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

 

 

 

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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

 

 

 

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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

 

 

 

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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

 

 

 

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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 
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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 Woolley MSc DABT FRCPath ERT 

 ForthTox Limited 

 

 

 

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Test Facility Study No. 495257
 

4. SUMMARY 

Alcohols, C18-22, distn. residues, is a chemical 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 during the period of organogenesis. 

Mated female Sprague Dawley rats were randomised 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 gestation, where the day of detection 

of mating was designated Day 0. Dose levels administered were 0, 100, 300 and 1000 

mg/kg/day. 

Animals were regularly monitored during gestation 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. residues, 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 weights did not suggest any obvious 

effect of treatment. 

The type and distribution of foetal abnormalities 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. 

 

 

 

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Test Facility Study No. 495257
 

5. INTRODUCTION 

Alcohols, C18-22, distn. residues, is a chemical 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 during 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, Edinburgh, 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 Compliance Statement page for date 

 of Study Director’s signature 

The rat is a standard rodent species for the developmental toxicity testing in animals required 

by regulatory authorities. The normal processes 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 and 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 study, 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 will be stored indefinitely in the Scientific 

Archive at Charles River, Preclinical Services, Edinburgh. 

 

 

 

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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 September 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 archive at Charles River, 

Edinburgh under the same storage conditions indicated above. 

A Certificate of Analysis for the batch 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 Study No. 425902) at ambient temperature in the 

dark. The test item was formulated by adding the appropriate volume 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 undertaken with regard to concentration and 

homogeneity. Samples (3 x 2 mL) were taken from formulations (including Control) 

prepared for use on Week 1 and 3 of treatment. 

 

 

 

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During Week 1, Group 4 formulation (100 mg/mL) was out with the acceptance criteria of 

less than 10% coefficient of variation. Reanalysis 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 formulation (30 and 100 mg/mL, respectively) 

was performed as the determined concentration was greater than ±15% of the actual 

concentration. Reanalysis of the formulation samples 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 Toxicology Support Laboratory at Charles River, 

Edinburgh, using a method validated by Charles 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 rats (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 approximately 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 second on Day 2 and the third on Day 3 (day of detection of a 

vaginal plug or sperm in a vaginal 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 implanted electronic identification chip identifying it 

individually within the study and which corresponded to that female’s number. 

Each animal was also given a cage card which was colour coded for treatment group and 

marked with the study number, animal number, cage number and treatment group. 

 

 

 

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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 arrival for signs of abnormality or disease. No 

such signs were found and the animals were accepted for use on the study.

6.7. Housing and Husbandry 

6.7.1. Environmental Conditions 

There was automatic control of light cycle, temperature and humidity in the animal room. 

Light hours were 0700-1900h. The target ranges for temperature and humidity were 21 ± 2°C 

and 55 ± 15% respectively, with a minimum 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 the humidity remained within the target 

range throughout the duration of the study. 

6.7.2. Room Sanitation 

Each day, floors were swept and then mopped 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 polycarbonate 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, Essex, UK was available to the animals ad libitum. The 

diet was supplied with a batch analysis for nutritive constituents and a range of significant 

 

 

 

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Test Facility Study No. 495257
 

contaminants. The analytical certificate for a batch 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, including a range of significant 

contaminants. The analytical certificate of a typical 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 representatives 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 animals 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 after 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 animal 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 animal did not receive its full dose. 

 

 

 

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On Day 15 of gestation (18 February 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 during 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 these detailed clinical 

observations were not included in the study protocol, the Study Director authorised these 

examinations and the examinations were within the spirit and intent 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 gestation 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; any 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 dissected out and weighed intact, then opened and the contents 

examined. The number of corpora lutea graviditatis in each ovary and the number and 

position of all implantation sites in the uterus were recorded. Each implant was classified as 

being live, a dead foetus (dead full term foetus that showed no evidence of maceration), or 

late embryonic death (macerated tissue identifiable as an embryo or foetus, with recognisable 

 

 

 

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external features such as tail, limbs, mouth and nares present; attached to distinct, identifiable 

placenta), or an early embryonic death (discrete, formless, discoloured tissue mass attached to 

the internal uterine wall; may be of varying size). 

Each foetus was examined for externally visible 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 potassium 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 examined for soft tissue abnormalities by a modified 

freehand sectioning technique derived 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. 

 

 

 

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7. RESULTS 

7.1. Analysis of Dosing Formulations (Appendix 3) 

The analysis of dosing formulations indicated acceptable accuracy 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 formulations prepared for use on Week 3 of 

dosing was excluded due to suspected contamination during the analytical process. 

7.2. Clinical Observations and Necropsy Findings (Table 1, Appendix 4) 

There were no clinical observations 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 consumption 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 incidence 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. 

 

 

 

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8. DISCUSSION 

At levels up to 1000 mg/kg/day Alcohols, C18-C22 distn. residues, 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 weights did not suggest any obvious 

effect of treatment. 

The type and distribution of foetal abnormalities and variants did not suggest any obvious 

effect of treatment. 

It was concluded that, under the conditions of this study, Alcohols C18-C22 distn. residues 

had no obvious effects on pregnancy when administered to rats during the period of 

organogenesis; there was no evidence of embryotoxicity or foetal abnormalities. The 

maternal and foetal no observed effect level (NOEL) were both considered to be 

1000 mg/kg/day. 

 

 

 

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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

 

 

 

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Test Facility Study No. 495257
Table 

Group Mean Body Weight (g) ± Standard Deviation (Pregnant 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 statistical significance achieved (P>0.05) 

2

 

 

 

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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

 

 

 

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Table 

Pregnancy Performance and Foetal Weights 

Group/Dose Level (mg/kg/day) 

1 

(0) 

2 

(100) 

3 

(300) 

4 

(1000) 

Number of animals mated 24 24 24 24 

Number pregnant 21 23 23 23 

Number of premature decedents 0 0 0 0 

Number of decedents pregnant 0 0 0 0 

Number 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

 

 

 

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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. 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. 

0 0 1(1) 0 

Partially split sternum 0 1(1) 0 0 

Rib(s) kinked 1(1) 0 0 0 

Thoracic and abdominal situs 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

 

 

 

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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 displacement 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 displaced 1(1) 1(1) 0 2(2) 

Testis(es) not fully descended to pelvic 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 from 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 

13th vestigial rib(s) 3(2) 1(1) 2(1) 1(1) 

13th 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 lumbar vertebra 7(5) 1(1) 4(4) 8(6) 

Complete supernumerary rib(s) on 14th 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) 

2nd and/or 4th metacarpal(s) 6(5) 2(2) 1(1) 2(2) 

 

Unossified 

5th 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 Analysis of Test Item 

1

 

 

Page 27

Test Facility Study No. 495257

saSOL 

Brunstll'e ttel, 9/09/2009 

CERTIFICATE o , ANALYSIS 

Product: 

LOt No.' 

Manufac turing date : 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 

OJ5S5/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 inspe ctor 

M. Sprung 

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

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

--. ,. , .. 1.'" "" :c.,·", :"~j:'-\l' .~.: 

-" ,..: --;". 

• ", .~ ;. ,. < 

1", .. < ,' -c ' .... :." ; ',.".-' ' __ '0(>,'0::',,_ 

:~":.':~-'. :,:,";~: ":' '"",C", • P"."""" "'_ :-" _,' ," ",~ " ..... , .. ' ' '' 'F'< _, "',,,, .:0' c' r:c - .... , , ,'" " 
Appendix 

GLP Certificate 

2

 

 

Page 28

Test Facility Study No. 495257

, DH) Department 

~ of Heallh 

THE DEPARTMENT OF HEALTH OF THE GOVERNMENT 

OF THE UNITED KINGDOM 

GOOD LABORATORY PRACTICE 

STATEMENT OF CQi\IPLIANCE 

l"'rl ACCORDANCE WITH DiRECTIVE: 20U~ EC 

TEST FACILITY 

Charles River Laboratories 

Tranent 

Edinburgh 

EH332NE 

DATE OF [NSI'I-:CTION 

20 to 23 April 2010 

ITSTTYI'E 

Analytical Chemistry 

Clinical Pathology 

Biological Safety Tests 

Ecosystems 

Environmenta l Fate 

Environmental Toxicity 

Mutagenicity 

PhysfChem . Testing 

Toxicology 

Virology 

A general inspection for compliance with the Principles of Good Laboratory Pract ice 

wa~ carried OUl at the above test facility as pan of the UK GLPCompliance Programme. 

At the time of inspection no deviations were found o f sufficient mag nitude [0 affec t 

the Vlllidity of non lini n 1 <;tu r1i c~ performed at these faci liti es. 

Dr. Andrew,1. Gra:r 

Head. UK GLP Monitoring 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, 77.1a, 31.4 31.4 - +4.7 

4b 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, 0.0206a 0 - - 

2 10 9.19, 10.2, 9.95 9.78 5.4 -2.2 

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

4b 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 

41 Staining on fur, dorsal neck 18-20 

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 

54 Two scab(s), on tail 10-20 

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

 

 

 

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Test Facility Study No. 495257
Appendix 

Individual Body Weights Data (g) 

Group 1, Control: 0 mg/kg/day 

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Individual Body Weights Data (g) 

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

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Individual Body Weights Data (g) 

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

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Individual Body Weights Data (g) 

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

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix 

Individual Food Consumption Data (g) 

Group 1, Control: 0 mg/kg/day 

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Individual Food Consumption Data (g) 

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

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Individual Food Consumption Data (g) 

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

Animal Day of Gestation 

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

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Individual Food Consumption Data (g) 

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

Animal Day of Gestation 

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

 

 

 

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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 listed. All other foetuses/litters 

examined in the study had no abnormalities detected. 

Major, deleterious (or potentially deleterious) abnormalities appear in capital letters. 

Foetuses with vestigial/reduced 13th rib(s) are categorised according to the length of the 

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

the longest supernumerary rib. 

Abbreviations used:

NAD = No abnormality detected 

a = 13th vestigial rib(s) 

b = 13th reduced rib(s) 

c = 13 complete ribs 

d = Vestigial supernumerary rib(s) on 1st lumbar vertebra 

e = Complete supernumerary rib(s) on 14th 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 remnant of thymus NAD c 

 6F 

3.77 

Left ureter dilated - - 

 7M 

3.82 

NAD Unilateral/bilateral 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 bilateral pre-pelvic 

vertebral arches) 

d 

13 7M 

4.05 

Additional liver lobe within median 

cleft 

NAD c 

14 4M 

4.12 

NAD Unilateral/bilateral 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 remnant of thymus 

Additional liver lobe within median 

cleft 

NAD c 

32 6M 

4.25 

NAD Unilateral/bilateral 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/bilateral rib 7 costal 

cartilage not attached to sternum 

c 

 9F 

3.81 

NAD Unilateral/bilateral 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/bilateral 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 bilateral 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 cranial 

displacement (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/bilateral rib 7 costal 

cartilage not attached to sternum 

c 

 9F 

3.51 

NAD Unilateral/bilateral 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 remnant 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 remnant of thymus NAD c 

72 6M 

4.23 

Left cervical remnant of thymus NAD c 

 12M 

4.42 

Left cervical remnant 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/bilateral 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 caudal 

displacement (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 remnant 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 remnant 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

 

 

 

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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 unilateral cranial 

displacement (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

 

 

 

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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

 

 

 

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Test Facility Study No. 495257
Appendix 

Litter Incidences of Number of Ribs 

Number of Ribs

a = 13th vestigial rib(s) 

b = 13th reduced rib(s) 

c = 13 complete ribs 

d = Vestigial supernumerary rib(s) on 1st lumbar vertebra 

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

Foetuses with vestigial/reduced 13th rib(s) are categorised according to the length of the shortest rib. 

Foetuses with supernumerary rib(s) are categorised according to the length of the longest 

supernumerary rib. 

9

 

 

 

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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

 

 

 

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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

 

 

 

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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. 2nd and/or 4th metacarpal(s) 

Unossified: 

10. 5th 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 caudal vertebral centra 

10

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Litter Incidences of Skeletal Ossification Parameters 

Group 1, Control: 0 mg/kg/day 

No. of Sternebrae 

Retarded Animal Parameter No. 

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

 

 

 

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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 Animal Parameter No. 

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

 

 

 

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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 Animal Parameter No. 

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

10

 

 

 

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Test Facility Study No. 495257
Appendix (continued) 

Litter Incidences of Skeletal Ossification Parameters 

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

No. of Sternebrae 

Retarded Animal Parameter No. 

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

10

 

 

 

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Test Facility Study No. 495257