Page 227 of 238-
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:

 —All 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.

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

Final Report - Page 228 of 238-
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.

Final Report - Page 229 of 238-
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.

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

Final Report - Page 230 of 238-
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.

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

Final Report - Page 231 of 238-
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.

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

Final Report - Page 232 of 238-
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.

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

Final Report - Page 233 of 238-
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.

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

Final Report - Page 234 of 238-
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 

Final Report - Page 235 of 238-
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.

Final Report - Page 236 of 238-
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

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

 CONT./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 

Final Report - Page 237 of 238-
PATHOLOGY REPORT PAGE : 88/ 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. : 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.

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

Final Report - Page 238 of 238-