## TEST FACILITY:

SPONSOR: FINAL REPORT

Test Facility Study No. 495257, Report No. 31326



# Alcohols, C18-22 Distn. Residues (CAS-No: 1160164-88-4): Developmental Toxicity Study in Rats

Charles River Tranent Edinburgh EH33 2NE UK

SASOL Germany GmbH Anckelmannsplatz 1 D-20537 Hamburg Germany

Page 1 of 71

## TABLE OF CONTENTS

TABLE OF CONTENTS 2

................................................................................................ LIST OF TABLES 4

.......................................................................................................... LIST OF APPENDICES 5
................................................................................................ 1. COMPLIANCE STATEMENT 6

.................................................................................. 2. QUALITY ASSURANCE STATEMENT 7
................................................................. 3. RESPONSIBLE PERSONNEL 8

.................................................................................. 4. SUMMARY 9

.................................................................................................................. 5. INTRODUCTION 10

........................................................................................................ 6. MATERIALS AND METHODS 11

................................................................................ 6.1. Test Item 11

................................................................................................................... 6.2. Vehicle Item 11

.............................................................................................................. 6.3. Preparation of Dosing Formulations 11

...................................................................... 6.4. Analysis of Dosing Formulations 11

............................................................................ 6.5. Location 12

..................................................................................................................... 6.6. Animals and Management 12

....................................................................................... 6.6.1. Animals 12

.................................................................................................................. 6.6.2. Animal Identification 12

............................................................................................ 6.6.3. Acclimatisation 13

...................................................................................................... 6.7. Housing and Husbandry 13

.......................................................................................... 6.7.1. Environmental Conditions 13

................................................................................... 6.7.2. Room Sanitation 13

.................................................................................................... 6.7.3. Caging 13

.................................................................................................................... 6.7.4. Cage Sanitation 13

..................................................................................................... 6.7.5. Environmental Enrichment 13

................................................................................. 6.7.6. Diet and Water 13

...................................................................................................... 6.8. Treatment Groups 14

.................................................................................................... Page 2 Test Facility Study No. 495257

## 6.8.1. Treatment Groups and Dose Levels 14

.................................................................... 6.8.2. Dose Levels 14

............................................................................................................. 6.8.3. Route and Means of Administration 14

................................................................... 6.9. Observations 15

............................................................................................................. 6.9.1. Clinical Observations 15

............................................................................................ 6.9.2. Body Weights 15

......................................................................................................... 6.9.3. Food Consumption 15

................................................................................................ 6.10. Terminal Studies 15

.................................................................................................... 6.10.1. Termination on Day 20 of Gestation 15

................................................................. 6.11. Statistical Analysis of Results 16

................................................................................ 7. RESULTS 17

..................................................................................................................... 7.1. Analysis of Dosing Formulations 17

............................................................................ 7.2. Clinical Observations and Necropsy Findings 17

...................................................... 7.3. Body Weights and Food Consumption Performance 17

........................................... 7.4. Pregnancy Performance and Foetal Weight 17

.......................................................... 7.5. Foetal Abnormalities and Variants 17

........................................................................ 8. DISCUSSION 18

............................................................................................................... Page 3 Test Facility Study No. 495257

## LIST OF TABLES

Table 1 : Group Incidence of Clinical Observations and Necropsy Findings 19

.................. Table 2 : Group Mean Body Weight (g) ± Standard Deviation (Pregnant Animals Only) 20

............................................................................................................................ ..... Table 3 : Group Mean Food Consumption (g) (Pregnant Animals Only) 21

........................ Table 4 : Pregnancy Performance and Foetal Weights 22

..................................................... Table 5 : Group Incidence of Major Foetal Abnormalities 23

............................................... Table 6 : Group Incidence of Minor Foetal Abnormalities and Variants 24

......................... Table 7 : Group Incidence of Skeletal Ossification Parameters 26

....................................... Page 4 Test Facility Study No. 495257

## LIST OF APPENDICES

Appendix 1 : Certificate of Analysis of Test Item 27

............................................................ Appendix 2 : GLP Certificate 28

........................................................................................... Appendix 3 : Analysis of Dosing Formulations 29

................................................................ Appendix 4 : Individual Clinical Observations and Necropsy Findings 31

.......................... Appendix 5 : Individual Body Weights Data (g) 35

.............................................................. Appendix 6 : Individual Food Consumption Data (g) 39

...................................................... Appendix 7 : Individual Pregnancy Data and Foetal Weights 43

.......................................... Appendix 8 : Individual Incidence of Foetal Abnormalities and Variants 47

....................... Appendix 9 : Litter Incidences of Number of Ribs 64

........................................................... Appendix 10 : Litter Incidences of Skeletal Ossification Parameters 67

.............................. Page 5 Test Facility Study No. 495257

### 1. COMPLIANCE STATEMENT

Test Facility Study No: 495257 

### Page 6 Test Facility Study No. 495257

Study Title: Alcohols, C18-22 Distn. Residues (CAS-No: 1160164-88-4): Developmental Toxicity Study in 

### Rats 

### 'I, the undersigned, hereby declare that this study was performed in accordance with the OECD Principles of Good Laboratory Practice as incorporated into the United Kingdom Statutory Instrument for GLP and as accepted by Regulatory Authorities throughout the European Community, United States of America (FDA and EPA) and Japan (MHLW, MAFF and METI).
The study was conducted according to the procedures herein described and this report represents a true and accurate record of the results obtained.'

lennifer Allan BSc Study Director Date

### Page 7 Test Facility Study No. 495257



## 2. QUALITY ASSURANCE STATEMENT

Test Facility Study No: 495257 Study Title: Alcohols, C18-22 Distn. Residues (CAS-No: 1160164-88-4): Developmental Toxicity Study in 

## Rats
The Charles River Quality Assurance Unit conducted a protocol review, protocol amendment review, study-based inspections and report audits on this study, as detailed below. Date(s) of QA Activity

04 February 2010 05 February 2010 08 February 2010 08 February 2010 22 February 2010 19 March 2010 14-17 June 2010 02 July 2010 Activity Date of Report to Management and Study Director

Protocol Review Dose Preparation Protocol Amendment 1 Review Dosing and Protocol Compliance Necropsy Visceral Examination Draft Report Audit Final Report Audit 04 February 2010 08 February 2010 08 February 2010 08 February 2010 22 February 2010 19 March 2010

17 June 2010 02 July 2010

Process-based inspections relevant to this study are scheduled once every quarter. The outcome of each inspection is reported to Management and, where relevant, the Study Director.

Facilities relevant to this study are included in the Charles River's annual facility inspection programme. The outcome of these inspections is reported to Management.

This report is considered to describe accurately and completely the procedures used in the study and the results obtained.

Chery 1 Rennie MSc Date Quality Assurance

## 3. RESPONSIBLE PERSONNEL Study Director: Jennifer Allan BSc

Report Compilation: Lisa Brady BSc

Animal Services Manager: Colin Reed MIAT RANtech

Senior Technician: Colin MacFarlane

Test Item Formulation and Analysis Under the Supervision of: Geoff Burns PhD BSc CBiol MSB

Head of Pathology: Alys Bradley BSc BVSc MAnimSc DipRCPath FRIPH MRCVS FRCPath

Statistical Analysis Under the Supervision of: Marion Thom MSc

Quality Assurance: Cheryl Rennie MSc

Report Peer Review: Adam W oolley MSc DABT FRCPath ERT ForthTox Limited Page 8 Test Facility Study No. 495257

## 4. SUMMARY Alcohols, C18-22, distn. residues, is a chemi cal being developed by the Sponsor. The test item was accepted for testing in rats to detect the effects on pregnant animals, when the material was administered duri ng the period of organogenesis. Mated female Sprague Dawley rats were rando mised into 3 test groups and a Control group (1% Carboxymethylcellulose with 0.2% Tween 80), each containing 24 animals. The animals were dosed by oral gavage over Days 6-19 inclusive of gestati on, where the day of detection of mating was designated Day 0. Dose le vels administered were 0, 100, 300 and 1000 mg/kg/day. Animals were regularly monitored during gesta tion for clinical signs of toxicity and for effects on body weight and food consumption performance. Animals were killed on Day 20 of gestation. The status of each implantation was recorded and the foetuses were weighed and examined for visceral and skeletal abnormalities, including the state of skeletal ossification. At levels up to 1000 mg/kg/ day Alcohols, C18-C22 distn. re sidues, there was no obvious effects of treatment on body weight gain, food consumption performance or clinical signs. The incidence of embryo-foetal deaths and mean foetal wei ghts did not suggest any obvious effect of treatment. The type and distribution of foetal abnorma lities and variants did not suggest any obvious effect of treatment. Under the conditions of this study, the maternal and foetal no observed effect level (NOEL) were both considered to be 1000 mg/kg/day. Page 9 Test Facility Study No. 495257

## 5. INTRODUCTION Alcohols, C18-22, distn. residues, is a chemi cal being developed by the Sponsor. The test item was accepted for testing in rats to detect the effects on pregnant animals, when the material was administered duri ng the period of organogenesis. This report describes the methods used and the results obtained in the study, which was carried out at Charles River, Tranent, Ed inburgh, EH33 2NE, UK, according to the following schedule: Study Initiation: 02 February 2010 Experimental Start Date: 05 February 2010 Experimental Completion Date: 30 March 2010 Study Completion Date: See Complia nce Statement page for date of Study Director’s signature The rat is a standard rodent species for the deve lopmental toxicity testing in animals required by regulatory authorities. The normal proce sses of gestation in rats and the specific background foetal pathology are well documented in this laboratory.

The oral route of administration was selected for this study as this is a likely route of exposure in man. This study is part of a programme of experiments designed to evaluate the toxicity of the test item to reproduction in experimental animals a nd was designed to be acceptable to EU, USA and Japanese regulatory authorities. The study design is based on OECD Guideline 414. All data generated and recorded during this stud y, will be stored in the Scientific Archive at Charles River, Preclinical Services Edinburgh for 2 years after issue of the final report. At the end of the 2 year period the Sponsor will be consulted regarding the disposal, transfer or continued storage of the raw data. The original signed copy of the final report w ill be stored indefinitely in the Scientific Archive at Charles River, Pr eclinical Services, Edinburgh. Page 10 Test Facility Study No. 495257

## 6. MATERIALS AND METHODS
6.1. Test Item A delivery of 900g of the test item (Alcohols, C18-22, Distn. Residues) was supplied by the Sponsor and received at Charles River on 11 Se ptember 2009. The test item was stored at ambient temperature in the dark at Charles River Dispensary.
Batch/Lot No: 03585/MA Description: Waxy/solid with yellowish colour Date Received: 11 September 2009 Purity / Content: 100% by definition Expiry: August 2013 Storage Conditions: Room temperature Supplier: Sasol Germany GmbH CAS No: 1160164-88-4 A reference sample of the test item has been retained in the study arch ive at Charles River, Edinburgh under the same storage conditions indicated above. A Certificate of Analysis for the ba tch used is presented in Appendix 1.
6.2. Vehicle Item The vehicle was 1% Carboxymethylcellulose (medium viscosity) with 0.2% Tween 80.
6.3. Preparation of Dosing Formulations The formulations were prepared at convenient intervals and were used within the 8 days stability period (established in Charles River St udy No. 425902) at ambient temperature in the dark. The test item was formulated by ad ding the appropriate vo lume of vehicle (1% Carboxymethylcellulose (medium viscosity) with 0.2% Tween 80) to required amounts of test item and mixed manually and magnetically stirred until a visibly homogeneous suspension was obtained. Formulations were magnetically stirred for at least 60 mins prior to and during both sampling and dosing.

Control animals received vehicle alone.

6.4. Analysis of Dosing Formulations Analysis of the dosing formulations was unde rtaken with regard to concentration and homogeneity. Samples (3 x 2 mL) were take n from formulations (including Control) prepared for use on Week 1 and 3 of treatment. Page 11 Test Facility Study No. 495257

## During Week 1, Group 4 formulation (100 mg/mL) was out with the acce ptance criteria of less than 10% coefficient of variation. Reanalys is of the formulation samples indicated that the results were within the acceptance criteria for this method. During Week 3, reanalysis of Group 3 and 4 fo rmulation (30 and 100 mg/mL, respectively) was performed as the determined concentra tion was greater than ±15% of the actual concentration. Reanalysis of the formulation samp les indicated that all results were within the acceptance criteria. Details of the formulation analysis results (from the re-analysed samples) are presented in Appendix 3. The analysis was undertaken by the Toxico logy Support Laboratory at Charles River, Edinburgh, using a method validated by Char les River (Charles River Study No. 425902, Method No. 2590). The results of that study showed the formulations were stable and homogeneous for 8 days at ambient dark.

6.5. Location The study was conducted within Block L, room 48, of the toxicology accommodation at Charles River, Edinburgh.

6.6. Animals and Management
6.6.1. Animals Ninety eight time mated female Sprague-Dawley ra ts (Crl:CD®(SD) strain), were received on 05 February 2010 from Charles River UK Limited, Margate, Kent, UK to provide 96 for the study. On despatch from supplier the animals weighed 196-265 g which was considered to be consistent with animals of appr oximately 9 weeks of age. The delivery consisted of 3 sub-batches, mated over 3 successive days. On arrival, one batch was on Day 1 of gestation, the s econd on Day 2 and the third on Da y 3 (day of detection of a vaginal plug or sperm in a vagi nal smear = Day 0 of gestation). No more than two females were mated by any one male.

6.6.2. Animal Identification Each animal received a subcutaneously implante d electronic identification chip identifying it individually within the st udy and which corresponded to that female’s number. Each animal was also given a cage card whic h was colour coded for treatment group and marked with the study number, animal number, cage number and treatment group. Page 12 Test Facility Study No. 495257

## 6.6.3. Acclimatisation
The animals were acclimatised in the Charles River animal room from arrival until commencement of treatment on Day 6 of gestation. All the animals were examined clinically on arri val for signs of abnormality or disease. No such signs were found and the animal s were accepted for use on the study.

6.7. Housing and Husbandry
6.7.1. Environmental Conditions There was automatic control of light cycle, te mperature and humidity in the animal room. Light hours were 0700-1900h. The target range s for temperature and humidity were 21 ± 2 ° C and 55 ± 15% respectively, with a minimu m of 15 air changes per hour. Daily monitoring indicated that temperature was outside the target range on one occasion (actual 18-22 ° C). Daily monitoring indicated that th e humidity remained within the target range throughout the duration of the study.

6.7.2. Room Sanitation Each day, floors were swept and then moppe d with a 0.5% solution of Tego 2000 (Th. Goldschmidt Limited, Ruislip, Middlesex, UK), an amphoteric biocide/cleanser. The room was washed with this solution at approximately weekly intervals.

6.7.3. Caging The animals were housed one per cage in solid-bottomed poly carbonate cages ( ca 48 x 37.5 x 25 cm); sterilised wood shavings were provided as bedding. A stainless steel food hopper and polycarbonate water bottle were provided for each cage. The cages were suspended on racks.

6.7.4. Cage Sanitation Cages, bedding and water bottles were changed at regular intervals, as appropriate.

6.7.5. Environmental Enrichment To provide environmental enrichment, wooden chewsticks were made available to the animals as appropriate.

6.7.6. Diet and Water
Food: Rat and Mouse Breeder Diet No. 3 (Expanded) SQC, supplied by Special Diets Services Ltd., Stepfield, Witham, E ssex, UK was available to the animals ad libitum . The diet was supplied with a batch analysis for nut ritive constituents and a range of significant Page 13 Test Facility Study No. 495257

## contaminants. The analytical certificate for a ba tch used during the study has been retained in the study archive. Water: The animals had access to domestic quality mains water ad libitum . The supply is analysed regularly for dissolved and suspended materials, in cluding a range of significant contaminants. The analytical certificate of a ty pical recent analysis has been retained in the study archive.

The food and water used were not considered to contain any additional substances in sufficient concentration to have any influence on the outcome of the study.

6.8. Treatment Groups Cages were allocated to treatment group by the use of randomly sequenced numbers, in such a way that each complete rack contained re presentatives from all treatment groups. It was ensured that females inseminated by the same male did not appear in the same group.

6.8.1. Treatment Groups and Dose Levels The treatment groups were constructed as follows:

Group Treatment (mg/kg/day) Animal Numbers
1 Control 0 1-24 2 Low dose 100 25-48 3 Intermediate dose 300 49-72 4 High dose 1000 73-96 

## Spare animals were number 97 and 98; these animal s were not considered to be part of the study as no replacement was necessary.

6.8.2. Dose Levels Dose levels were agreed with the Sponsor afte r evaluation of existing relevant toxicological data.

6.8.3. Route and Means of Administration The animals were dosed once daily by oral gavage at a dose volume of 10 mL per kg body weight, using a plastic gavage. The volume to be administered to each animal was determined on each day by the weight of the anim al as measured at the time of administration. Animals were dosed over Days 6-19 inclusive of gestation (Day 0 = day of detection of mating). On Day 19 of gestation (23 February 2010) Animal 69 (Group 3) bit through the gavage during the dosing procedure; this an imal did not receive its full dose. Page 14 Test Facility Study No. 495257

## On Day 15 of gestation (18 Fe bruary 2010) Animal 39 (Group 2) refluxed a large amount of test item and therefore did not receive its full dose. These minor deviations from the dosing regimen were considered not to have affected the overall outcome or integrity of the study.

6.9. Observations
6.9.1. Clinical Observations All the animals were checked for viability early in the morning and again as late as possible in each day, and for reaction to treatment duri ng each day. The nature, onset, duration and intensity of signs were recorded. In addition to this, the animals were given a detailed clinical examination, once prior to the start of dosing and daily from commencement of dosing. Although th ese detailed clinical observations were not included in the study protocol, the Study Director authorised these examinations and the examinations were with in the spirit and inte nt of the protocol.

6.9.2. Body Weights Body weights were recorded on Days 4 and 6-20 of gestation. For brevity, only data for Days 4, 6, 9, 13, 17 and 20 are presented in this report.

6.9.3. Food Consumption The weight of food consumed by each animal was recorded daily, commencing on Day 4 of gestation (weighed quantity first offered on Day 3).

6.10. Terminal Studies Animals were killed on Day 20 of gestati on by exposure to carbon dioxide followed by exsanguination. Foetuses were killed by chilling.

6.10.1. Termination on Day 20 of Gestation The adult animals were subjected to a gross necropsy, in which the thoracic and abdominal contents were examined macroscopically; an y findings were recorded and representative samples of abnormal tissues were taken and fixed in neutral buffered 10% formalin, as appropriate. The maternal carcass was then discarded. The reproductive tract was dissect ed out and weighed intact, th en opened and the contents examined. The number of corpora lutea gravid itatis in each ovary and the number and position of all implantation sites in the uterus we re recorded. Each implant was classified as being live, a dead foetus (dead full term foet us that showed no evidence of maceration), or late embryonic death (macerated tissue identifiabl e as an embryo or foetus, with recognisable Page 15 Test Facility Study No. 495257

## external features such as tail, limbs, mouth and nares present; at tached to distinct, identifiable placenta), or an early embryonic d eath (discrete, formless, discol oured tissue mass attached to the internal uterine wall; ma y be of varying size). Each foetus was examined for externally visi ble abnormalities, individually identified within the litter, and the weights of the live foetuses in the litter were recorded. The foetuses were sexed during subsequent dissection procedures. Half of the viable foetuses from each uterus were fixed in methylated ethyl alcohol , the remaining half in Bouin’s fluid. Following initial fixation, the foetuses fixed in alcohol were examined by open dissection for abnormalities of the thoracic and abdominal viscera. These viscera were then discarded. The eviscerated carcasses were macerated in pota ssium hydroxide, the skeletons stained with Alizarin Red S, then the foetuses cleared with aqueous glycerol solutions. These preparations were examined for the presence of skeletal abnormalities and for the extent of ossification.

The foetuses fixed in Bouin’s fluid were exam ined for soft tissue abnormalities by a modified freehand sectioning technique deri ved from the Wilson technique.

6.11. Statistical Analysis of Results Statistical analysis was performed on maternal body weight gain over Days 6-20 of gestation and on mean foetal weight. Maternal body weight gain was subjected to analysis of variance and foetal weight was analysed by Kruskal-Wallis test. These tests were 2-sided and performed at the 5% significant level using in-house software. Pairwise comparisons were only performed against the Control group. For the other parameters, no formal statistical analyses were considered necessary; interpretation of the data being by inspection of the individual and group values. Page 16 Test Facility Study No. 495257

## 7. RESULTS
7.1. Analysis of Dosing Fo rmulations (Appendix 3) The analysis of dosing formula tions indicated acceptable accur acy of formulation (±13.7% of nominal concentration). The low coefficients of variation (<5.5%) indicated that the formulations were homogeneous. One Group 1 sample result from analysis for fo rmulations prepared for use on Week 3 of dosing was excluded due to suspected contam ination during the analytical process.

7.2. Clinical Observations and Necrops y Findings (Table 1, Appendix 4)
There were no clinical observati ons or necropsy findings that were considered to be related to treatment with Alcohols, C18-C22 distn. residues.
7.3. Body Weights and Food Consumption Performance (Tables 2-3, Appendices 5-6) Group mean body weight gains and food consumpti on performance in all groups were similar to Control throughout the treatment period.
7.4. Pregnancy Performance and Foetal Weight (Table 4, Appendix 7) Pregnancy performance was similar in all groups . At 1000 mg/kg/day, the slight increase in early embryonic deaths was due to Animal 75 with 6 embryonic deaths. In the absence of any similar deaths in this group, this incide nce was considered to be incidental.
There was no obvious effect of treatment at any dose on mean foetal weights compared to Control (P>0.05).

7.5. Foetal Abnormalities and Variants (Tables 5-7, Appendices 8-10) The types and distribution of the major and minor foetal abnormalities did not indicate any association with treatment. Considering the ossification parameters together , there was no obvious effect on the state of skeletal ossification. Page 17 Test Facility Study No. 495257

## 8. DISCUSSION At levels up to 1000 mg/kg/ day Alcohols, C18-C22 distn. re sidues, there was no obvious effects of treatment on body weight gain, food consumption performance or clinical signs. The incidence of embryo-foetal deaths and mean foetal wei ghts did not suggest any obvious effect of treatment. The type and distribution of foetal abnorma lities and variants did not suggest any obvious effect of treatment. It was concluded that, under the conditions of this study, Al cohols C18-C22 distn. residues had no obvious effects on pregnancy when ad ministered to rats during the period of organogenesis; there was no evidence of embr yotoxicity or foetal abnormalities. The maternal and foetal no observed effect le vel (NOEL) were both considered to be 1000 mg/kg/day. Page 18 Test Facility Study No. 495257

## Table Group Incidence of Clinical Observations and Necropsy Findings

Group/Dose Level (mg/kg/day) 1 2 3 4 Observation/Finding (0) (100) (300) (1000) Staining on fur, head / dorsal neck / muzzle / limb(s) 6 5 1 0 Flaky skin / scab(s) on tail 1 0 1 0 Sparse hair 0 1 5 0 Lid(s) encrusted 0 1 0 0 Tail, missing at tip 0 0 1 0 Scab(s) on dorsal neck 0 0 0 1 Enlarged spleen 0 0 0 1 Total number of females 24 24 24 24 

## 1 Page 19 Test Facility Study No. 495257

## Table Group Mean Body Weight (g) ± Standard Deviation (P regnant Animals Only)

Group/Dose Level (mg/kg/day) 1 2 3 4 Day of Gestation (0) (100) (300) (1000) 4 242 ± 15 250 ± 15 248 ± 18 248 ± 18
6 255 ± 16 263 ± 16 262 ± 19 258 ± 18

9 270 ± 17 279 ± 20 278 ± 20 275 ± 19

13 297 ± 21 306 ± 21 305 ± 22 301 ± 20

17 341 ± 26 347 ± 27 343 ± 30 342 ± 24

20 388 ± 30 393 ± 35 390 ± 37 389 ± 29 Gain Days 6-20 † 133 ± 17 130 ± 23 127 ± 23 131 ± 15

% of Control - 97 96 98

† = Statistically analysed; no statis tical significance achieved (P>0.05) 

## 2 Page 20 Test Facility Study No. 495257

## Table Group Mean Food Consumption (g) (Pregnant Animals Only)

Group/Dose Level (mg/kg/day) 1 2 3 4 Day of Gestation (0) (100) (300) (1000) 4 25 26 25 26
5 26 26 26 27
6 26 26 27 26
7 26 26 26 27
8 26 27 27 26
9 26 25 27 28
10 25 27 27 27
11 26 27 27 27
12 27 29 28 28
13 28 29 28 29
14 28 29 27 28
15 29 28 29 29
16 31 30 30 30
17 32 31 30 30
18 32 31 32 31
19 31 31 30 30
20 29 28 28 27 Days 7-20 396 398 396 397 

## 3 Page 21 Test Facility Study No. 495257

## Table Pregnancy Performance and Foetal Weights

Group/Dose Level (mg/kg/day) 1 (0) 2 (100) 3 (300) 4 (1000) N umber of animals mate d 24 24 24 24
N umber pregnant 21 23 23 23
N umber of premature decedents 0 0 0 0
N umber of decedents pregnant 0 0 0 0
N umber pregnant at Day 20 necropsy 21 23 23 23 Pregnancy frequency as % 88 96 96 96 Total corpora lutea graviditatis 293 331 304 320 Total number of implants 280 300 294 313 Pre-implantation loss as % 4 9 3 2 Total live implants (%) 270 (96) 292 (97) 280 (95) 296 (95) Total dead implants (%) 10 (4) 8 (3) 14 (5) 17 (5) Total early embryonic deaths (%) 9 (3) 8 (3) 14 (5) 16 (5) Total late embryonic deaths (%) 1 (0.4) 0 0 1 (0.3) Total dead foetuses (%) 0 0 0 0 Mean corpora lutea graviditatis 14.0 ± 2.0 14.4 ± 2.4 13.2 ± 3.0 13.9 ± 2.0 Mean implants 13.3 ± 2.7 13.0 ± 3.6 12.8 ± 3.2 13.6 ± 2.4 Mean live implants 12.9 ± 2.6 12.7 ± 3.7 12.2 ± 3.5 12.9 ± 3.1 Mean dead implants 0.5 ± 0.6 0.3 ± 0.6 0.6 ± 0.9 0.7 ± 1.4 Mean early embryonic deaths 0.4 ± 0.5 0.3 ± 0.6 0.6 ± 0.9 0.7 ± 1.3 Mean late embryonic deaths 0.05 ± 0.2 0 0 0.04 ± 0.2
Mean dead foetuses 0 0 0 0 Total live male foetuses (%) 136 (50) 136 (47) 142 (51) 144 (49) Total live female foetuses (%) 134 (50) 156 (53) 138 (49) 152 (51) Live foetal sex ratio (M:F ) 1:0.99 1:1.15 1:0.97 1:1.06 Mean total uterus weight (g) 80 ± 15 80 ± 21 81 ± 13 82 ± 17 Mean litter mean foetal weight (g) † 3.87 ± 0.28 3.93 ± 0.30 3.95 ± 0.29 3.96 ± 0.16

Means are given ± Standard Deviation † = Statistically analysed; no statistical significance achieved (P>0.05) 

## 4 Page 22 Test Facility Study No. 495257

## Table Group Incidence of Major Foetal Abnormalities

Group/Dose Level (mg/kg/day)

1 2 3 4 (0) (100) (300) (1000) Abnormality

Incidence of Foetuses (Litters) Lower jaw shortened. Mandi bles shortened and fused with incisor sockets absent, nasal bones fused, incisive bones fused, palatine bone and maxillary processes fused, misshapen and incompletely ossified. Basisphenoid misshapen and incompletely ossified with pterygoid processes absent. Tympanic rings medially displaced. 0 0 1(1) 0

Partially split sternum 0 1(1) 0 0
Rib(s) kinked 1(1) 0 0 0

Thoracic and abdominal s itus inversus 0 1(1) 0 0
Number with major abnormality 1(1) 2(2) 1(1) 0 Total number examined 270(21) 292(23) 280(22) 296(23) 

## 5 Page 23 Test Facility Study No. 495257

## Table Group Incidence of Minor Foetal Abnormalities and Variants

Group/Dose Level (mg/kg/day)

1 2 3 4 (0) (100) (300) (1000) Abnormality/Variant

Incidence of Foetuses (Litters) Visceral Subcutaneous haemorrhage: Head 2(1) 0 2(2) 5(5) Trunk 1(1) 0 1(1) 0 Limbs/Tail 0 1(1) 0 0 Haemorrhage dorsal fat pad region 0 2(2) 0 0 Thyroid reduced (in size) 0 0 1(1) 0 Cervical remnant of thymus 1(1) 2(2) 5(4) 5(4) Small interventricular septal defect 0 0 0 1(1) Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe 4(3) 6(6) 1(1) 2(2)
Tendinous region of diaphragm locally thinned with protrusion of median liver lobe 0 2(1) 2(2) 2(1)
Additional liver lobe within median cleft 16(9) 21(12) 18(13) 17(13) Hepatic haemorrhage 0 0 1(1) 2(2) Intra-abdominal haemorrhage 0 0 1(1) 0 Kidney minimal caudal disp lacement 0 1(1) 1(1) 0 Renal pelvis dilated 2(2) 7(4) 0 1(1) Ureter(s) dilated 2(2) 2(2) 0 1(1) Testis(es) medially disp laced 1(1) 1(1) 0 2(2) Testis(es) not fully descended to pe lvic position 2(2) 1(1) 1(1) 1(1) Umbilical artery left-sided 0 1(1) 1(1) 0 Number with minor abnormality/variant 26(10) 41(19) 32(18) 37(18) Number examined by Wilson sectioning 136(21) 147(23) 141(22) 146(23) Total number examined 270(21) 292(23) 280(22) 296(23) 

## 6 Page 24 Test Facility Study No. 495257

## Table (continued) Group Incidence of Minor Foetal Abnormalities and Variants

Group/Dose Level (mg/kg/day)

1 2 3 4 (0) (100) (300) (1000) Parameter

Incidence of Foetuses (Litters) Skeletal Cranial bones unossified/incompletely ossified area(s) 1(1) 1(1) 0 1(1) Scapula misshapen, sternebra flattened 0 0 0 1(1) Cervical rib(s) 1(1) 1(1) 2(1) 0 Rib(s) connected, thoracic vertebral arches fused, thoracic vertebra hemicentric 0 1(1) 0 0
Rib(s) minimally kinked 0 0 0 1(1) Rib(s) incompletely ossified 1(1) 2(2) 0 0 Additional ossified area arising fr om sternebra 1(1) 3(3) 0 3(3) Rib(s) costal cartilages asymmetrically aligned 2(2) 5(5) 2(2) 2(2) Unilateral/bilateral rib 7 costal cartilage not attached to sternum 2(2) 4(3) 4(2) 1(1) Pelvic girdle cranial displacement: Unilateral 0 0 1(1) 1(1) Bilateral 0 0 1(1) 0 Pelvic girdle caudal displacement: Unilateral 0 0 0 1(1) Bilateral 1(1) 0 0 0 Number with minor abnormality/variant 9(6) 14(10) 5(3) 11(8) Total number examined skeletally 134(21) 145(23) 139(22) 150(23)
Number of ribs
13 th vestigial rib(s) 3(2) 1(1) 2(1) 1(1)

13 th reduced rib(s) 0 3(3) 1(1) 0 13 complete ribs 123(21) 140(23) 132(22) 141(23) Vestigial supernumerary rib(s) on 1st lu mbar vertebra 7(5) 1(1) 4(4) 8(6) Complete supernumerary rib(s) on 14 th thoracic vertebra 1(1) 0 0 0 

## 6 Page 25 Test Facility Study No. 495257

## Table Group Incidence of Skeletal Ossification Parameters

Group/Dose Level (mg/kg/day)

1 2 3 4 (0) (100) (300) (1000) Abnormality

Incidence of Foetuses (Litters) Incomplete ossification affecting

> 4 skull bones 5(4) 11(6) 7(5) 3(2)

< 3 skull bones 31(17) 41(14) 28(15) 34(16) Cervical vertebral arch(es) 6(6) 4(2) 0 1(1) Thoracic centrum(a) 14(9) 7(6) 9(8) 3(3) Lumbar vertebral arch(es) 2(2) 0 0 0 Pubis(es) 9(7) 8(5) 1(1) 6(4) Ischium(a) 3(3) 2(1) 0 0 Sacral vertebral arch(es) 29(10) 29(9) 12(8) 15(9)
2 nd and/or 4 th metacarpal(s) 6(5) 2(2) 1(1) 2(2)

Unossified
5 th metacarpal(s) 52(16) 48(13) 28(14) 40(14)

Ossified Anterior arch of atlas ossified 31(13) 41(18) 40(15) 40(17) >2 cervical vertebral centra ossified 5(3) 6(3) 4(4) 11(5)
One or more sacrocaudal vertebra with connection between centrum and arch(es) 31(10) 47(15) 56(18) 62(19)
Phalangeal elements ossified 5(5) 6(4) 17(9) 13(8)
Mean number of caudal vertebral centra 4.1 4.2 4.2 4.2

Number of sternebrae retarded: 0 64(20) 81(22) 81(20) 89(23) 1 45(17) 46(21) 39(20) 49(17) 2 22(11) 17(9) 17(9) 11(8) >2 3(2) 1(1) 2(1) 1(1) Total number examined skeletally 134(21) 145(23) 139(22) 150(23) 

## 7 Page 26 Test Facility Study No. 495257

## Appendix Certificate of Analys is of Test Item 1 Page 27 Test Facility Study No. 495257



## saSOL

Brunstll' e ttel, 9/09/2009

CERTIFICATE 

### o , ANALYSIS

Product: LOt No.' Manuf ac turi n g dat e : Expi ry date,

Hydroxyl 

### . Ii' UDb

.. r Beter 00. Acid No. W.ter Iodine No.

Sasol Germany GrnbH P.O. BOX 116 0 0

- 25534 Brunsbuettel Aleohots, C18-22. distn. Residues OJ5 S5/KA 25/ 08/2009 09/2013

[1119' 1t0H/gI 

# ". ["g " oll/g] 41,17 [mg ItOH/g] 0.09 (wt.') 0,02 h'g 1/100'"9'1 S.H (S9BIRN2)

Phone: 049 (0)4952/392

· 0 Fax: 0 49 (0)4952/3285 Best regards Works insp e ctor M. Sprung

,- "" ", ., ',< .,, "

.....



## -" ' ' ''' : ''. , ,'_"" c , ' ""

..... ,-. ' --. 

## ,.

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## Appendix GLP Certificate 2 Page 28 Test Facility Study No. 495257



# ,

D

H) Department

# ~ of Heallh

THE DEPARTMENT OF HEALTH OF THE GOVERNMENT OF THE UNITED KINGDOM
GOOD LABORATORY PRACTICE

STATEMENT OF CQi\ IPLIAN CE l"'rl ACCORDANCE WITH DiRE C TIVE:**20U~ EC** 

TEST FACILITY



### Charles River Laborato ri es Tranent Edinburgh 

### EH332NE

DATE O F [ NS I'I- :CT ION


### 20 

### to 23 April 2010 ITSTTYI' E

Analytical Chemistry Clinical Patho l ogy 

### Biologica l Safety Tests Ecosystems Environmenta l Fate Environmental Toxicity Mutagenicity PhysfChem

. Testing Toxicology Viro l ogy



### A general in s p ectio n for compliance wi t h the Principles of Good La bo r atory Pra ct i ce**wa~** ca rr i ed OUl at t h e above t es t f ac i l i ty as p an of t h e U K GLPC o mplian ce Programm e.


### At the tim e of inspectio n n o dev i a t ions were found o f s u fficie nt m ag nitu de [0 aff ec t th e 

### Vlllidity of**non lini** **n** 1**<;tu r1i** **c~** p erformed a t the se f aci liti es.

Dr

. Andrew,1. G ra : r Head. UK GLP Monitor i ng Authority

## Appendix Analysis of Dosing Formulations

Formulations prepared for use on Week 1 of dosing

Dose Group Nominal Concentration

(mg/mL) Found Concentration

(mg/mL) Mean Found (mg/mL) Coefficient of Variation (%) % Difference from Nominal

1 0 0; 0; 0 0 - -

2 10 10.7, 10.0, 10.8 10.5 4.2 +5.0

3 30 31.4, 77.1 a , 31.4 31.4 - +4.7

4 b 100 101, 102, 102 102 0.6 +2.0

a = Sample not included due to suspect analytical preparation error b = Results reported from re-analysis of suspected analytical error. 

## 3 Page 29 Test Facility Study No. 495257

## Appendix (continued) Analysis of Dosing Formulations

Formulations prepared for use during Week 3 of dosing

Dose Group Nominal Concentration

(mg/mL) Found Concentration

(mg/mL) Mean Found (mg/mL) Coefficient of Variation (%) % Difference from Nominal

1 0 0, 0, 0.0206 a 0 - -

2 10 9.19, 10.2, 9.95 9.78 5.4 -2.2

3 b 30 33.7, 33.9, 34.6 34.1 1.4 +13.7

4 b 100 106, 105, 104 105 1.0 +5.0

a = Sample excluded due to suspected contamination of analytical sample. b = Results reported from re-analysis of suspected analytical error. 

## 3 Page 30 Test Facility Study No. 495257

## Appendix Individual Clinical Observations and Necropsy Findings

Group/ Dose Level (mg/kg/day) Animal Number Clinical Observations Day(s) of Gestation Recorded Necropsy Findings

Staining on fur, head 3 1 Flaky skin on tail 3, 6-20 Tail, flaky skin
Staining on fur, head 3 2 NAD 6-20 NAD
3 NAD 3, 6-20 NAD Staining on fur, dorsal neck 6-19 4 NAD 3, 20 NAD
5 NAD 3, 6-20 NAD 6 NAD 3, 6-20 NAD Staining on fur, dorsal neck 17-20 7 NAD 3, 6-16 Skin staining, dorsal neck, brown 8 NAD 3, 6-20 NAD 9 NAD 2, 6-20 NAD Staining on fur, dorsal neck 15-20 10 NAD 2, 6-14 NAD
11 NAD 2, 6-20 NAD 12 NAD 2, 6-20 NAD 13 NAD 2, 6-20 NAD 14 NAD 2, 6-20 NAD 15 NAD 2, 6-20 NAD 16 NAD 2, 6-20 NAD 17 NAD 1, 6-20 NAD 18 NAD 1, 6-20 NAD 19 NAD 1, 6-20 NAD 20 NAD 1, 6-20 NAD Staining on fur, head 1, 6-12 21 NAD 13-20 NAD
22 NAD 1, 6-20 NAD 23 NAD 1, 6-20 NAD 1 (0)

24 NAD 1, 6-20 NAD NAD = No Abnormality Detected 

## 4 Page 31 Test Facility Study No. 495257

## Appendix (continued) Individual Clinical Observations and Necropsy Findings

Group/ Dose Level (mg/kg/day) Animal Number Clinical Observations Day(s) of Gestation Recorded Necropsy Findings

Staining on fur, head 3, 6-8 25 NAD 9-20 NAD
26 NAD 3, 6-20 NAD 27 NAD 3, 6-20 NAD Staining on fur, muzzle 17 28 NAD 3, 6-16, 18-20 NAD

29 NAD 3, 6-20 NAD 30 NAD 3, 6-20 NAD 31 NAD 3, 6-20 NAD Two area(s) of sparse hair 17-20 32 NAD 3, 6-16 Hair loss, ventral thorax and abdomen 33 NAD 2, 6-20 NAD 34 NAD 2, 6-20 NAD 35 NAD 2, 6-20 NAD 36 NAD 2, 6-20 NAD 37 NAD 2, 6-20 NAD 38 NAD 2, 6-20 NAD 39 NAD 2, 6-20 NAD 40 NAD 2, 6-20 NAD Lid(s) encrusted in, right eye 7-12 Staining on fur, dorsal neck 18-20 41 NAD 1, 6, 13-17 NAD

Staining on fur, dorsal neck 13-20 42 NAD 1, 6-12 Staining on fur, dorsal neck
Staining on fur, limb(s) 15 43 NAD 1, 6-14, 16-20 NAD

44 NAD 1, 6-20 NAD 45 NAD 1, 6-20 NAD 46 NAD 1, 6-20 NAD 47 NAD 1, 6-20 NAD 2 (100)

48 NAD 1, 6-20 NAD NAD = No Abnormality Detected 

## 4 Page 32 Test Facility Study No. 495257

## Appendix (continued) Individual Clinical Observations and Necropsy Findings

Group/ Dose Level (mg/kg/day) Animal Number Clinical Observations Day(s) of Gestation Recorded Necropsy Findings

Two area(s) of sparse hair 16-20 49 NAD 3, 6-15 NAD
50 NAD 3, 6-20 NAD 51 NAD 3, 6-20 NAD Two area(s) of sparse hair 16-20 52 NAD 3, 6-15 NAD
Two area(s) of sparse hair 16-20 53 NAD 3, 6-15 Hair loss, ventral thorax and abdomen Tail, missing at tip 10-20 Two scab(s), on tail 10-20 54 NAD 3, 6-9 NAD

55 NAD 3, 6-20 NAD 56 NAD 3, 6-20 NAD Two area(s) of sparse hair 15-20 57 NAD 2, 6-14 NAD
58 NAD 2, 6-20 NAD Two area(s) of sparse hair 15-20 59 NAD 2, 6-14 NAD
60 NAD 2, 6-20 NAD 61 NAD 2, 6-20 NAD 62 NAD 2, 6-20 NAD 63 NAD 2, 6-20 NAD 64 NAD 2, 6-20 NAD 65 NAD 1, 6-20 NAD 66 NAD 1, 6-20 NAD 67 NAD 1, 6-20 NAD 68 NAD 1, 6-20 NAD 69 NAD 1, 6-20 NAD 70 NAD 1, 6-20 NAD 71 NAD 1, 6-20 NAD Staining on fur, head 1, 6-10 3 (300)

72 NAD 11-20 NAD NAD = No Abnormality Detected 

## 4 Page 33 Test Facility Study No. 495257

## Appendix (continued) Individual Clinical Observations and Necropsy Findings

Group/ Dose Level (mg/kg/day) Animal Number Clinical Observations Day(s) of Gestation Recorded Necropsy Findings

73 NAD 3, 6-20 NAD 74 NAD 3, 6-20 NAD 75 NAD 3, 6-20 NAD 76 NAD 3, 6-20 NAD 77 NAD 3, 6-20 NAD 78 NAD 3, 6-20 NAD 79 NAD 3, 6-20 NAD 80 NAD 3, 6-20 NAD Scab(s) on dorsal neck 7-14 81 NAD 2, 6, 15-20 NAD
82 NAD 2, 6-20 NAD 83 NAD 2, 6-20 NAD 84 NAD 2, 6-20 NAD 85 NAD 2, 6-20 NAD 86 NAD 2, 6-20 NAD 87 NAD 2, 6-20 NAD 88 NAD 2, 6-20 NAD 89 NAD 1, 6-20 NAD 90 NAD 1, 6-20 NAD 91 NAD 1, 6-20 NAD 92 NAD 1, 6-20 Spleen enlarged 93 NAD 1, 6-20 NAD 94 NAD 1, 6-20 NAD 95 NAD 1, 6-20 NAD 4 (1000)

96 NAD 1, 6-20 NAD NAD = No Abnormality Detected 

## 4 Page 34 Test Facility Study No. 495257

## Appendix Individual Body Weights Data (g)

Group 1, Control: 0 mg/kg/day
Day of Gestation Animal Number 4 6 9 13 17 20
1 245 247 261 278 317 368
2 245 253 273 297 345 388
3 247 259 277 308 355 407
4 252 260 279 309 356 422 (5) 266 275 286 306 299 293 (6) 214 222 222 231 233 243
7 214 226 236 263 295 339 (8) 240 246 254 264 265 274
9 243 249 264 281 325 367
10 225 236 251 279 312 358
11 243 254 275 309 359 409
12 258 270 281 312 371 426
13 261 278 294 328 369 416
14 226 236 250 280 313 363
15 273 287 301 336 387 442
16 227 238 250 278 315 361
17 237 252 271 290 330 371
18 230 241 253 270 309 347
19 242 260 275 300 350 388
20 254 270 289 318 367 425
21 243 265 283 307 351 383
22 263 279 297 324 378 425
23 231 246 264 286 327 378
24 224 245 256 277 326 362
( ) = Not pregnant 

## 5 Page 35 Test Facility Study No. 495257

## Appendix (continued) Individual Body Weights Data (g)

Group 2, Low dose: 100 mg/kg/day
Day of Gestation Animal Number 4 6 9 13 17 20 25 271 280 296 327 376 424 26 260 275 292 317 342 386 27 257 262 280 303 326 359 28 245 256 273 303 340 401 29 256 266 279 310 347 391 30 261 270 289 318 368 429 (31) 234 249 263 276 291 298 32 243 253 263 298 331 379 33 230 243 257 282 307 333 34 251 265 275 307 352 402 35 258 272 290 326 377 430 36 222 234 247 275 311 347 37 261 268 283 314 362 405 38 246 258 272 303 351 399 39 261 281 294 324 369 417 40 231 240 255 270 310 347 41 216 226 229 258 292 346 42 261 275 303 326 373 425 43 270 291 315 346 391 451 44 258 274 289 312 356 402 45 264 280 304 325 376 431 46 247 262 278 302 346 381 47 237 252 265 285 308 330 48 249 264 282 313 363 413
( ) = Not pregnant 

## 5 Page 36 Test Facility Study No. 495257

## Appendix (continued) Individual Body Weights Data (g)

Group 3, Intermediate dose: 300 mg/kg/day
Day of Gestation Animal Number 4 6 9 13 17 20 49 234 244 256 274 277 289 50 256 275 292 320 354 410 51 206 219 228 250 273 308 52 214 226 240 268 302 352 53 271 284 298 319 361 406 54 273 284 301 337 372 429 55 253 273 287 315 356 411 56 260 280 293 318 351 401 57 245 255 277 297 335 387 58 235 245 257 284 322 361 59 268 277 287 316 362 404 60 279 293 305 341 397 438 61 229 243 257 285 318 352 62 251 264 275 308 344 394 63 247 253 267 293 335 384 64 252 262 277 303 344 389 65 240 258 277 303 354 408 66 247 265 289 309 352 404 67 239 253 268 299 343 394 68 249 266 286 316 358 403 (69) 220 223 225 228 233 244 70 240 257 276 304 348 393 71 249 270 288 312 352 404 72 269 288 306 334 386 443
( ) = Not pregnant 

## 5 Page 37 Test Facility Study No. 495257

## Appendix (continued) Individual Body Weights Data (g)

Group 4, High dose: 1000 mg/kg/day
Day of Gestation Animal Number 4 6 9 13 17 20 73 240 251 265 296 340 401 74 235 247 261 284 321 355 75 246 258 279 307 344 386 76 255 267 284 314 362 423 77 278 283 294 321 363 423 78 272 281 292 318 357 414 79 251 257 282 309 350 402 80 236 242 258 275 306 348 81 225 233 250 277 319 363 82 245 258 278 306 351 403 83 234 248 257 283 318 366 84 276 286 297 332 372 428 85 219 231 242 271 307 346 86 235 240 265 287 328 377 87 255 263 278 303 342 381 88 256 268 290 321 359 412 89 258 271 288 318 368 419 90 262 272 296 313 360 404 91 223 235 249 274 315 355 92 226 239 256 276 310 348 93 281 298 317 342 397 442 94 248 260 276 298 334 368 95 238 254 275 295 338 382 (96) 235 252 267 275 277 284
( ) = Not pregnant 

## 5 Page 38 Test Facility Study No. 495257

## Appendix Individual Food Consumption Data (g)

Group 1, Control: 0 mg/kg/day
Day of Gestation Animal Number 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1 22 30 23 26 29 27 24 15 25 29 28 28 28 30 32 31 28 2 25 27 24 25 26 28 26 26 26 24 26 29 32 31 30 31 28 3 27 26 30 30 28 28 29 28 31 28 28 29 31 31 32 31 26 4 26 24 26 25 25 26 25 27 30 30 30 31 33 34 39 34 37 (5) 27 23 26 25 24 33 27 27 26 27 23 18 22 26 18 17 21 (6) 18 23 23 23 20 17 21 22 20 18 21 20 19 17 21 20 19 7 21 23 22 21 22 22 23 23 23 25 25 26 28 25 28 28 26 (8) 28 26 26 23 23 23 25 21 25 23 26 21 22 23 24 19 21 9 18 24 18 23 22 24 20 24 26 22 25 27 27 29 29 30 25 10 24 24 24 24 27 19 20 24 23 23 25 23 29 22 30 32 25 11 20 27 23 27 26 29 24 27 29 30 29 33 34 32 31 33 31 12 30 28 27 28 27 26 27 27 28 30 26 31 34 41 33 34 32 13 26 28 28 29 29 27 32 33 32 32 36 34 35 35 38 32 34 14 26 28 22 25 23 26 21 25 24 27 22 26 30 28 29 28 28 15 29 31 32 29 28 36 28 31 34 32 33 37 34 35 39 34 32 16 24 26 25 26 24 26 24 24 26 28 26 26 26 29 31 31 27 17 28 27 25 29 26 27 28 27 26 26 29 28 31 31 31 31 30 18 24 21 24 22 23 21 21 22 21 23 22 27 25 31 23 26 25 19 25 24 27 25 23 25 25 25 26 28 24 27 30 33 27 29 25 20 29 25 27 28 26 28 26 29 29 31 30 31 30 35 30 32 30 21 27 28 28 27 28 30 31 36 32 34 33 34 39 37 37 34 31 22 31 24 29 28 28 30 30 29 32 32 35 32 37 39 36 36 33 23 25 24 26 26 24 25 23 26 28 23 31 20 28 29 29 29 26 24 23 25 26 23 25 23 23 26 25 27 24 29 28 34 32 24 24
( ) = Not pregnant 

## 6 Page 39 Test Facility Study No. 495257

## Appendix (continued) Individual Food Consumption Data (g)

Group 2, Low dose: 100 mg/kg/day
Day of Gestation Animal Number 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 25 30 24 30 28 29 28 30 28 32 31 32 29 34 34 31 31 29 26 23 29 28 28 28 27 28 25 30 27 28 27 29 29 29 34 28 27 24 24 21 26 27 26 27 26 29 29 30 27 32 28 31 29 30 28 18 23 24 23 26 24 25 26 27 26 24 24 28 27 28 31 26 29 23 28 28 23 27 27 27 26 31 30 31 26 33 31 31 28 29 30 25 25 27 26 26 28 30 26 30 30 29 33 31 30 33 33 28 (31) 22 25 28 28 27 26 25 26 24 23 26 22 24 26 21 30 22 32 25 24 25 25 23 23 26 24 31 30 28 28 29 31 29 31 25 33 24 25 24 24 40 10 26 27 25 28 30 26 28 27 32 30 27 34 25 30 27 27 27 23 28 28 28 29 28 29 29 34 29 33 27 35 24 27 26 27 26 26 28 27 32 33 33 35 36 37 38 36 32 36 22 23 21 24 21 22 24 25 24 26 23 26 25 27 26 29 24 37 25 24 23 27 28 23 28 29 28 30 30 28 28 35 30 32 26 38 25 26 26 24 27 26 27 27 30 27 28 30 30 33 33 31 24 39 28 35 27 27 31 27 27 31 34 28 31 30 29 31 32 32 28 40 28 20 24 28 22 28 22 22 21 25 25 24 28 27 27 26 24 41 22 18 21 16 23 17 23 25 24 25 26 26 24 30 32 31 27 42 30 32 28 32 29 30 32 30 30 29 32 30 31 32 32 32 30 43 27 33 29 32 27 31 32 32 31 34 32 33 33 33 36 32 31 44 30 28 28 24 25 26 29 29 30 27 30 29 32 33 31 31 29 45 32 28 28 29 27 32 29 30 28 33 32 31 35 34 34 33 34 46 26 27 25 25 26 27 26 27 24 29 28 28 32 29 23 33 26 47 26 24 24 24 24 24 25 23 26 25 25 25 26 27 28 27 24 48 31 31 31 30 30 29 31 30 32 33 28 31 31 30 29 30 28
( ) = Not pregnant 

## 6 Page 40 Test Facility Study No. 495257

## Appendix (continued) Individual Food Consumption Data (g)

Group 3, Intermediate dose: 300 mg/kg/day
Day of Gestation Animal Number 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 49 21 24 26 26 26 29 23 26 25 25 22 21 24 23 19 22 25 50 20 27 31 25 31 28 27 28 28 26 26 28 29 27 28 29 33 51 20 22 21 20 22 21 22 23 24 24 21 26 33 24 23 28 24 52 23 20 27 24 26 26 26 27 27 26 25 30 33 33 34 31 30 53 24 31 30 28 31 30 28 28 28 30 29 30 34 31 32 31 31 54 28 25 31 27 30 30 33 34 30 36 32 30 37 32 33 33 31 55 28 24 28 28 29 34 25 31 29 28 30 30 34 30 30 36 28 56 27 29 28 27 28 27 28 29 29 30 29 31 33 33 34 33 30 57 25 28 22 25 29 23 25 27 26 25 27 27 29 23 34 31 27 58 24 27 24 25 28 26 28 25 30 30 27 32 31 32 34 31 27 59 30 31 24 27 21 25 28 27 25 26 26 25 27 27 29 28 20 60 30 31 31 30 29 29 32 28 32 35 31 35 32 37 37 29 30 61 22 25 25 23 25 26 26 25 26 25 25 24 26 24 25 26 23 62 22 28 26 26 25 24 27 24 30 27 24 26 29 28 38 29 28 63 25 27 26 29 25 28 24 25 27 28 26 30 29 29 34 30 29 64 24 27 21 23 29 25 28 27 24 27 26 27 29 26 33 27 23 65 28 24 27 24 28 25 25 27 28 27 28 33 30 34 33 30 29 66 28 28 29 29 28 29 29 28 28 31 28 32 27 35 32 31 29 67 23 22 25 22 23 24 24 26 23 27 26 31 25 29 32 28 25 68 27 27 26 28 28 28 30 29 30 31 33 29 32 34 35 34 30 (69) 23 17 20 22 20 14 18 20 20 15 19 19 15 15 17 18 16 70 25 26 28 26 27 28 29 26 32 30 29 29 29 32 30 33 28 71 24 24 26 24 23 25 25 26 28 29 29 31 30 34 32 32 29 72 29 26 29 27 28 26 30 30 31 32 31 32 32 34 35 33 31
( ) = Not pregnant 

## 6 Page 41 Test Facility Study No. 495257

## Appendix (continued) Individual Food Consumption Data (g)

Group 4, High dose: 1000 mg/kg/day
Day of Gestation Animal Number 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 73 26 29 25 26 28 32 23 27 28 31 28 28 30 34 36 36 29 74 21 28 27 30 27 29 27 29 27 28 27 26 28 29 25 30 27 75 26 31 23 27 29 31 30 27 31 30 32 35 38 33 36 36 32 76 23 28 27 27 29 29 27 25 28 29 32 29 32 33 32 34 30 77 29 28 28 27 28 27 26 29 30 29 34 29 31 28 31 32 28 78 24 29 28 28 30 27 27 25 28 25 30 26 27 29 32 30 26 79 21 23 26 28 28 33 27 28 26 30 27 26 31 32 30 29 24 80 24 28 28 28 27 30 27 25 25 28 28 27 33 26 30 25 26 81 26 24 24 24 23 23 25 25 25 28 23 28 26 27 28 30 24 82 27 30 26 28 29 28 29 29 31 33 29 30 31 31 32 33 28 83 21 28 26 22 22 26 24 26 26 27 22 28 29 29 28 27 27 84 32 30 29 29 27 28 30 28 29 33 27 31 30 33 33 33 29 85 22 25 21 21 23 24 25 25 26 26 26 26 29 26 30 25 24 86 27 25 26 25 24 29 25 26 26 30 24 30 27 30 32 28 25 87 26 27 27 29 27 28 26 28 26 30 29 28 29 27 31 25 27 88 33 33 23 33 25 35 29 31 30 32 28 31 34 30 33 33 28 89 32 30 34 31 32 30 33 33 37 35 32 34 34 34 32 34 25 90 27 26 23 28 25 26 28 26 22 27 26 29 30 31 32 31 22 91 22 26 22 23 22 24 23 25 23 26 25 26 26 28 26 25 26 92 24 25 25 22 24 24 23 23 24 27 24 24 28 27 26 28 26 93 31 26 30 30 - 28 29 27 30 30 29 33 36 36 33 37 28 94 30 27 24 25 25 27 24 27 28 27 29 29 29 30 30 31 30 95 27 24 26 25 25 28 26 27 29 27 26 28 28 30 27 28 25 (96) 25 26 30 27 24 34 26 28 25 25 20 20 22 24 19 23 22
( ) = Not pregnant - = Food consumption not recorded in error 

## 6 Page 42 Test Facility Study No. 495257

## Appendix Individual Pregnancy Data and Foetal Weights

Group 1, Control: 0 mg/kg/day

Animal Number Corpora Lutea Graviditatis Total Implant

Sites Early Embryonic

Deaths Late Embryonic

Deaths Dead Foetuses Live Implants Uterus Weight

(g) Mean Foetal Weight (g) ± SD 1 17 16 1 0 0 15 77 3.18 ± 0.21 2 14 14 1 0 0 13 76 3.72 ± 0.29 3 15 15 0 0 0 15 94 4.12 ± 0.23 4 16 16 1 0 0 15 96 3.88 ± 0.30 (5) 0 0 - - - - - - (6) 0 0 - - - - - - 7 10 10 0 0 0 10 65 4.26 ± 0.19 (8) 0 0 - - - - - - 9 14 14 1 0 0 13 80 3.92 ± 0.20 10 14 13 1 0 0 12 76 3.82 ± 0.22 11 14 14 0 0 0 14 92 4.07 ± 0.29 12 17 17 0 0 0 17 99 3.35 ± 0.26 13 12 12 0 0 0 12 78 4.03 ± 0.26 14 12 12 0 0 0 12 79 3.97 ± 0.20 15 15 15 0 0 0 15 101 4.21 ± 0.28 16 14 14 1 0 0 13 79 3.78 ± 0.21 17 11 11 0 0 0 11 69 3.72 ± 0.22 18 13 13 1 1 0 11 65 3.61 ± 0.17 19 16 13 1 0 0 12 74 3.87 ± 0.28 20 17 17 0 0 0 17 99 3.65 ± 0.25 21 11 5 0 0 0 5 36 4.21 ± 0.69 22 14 13 0 0 0 13 78 3.75 ± 0.19 23 14 14 0 0 0 14 91 3.91 ± 0.22 24 13 12 1 0 0 11 73 4.18 ± 0.37

SD = Standard deviation ( ) = Not Pregnant 

## 7 Page 43 Test Facility Study No. 495257

## Appendix (continued) Individual Pregnancy Data and Foetal Weights

Group 2, Low dose: 100 mg/kg/day

Animal Number Corpora Lutea Graviditatis Total Implant

Sites Early Embryonic

Deaths Late Embryonic

Deaths Dead Foetuses Live Implants Uterus Weight

(g) Mean Foetal Weight (g) ± SD 25 17 15 0 0 0 15 96 3.97 ± 0.26 26 12 10 1 0 0 9 65 4.11 ± 0.31 27 12 6 0 0 0 6 39 3.67 ± 0.21 28 15 15 0 0 0 15 90 3.77 ± 0.27 29 15 13 1 0 0 12 78 4.06 ± 0.37 30 14 14 0 0 0 14 94 4.35 ± 0.22 (31) 0 0 - - - - - - 32 13 13 0 0 0 13 82 4.05 ± 0.50 33 9 6 1 0 0 5 33 3.68 ± 0.33 34 14 14 0 0 0 14 87 3.80 ± 0.51 35 14 14 0 0 0 14 90 4.03 ± 0.18 36 12 10 0 0 0 10 66 4.03 ± 0.15 37 16 14 1 0 0 13 86 4.15 ± 0.25 38 15 15 0 0 0 15 94 4.01 ± 0.22 39 16 16 0 0 0 16 96 3.76 ± 0.15 40 14 14 1 0 0 13 77 3.80 ± 0.12 41 14 14 1 0 0 13 75 3.17 ± 0.21 42 15 14 0 0 0 14 89 3.92 ± 0.24 43 21 19 0 0 0 19 115 3.73 ± 0.28 44 15 15 2 0 0 13 82 3.85 ± 0.22 45 15 15 0 0 0 15 94 4.00 ± 0.23 46 13 13 0 0 0 13 86 4.20 ± 0.14 47 12 4 0 0 0 4 31 4.75 ± 0.18 48 18 17 0 0 0 17 100 3.60 ± 0.28

SD = Standard deviation ( ) = Not Pregnant 

## 7 Page 44 Test Facility Study No. 495257

## Appendix (continued) Individual Pregnancy Data and Foetal Weights

Group 3, Intermediate dose: 300 mg/kg/day

Animal Number Corpora Lutea Graviditatis Total Implant

Sites Early Embryonic

Deaths Late Embryonic

Deaths Dead Foetuses Live Implants Uterus Weight

(g) Mean Foetal Weight (g) ± SD 49 4 3 3 0 0 0 - - 50 14 14 1 0 0 13 81 3.65 ± 0.22 51 9 7 0 0 0 7 44 3.75 ± 0.25 52 10 9 0 0 0 9 62 4.46 ± 0.18 53 12 12 0 0 0 12 78 4.04 ± 0.33 54 14 14 0 0 0 14 86 3.81 ± 0.33 55 15 15 0 0 0 15 90 3.82 ± 0.28 56 13 13 2 0 0 11 77 4.44 ± 0.19 57 13 13 1 0 0 12 77 4.20 ± 0.22 58 9 9 0 0 0 9 67 4.62 ± 0.20 59 16 16 0 0 0 16 101 3.87 ± 0.24 60 16 16 1 0 0 15 91 3.73 ± 0.24 61 15 13 2 0 0 11 71 3.99 ± 0.14 62 15 14 1 0 0 13 81 3.59 ± 0.17 63 14 14 0 0 0 14 88 4.07 ± 0.19 64 14 14 0 0 0 14 86 3.94 ± 0.17 65 15 15 0 0 0 15 87 3.70 ± 0.25 66 16 16 1 0 0 15 91 3.85 ± 0.31 67 13 13 0 0 0 13 86 4.07 ± 0.19 68 14 12 0 0 0 12 70 3.63 ± 0.19 (69) 0 0 - - - - - - 70 17 17 2 0 0 15 94 3.71 ± 0.31 71 11 11 0 0 0 11 70 3.75 ± 0.50 72 15 14 0 0 0 14 93 4.19 ± 0.24

SD = Standard deviation ( ) = Not Pregnant 

## 7 Page 45 Test Facility Study No. 495257

## Appendix (continued) Individual Pregnancy Data and Foetal Weights

Group 4, High dose: 1000 mg/kg/day

Animal Number Corpora Lutea Graviditatis Total Implant

Sites Early Embryonic

Deaths Late Embryonic

Deaths Dead Foetuses Live Implants Uterus Weight

(g) Mean Foetal Weight (g) ± SD 73 15 15 0 0 0 15 94 4.02 ± 0.31 74 13 13 1 0 0 12 76 3.88 ± 0.17 75 12 11 6 0 0 5 36 4.31 ± 0.21 76 16 16 0 0 0 16 98 3.95 ± 0.22 77 16 16 0 0 0 16 101 3.90 ± 0.23 78 15 15 0 0 0 15 96 4.10 ± 0.24 79 15 15 0 0 0 15 97 4.07 ± 0.12 80 11 10 0 0 0 10 65 4.10 ± 0.17 81 13 13 2 1 0 10 74 3.90 ± 0.63 82 16 16 1 0 0 15 94 3.96 ± 0.20 83 14 14 1 0 0 13 77 3.81 ± 0.24 84 14 14 0 0 0 14 91 4.04 ± 0.26 85 11 10 1 0 0 9 62 4.04 ± 0.19 86 15 15 1 0 0 14 82 3.63 ± 0.17 87 13 12 0 0 0 12 80 4.16 ± 0.42 88 16 16 0 0 0 16 91 3.85 ± 0.19 89 15 15 0 0 0 15 98 4.00 ± 0.23 90 15 15 0 0 0 15 94 3.94 ± 0.19 91 13 12 0 0 0 12 76 3.95 ± 0.20 92 12 11 1 0 0 10 61 3.81 ± 0.24 93 17 17 0 0 0 17 102 3.80 ± 0.29 94 9 8 1 0 0 7 51 4.19 ± 0.41 95 14 14 1 0 0 13 80 3.76 ± 0.17 (96) 0 0 - - - - - -

SD = Standard deviation ( ) = Not Pregnant 

## 7 Page 46 Test Facility Study No. 495257

## Appendix Individual Incidence of Foetal Abnormalities and Variants

Notes : Only those foetuses/litters with abnormalities/variants are liste d. All other fo etuses/litters examined in the study had no abnormalities detected. Major, deleterious (or potentially deleteri ous) abnormalities appear in capital letters. Foetuses with vestigial/reduced 13 th 

## rib(s) are categorised acc ording to the length of the shortest rib. Foetuses with supernumerary rib( s) are categorised accord ing to the length of the longest supernumerary rib.

Abbreviations used: NAD = No abnormality detected

a = 13 th 

## vestigial rib(s)

b = 13 th 

## reduced rib(s) c = 13 complete ribs d = Vestigial supernumerary rib(s) on 1 st 

## lumbar vertebra e = Complete supernumerary rib(s) on 14 th 

## thoracic vertebra 8 Page 47 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 1, Control: 0 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

2 7M 3.92 Additional liver lobe within median cleft Right testis medially displaced - -

12M 3.72 NAD Right frontal discrete unossified/incompletely ossified area(s) c

3 8M 3.87 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

10M 4.33 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe Bilateral testis not fully descended to pelvic position - -

11M 4.14 Additional liver lobe within median cleft NAD c

13M 3.84 Additional liver lobe within median cleft NAD c

15F 3.75 Additional liver lobe within median cleft NAD c

4 8F 3.52 NAD Left cervical rib c

9 2F 3.61 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

3F 4.04 Left cervical re mnant of thymus NAD c

6F 3.77 Left ureter dilated - -

7M 3.82 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum a 

## 8 Page 48 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 1, Control: 0 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

10 11M 4.23 Additional liver lobe within median cleft - -

12F 3.70 Additional liver lobe within median cleft NAD c

12 4F 3.28 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

10F 2.64 NAD Pelvic girdle bilateral caudal displacement (27 bi lateral pre-pelvic vertebral arches) d

13 7M 4.05 Additional liver lobe within median cleft NAD c

14 4M 4.12 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum a

12M 4.12 NAD RIGHT RIB(S) 11 KINKED Left rib(s) 10 incompletely ossified Right rib(s) 8 to 12 incompletely ossified Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

15 1F 3.97 Subcutaneous haemorrhage lower jaw NAD c

2F 4.23 Additional liver lobe within median cleft - -

10M 3.99 Right testis not fully descended to pelvic position - -

12M 4.42 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe

Additional liver lobe within median cleft - - 

## 8 Page 49 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 1, Control: 0 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

15 (cont) 13M 4.24 Subcutaneous haemorrhage lower jaw Additional ossified area arising from sternebra 6 c

15F 4.00 Additional liver lobe within median cleft NAD c

17 6M 3.30 Additional liver lobe within median cleft Right renal pelvis dilated - -

18 3M 3.39 Subcutaneous haemorrhage ventral cervical region - -

8M 3.50 Additional liver lobe within median cleft NAD c

20 1F 3.06 Additional liver lobe within median cleft - -

13F 3.56 Additional liver lobe within median cleft - -

17M 4.04 Additional liver lobe within median cleft - -

22 4F 3.71 Additional liver lobe within median cleft NAD c

13F 3.53 Left renal pelvis dilated

Left ureter dilated - - 

## 8 Page 50 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 2, Low Dose: 100 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

25 3M 4.12 NAD Right rib(s) 11,12 incompletely ossified c

6F 3.96 Additional liver lobe within median cleft - -

26 1M 4.69 Left renal pelvis dilated - -

2M 4.33 Bilateral renal pelvis dilated NAD c

3F 3.93 Additional liver lobe within median cleft - -

4F 4.34 Additional liver lobe within median cleft Left renal pelvis dilated NAD c

6F 3.78 Additional liver lobe within median cleft NAD c

7M 3.91 Additional liver lobe within median cleft - -

9M 4.27 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

28 4M 4.02 Additional liver lobe within median cleft NAD c

9F 3.51 Right renal pelvis dilated - -

10M 4.03 Additional liver lobe within median cleft NAD c 

## 8 Page 51 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 2, Low Dose: 100 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

29 5F 3.02 NAD STERNUM PARTIALLY SPLIT Left rib(s) 1 incompletely ossified Right rib(s) 4,5 connected, right thoracic vertebral arches 4,5 fused

Thoracic vertebra 5 hemicentric c

8M 4.22 Tendinous region of diaphragm locally thinned with protrusion of median liver lobe - -

9F 3.96 Additional liver lobe within median cleft NAD c

10F 3.91 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

11M 4.47 Tendinous region of diaphragm locally thinned with protrusion of median liver lobe NAD c

30 1M 4.64 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

14M 4.36 Left cervical re mnant of thymus

Additional liver lobe within median cleft NAD c

32 6M 4.25 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum b

33 5M 4.12 Additional liver lobe within median cleft NAD c 

## 8 Page 52 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 2, Low Dose: 100 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

34 2F 4.19 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

4M 4.18 NAD Left cervical rib c

6F 3.88 Additional liver lobe within median cleft Umbilical artery left-sided NAD c

8F 3.78 Subcutaneous annular haemorrhage tail NAD c

11M 3.92 Haemorrhage dorsal fat pad region Right testis medially displaced - -

12F 3.20 Additional liver lobe within median cleft NAD c

35 1F 3.92 NAD Left frontal small discrete unossified/incompletely ossified area(s) c

4M 3.97 Additional liver lobe within median cleft - -

37 3M 4.20 Left renal pelvis dilated NAD c

10F 4.32 Right renal pelvis dilated

Bilateral ureter dilated - -

13M 4.24

` NAD Additional ossified area arising from sternebra 6 Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

38 7M 4.18 Additional liver lobe within median cleft - - 

## 8 Page 53 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 2, Low Dose: 100 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

39 1M 3.78 Additional liver lobe within median cleft NAD c

5F 3.63 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum c

9F 3.81 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum a

11M 3.94 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

13F 3.61 Additional liver lobe within median cleft NAD c

15M 3.93 Right testis not fully descended to pelvic position Additional ossified area arising from sternebra 6 b

40 8F 3.85 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe NAD c

41 1F 3.10 Right cervical remnant of thymus NAD c

3M 3.31 Additional liver lobe within median cleft NAD c

6M 2.87 THORACIC AND ABDOMINAL SITUS INVERSUS

Additional liver lobe within median cleft - -

9M 3.35 Additional liver lobe within median cleft NAD c

11M 3.11 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum b 

## 8 Page 54 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 2, Low Dose: 100 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

43 2M 3.69 Additional liver lobe within median cleft - -

9F 3.65 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

44 1F 3.71 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

45 5F 3.90 NAD Additional ossified area arising from sternebra 6 Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

8F 3.93 Additional liver lobe within median cleft - -

46 7F 4.33 Right kidney minimal caudal displacement - -

11F 4.12 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

47 1F 4.70 Left renal pelvis dilated

Left ureter dilated NAD c

48 13F 3.45 Haemorrhage dorsal fat pad region - - 

## 8 Page 55 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 3, Intermediate Dose: 300 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

50 5M 4.05 Tendinous region of diaphragm locally thinned with protrusion of median liver lobe - -

7M 3.25 LOWER JAW SHORTENED MANDIBLES SHORTENED AND FUSED WITH INCISOR SOCKETS ABSENT

NASAL BONES FUSED

INCISIVE BONES FUSED

PALATINE BONE AND MAXILLARY PROCESSES FUSED, MISSHAPEN AND INCOMPLETELY OSSIFIED

BASISPHENOID MISSHAPEN AND INCOMPLETELY OSSIFIED WITH PTERYGOID PROCESSES ABSENT

TYMPANIC RINGS MEDIALLY DISPLACED c

8F 3.74 Additional liver lobe within median cleft - -

51 1F 3.79 NAD Bilateral cervical rib

Unilateral/bilateral rib 7 costal cartilage not attached to sternum Pelvic girdle bilateral cranial displacement (25 bi lateral pre-pelvic vertebral arches) a

3F 3.32 NAD Bilateral cervical rib

Unilateral/bilateral rib 7 costal cartilage not attached to sternum Bilateral rib(s) 5 costal cartilages asymmetrically aligned at point of attachment to sternum Pelvic girdle unilateral cranialdisplacement (26 left, 25 right prepelvic vertebral arches) a 

## 8 Page 56 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 3, Intermediate Dose: 300 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

51 (cont) 6M 3.78 Left testis not fully descended to pelvic position - -

7F 4.14 Subcutaneous haemorrhage lower jaw NAD c

52 3M 4.57 Subcutaneous haemorrhage right cervical region - -

54 7F 2.87 Left side of thyroid reduced (in size) - -

56 10M 4.59 Umbilical artery left-sided NAD c

57 3F 4.02 Additional liver lobe within median cleft NAD c

8F 4.11 Additional liver lobe within median cleft - -

58 5M 4.70 Additional liver lobe within median cleft - -

59 7M 3.94 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum c

9F 3.51 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum c

12M 4.09 Additional liver lobe within median cleft - -

60 1F 3.11 Hepatic haemorrhage right median lobe - -

9M 3.73 Additional liver lobe within median cleft - -

11M 3.80 Intra-abdominal haemorrhage Tendinous region of diaphragm locally thinned with protrusion of median liver lobe - - 

## 8 Page 57 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 3, Intermediate Dose: 300 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

61 7F 4.11 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

11F 3.86 Additional liver lobe within median cleft NAD c

62 2F 3.64 Additional liver lobe within median cleft NAD c

8M 4.00 Bilateral cervical remnant of thymus NAD c

63 14M 4.15 Additional liver lobe within median cleft - -

64 5M 3.98 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

65 7F 3.72 Additional liver lobe within median cleft NAD c

8F 3.63 Right kidney minimal caudal displacement - -

66 7F 3.80 Additional liver lobe within median cleft - -

8M 4.04 Additional liver lobe within median cleft NAD c

11F 3.87 Additional liver lobe within median cleft - -

13F 3.64 Additional liver lobe within median cleft - -

68 1F 3.44 Additional liver lobe within median cleft - -

4F 3.57 Left cervical re mnant of thymus

Additional liver lobe within median cleft NAD c 

## 8 Page 58 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 3, Intermediate Dose: 300 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

70 1F 3.48 Additional liver lobe within median cleft - -

5M 4.16 Subcutaneous haemorrhage lower jaw - -

12F 3.51 Left cervical re mnant of thymus NAD c

72 6M 4.23 Left cervical re mnant of thymus NAD c

12M 4.42 Left cervical re mnant of thymus

Additional liver lobe within median cleft NAD c 

## 8 Page 59 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 4, High Dose: 1000 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

73 6F 4.14 Additional liver lobe within median cleft - -

13F 3.80 Additional liver lobe within median cleft NAD d

14F 3.74 Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

75 1F 4.14 NAD Unilateral/bilate ral rib 7 costal cartilage not attached to sternum c

4F 4.24 Additional liver lobe within median cleft - -

5M 4.58 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

76 1F 3.75 Additional liver lobe within median cleft - -

77 2M 3.84 Right testis medially displaced - -

6M 4.09 Subcutaneous haemorrhage lower jaw - -

9F 3.69 NAD Left frontal discrete unossified/incompletely ossified area(s) c

12F 4.28 Right ureter dilated - -

78 3F 3.85 Hepatic haemorrhage left lateral lobe - -

6F 4.06 Additional liver lobe within median cleft NAD c

8M 4.11 Right cervical remnant of thymus NAD c 

## 8 Page 60 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 4, High Dose: 1000 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

80 5F 3.90 Right cervical remnant of thymus - -

81 1M 4.51 Right renal pelvis dilated NAD c

3F 2.76 NAD Pelvic girdle unilateral caudaldisplacement (26 left, 27 right prepelvic vertebral arches) c

5M 3.84 NAD Left scapula misshapen

Sternebra 6 flattened d

8M 4.68 Additional liver lobe within median cleft - -

82 1F 3.48 Left cervical re mnant of thymus Tendinous region of diaphragm locally thinned with minimal protrusion of median liver lobe - -

4F 3.81 Tendinous region of diaphragm locally thinned with protrusion of median liver lobe NAD c

8F 3.88 Left cervical re mnant of thymus

Additional liver lobe within median cleft NAD c

13F 4.18 Tendinous region of diaphragm locally thinned with protrusion of median liver lobe - -

15M 4.09 Left testis not fully descended to pelvic position - -

83 7M 3.88 Additional liver lobe within median cleft Additional ossified area arising from sternebra 6 c 

## 8 Page 61 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 4, High Dose: 1000 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

84 3M 4.23 Additional liver lobe within median cleft - -

5M 3.86 Subcutaneous haemorrhage nasal - -

10F 4.03 Additional liver lobe within median cleft NAD c

86 1M 3.74 Additional liver lobe within median cleft - -

14F 3.58 Additional liver lobe within median cleft NAD c

88 10F 3.58 NAD Bilateral rib(s) 7 costal cartilages asymmetrically aligned at point of attachment to sternum c

14F 3.94 Additional liver lobe within median cleft NAD c

16F 3.79 NAD Additional ossified area arising from sternebra 6 c

89 3F 4.05 NAD Pelvic girdle un ilateral cranialdisplacement (26 left, 25 right prepelvic vertebral arches) a

4M 4.34 Additional liver lobe within median cleft - -

8F 3.89 Additional liver lobe within median cleft - -

10M 4.22 Subcutaneous haemorrhage right pinna region - -

12F 3.94 Hepatic haemorrhage left lateral lobe - -

15F 3.89 Right cervical remnant of thymus NAD c 

## 8 Page 62 Test Facility Study No. 495257

## Appendix (continued) Individual Incidence of Foetal Abnormalities and Variants

Group 4, High Dose: 1000 mg/kg/day
Abnormality

Animal Number Foetus Number/

Sex/ Weight

(g) Visceral Skeletal Ribs

90 3M 4.08 Right testis medially displaced - -

91 10M 4.06 Additional liver lobe within median cleft - -

12M 4.18 Subcutaneous haemorrhage nasal - -

92 1M 3.92 Small interventricular septal defect - -

10M 3.98 NAD Left rib(s) 5, 6 minimally kinked Right rib(s) 4 to 8,11 minimally kinked c

93 5F 3.91 NAD Additional ossified area arising from sternebra 6 c

16M 4.07 Subcutaneous haemorrhage nasal - -

95 10F 3.50 Additional liver lobe within median cleft - - 

## 8 Page 63 Test Facility Study No. 495257

## Appendix Litter Incidences of Number of Ribs

Number of Ribs

a = 13 th 

### vestigial rib(s)

b = 13 th 

### reduced rib(s) c = 13 complete ribs d = Vestigial supernumerary rib(s) on 1 st 

### lumbar vertebra e = Complete supernumerary rib(s) on 14 th 

### thoracic vertebra

Foetuses with vestigial/reduced 13 th 

### rib(s) are categorised according to th e length of the shortest rib. Foetuses with supernumerary rib(s) are categorised according to the length of the longest supernumerary rib. 

## 9 Page 64 Test Facility Study No. 495257

## Appendix (continued) Litter Incidences of Number of Ribs

Group 1: 0 mg/kg/day Group 2: 100 mg/kg/day

Number of Ribs Number of Ribs Animal Number Number of Foetuses Examined a b c d e Animal Number Number of Foetuses Examined a b c d e 1 8 0 0 8 0 0 25 8 0 0 8 0 0 2 6 0 0 6 0 0 26 4 0 0 4 0 0 3 8 0 0 8 0 0 27 3 0 0 3 0 0 4 7 0 0 7 0 0 28 7 0 0 7 0 0 7 5 0 0 5 0 0 29 6 0 0 6 0 0 9 7 2 0 4 1 0 30 7 0 0 7 0 0 10 6 0 0 6 0 0 32 6 0 1 5 0 0 11 7 0 0 7 0 0 33 3 0 0 3 0 0 12 8 0 0 5 2 1 34 7 0 0 6 1 0 13 6 0 0 6 0 0 35 7 0 0 7 0 0 14 6 1 0 5 0 0 36 5 0 0 5 0 0 15 8 0 0 8 0 0 37 7 0 0 7 0 0 16 6 0 0 6 0 0 38 7 0 0 7 0 0 17 6 0 0 6 0 0 39 8 1 1 6 0 0 18 5 0 0 4 1 0 40 6 0 0 6 0 0 19 6 0 0 6 0 0 41 7 0 1 6 0 0 20 8 0 0 8 0 0 42 7 0 0 7 0 0 21 3 0 0 2 1 0 43 10 0 0 10 0 0 22 6 0 0 6 0 0 44 6 0 0 6 0 0 23 7 0 0 7 0 0 45 8 0 0 8 0 0 24 5 0 0 3 2 0 46 6 0 0 6 0 0 47 2 0 0 2 0 0 48 8 0 0 8 0 0 

## 9 Page 65 Test Facility Study No. 495257

## Appendix (continued) Litter Incidences of Number of Ribs

Group 3: 300 mg/kg/day Group 4: 1000 mg/kg/day

Number of Ribs Number of Ribs Animal Number Number of Foetuses Examined a b c d e Animal Number Number of Foetuses Examined a b c d e 50 6 0 0 6 0 0 73 8 0 0 7 1 0 51 4 2 0 2 0 0 74 6 0 0 6 0 0 52 4 0 0 4 0 0 75 3 0 0 3 0 0 53 6 0 0 6 0 0 76 8 0 0 8 0 0 54 7 0 0 6 1 0 77 8 0 0 7 1 0 55 8 0 0 7 1 0 78 7 0 0 7 0 0 56 5 0 0 5 0 0 79 8 0 0 6 2 0 57 6 0 0 6 0 0 80 5 0 0 5 0 0 58 4 0 0 4 0 0 81 5 0 0 4 1 0 59 8 0 0 8 0 0 82 7 0 0 7 0 0 60 7 0 0 7 0 0 83 7 0 0 7 0 0 61 6 0 1 5 0 0 84 7 0 0 7 0 0 62 6 0 0 5 1 0 85 5 0 0 5 0 0 63 7 0 0 6 1 0 86 7 0 0 7 0 0 64 7 0 0 7 0 0 87 6 0 0 6 0 0 65 8 0 0 8 0 0 88 8 0 0 8 0 0 66 7 0 0 7 0 0 89 8 1 0 7 0 0 67 7 0 0 7 0 0 90 7 0 0 6 1 0 68 6 0 0 6 0 0 91 6 0 0 4 2 0 70 7 0 0 7 0 0 92 5 0 0 5 0 0 71 6 0 0 6 0 0 93 9 0 0 9 0 0 72 7 0 0 7 0 0 94 3 0 0 3 0 0 95 7 0 0 7 0 0 

## 9 Page 66 Test Facility Study No. 495257

## Appendix Litter Incidences of Skeletal Ossification Parameters
Key to Parameter Numbers Incomplete ossification affecting:


## 1. ≥ 4 skull bones
2. ≤ 3 skull bones 

## 3. Cervical vertebral arch(es) 4. Thoracic centrum(a) 5. Lumbar vertebral arch(es) 6. Pubis/es 7. Ischium/a 8. Sacral vertebral arch(es) 9. 2 nd 

## and/or 4 th 

## metacarpal(s) Unossified: 10. 5 th 

## metacarpal(s) Ossified: 11. Anterior arch of atlas ossified 12. >2 cervical vertebral centra ossified 13. One or more sacrocaudal vertebra with connection between centrum and arch(es) 14. Phalangeal elements ossified 15. Mean number of cauda l vertebral centra 10 Page 67 Test Facility Study No. 495257

## Appendix (continued) Litter Incidences of Skeletal Ossification Parameters

Group 1, Control: 0 mg/kg/day

No. of Sternebrae Retarded Parameter No. Animal

No. No. of Foetuses Examined 0 1 2 >2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1 8 1 4 2 1 0 1 0 0 0 0 0 1 0 4 2 0 0 1 3.8 2 6 4 2 0 0 0 3 0 1 0 0 0 0 0 0 0 0 0 0 3.8 3 8 2 5 1 0 2 2 0 0 0 1 0 2 0 0 4 1 5 1 4.5 4 7 4 2 1 0 0 0 0 2 0 0 0 0 0 3 1 0 0 1 3.6 7 5 5 0 0 0 0 1 0 0 0 0 0 0 0 1 2 3 4 0 5.2 9 7 3 4 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 4.3 10 6 4 0 2 0 0 1 0 0 0 0 0 0 0 2 2 0 1 0 4.2 11 7 4 3 0 0 0 0 0 1 0 0 0 2 0 2 3 0 2 0 4.3 12 8 1 5 0 2 0 5 1 2 0 3 0 2 2 7 2 0 0 0 3.8 13 6 2 1 3 0 0 1 0 1 0 0 0 3 0 2 0 0 0 0 4.2 14 6 2 2 2 0 1 3 1 1 1 1 0 3 1 1 0 0 0 0 4.2 15 8 8 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 5 0 4.4 16 6 4 1 1 0 0 1 0 0 0 0 0 0 0 1 3 1 5 0 4.2 17 6 0 2 4 0 1 1 1 1 1 1 1 5 0 6 0 0 0 0 3.2 18 5 1 1 3 0 0 3 1 0 0 1 1 3 1 5 3 0 0 0 3.4 19 6 1 3 2 0 0 2 1 1 0 1 0 6 1 6 0 0 0 0 3.5 20 8 4 4 0 0 0 0 0 4 0 0 0 0 0 4 0 0 0 0 4.0 21 3 2 1 0 0 0 1 0 0 0 0 0 0 0 0 1 0 1 0 4.3 22 6 6 0 0 0 0 2 0 0 0 0 0 0 0 1 1 0 2 0 4.3 23 7 3 3 1 0 1 1 1 0 0 1 1 2 1 6 6 0 1 0 4.0 24 5 3 2 0 0 0 1 0 0 0 0 0 0 0 0 1 0 5 1 4.8 

## 10 Page 68 Test Facility Study No. 495257

## Appendix (continued) Litter Incidences of Skeletal Ossification Parameters

Group 2, Low Dose: 100 mg/kg/day

No. of Sternebrae Retarded Parameter No. Animal

No. No. of Foetuses Examined 0 1 2 >2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 25 8 3 4 1 0 2 5 2 0 0 3 2 3 0 7 1 0 0 0 4.1 26 4 3 1 0 0 0 2 0 1 0 0 0 0 0 2 2 0 0 0 3.8 27 3 2 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 4.0 28 7 6 1 0 0 1 1 0 0 0 0 0 1 0 3 0 0 0 0 4.0 29 6 4 1 0 1 0 0 0 1 0 0 0 0 0 0 5 0 2 1 4.7 30 7 5 2 0 0 0 2 0 0 0 0 0 0 0 0 1 0 4 1 4.7 32 6 4 0 2 0 0 0 0 0 0 0 0 0 0 0 2 0 4 0 4.3 33 3 2 1 0 0 0 1 0 1 0 0 0 0 0 2 2 0 0 0 4.0 34 7 5 2 0 0 0 0 0 0 0 0 0 2 0 0 0 0 5 0 4.1 35 7 3 4 0 0 1 6 0 0 0 2 0 6 0 4 0 0 0 0 4.1 36 5 2 2 1 0 0 1 0 1 0 0 0 0 0 0 1 0 1 0 4.4 37 7 6 1 0 0 0 0 0 0 0 0 0 0 0 0 6 3 6 2 4.7 38 7 3 3 1 0 0 0 0 0 0 0 0 0 0 0 3 1 5 0 4.7 39 8 2 6 0 0 0 7 0 0 0 1 0 7 0 4 2 0 0 0 4.0 40 6 5 1 0 0 4 1 2 0 0 1 0 3 0 5 2 0 0 0 3.7 41 7 0 1 6 0 0 3 0 0 0 0 0 0 0 7 1 0 0 0 3.1 42 7 6 1 0 0 0 0 0 2 0 0 0 0 0 0 4 0 4 2 4.1 43 10 3 6 1 0 0 0 0 0 0 0 0 0 0 4 3 0 3 0 4.0 44 6 3 1 2 0 2 2 0 0 0 0 0 3 1 2 0 0 1 0 4.0 45 8 6 2 0 0 0 4 0 1 0 0 0 3 0 1 3 0 3 0 4.3 46 6 2 3 1 0 1 4 0 0 0 1 0 1 1 3 1 0 5 0 4.7 47 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 5.5 48 8 4 2 2 0 0 2 0 0 0 0 0 0 0 4 0 0 1 0 4.0 

## 10 Page 69 Test Facility Study No. 495257

## Appendix (continued) Litter Incidences of Skeletal Ossification Parameters

Group 3, Intermediate Dose: 300 mg/kg/day

No. of Sternebrae Retarded Parameter No. Animal

No. No. of Foetuses Examined 0 1 2 >2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 50 6 1 3 2 0 1 0 0 0 0 0 0 1 0 2 1 0 1 0 3.7 51 4 2 1 1 0 0 0 0 1 0 0 0 0 0 0 0 1 4 2 4.8 52 4 3 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 5.0 53 6 4 2 0 0 2 2 0 1 0 0 0 0 0 1 3 0 4 2 4.2 54 7 7 0 0 0 0 1 0 0 0 0 0 0 0 1 3 0 5 0 4.6 55 8 5 3 0 0 0 1 0 0 0 0 0 0 0 1 2 0 3 1 3.6 56 5 5 0 0 0 0 2 0 0 0 0 0 0 0 0 1 1 3 0 4.6 57 6 5 1 0 0 0 2 0 0 0 0 0 0 0 0 3 0 6 1 4.5 58 4 3 1 0 0 0 2 0 0 0 0 0 0 0 1 4 0 3 3 4.5 59 8 0 2 6 0 1 4 0 0 0 0 0 0 0 3 0 0 4 0 3.9 60 7 4 2 1 0 0 1 0 0 0 0 0 1 0 1 1 0 2 1 4.3 61 6 4 2 0 0 0 1 0 0 0 0 0 1 0 0 5 0 0 0 3.8 62 6 1 2 3 0 0 1 0 0 0 1 0 2 0 3 0 0 0 0 3.3 63 7 6 1 0 0 2 4 0 1 0 0 0 4 1 3 2 0 0 0 4.1 64 7 6 1 0 0 1 0 0 1 0 0 0 0 0 1 4 0 5 3 4.0 65 8 5 2 1 0 0 0 0 0 0 0 0 0 0 2 2 0 1 0 4.0 66 7 5 1 1 0 0 2 0 1 0 0 0 1 0 3 0 0 1 0 4.0 67 7 4 2 1 0 0 1 0 2 0 0 0 0 0 0 4 1 1 1 4.7 68 6 2 4 0 0 0 0 0 0 0 0 0 0 0 0 3 0 3 0 4.2 70 7 4 3 0 0 0 2 0 0 0 0 0 1 0 3 0 0 2 0 4.0 71 6 0 3 1 2 0 0 0 1 0 0 0 1 0 3 2 0 0 0 3.2 72 7 5 2 0 0 0 2 0 1 0 0 0 0 0 0 0 1 7 3 5.0 

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## Appendix (continued) Litter Incidences of Skeletal Ossification Parameters

Group 4, High Dose: 1000 mg/kg/day

No. of Sternebrae Retarded Parameter No. Animal

No. No. of Foetuses Examined 0 1 2 >2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 73 8 3 4 1 0 0 4 0 0 0 1 0 2 0 4 2 0 1 0 3.9 74 6 2 3 1 0 0 0 0 0 0 0 0 0 0 1 1 0 3 2 4.0 75 3 2 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 3 1 5.0 76 8 5 3 0 0 0 2 0 0 0 0 0 0 0 0 2 2 7 2 4.1 77 8 8 0 0 0 0 0 0 0 0 0 0 1 0 2 2 0 4 1 4.5 78 7 3 4 0 0 0 0 0 0 0 1 0 1 0 0 3 1 4 0 4.9 79 8 3 5 0 0 0 1 0 0 0 0 0 0 0 0 1 0 7 0 4.0 80 5 5 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 2 0 4.0 81 5 1 2 2 0 0 0 0 0 0 0 0 0 0 1 0 1 1 1 3.8 82 7 4 3 0 0 0 2 0 0 0 0 0 0 0 4 1 0 5 0 4.0 83 7 7 0 0 0 0 3 0 0 0 0 0 1 1 3 2 0 0 0 4.1 84 7 5 2 0 0 0 1 0 0 0 0 0 0 0 0 5 5 6 0 4.6 85 5 3 2 0 0 0 1 0 0 0 0 0 0 0 2 1 0 3 1 4.4 86 7 2 2 3 0 0 3 0 1 0 0 0 1 0 2 1 0 1 0 4.3 87 6 3 2 0 1 0 3 1 0 0 2 0 2 0 3 5 0 4 0 3.8 88 8 7 1 0 0 0 0 0 0 0 0 0 0 0 0 6 2 4 4 4.6 89 8 5 2 1 0 0 4 0 0 0 0 0 0 0 2 0 0 0 0 4.0 90 7 3 4 0 0 0 2 0 1 0 0 0 0 0 0 3 0 1 1 4.1 91 6 3 2 1 0 2 1 0 1 0 2 0 3 1 5 0 0 0 0 3.8 92 5 2 2 1 0 1 3 0 0 0 0 0 0 0 2 0 0 1 0 4.0 93 9 9 0 0 0 0 0 0 0 0 0 0 1 0 2 3 0 3 0 4.1 94 3 3 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 2 0 4.7 95 7 1 6 0 0 0 2 0 0 0 0 0 3 0 7 0 0 0 0 3.7 

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