4 L££2£ — 

# Si— —~ " April 02, 1987 

FINAL REPORT 

TK 12443 

TERATOLOGY STUDY IN RATS 

GU PROJECT NO. 840862 

TTNUVCi4 ^3V 

SEN T T O 

CORPORATE TOX: YES BN O D 

DATE: V^A? . 

P & A PRODUC T SAFET Y 

200202/GF, WE, FR 

This document is directed to USEPA pursuant the Toxic Substances Control Act (TSCA). This document is the 

property of the sponsor and may be used only for that purpose intended by the sponsor and as authorized under 

applicable law. Every other or additional use, exploitation, reproduction, publication or submission to other parties 

requires the written permission of the sponsor, except as otherwise required by applicable law (e.g., TSCA). The use of 

these studies/documents for regulatory, registration or other commercial purposes [including but not limited to 

Registration, Evaluation, Authorization and Restriction of Chemical Substances (REACH)], without the express 

written permission of the sponsor is unauthorized and strictly prohibited. 
ZF GU 

GU 1.1 QSE 

GUhLITY ASSURANCE STATEHEHT 

For« 301 C 

STUDY TITLE ; 

TK 12443 

TE:RATOLOGY STUDY I N RATS 

Sponsor ;

Test No, : 840862 

Study director ; , 

QAI HaMe 

THE QUALITY ASSURANCE INSPECTIQN(S) HAS (OE ) PERFDRHEIi OH THE FQILOWING DftTE(£) 

1 26,07.8 5 

3 ;;>9.0 8,8 5 

5 28,02,8 6 

4 0 9,10,8 5 

6 15.12,8 6 FINA L REPORT AUD" 

THE FINDINGS HERE REPORTED TO THE STUDY DIRECTOR AND TO THE HANAGEHENT CH THE FDLLOviING DATE(S); 

1 26,07,8 5 

3 29,08,8 5 

5 07,03.8 6 

4 0 9,10,8 5 

6 16,12' , 86 

QSE/QAU «ar,aqer ;

12,03,87 , 

Siqnature Date 

Distribution i\ / Sfjdij director 0 GU 1,1 File 
TERATOLOGY STUDY IN RATS Page-I 

GU Project No. 840862 Test Article: TK 12443 

TABLE OF CONTENTS 

1 Introduction 1 

2 Suminary and conclusion 3 

3 Personnel 7 

4 Time schedule 8 

5 Materials and Methods 9 

5 .1 Test material 9 

5 . 2 Experimental animals 10 

5.2.1 Species, stock, source 10 

5.2.2 Husbandry ' 10 

5.2.3 Diet 11 

5.2.4 Water 11 

5 . 3 Procedure 11 

5.3.1 Mating and acclimation 11 

5.3.2 Identification, randomisation and housing of 

dams 12 

5.3.3 Dose-levels 12 

5.3.4 Preparation of test article, administration... 12 

5.3.5 Content analysis 13 

5.3.6 Group identification 13 

5.3.7 Observations on dams during life phase 13 

5.3.8 Euthanasia 14 

5.3.9 Observations on dams at sacrifice 14 

5.3.10 Observation on fetuses 15 

5.3.10.1 Gross examination 15 

5.3.10.2 Visceral examination 16 

5.3.10.3 Skeletal examination 17 

5.3.11 Classification of fetal findings 18 

5.4 Statistical analysis 19 

5 . 5 Deviations from the protocol 20 

6 References 21 

7 Archives 22 

8 Results •- . . . 23 

8 .1 Observations in dams 23 

8.1.1 Maternal clinical examination 23 

8.1.1.1 Table: Summarized maternal clinical 

observations 24 

8.1.2 Mortality 2 5 

8.1. 3 Materna l body-weigh t gai n 26 

8.1.3. 1 TABLE: Mean body vzeights of dams (i n 

g) 27 

8.1.3.2 FIGURE: Mean body weights of dams (in 

g) • 28 

8.1.4 Maternal body-weight changes 29 

8.1.4.1 TABLE : Mean maternal body-weight 

changes during gestation 30 
TERATOLOGY STUDY IN RATS Page-II 

GU Project No. 840862 Test Article: TK 12443 

TABLE OF CONTENTS (cont'd) 

8.1.5 "Corrected" body weights at necropsy near term 31 

8.1.5.1 TABLE: Mean "corrected" body weight of 

dams 3 2 

8.1.6 Food consumption 33 

8.1.6.1 TABLE : Food consumption during 

gestation (in g) 34 

8.1.6.2 FIGURE : Group mean food consumption 

during gestation (in g) 35 

8.1.7 Maternal postmortem examination 36 

8.1.7.1 TABLE: Summary of maternal postmortem 

examination 37 

8.1.8 Examination of ovaries, uterus and uterine 

contents 38 

• 8.1.8.1 TABLE: Summary of cesarean section, 

pregnancy data 40 

8.1.8.2 TABLE: Summary of cesarean section, 

uterine data(1) 41 

8.1.8.3 TABLE: Summary of cesarean section, 

uterine data(2) 4 3 

8.1.8.4 TABLE: Summary of ceasarean section, 

fetal data . 44 

8 . 2 Observations in fetuses 45 

8.2.1 External examination of the fetuses 45 

8.2.1.1 TABLE: Summary of fetal external 

anomalies and/or malformations 46 

8.2.2 Fetal visceral examination 4 7 

8.2.3 . Ossification of fetal skeletons 4 8 

8.2.3.1 TABLE: Summary of fetal skeletal 

anomalies and/or malformations ~ 50 

8.2.3.2 TABLE: Summarized data of delayed 

skeletal maturation 52 

8.2.4 Summarized fetal abnormalities 56 

8.2.4.1 TABLE: Summary of all fetal anomalies 

and/or malformations 57 

Appendices 58 

9.1 Statistical analysis 58 

9.1.1 Body weights 59 

9.1.2 Body weight changes 70 

9.1.3 "Corrected" body weights 7 4 

9.1.4 Food Consumption 76 

9.1.5 Uterine data 80 

9.1.6 Fetal skeletal findings 89 

9.2 Individual Data 149 

9.2.1 Individual Maternal Clinical Observations 149 

9.2.2 Body weight (individual values) 245 

9.2.3 Body weight changes (individual values ) 257 

9.2.4 "Corrected" body weights (individual values). . 261 

9.2.5 Food consumption (individual values) 269 

9.2.6 Maternal necropsy findings (individual values) 27 3 

9.2.7 Uterine data: part 1 (individual values) 281 
TERATOLOGY STUDY IN RATS Page-Ill 

GU Project No. 840862 Test Article: TK 12443 

TABLE OF CONTENTS (cont'd) 

9.2.8 Uterine data: part 2, continued (individual 

values) 293 

9.2.9 Fetal data 305 

9 . 3 Randomization 361 

9.4 Matingtable 363 

9.5 Concentration of Test Article in the Vehicle 367 

10 Distribution 368 
TERATOLOGY STUDY IN RATS 1 

GU Projec t No. 840862 Test Article : TK 12443 

1 . INTRODUCTION 

At th e request of th e Plastic s and Additive s Division ,

 a teratogenicit y stud y i n rats was conducte d i n orde r t o determin e possibl e advers e effects on th e embryoni c and/o r feta l developmen t of th e tes t articl e followin g th e 

administratio n from day 6 unti l day 15 of pregnancy . 

The stud y wa s carrie d ou t a t th e

The main feature s of thi s stud y followe d th e OECD guideline s for 

testin g of chemicals, "Teratogenicity " no. 414, adopted May 12, 1981. 

The stud y was performe d i n accordanc e wit h th e Principle s of Good 

Laborator y Practice , adopted May 12, 1981 by th e OECD Council and was 

subjecte d t o periodi c qualit y assuranc e evaluation . 
TERATOLOGY STUDY IN RATS 2 

GU Project No. 840862 Test Article: TK 12443 

This report presents the results of the investigation as compiled by 

the undersigned": 

Study Director

date: '^f^r'A 2^ >tf^^ 

Study supervisor

date: Q .0[\, \\l' ^ 

Reviewed and approved

(Facility Management) 

date: 
TERATOLOGY STUDY IN RATS 3 

GU Project No. 840862 Test Article: TK 12443 

SUMMARY AND CONCLUSION 

In this study TK 12443 was evaluated for possible embryotoxic activity and teratogenic potency in the rat. 

Based on the results of a previously conducted preliminary teratology 

study, the daily doses were selected at 0, 300, 1000 and 3000 mg/kg 

of body weight. The test substance was suspended in the 1:1 mixture 

of distilled water and polyethylene glycol 400 (PEG 400) and administered orally by intubation once daily from day 6 until day 15 of 

pregnancy, inclusive. 

The females were checked daily for clinical signs, symptoms and mortalities as well as body-weight changes,- food consumption was determined at five-days intervals, i. e. at least once a week. The females 

were killed short time prior to expected delivery and submitted to 

macroscopic pathological examination. The uteri were dissected and 

contents examined. Live fetuses were weighed, sexed and evaluated for 

external, visceral and/or skeletal abnormalities. 

The results of the study can be summarized as follows: 

Maternal data 

Clinical signs and symptoms 

No clinical signs or symptoms were recorded to occur as a consequence 

of treatment with the test substance. 

A fev.' animals, such as two from the control group, five from the lowdose group and one from each the intermediate and high dose groups 

developed some necrotic areas on the skin which were not considered 

to be due to the treatment. 

Mortality 

No spontaneous death was observed and no interim sacrifice by reasons 

of ill health was to be performed throughout the periods of treatment 

and post-treatment. 

Body-weight gain 

On the basis of the statistical evaluation of data, body weight as 

well as body-weight changes were found to be comparable for all 

groups. 

Also the "corrected body weight" as determined at sacrifice near term 

and based on final body weight minus weight of the uterus including 

contents, was not significantly altered in the experimental groups. 
TERATOLOGY STUDY IN RATS 4 

GU Project No. 840862 Test Article: TK 12443 

Food consumption 

No decrease in food consumption was noted for the three dose groups. 

Macroscopic pathological examination 

at sacrifice near term 

No changes were recorded which might be related to the treatment with 

the test substance. 

Reproduction data established 

at sacrifice near term 

The pregnancy rates were comparable for all groups at 92 % to 100 %. 

The examination of the uteri and uterine contents did not reveal any 

alteration attributable to the treatment of dams with the test 

substance. 

Embryo and fetolethality occurred at a certain incidence similar for 

all groups. 

No experimental significance was attached to partial abortion of the "^ 

litter as observed in one dam each of the intermediate and high dose 

groups. 

At 3000 mg/kg a slightly increased mean number of corpora lutea and '^ 

decreased mean number of implantation sites resulted in an elevated 

ratio of these parameters (corpora lutea / implantation sites) in 

comparison with the control group. As both the aforementioned changes 

concerning numbers of corpora lutea and implantation sites did not 

show a statistically significant difference from the corresponding 

control data, the latter result was not attributed to the dams' 

treatment. 

Fetal data 

Examination of fetuses surviving to 

sacrifice near term 

On the comparison of the group means of fetal body weights, a significant reduction was recorded for the 1000 mg/kg group. In this intermediate dose group also an increased delay of skeletal maturation was 

found. In the absence of comparable results from the high-dose group, 

however, no experimental significance was assumed for this finding. 
TERATOLOGY STUDY IN RATS 5 

GU Project No. 840862 Test Article: TK 12443 

Occasional significant differences from the control were also noted 

for the ossification rates of several skeletal elements in the 

fetuses of the low and high dose groups. In the view of great 

variations within the groups these results were not attributed to 

treatment, too. 

The external examination of the live fetuses revealed two malformations : 

- a fetus of the control group showed generalized oedema 

- a fetus of the high-dose group showed an omphalocele 

Omphalocele as indicating failure of ventral closure during late 

stages of embryonic development is a type of malformation also 

recorded to occur spontaneously in the stock of rats used for this 

study. The one instance observed among the high-dose fetuses of the 

present study was also considered to be of a spontaneous origin and 

not related to the treatment. 

The skeletal assessment on about two thirds of live fetuses per 

litter revealed anomalies exclusively consistent with irregular ossification of sternebrae : 

- 4 fetuses (4 litters) of the control group 

- 4 fetuses from 3 litters of the 300 mg/kg dose group 

- 2 fetuses (2 litters) of the 1000 mg/kg dose group 

- 6 fetuses from 3 litters of the 3000 mg/kg dose group 

were affected in this respect, the "per litter" as well as "poi 

fetus" incidences being similar for all groups. 

No visceral malformations or anomalies were detected by applying the 

slicing technique on about one third of live fetuses per litter. 

y 
TERATOLOGY STUDY IN RATS 6 

GU Project No. 840862 Test Article: TK 12443 

CONCLUSION 

In this teratology study on the rat TK 12443 was devoid of an embryotoxic activity and teratogenic potency following the oral administration of daily doses of 300, 1000 and 3000 mg/kg to the dams 

through days 6 until 15 of pregnancy. Statistically significant deviations from the control data concerning a slightly reduced fetal 

body weight at 1000 mg/kg and delay of skeletal maturation as also, 

in particular, noted for this intermediate dose group, were not considered to be due to the dams' treatment with the test substance. 

Furthermore, there was no maternal toxicity recorded for the three 

dose groups. In the view of the foregoing results no obvious "maximum 

tolerated dose level" was attained in this study. Physico-chemical 

properties of large amounts of test substance in the water-PEG mixture used as a vehicle did not allow treatment at doses higher than 

3000 mg/kg under the present experimental conditions, however. 
TERATOLOGY STUDY IN RATS 7 

GU Project No. 840862 Test Article: TK 12443 

3. PERSONNEL 

Study director

Teratologist 

Experimental Supervisor Mr. B. Schmidt 

Technical assistants

Mr. J. Stratz 

Statistical analysis

Reporting
TERATOLOGY STUDY IN RATS 8 

GU Project No. 840862 Test Article: TK 12443 

4. TIME SCHEDULE 

Arrival of females 

(commencement of 

acclimation) August 05, 1985 

Starting date of 

experiment-'- August 06, 1985 

Starting date of dosing August 12, 1985 

Date of Cesarean section August 27 - 30, 1985 

Termination date of 

experiment November 11, 1985 

Date of release of Final 

Draft Report June 30, 1986 

1. Assignment of the first subgroup being evident of successful 

mating to the corresponding dose groups 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article: TK 12443 

5.1. Test material 

5. MATERIALS AND METHODS 

Code No: 

Trade name: 

Batch No: 

Description: 

Purity: 

Solubility: 

Received: 

Amount received: 

Expiry date: 

Stability: 

Storage: 

Vehicle or solvent: 

Safety Precautions: 

TK 12443 

TINUVIN 234 

EN 02885.32 (commercial grade) 

solid 

99.7 % 

insoluble in water 

August 22, 1984 

10 kg 

to be provided by the sponsor 

ascertained by the sponsor 

room temperature 

1:1 mixture of distilled water and 

Polyethylene Glycol 400 (pract., 

FLUKA AG, Buchs, Switzerland) 

routine hygienic procedures were 

considered to be sufficient to 

assure health and safety of all 

personnel 
TERATOLOGY STUDY IN RATS 10 

GU Project No. 840862 Test Article: TK 12443 

5.2. Experimental animals 

5.2.1. Species, stock, source 

Species: Albino rat 

Stock: Tif: RAIf(SPF), hybrids of RII/1 x 

RII/2 

Source: Animal Production,

and 

Initial mean body weight 

of females: 180 - 200 g 

Initial age of females: about 2 months 

Initial number of mated 

females per group: 24 

5.2.2. Husbandry 

The experiment was carried out under conventional standard 

laboratory conditions. The animals were housed in groups of 4 

in Macrolon cages' with a wire mesh top and with standardised 

granulated soft wood (Societe Parisienne des Sciures Pantin) 

serving as bedding material. 

The animal room was air conditioned: 

Temperature: 21°C + 1°C 

Relative humidity: 55% + 15% 

Ventilation: about 16 air changes/hour 

Light cycle: 12 hours light per day ( 6 a.m. -

6p.m. ) 

Neithe r insecticide s no r othe r chemicals wer e applie d i n th e 

anima l room wit h th e exceptio n of th e disinfectan t BRADOPHEN 

F o r treatmen t o f loca l ski n necrosis , th e antibioti c 

TYROSOLVIN^ was locall y applied . 
TERATOLOGY STUDY IN RATS 11 

GU Project No. 840862 Test Article: TK 12443 

5.2.3. Diet 

Pelleted, certified standard diet (Nafag No. 890 Tox) was 

provided ad libitum. All batches of diet were assayed for 

composition and contaminant levels by the manufacturer. 

Analytical results are lodged at the animal supply office 

5.2.4. Water 

Tap water was available ad libitum from plastic bottles. The 

drinking water quality fulfilled the specifications of the 

"Schweizerisches Lebensmittelbuch" (Ed. 1972). The results of 

the routine chemical examination of water at source 

(Grundwasserfassung Stein) as conducted periodically by the 

water authority (Baudepartement des Kantons Aargau, Abteilung 

Gewaesserschutz) are available to as well as 

the results of inhouse chemical analysis by the analytical 

laboratories of the . 

5.3. Procedure 

5.3.1 . Matin g and acclimatio n 

Nulliparou s femal e rat s were mated overnigh t wit h male s of 

prove n fertilit y a t a rati o of 3 female s t o 1 mal e i n rack s 

containin g modifie d mating cages. Each cage was subdivided int o 

two part s by a shutter , separatin g th e sexe s unti l abou t 3 

a.m. , when th e shutte r opened by means of an automati c device . 

At 7 a.m. t o 9 a.m. , successful mating was determined eithe r by 

t h e presenc e o f a vagina l plu g o r by th e presenc e of 

spermatozo a i n th e vagina l smear. This day was designate d day 

"0" of pregnancy . 

Acclimatio n unde r tes t condition s di d tak e plac e durin g th e 

perio d of time between allocatio n t o th e corresponding group on 

day 0 and th e firs t treatmen t on day 6 post coitum. 

Mating table s ar e shown i n th e Appendix section . 
TERATOLOGY STUDY IN RATS 12 

GU Projec t No. 840862 Test Article : TK 12443 

5.3.2 . Identification , randomisation and housing of dams 

The mated females were allocate d t o experimenta l and contro l 

group s by usin g a metho d of randomizatio n by weigh t 

stratificatio n a s shown i n th e Appendix section . Afte r 

allocation , th e females were identifie d individually by colour 

cod e on th e tai l (i.e . a dash-do t code , painte d wit h a 

felt-tippe d waterproof marker) and placed in groups of 4 in 

Macrolon cages. The cages were identified by a coloured label 

according t o th e group, th e code number of the test material , 

th e dose and th e date s of treatmen t and autopsy. 

5.3.3. Dose-levels 

The dose-levels were selected on the basis of a previously 

conducted preliminary teratogenicity study. 

Groups of each 12 pregnant rats were treated with 0, 1000 mg/kg 

and 3000 mg/kg body weight from day 6 until day 15 of pregnancy 

with the test substance. 

The results from this study can be summarized as follows: 

The females of both the experimental groups remained unaffected 

by the treatment. Food consumption, body \i7eight development,, 

general health and all litter parameters were comparable lo 

those of the control group. One female of the control group 

died on day 20 post coitum: Necropsy revealed bloody liquid in 

the uterus; One malformation was found amongst the fetuses ot 

the control group (cleft palate in combination with 

maldeveloped tongue). 

Due to physicochemical restraints of the test article, the high 

dose was limited to 3000 mg/kg body weight. 

Based on the foregoing results, it was decided that the high 

dose should be 3 000 mg/kg, the indermediate dose 1000 mg/kg and 

the low dose 300 mg/kg, a dose expected to yield a no-effeci 

level. 

5.3.4. Preparation of test article, administration 

TK 1244 3 V7as suspended in a 1:1 mixture of distilled water and 

polyethylene glycol 400 (practical grade, FLUKA AG, Buchs, 

Switzerland) and administered orally by gavage from day 6 until 

day 15 of pregnancy, inclusive. 
TERATOLOGY STUDY IN RATS 13 

GU Project No. 840862 Test Article: TK 12443 

The suspensions of the test material were freshly prepared 

daily and the homogeneity of the suspensions was maintained by 

means of a magnetic stirrer. The volume administered was 10 

ml/kg and adjusted to actual daily body weights. The content 

analysis of the test article suspensions showed values ranging 

from 93.5 to 100.8 % of the nominal values. The results are 

shown in Appendix 9.5. 

.The suspensions prepared contained 0 mg/ml, 30 mg/ml, 100 mg/ml 

and 300 mg/ml of TK 12443. 

5.3.5. Content analysis 

Content analysis of the different concentrations of TK 1244 3 

was performed by the central analytical laboratory of 

 from samples taken from this study on August 

22, 1985. 

5.3.6. Group identification 

The experimental design was as follows: 

Group 

Vehicle control 

Low dose 

Intermediate dose 

High dose 

Dose 

level 

mg/kg 

0 

300 

1000 

3000 

Female 

numbers 

1-2 4 

25 - 48 

49 - 72 

73 - 96 

Colour 

of cage 

labels 

blue 

green 

yellow 

red 

Cage 

numbers 

1 - 6 

7-1 2 

13 - 18 

19 - 24 

5.3.7. Observations on dams during life phase 

The following parameters were recorded on dams during the 

experiment: 

Mortality daily 

Signs of Abortion daily 

General healtli condition daily 

Body weight daily 

Food consumption days 6, 11, 16 and 21 of pregnancy 
TERATOLOGY STUDY IN RATS 14 

GU Project No. 840862 Test Article: TK 12443 

The mean daily food consumption was calculated as follows : 

food consumption (g) per period 

days per period x no. of animals per cage 

5.3.8. Euthanasia 

Dams were killed by carbon dioxide inhalation (dry ice) on day 

21 of pregnancy and fetuses were removed by Cesarean section 

and also killed by carbon dioxide inhalation. 

5.3.9. Observations on dams at sacrifice 

At necropsy the following parameters were recorded: 

- Macroscopic pathological examination of the main organs of 

the thoracic and abdominal cavities, in particular the 

genitals. 

- Number of corpora lutea in each ovary 

- Weight of the uterus including contents 

- Uterine contents: 

-- number and location of live and dead fetuses in the 

uterine horns 

-- number and location of intrauterine resorption sites 

(early/late ) 

[early embryonal resorptions: implantation sites without 

placenta; late embryonal/fetal resorptions: implantation 

sites with placenta; abortions: "empty" implantation 

sites with white or yellow stained nodules in the uterus 

horn visible from the outside]. 

Uterine horns showing no implantation sites were placed 

into an aqueous solution of ammonium sulfide to 

visualize possible haemorrhagic alterations of such 

sites , according to the method of Salewsky < 1 >. 
TERATOLOGY STUDY IN RATS 15 

GU Project No. 840862 Test Article: TK 12443 

5.3.10. Observation on fetuses 

After beeing removed from the uterus, the fetuses were 

submitted to: 

- sex-determination (on the basis of ano-genital distance) 

- careful external (gross) inspection 

- body weight determination 

Assignment to either individual visceral or individual skeletal 

evaluation (at a 1 : 2 ratio) was computer-generated. In case 

of gross anomaly and/or malformation, however, fetuses were 

allocated to one of the two techniques depending on type and 

incidence of the finding. 

The live fetuses were then killed by carbon dioxide inhalation 

and processed for visceral or skeletal examination. 

5.3.10.1.Gross examination 

The live fetuses were subjected to careful external inspection, 

special attention being attached tO: 

- extremities or parts thereof (e.g. absent, shortened, 

deformed, additional) 

- tail (e.g. absent, shortened, "kinked") 

- trunk (e.g. failure of closure of spinal cord, atresia ot 

body orifices, omphalocele) 

- head (e.g. absent, reduced, deformed) 

brain (e.g. cranioschiosis, encephalocele, exencephaly 

rhinencephaly) 

- eyes (e.g. absent, reduced; "open eyes") 

- pinnae (e.g. absent) 

- jaws (e.g. absent, shortened) 

- oral orifice (e.g. absent) 
TERATOLOGY STUDY IN RATS 16 

GU Project No. 840862 Test Article: TK 12443 

- cleft lip and/or cleft jaws and/or cleft palate 

all body regions (e.g. generalized or localized oedema, 

haemorrhage) 

5.3.10.2.Visceral examination 

The viscera of one third of the fetuses per litter were 

examined according to the slicing technique of Wilson < 2 >: A 

solution containing ethyl alcohol, formaldehyde and acetic acid 

served as a fixative. Before slicing, the fetuses were placed 

into an aqueous solution of ammonium hydrogen carbonate, rinsed 

in tap water and then frozen for several hours. All specimens 

were finally stored individually, i.e. per fetus, in a mixture 

of ethanol and glycerol. 

Inspection of the viscera of head and trunk included, in 

particular, the following organs and organ systems: 

Skin 

Central nervous system: brain (olfactory bulbs, cerebrum, 

lateral and medial ventricles), 

spinal cord, eyes (lenses, 

vitreous, retina) 

Body cavities: pericardial cavity, pleural 

cavity, diaphragm 

Respiratory system: nasal cavity, nasal septum, 

choanae, trachea, bronchi, lungs 

Digestive system: oral cavity, palate, tongue, 

oesophagus, stomach, intestine, 

rectum, liver 

Endocrine system: thyreoidea, pancreas, adrenals, 

thymus 

Circulatory system: spleen, heart (atria, ventricles, 

septum), major vessels 

Excretory system: kidneys (renal papillae, renal 

pelvis), ureters, urinary bladder 

Genital system: testes, epididymides, deferent 

ducts, seminal vesicles; ovaries, 

oviducts, uterus 
TERATOLOGY STUDY IN RATS 17 

GU Project No. 840862 Test Article: TK 12443 

In case of eventual discrepancy in sex determination between 

external inspection and slicing technique, the sex was 

corrected in accordance with the results of the latter. 

5.3.10.3.Skeletal examination 

Skeletal assessment in two thirds of the fetuses per litter was 

accomplished following staining according to the technique of 

Dawson < 3 > : After clearing with potassium hydroxide and 

staining with alizarin red S, the specimens were, by several 

steps, finally passed into glycerol. 

This type of examination covered, apart from revealing possible 

instances of skeletal anomalies and/or malformations, also the 

state of skeletal maturation of the fetuses shortly before term 

on day 21 post coitum. 

Routine investigation of the fetuses comprehended skeletal 

elements where alterations usually occur and are reliably 

detected; the other ones, in braces [}, were referred to, if 

indicated: 

Cranial skeleton: 

Axial skeleton: 

Appendicular skeleton: 

nasals, frontals, parietals, 

interparietals, supraoccipital, 

exoccipitals, { basioccipital, 

premaxillae, maxillae, zygomas, 

squamosals, lacrimals, vomer, 

palatines, ethmoid, presphenoid, 

alisphenoids, basisphenoid, 

pterygoids, tympanic annuli, body 

of hyoid, mandibles } 

vertebrae (body and arches; 

cervical, thoracic, lumbar, 

sacral, caudal), ribs, sternebrae 

shoulder girdle: clavicles, 

scapulae 

pelvic girdle: ilia, ischia, 

[pubes} 

upper extremities: humeri, ulnae, 

radii, metacarpals, proximal 

phalanges, distal phalanges 

lower extremities: femora, tibiae, 

fibulae, calcanei, metatarsals, 

proximal phalanges, distal 

phalanges metacarpals, proximal 

phalanges, distal phalanges 

lower extremities: femora, tibiaf 

fibulae, calcanei, metatarsals, 

proximal phalanges, distal 

phalanges 
TERATOLOGY STUDY IN RATS 18 

GU Project No. 840862 Test Article: TK 12443 

5.3.11. Classification of fetal findings 

Normogenesis: Organs and organ systems of an animal species 

develop within a range of norm. As a consequence of 

individual genetic differences and/or random 

alterations of environmental conditions during 

development, organs and organ systems display a 

certain degree of variability, particularly with 

respect to the status of the ossification of 

skeletal elements. These instances of variations 

may also be termed variants and are, depending e.g. 

upon the extent of still incomplete or still absent 

ossification, either classified as normal or 

eventually considered to be indicative'of a delay 

of physiological growth of the fetus. 

Teratogenesis: Development outside the normal range . With 

respect to the implications concerning postnatal 

life, maldevelopment may be roughly differentiated 

as follows: 

Malformations are types of severe abnormal 

development, irreparable and in general 

incompatible with healthy postpartum development of 

the young animals. 

Anomalies are minor differences from "normal" 

development (e.g. supernumary ossification center 

of the sternum, occurrence of a 14th pair of ribs, 

fusion of the basis of two ribs, dilatation of the 

renal pelvis, herniation of the diaphragm, cysts, 

haemorrhage, haematoma) which are not considered to 

impair normal postpartum development of the animal. 
TERATOLOGY STUDY IN RATS 19 

GU Project No. 840862 Test Article: TK 12443 

5.4. Statistical analysis 

General 

All values listed in the statistics section of this report were 

analysed by the Student's t-test < 4 >, except for the analysis 

of fetal anomalies, which v/ere analysed by the CHI-square test 

< 5 >. 

Statistical analysis is performed to draw attention to distinct 

values'. A statisticall y significant difference between two 

values does not necessarily imply biological relevance of that 

deviation and is not conclusive for a treatment related effect. 

Hence, the responsibl e scientist may not comment on 

statistically significant values lying within the physiological 

range and on the other hand may comment on statistically not 

significant values, which differ substantially from the 

expected normal values. 

Explanation of signs and remarks 

* significant at p<0.05 (t test) 

-1- significant at p=0.05 (CHI-square test) 

-I--I- significant at p=0.01 (CHI-square test) 

•+++ significan t a t p=0.00 1 (CHI-squar e test ) 

N number of sample s o r number of animals 
TERATOLOGY STUDY IN RATS 20 

GU Project No. 840862 Test Article: TK 12443 

5.5. Deviations from the protocol 

Apart from amendment no. 1 (replacment of the study director by 

April 01, 1986, which was after the in-life phase) no further 

deviations to the protocol have been made which needed a 

written amendment. 

Amendment no. 

1 . REASON FOR AMENIMENT 

T h e studydirecto r a s lef t GU 2. 1 

Toxicolog y a s by Apri l 01 , 1986 . 

2. AMENDMENT 

The in-life phase of this study was conducted by

as study director. Since left GU 2.1 Toxicology as 

by April 01, 1986,- the final report was generated by

 has 

reviewed the report and signed as study director. 

There were no known circumstances that could have affected the 

quality and/or integrity of the data. 
TERATOLOGY STUDY IN RATS 21 

GU Project No. 840862 Test Article: TK 12443 

6. REFERENCES 

< 1 > Salewsky,E. ( 1964 ).Arch.Ex.Path.Pharmak. 247, 367 -

368. 

< 2 >, Wilson,J.G. in : Teratology,Principles and Techniques : 

J.G.Wilson and J.Warkany,eds.,The University of Chicago 

Press, Chicago and London ( 1965 ), pp. 265 - 277 

< 3 > Dawson,A.B. ( 1926 ). Stain Tech. 1, 123 - 124. 

< 4 > Brownlee, K. A. ( 1965 ). Statistical theory and ' 

methodology in Science and engineering.John Wiley & Sons, 

< 5 > Ostle, B. ( 1972 ). Statistics in Research. Iowa State 

University Press. 
TERATOLOGY STUDY IN RATS 2 2 

GU Project No. 840862 Test Article: TK 12443 

7. ARCHIVES 

 Raw data , protocol , 

repor t and specimens of laborator y investigation s ar e properl y store d 

a t thi s location . 
TERATOLOGY STUDY IN RATS 23 

GU Project No. 840862 Test Article: TK 12443 

8. RESULTS 

8.1. Observations in dams 

8.1.1. Maternal clinical examination 

The administration of test substance did not induce any obvious 

clinical signs or symptoms in the dams of the dose groups in 

comparison with the vehicle control. 

During the period of treatment necrotic areas of the skin of 

the back, around the right eye and cheek were observed to occur 

unrelated to dosing on females nos. 17 and 19 (control group), 

nos. 30, 41, 43, 44 and 45 (low dose group) , no. 52 

(intermediate dose group) and no. 92 (high dose group). The 

individual findings are listed in the Appendix 9.2.1. 

The necrotic areas of the aforementionend females were locally 

treated with Tyrosolvin , an antibiotic not considered to have 

adversely affected the course of the experiment" in these 

animals. 

For female no. 96 (high dose group) premature birth of three 

fetuses was observed on day 21 post coitum. Since body weight 

and uterus weight could not be determined on the day of 

expected delivery (day 21 p.c) , this female was excluded from 

calculation of the corresponding means. The animal was 

considered, however, for means concerning pregnancy and fetal 

data. 
TERATOLOGY STUDY IN RATS 24 

GU Project No. 840862 Test Article: TK 12443 

8.1.1.l.Table: Summarized maternal clinical observations 

Dose(mg/kg) 

Mated dams 

day : 0- 5 

Dams examined 

Dams w/o findin 

Dams with : 

Total 

day : 6-1 6 

Dams examined 

Dams w/o findin 

Dams with : 

dorsal 

necrotic 

area 

necrotic 

area of 

the cheek 

necrotic 

area 

around 

the right 

eye 

Total 

g 

g 

group 1 

0 

24 

24 

24 

0 

24 

22 

02 

00 

00 

02 

group 2 

300 

24 

24 

24 

0 

24 

19 

03 

02 

00 

05 

group 3 

1000 

24 

24 

24 

0 

24 

23 

01 

00 

00 

Ql 

group 4 

3000 

24 

24 

24 

0 

^ 

24 

23 

01 

00 

01 

01 

day : 17-2 1 

Dams examined 

Dams w/o finding 

Dams with : 

Total 

24 

24 

0 

24 

24 

0 

24 

24 

0 

24 

24 

0 
TERATOLOGY STUDY IN RATS 2 5 

GU Project No. 840862 Test Article: TK 12443 

8.1.2 . Mortalit y 

In th e cours e of thi s teratogenicit y stud y no femal e die d 

spontaneousl y nor had t o be kille d i n moribund condition . 
TERATOLOGY STUDY IN RATS 26 

GU Projec t No. 84086 2 Tes t Article : TK 1244 3 

8.1.3 . Materna l body-weigh t gai n 

F o r mean materna l bod y weight s durin g gestatio n (Table s and 

Figure ) se e th e followin g pages ; fo r individua l bod y weigh t 

durin g gestatio n a s wel l a s statistica l evaluatio n se e 

Appendice s 9.2. 2 an d 9.1.1 , respectively . 

As shown on th e followin g Tabl e and Figur e th e mean body weigh t 

w a s simila r fo r al l groups . 
TERATOLOGY STUDY IN RATS 27 

GU Project No. 840862 Test Article: TK 12443 

8.1.3.1.TABLE: Mean body weights of dams (in g) 

Dose(mg/kg) 

pregnant females 

day: 0 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 

18 

19 

20 

21 

group 1 

0 

21 

194 

202 

209 

• 214 

218 

222 

226 

229 

234 

241 

248 

254 

261 

265 

276 

285 

299 

311 

329 

345 

359 

365 

1 

5 

2 

0 

1 

4 

8 

0 

5 

1 

1 

1 

5 

8 

2 

1 

1 

9 

7 

1 

1 

1 

group 2 

300 

24 

194.9 

204 .4 

211.3 

215.0 

219.3 

223.5 

226.9 

230.5 

236.2 

242.7 

250.1 

256.3 

263.2 

269.4 

276.2 

287.1 

298.8 

313.9 

330.3 

346.5 

362.2 

368.8 

group 3 

1000 

24 

197.2 

206.6 

210.6 

215.7 

220.3 

225.2 

228.2 

231.8 

238.0 

243.8 

252.0 

258.7 

264.8 

270.7 

278.2 

288. 8 

300.5 

315.0 

332.8 

348.6 

363.3 

368.3 

group 4 

3000 

23 

196.5 

2 0 5.2 

212.0 

216.8 

220.5 

224.9 

229. 2 

232.8 

238.7 

245.0 

252.4 

259.3 

265.9 

271.1 

278.2 

287.1 

299. 2 

314.6 

329.4 

344.4 

357.6 

362. 5 
TERATOLOGY STUDY IN RATS 28 

GU Project No. 840862 Test Article: TK 12443 

8.1.3.2.FIGURE: Mean body weights of dams (in g) 

390 

370 . 

350 _ 

330 

310 

290 . 

270 . 

250 . 

230 _ 

210 

190 

Vehicle control 

300 mg/kg day 

1000 mg/kg day 

3000 mg/kg day 

0 8 10 12 1 

r — I \ \— 

4 16 18 20 

Days post coitum 
TERATOLOGY STUDY IN RATS 29 

GU Project No. 840862 Test Article: TK 12443 

8.1.4. Maternal body-weight changes. 

For mean maternal body-weight changes during gestation see the 

following page; for individual body-weight changes and their 

statistical analysis see Appendices 9.2.3 and 9.1.2, respectively. 

In the intermediate dose group body weight was superior to that 

of the control group during days 6 through 11 of pregnancy 

(significant difference confirmed by Student's t test, p < 

0.05) . 

No other differences and no treatment-related changes were 

observed. 
TERATOLOGY STUDY IN RATS 30 

GU Project No. 840862 Test Article: TK 12443 

8.1.4.1.TABLE : Mean maternal body-weight changes during 

gestation 

group 1 group 2 group 3 group 4 

Dose(mg/kg) 0 300 1000 3000 

Pregnant dams 21 24 24 23 

0 - 6 32.9 32.0 31.0 32.8 

6-1 1 27.3 29.4 30.5* 30.1 

11-1 6 45.0 42.5 41.8 39.8 

16-2 1 66.0 70.0 67.8 63.3 

0-2 1 171.0 173.9 171.1 166.0 

6-2 1 138.3 142.0 140.1 133.2 

6-1 6 72.3 71.9 72.3 69.9 
TERATOLOGY STUDY IN RATS 31 

GU Project No. 840862 Test Article: TK 12443 

8.1.5. "Corrected" body weights at necropsy near term 

The mean "corrected" body weight data of the dams are 

summarized on the following page; the individual "corrected" 

body weights and their respective statistical analysis are 

listed in the Appendices 9.2.4 and 9.1.3, respectively. 

No treatment-related change of the corrected body weight was 

observed in the experimental groups as compared with the 

control group. 
TERATOLOGY STUDY IN RATS 32 

GU Project No. 840862. Test Article: TK 12443 

8.1.5.1.TABLE: Mean "corrected" body weight of dams 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

pregnant dams 21 24 24 23 

body weight (g) : 

day 6 227 227 228 229 

day 21 365 369 368 362 

gravid uterus 

weight (g) . 113 108 111 103 

"corrected" body 

weight (g) 

"corrected" body: 

weight gain ii 

"corr." bodyweight gain in %^ 11 15 13 13 

weight (g)^ 252 261 258 260 

weight gain in g^ 26 34 29 30 

2. "corrected" body weight is the difference of the body weigh; 

(day21) minus the uterus weight 

3. "corrected" body-weight gain is equal to the difference of th-.-

"corrected" body weight (day 21) minus body weight (day 6) 

4. "corrected" body-weight gain is equal to the "corr." body-weiuht 

gain divided by the body weight (day 6), times 100 
TERATOLOGY STUDY IN RATS 3 3 

GU Project No. 840862 Test Article: TK 12443 

8.1.6. Food consumption 

Mean food consumption is presented on the following Table and 

Figure. The individual food consumption was calculated from the 

food consumption per cage and the number of animals present. 

The values collected as well as their statistical analysis are 

given in the Appendices 9.2.5 and 9.1.4, respectively. 

The food consumption during pre-treatment, treatiment and posttreatment periods was comparable for the control group, the low 

and intermediate dose groups. 

The slight but statistically significant increase in food 

consumption noted for the high-dose group during days 6-11 and 

6-16, respectively, v/as considered to be unrelated to the 

treatment (t test, p < 0.05). 
TERATOLOGY STUDY IN RATS 34 

GU Project No. 840862 Test Article: TK 12443 

8.1.6.1.TABLE : Food consumption during gestation (in g) 

group 1 group 2 group 3 group 4 

Dose(mg/kg) 0 300 1000 3000 

No. of dams 24 24 24 24 

days : 

0 - 6 19.07 19.42 19.50 19.72 

6-1 1 22.14 22.84 23.03 23.87* 

11 - 16 25.07 25.96 25.89 26.30 

16 - 21 23.61 25.76 24.54 25.10 

0-2 1 22.31 23.30 23.06 23.56 

6-2 1 23.61 24.85 24.49 25.09 

6-1 6 23.60 24.40 24.46 25.09* 
TERATOLOGY STUDY IN RATS 3 5 

GU Project No. 840862 Test Article: TK 12443 

8.1.6.2.FIGURE : Group mean food consumption during 

gestation (in g) 

27 . 

25 . 

23 . 

21 . 

19 . 

17 . 

15 -

-'•'Tr.'rrv. 

Vehicle control 

300 mg/kg day 

— 1000 mg/kg day 

— 3000 mg/kg day 

, 

11 16 21 

Days post CO i turn 
TERATOLOGY STUDY IN RATS 36 

GU Project No. 840862 Test Article: TK 12443 

8.1.7. Maternal postmortem examination 

For summarized gross postmortem observations on the animals see 

the following pages; the individual data are listed in the 

Appendix 9.2.6. 

Female no. 55 (intermediate dose group) was found to have 

aborted part of her litter. 

Female no. 77 (high-dose group) aborted part of her litter. 

Female no. 78 (also from the high-dose group) showed some 

haemorrhagic changes of the uterine epithelium. Among the 15 

implantations of this dam, including 13 live fetuses, one dead 

fetus with disintegrating placenta was found. 

Female no. 86 (.high-dose group) showed aplasia of the left 

uterine horn; in the right uterine horn implantations were 

found. 

In the control group females nos. 9 and 23 were not bearing 

implantation sites and, therefore, excluded from calculation of 

means. 

Female no. 15 from the contirol group had one dead fetus only 

and was also excluded from calculation of means. 

No further remarkable findings were recorded at necropsy. 
TERATOLOGY STUDY IN RATS 37 

GU Project No. 840862 Test Article: TK 12443 

8.1.7.1.TABLE: Summary of maternal postmortem examination 

Dose(mg/kg) 

Mated females 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

24 24 24 24 

Females 

examined 

Females 

without 

macroscopic 

pathol. 

findings on 

day 21 p.c.: 

Females killed 

for humane 

reasons : 

24 

24 

00 

24 

24 

00 

24 

23 

00 

24 

21 

00 

Females w 

cesarean 

section 

Females 

without 

pregnancy : 

Dams V7 total 

resorptions 

Dams w preterm 

delivery : 

24 

02 

00 

00 

24 

00 

00 

00 

24 

00 

00 

00 

24 

00 

00 

01 

Females w 

spont. death 

Females w 

findings 

00 

00 

00 

00 

00 

0 1 

00 

03 

5. no. 55 : partia l abortio n 

6 . no . 77 : partia l abortion , no 78. : uteru s v/it h haemorrluui i 

changes; no . 86: lef t uterus-hor n absen t 
TERATOLOGY STUDY IN RATS 3 8 

GU Project No. 840862 Test Article: TK 12443 

8.1.8. Examination of ovaries, uterus and uterine contents 

The summarized data on Cesarean section are tabulated on the 

following pages. For individual ovarian, uterine and litter 

data see Appendices 9.2.7 and 9.2.8. The statistical analysis 

of these data is presented in the Appendix 9.1.5. 

The mean number of corpora lutea was slightly but not 

significantly increased at 1000 mg/kg and 3000 mgAg/ the mean 

number of implantation sites slightly increased at 1000 mg/kg 

and slightly reduced at 3000 mg/kg (also no statistically 

significant difference from the control). As a consequence of 

slightly increased number of corpora lutea and reduced number 

of implantation sites at 3000 mg/kg the pre-implantation loss 

(ratio corpora lutea / implantation sites) in this high dose 

group v;as superior to that determined for the control group. 

The pregnancy rates of the dams surviving to term were 

confirmed by the presence of implantation sites and determined 

at 91.7 % (control group) and 100 % (experimental groups). 

For one female each of the 1000 mg/kg group (no. 55) and the 

3000 mg/kg group (no. 77) partial abortion of the litter was 

recorded. 

No total abortion of a litter was observed in any of the 

groups. 

In a further dam of the high-dose group (no. 96) premature 

birth of part of the litter (3/18 fetuses) occurred a few hours 

prior to planneca sacrifice. This litter was excluded from 

uterine-data (Table 8.1.8.) but considered for external 

examination as well as visceral and skeletal assessment. 

The rates of embryo and fetolethality (resorptions indicating 

post-implantation loss) were found to be similar for all 

groups. 

One dead fetus was found amongst a litter of the high-dose 

group (female no. 78). The uterine contents of a female from 

the control group consisted of one dead fetus only. 

In the high-dose group the mean litter size showed a slight but 

statistically not significant reduction and remained unchanged 

in the low and intermediate dose groups. 

The average number of male and female fetuses per litter was 

similar for all groups. 

The male-to-female sex ratios v/ere comparable for all groups in 

this study. 
TERATOLOGY STUDY IN RATS 39 

GU Projec t No. 84086 2 Tes t Article : TK 1244 3 

T h e averag e bod y weigh t o f th e liv e fetuse s wa s no t 

significantl y altere d i n th e experimenta l group s on th e per -

litte r basis . 

Comparin g th e mean feta l bod y weight s per ' group , however , a 

significan t reductio n of th e averag e femal e body weigh t i n th e 

l o w dos e grou p ( t test , p < 0.05 ) an d o f th e averag e male , 

averag e femal e an d overal l averag e bod y weigh t o f th e 

intermediat e dos e grou p (p< 0.05 ) wa s observed . Th e latte r 

finding s wer e no t assume d t o b e o f a n experimenta l 

significance . 
TERATOLOGY STUDY IN RATS 40 

GU Project No. 840862 Test Article: TK 12443 

8.1.8.l.TABLE: Summary of cesarean section, pregnancy data 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

mated females 

females sacrificed 

day 21 p.c. 

females w 

deciduomata 

pregnant females 

( %7 

dams w partial 

abortion 

(%) 

dams w partial 

premat. birth at day 

24 

24 

0 

22 

91.7 

0 

0 

24 

24 

0 

24 

100 

0 

0 

24 

24 

0 

24 

100 

1 

4.2 

24 

24 

0 

24 

100 

1 

4.2 

21 

(%) 

dams w total resorp. 

(%) . 

dams w part, resorp. 

(%) 

dams w live fetuses 

(%) 

37 

87 

0 

0 

0 

0 

9 

.5 

21-

.5 

0 

0 

0 

0 

15 

62.5 

24 

100 

0 

0 

0 

0 

13 

54.2 

24 

100 

1 

4.2 

0 

0 

14 

58.3 

23 

100 

7. %-values are indicated as percent of mated females 

8. Female no. 96 excluded from all furhter calculations due to 

partial premature birth of part of its litter 
TERATOLOGY STUDY IN RATS 41 

GU Project No. 840862 Test Article: TK 12443 

8.1.8.2.TABLE: Summary of cesarean section, uterine data(l) 

Cesarean section (mean values): uterine data 1 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

mated females 

pregnant females 

alive at day 21 

dams w live fetuses 

24 

22 

21 

24 

24 

24 

24 

24 

24 

24 

24 

23 

Corpora lutea : 

total no 

mean no 

339 383 395 389 

16.1 16.0 16.9 16.9 

Implant.sites : 

total no 

mean no 

pre-implantation 

loss (%)^ 

implantation 

efficiency (%) 

Early resorp. 

total no 

mean no 

g. 11 

10 

322 

15.3 

6.6 

93.4 

10 

0.48 

3.1 

365 384 

15.2 16.0 

5.7 

94.3 

21 

o;88 

5.8 

7.6 

92.4 

23 

0.96 

6.0 

330 

14.3 

15.0 

85.0 

20 

0.87 

6.1 

Late resorp. : 

total no 

mean no 

Total resorp. 

total no 

mean no 

1 

0.05 

0.3 

11 

0.52 

3.4 

21 

0.88 

5.8 

1 

0.04 

0.3 

24 

1.00 

6.3 

2 

0.08 

0.6 

22 

0.96 

6.7 

9. %-values are indicated as per cent of total number of corpora 

lutea 

10. early resorptions = embryonic resorptions, late resorptions = 

fetal resorptions 

11. %-values are indicated as per cent of total implantations 
TERATOLOGY STUDY IN RATS 4 2 

GU Project No. 840862 Test Article: TK 12443 

Cesarean section (mean values): uterine data 1 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Dead fetuses : 

total no 0 0 0 1 

mean no 0 0 0 0.04 

% 0 0 0 0.3 

All dead implants 

total no 11 21 24 23 

mean no 0.52 0.88 1.00 0.96 

% 3.4 '5.8 6.3 7.0 

Post-implantation 

loss (%) 3.4 5.8 6.3 7.0 

12. dead implants = resorptions -i- dead fetuses 
TERATOLOGY STUDY IN RATS 43 

GU Project No. 840862 Test Article: TK 12443 

8.1.8.3.TABLE: Summary of cesarean section, uterine data(2) 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

mated dams 24 24 24 24 

pregnant dams alive 

at day 21 

dams V7 live fetuses 

total live fetuses 

litter size 

22 

21 

311 

,14.8 

24 

24 

344 

14.3 

24 

24 

359 

15.0 

24 

23 

306 

13.3 

Fetal viability 

(%)13 

left uterus 

right uterus 

total 

Male fetuses : 

total 

per litter 

Female fetuses : 

total 

per litter 

Sex-ratio : 

per litter 

per group 

dams w dead fetuses 

(%)14 

100 

100 

100 

142 

6.8 

169 

8.0 

0.46 

0.46 

0 

0 

100 

100 

100 

165 

. 6.9 

179 

7.5 

0.49 

0.48 

0 

0 

100 

100 

100 

165 

6.9 

194 

8.1 

0.46 

0.46 

0 

0 

99.3 

100 

99.7 

155 

6.7 

151 

6.6 

0.50 

0.51 

1 

4.3 

13. % viable fetuses of total (dead and viable) fetuses 

14. %-values as per cent of dams with live fetuses 
TERATOLOGY STUDY IN RATS 44 

GU Project No. 840862 Test Article: TK 12443 

8.1.8.4.TABLE: Summary of ceasarean section, fetal data 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

mated females 

pregnant dams alive 

at day 21 

litters evaluated 

no. live fetuses 

gravid uterus weight 

(g) 

litter weight (g) 

mean body weight (g) 

per litter: 

24 24 24 24 

21 

21 

311 

113 

1.8 

24 

24 

344 

108 

78.4 

24 

24 

359 

111 

79.9 

23 

23 

306 

103 

72.6 

male fetuses 

female fetuses 

total 

mean body weight (g) 

per group: 

male fetuses 

female fetuses 

total 

5 

• 5 

5 

5 

5 

5 

7 

4 

5 

7 

4 

5 

5.7 

5.3 

5.5 

5.7 

5.3* 

5.5 

5.5 

5.2 

5.4 

5.5* 

5.2* 

5.3* 

5 

5 

5 

5 

5 

5 

6 

4 

5 

6 

4 

5 
TERATOLOGY STUDY IN RATS 45 

GU Project No. 840862 Test Article: TK 12443 

8.2. Observations in fetuses 

8.2.1. External examination of the fetuses 

For summary of findings see the following pages. For individual 

findings see Appendix 9.2.9, for the respective statistical 

analysis see Appendix 9.1.6. 

The following two malformations were found: 

Group 1 (Control): 

Group 4 (3000 mg/kg): 

no. 19/R 03 (male): 

generalized oedema 

no. 84/L 04 (female): 

omphalocele 

No malformations or anomalies were recorded for the low and 

intermediate dose groups. 
TERATOLOGY STUDY IN RATS 46 

GU Project No. 840862 Test Article: TK 12443 

8.2.1. l.TABLE: Summary of fetal external anomalies cind/or 

malformations 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

litters evaluated 

fetuses examined 

21 

311 

24 

344 

24 

359 

24 

324 

externally malf. 

fetuses : 

total 

(%) 

per litter 

(%) 

litters w externa 

malformed fetuses 

total 

(%) 

Ily 

0, 

0. 

0, 

4, 

1 

.32 

.05 

.32 

1 

.76 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0. 

0. 

0. 

4. 

1 

.31 

.04 

.30 

1 

.17 
TERATOLOGY STUDY IN RATS 4 7 

GU Project No. 840862 Test Article: TK 12443 

8.2.2. Fetal visceral examination 

The individual fetal data are listed in Appendix 9.2.9. 

No malformations or anomalies were detected in any of the 

groups, experimental and control, by applying the slicing 

technique. 
TERATOLOGY STUDY IN RATS 48 

GU Project No. 840862 Test Article: TK 12443 

8.2.3. Ossification of fetal skeletons 

For summary of fetal skeletal findings see the following pages. 

For individual fetal skeletal findings see Appendix 9.2.9, for 

their statistical analysis see Appendix 9.1.6. 

Abnormal ossification 

The following anomalies were noted: 

Group 1 

(control) no. 13/R 02 (female): 

6th sternebr a irregularl y ossifie d 

no. 19/R 03 (male): 

1st sternebra irregularly ossified 

no. 20/R 04 (female): 

1st and 2nd sternebrae fused 

no. 22/R 01 (female): 

6th sternebra irregularly ossified 

Group 2 

(300 mg/kg) no. 25/R 06 (male): 

1st and 2nd sternebrae fused 

no. 39/L 01 (male): 

1st sternebra irregularly ossified 

no. 39/L 09 (male): 

1st and 2nd sternebrae fused 

no. 45/R 02 (female): 

1st sternebra irregularly ossified 

Group 3 

(1000 mg/kg) no. 49/L 07 (male): 

1st and 2nd sternebrae fused 

no. 70/L 03 (female): 

1st and 2nd sternebrae fused 

Group 4 

(3000 mg/kg) no. 76/L 05 (female): 

1st and 2nd sternebrae fused 

n o . 76/L 06 (male): 

1 st and 2nd sternebra e fuse d 
TERATOLOGY STUDY IN RATS 4 9 

GU Project No. 840862 Test Article: TK 12443 

no. 76/L 07 (female): 

1st and 2nd sternebrae fused 

Group 4 ctd. no. 89/L 04 (female): 

1st sternebra irregularly ossified 

(bipartite into two unequal 

centers) 

no. 95/L 03 (male): 

1st and 2nd sternebrae fused 

no. 95/R 08 (male): 

1st and 2nd sternebrae fused 

R right L left 

A l l foregoin g finding s concer n th e ossificatio n of sternebrae . 

No significan t difference s were observed betv/een th e thre e dose 

group s and th e contro l group . 
TERATOLOGY STUDY IN RATS 50 

GU Project No. 840862 Test Article: TK 12443 

8.2.3.l.TABLE: Summary of fetal skeletal anomalies and/or 

malformations 

Dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

Litters evaluated 

Fetuses examined 

Malformations: 

Fetuses affected: 

total 

(%) 

per litter 

(%) 

Litters affected: 

total 

(%) 

Anomalies: 

Fetuses affected: 

total 

{%) 

per litter 

(%) 

Litters affected: 

total 

(%) 

Fetuses w delayed 

skel. maturation : 

total 

(%) 

per litter 

(%) 

Litters w delayed 

skel. maturation : 

total 

(%) 

21 

210 

0 

-

0 

-

0 

-

4 

1.90 

0.19 

1.31 

4 

19.0 

208 

99.0 

9.90 

99.2 

21 

100 

24 

230 

0 

-

0 

-

0 

-

4 

1.74 

0.17 

1.19 

3 

12.5 

230 

100.0 

9.58 

100.0 

24 

100 

24 

239 

0 

-

0 

— 

0 

— 

2 

0.84 

0.08 

0.51 

2 

8.3 

237 

99.2 

9.88 

99.4 

24 

100 

24 

216 

0 

-

0 

— 

0 

-

6 

2.78 

0.25 

1.66 

3 

12.5 

216 

100.0 

9.00 

100.0 

24 

100 
TERATOLOGY STUDY IN RATS 51 

GU Project No. 840862 Test Article.: TK 12443 

Skeletal maturation 

On the following Table the skeletal maturation is shown for the 

fetuses of the control group and the three dose groups. 

For the experimental groups some statistically significant 

deviations from the control group were noted (CHI-square test, 

p < 0.05 - 0.001). 

Delayed ossification (as indicated by still absent or poor or 

incomplete ossification) was observed, in particular, in the 

fetuses from the intermediate dose group, concerning: 

- centres of cervical vertebrae 

- metatarsal 1 

- fore paw: proximal phalangeal nuclei 2 and 5 

(no. 5 also affected at 3000 mg/kg) 

- rear paw: proximal phalangeal nuclei 2-5 

(nos. 2-4 also affected at 300 mg/kg; nos. 3 and 4 at 

3000 mg/kg) 

- 1st sternebra 

- center of 10th thoracic vertebra 

In the absence of any dose-relationship, i. e. an accumulation 

of findings in the intermediate dose group, no experimental 

significance was attributed to the foregoing findings. 
TERATOLOGY STUDY IN RATS 5 2 

GU Project No. 840862 Test Article: TK 12443 

8.2.3.2.TABLE: Summarized data of delayed skeletal 

maturation 

dose (mg/kg) 

litters evaluated 

fetuses examined 

ossification still absoit 

(no. of fetuses): 

Center of 

cervic.vertebr. 1 

g roup 1 

0 

21 

210 

161 

g roup 2 

300 

24 

230 

187 

group 3 

1000 

24 

239 

192 

g roup 4 

3000 

24 

216 

145 • 

15 

2 

3 

4 

5 

6 

7 

Sternebra 2 

Sternebra 5 

Rib 13 (R) 

Rib 13 (L) 

Rib 13 (L+R)-

Rib 13 (total) 

Metacarpals 5 (L+R) 

Calcaneus (R) 

Calcaneus (L) 

Calcanei (L+R) 

Calcanei (total) 

Metatarsal 1 (R) 

Metatarsal 1 (L) 

Metatarsal 1 (L+R) 

Metatarsal 1 (total) 

ant.dist.phal. 

nucleus 5 (L) 

ant.prox.phal. 

nucleus 2 

2 

2 

2 

3 

4 

4 

4 

(R) 

(L) 

(L+R) 

(total) 

(L+R) 

(L) 

(R) 

(L+R) 

187 

68 

37 

23 

17 

0 

1 

0 

2 

0 

1 

3 

0 

2 

9 

178 

189 

0 

1 

6 

7 

0 

202 

75 

50 

36 

19 

1 

1 

1 

2 

1 

1 

4 

0 

6 

10 

191 

207 

2 

2 

10 

14 

0 

213 

92 

67 

48 

25 

3 

0 

0 

0 

1 

1 

2 

0 

4 

10 

184 

198 

1 

2 

17 

20 

+ + 

+ + 

+ + 

183 

55 

35 

21 

17 

2 

2 

0 

0 

0 

0 

0 

1 

9 

8 

156 

173 

1 

0 

11 

12 

0 

0 

1 

2 

3 

0 

0 

1 

0 

1 

3 

5 

9 

0 

0 

0 

0 

0 

6 

12 + 

18 + + 

0 

1 

0 

0 

0 

1 

5 

6 

1 

0 

1 

1 

+ + 

15. L+R= left and right 
TERATOLOGY 

GU Project No. 840862 

dose (mg/kg) 

4 (total) 

5 (R) 

5 (L) 

5 (L+R) 

5 (total) 

post.prox.phal. 

nuclei 2 (R) 

2 (L) 

2 (L+R) 

2 (total) 

3 (R) 

3 (L) 

3 (L+R) 

, 3 (total) 

4 (R) 

4 (L) 

4 (L+R) 

4 (total) 

5 (R) 

5 (L) 

5 (L+R) 

5 (total) 

poorly ossified: 

Sternebrae 1 

2 

3 

5 

6 

Metacarpal 5 (R) 

ant.prox.phal. 

nucleus 2 (R) 

2 (L) 

2 (L+R) 

2 (total) 

3 (L) 

3 (R) 

3 (total) 

4 (L) 

4 (R) 

4 (L+R) 

4 (total) 

5 (R) 

5 (L) 

5 (L+R) 

5 (total) 

Calcaneus (R) 

Calcaneus (L) 

Calcanei (L+R) 

group 1 

0 

1 

2 

4 

4 

10 

11 

6 

22 

39 

6 

3 

10 

19 

6 

2 

11 

19 

18 

11 

54 

83 

3 

5 

0 

2 

0 

0 

2 

2 

0 

4 

0 

1 

1 

0 

1 

0 

1 

6' 

2 

3 

11 

2 

2 

2 

STUDY IN 

group 2 

300 

0 

5 

7 

6 

18 

16 

9 

38 

63 

8 

3 

32 

43 

8 

2 

31 

41 

19 

15 

76 

110 

8 

2 

0 

5 

3 

0 

2 

3 

6 

11 

0 

0 

0 

0 

0 

0 

0 

6 

10 

8 

24 

2 

0 

0 

RATS 

Test Articl 

group 3 

+ 

++ 

++ 

++ 

++ 

-1-

+ 

+ 

1000 

1 

2 

10 

18 

30 

17 

8 

59 

84 

12 

3 

38 

52 

14 

4 

36 

54 

13 

12 

98 

123 

12 

0 

0 

2 

4 

0 

2 

2 

0 

4 

0 

0 

0 

0 

0 

0 

0 

8 

8 

5 

21 

1 

3 

1 

53 

e: TK 12443 

group 4 

++ 

++ 

+++ 

+++ 

+++ 

+++ 

+++ 

+++ 

+++ 

+ 

+ 

+ 

3000 

2 

3 

10 

8 

21 + 

16 

6 

33 

55 

7 

2 

27 + + 

36 + 

4 

2 

28 + + 

34 + 

15 

11 

68 

94 

3 

1 

1 

3 

1 

2 

1 

4 

0 

5 

1 

0 

1 

1 

0 

1 

2 

4 

2 

4 

10 

5 

2 

0 
TERATOLOGY STUDY IN 

GU Project No. 840862 

RATS 

Test Article: TK 

54 

12443 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

Calcanei (total) 

Metatarsal 1 (R) 

post.p 

nuclei 

Short 

Short 

Short 

Short r 

dumbbellCenter 

cervic 

Center 

thorac 

rox.phal. 

2 (R) 

2 (L) 

2 (L+R) 

2 (total) 

3 (R) 

3 (L) 

3 (L+R). 

3 (total) 

4 (R) 

4 (L) 

4 (L+R) 

4 (total) 

5 (R) 

5 (L) 

5 (L+R) 

5 (total) 

rib 13 (R) 

rib 13 (L) 

rib 13 (L+R) 

ib 13 (total) 

shaped: 

of 

.vertebr. 1 

2 

of 

.vertebr. 5 

8 

9 

10 

11 

12 

6 

2 

2 

3 

2 

7 

1 

1 

1 

3 

0 

1 

0 

1 

9 

13 

1 

23 

8 

4 

1 

13 

9 

0 

0 

0 

0 

0 

3 

1 

2 

0 

2 

2 

1 

5 

2 

2 

2 

6 

2 

2 

2 

6 

8 

9 

8 + 

25 

7 

7 

3 

17 

6 

1 

1 

2 

0 

1 

3 

2 

5 

0 

3 

0 

1 

4 

0 

2 

0 

2 

0 

1 

1 

2 

4 

5 + 

1 

10 + + 

5 

7 

3 

15 

9 

0 

0 

0 

0 

5 + 

3 

1 

7 

0 

1 

0 

0 

1 

0 

1 

1 

2 

0 

1 

1 

2 

6 

5 

1 

12 

5 

4 

3 

12 

16 

0 

0 

0 

3 

4 

4 

2 

bipartite : 

Center of 

cervic.vertebr. 

Center of 

thorac.vertebr. 1 

10 

11 

12 

13 

10 14 10 22 + 

0 

0 

1 

1 

0 

1 

0 

1 

1 

1 

0 

2 

1 

1 

0 

0 

0 

0 

0 

0 
TERATOLOGY STUDY IN RATS 5 5 

GU Project No. 840862 Test Article: TK 12443 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

OSS. incomplete : 

Sternebra e 3 

4 

5 

0 

0 

3 

1 

1 

3 

0 

2 

5 

0 

0 

4 
TERATOLOGY STUDY IN RATS 56 

GU Project No. 840862 Test Article: TK 12443 

8.2.4. Summarized fetal abnormalities 

One instance of gross malformation was recorded for each the 

control group (generalized oedema) and the high-dose group 

(omphalocele). 

No gross malformations were observed in the low and 

intermediate dose groups. 

There were no visceral or skeletal malformations found in any 

of the groups. 

Some skeletal anomalies were found to occur at similar 

incidences among the fetuses of all groups, experimental and 

control. Most of these anomalies were consistent with 

synostosis of sternebrae 1 and 2. The occurrence of irregular 

ossification of sternebrae 1 or 6 was also noted. 

The findings concerning skeletal maturation were not considered 

to be consistent with anomalies or malformations. 

All findings on external, visceral and skeletal abnormalities 

are listed on the following Table. The individual data are 

represented in the Appendix 9.2.9, their statistical analysis 

in the Appendix 9.1.6. 
TERATOLOGY STUDY IN RATS 57 

GU Projec t No. 840862 Test Article : TK 12443 

8.2.4.l.TABLE: Summary of al l feta l anomalie s and/o r 

malformation s 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

litters evaluated 

fetuses w gross 

malf. 

fetuses examined 

fetuses w visceral 

anomalies 

fetuses w visceral 

malf. 

fetuses examined 

fetuses w skeletal 

malf. 

fetuses w skeletal 

anomalies 

fetuses examined 

Total no 

malf./anomalous 

fetuses 

Total no fetuses 

examined 

% anomalous/malf. 

fetuses 

21 

1 

311 

0 

101 

0 

16 

0 

4 

210 

3ir 

1.29 

24 

0 

344 

.0 

0 

114 

0 

4 

230 

344 

24 

0 

359 

0 

0 

120 

0 

2 

239 

359 

24 

1 

324 

0 

0 

108 

0-

216 

1.16 0.56 

324 

2.2i 

16. Excluded 2 fetuses from female no. 19 (nos. L 05 and R 02) 

selected by mistake for skeletal assessment (there included) 
TERATOLOGY STUDY IN RATS 58 

GU Project No. 840862 Test Article: TK 12443 

APPENDICES 

9.1. Statistical analysis 

Student',s t-test has been applied to all the data listed in 

this section, except for the analysis of anomalies, to which 

the CHI-square test was applied. 

* : values different at the 5%-confidence level (t-Test) 

+ : values different at the 5%-confidence level 

(CHI-square-test) 

++ : values different at the 1%-confidence level 

(CHI-square-test) 

+++ : values different at the 0.1%-confidence level 

(CHI-square-test) 

N : number of values evaluated 

S.D. : standard deviation 
TERATOLOGY STUDY IN RATS 59 

GU Project No. 840862 Test Article: TK 12443 

9.1.1. Body weights 

Analysis of Body weight data (dams) 

Day 0: 

group 1 group 2 group 3 

dose (mg/kg) 0 300 1000 

group 4 

3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign 

21 

176 

212 

194 

8.3 

24 

176 

212 

195 

9.8 

24 

179 

214 

197 

9.3 

23 

180 

214 

196 

8.5 

Day 1: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign, 

21 

187 

219 

203 

8.5 

24 

181 

222 

204 

10.0 

24 

187 

220 

207 

8.8 

23 

180 

226 

205 

11.2 
TERATOLOGY STUDY IN RATS 60 

GU Project No. 840862 Test Article: TK 12443 

Day 2: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

190 

225 

209 

8.2 

24 

189 

229 

211 

10.6 

24 

194 

223 

211 

8.7 

23 

189 

234 

212 

11.0 

Day 3: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N • 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

196 

2-32 

214 

8.4 

24 

195 

228 

215 

9.2 

24 

195 

229 

216 

9.2 

23 

193 

239 

217 

11.1 
TERATOLOGY STUDY IN RATS 61 

GU Project No. 840862 Test Article: TK 12443 

Day 4: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

199 

232 

218 

8.6 

24 

194 

236 

219 

10.8 

24 

200 

231 

220 

9.8 

23 

200 

245 

221 

11.5 

Day 5: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat. sign 

21 

206 

238 

222 

7.7 

24 

198 

24 0 

224 

10.8 

24 

204 

240 

225 

9.5 

23 

203 

253 

225 

12.0 
TERATOLOGY STUDY IN RATS 62 

GU Project No. 840862 Test Article: TK 12443 

Day 6: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

208 

243 

227 

8.3 

24 

201 

247 

227 

11.6 

24 

208 

240 

228 

10.4 

23 

207 

253 

229 

11.2 

Day 7: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign 

21 

210 

245 

229 

8.8 

24 

201 

251 

231 

11.5 

24 

212 

250 

232 

10.5 

23 

204 

256 

233 

12.6 
TERATOLOGY STUDY IN RATS 63 

GU Project No. 840862 Test Article: TK 12443 

Day 8: 

dose (rag/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

212 

254 

234 

9.9 

24 

210 

258 

236 

12.1 

24 

215 

255 

238 

11.1 

23 

215 

275 

239 

14.5 

Day 9: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000' 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

221 

260 

241 

9.8 

24 

216 

269 

243 

12.0 

24 

223 

259 

244 

10.4 

23 

219 

271 

245 

14 .0 
TERATOLOGY STUDY IN RATS 64 

GU Project No. 840862 Test Article: TK 12443 

Day 10: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat. sign 

21 

228 

266 

248 

0.1 

24 

221 

274 

250 

12.2 

24 

228 

274 

252 

11.2 

23 

228 

292 

252 

15.4 

Day 11: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

227 

274 

254 

11.4 

24 

227 

286 

256 

13.6 

24 

234 

279 

259 

11.4 

23 

233 

294 

259 

15.8 
TERATOLOGY STUDY IN RATS 65 

GU Project No. 840862 Test Article: TK 12443 

Day 12: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat. si gn. 

21 

236 

281 

261 

11.7 

24 

233 

293-

263 

13.8 

24 

236 

287 

265 

12.1 

23 

240 

312 

266 

17.2 

Day 13: 

dose (mg/kg 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

239 

289 

266 

12.9 

24 

235 

303 

269 

5.1 

24 

242 

296 

271 

12.2 

23 

241 

313 

271 

17.2 
TERATOLOGY STUDY IN RATS 66 

GU Project No. 840862 Test Article: TK 12443 

Day 14: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat. si gn. 

21 

245 

298 

276 

13.6 

24 

243 

317 

276 

15.4 

24 

249 

309 

278 

13.6 

23 

245 

328 

278 

19.4 

Day 15: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

253 

310 

285 

15.2 

24 

249 

330 

287 

17.1 

24 

258 

326 

289 

14.5 

23 

257 

342 

287 

20.3 
TERATOLOGY STUDY IN RATS 67 

GU Project No. 840862 Test Article: TK 12443 

Day 16: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign 

21 

271 

324 

299 

15.0 

24 

261 

347 

299 

17.9 

•• 2 4 

272 

358 

301 

15.5 

23 

265 

364 

299 

22.6 

Day 17: 

dose (mg/kg; 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

279 

340 

312 

6.4 

24 

277 

367 

314 

19.3 

24 

284 

358 

315 

17.0 

23 

272 

387 

315 

24.7 
TERATOLOGY STUDY IN RATS 6 8 

GU Project No. 840862 Test Article: TK 12443 

Day 18: 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+S. D. 

stat.si gn. 

21 

296 

363 

330 

17.0 

24 

286 

393 

330 

22.1 

24 

303 

380 

333 

18.2 

23 

275 

412 

329 

29.2 

Day 19: 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D 

stat si gn. 

21 

308 

379 

345 

19.9 

24 

298 

414 

347 

23.5 

24 

317 

406 

349 

20.9 

23 

280 

435 

344 

32.3 
TERATOLOGY STUDY IN RATS 69 

GU Project No. 840862 Test Article: TK 12443 

Day 20: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

317 

399 

359 

21.4 

24 

321 

424 

362 

24.0 

24 

329 

421 

363 

22.0 

23 

282 

458 

358 

36.5 

Day 21: 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 .300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. si gn. 

21 

326 

415 

365 

25.0 

24 

329 

433 

' 369 

25.1 

24 

318 

430 

368 

27.2 

23 

288 

460 

362 

35.8 
TERATOLOGY STUDY IN RATS 70 

GU Project No. 840862 Test Article: TK 12443 

9.1.2. Body weight changes 

Day 0-6 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

25.7 

43.1 

32.9 

4.3 

24 

20.7 

48.3 

32.0 

6.9 

24 

24.1 

50.4 

31.0 

5.7 

23 

15.6 

48.4 

32.8 

6.8 

Day 6-11 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 . 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

2 1 

19. 0 

37. 3 

27. 3 

4 . 9 

24 

2 0 . 9 

42. 9 

29. 4 

5 . 3 

24 

21. 5 

40. 3 

30. 5 

4 . 3 

23 

19. 7 

45. 1 

30. 1 

6 . 1 
TERATOLOGY STUDY IN RATS 71 

GU Project No. 840862 Test Article: TK 12443 

Day 11-16 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

m m . 

max. 

mean 

+S.D . 

stat.sig n 

21 

28. 5 

58. 7 

45. 0 

6 . 2 

24 

32. 7 

61. 6 

42. 5 

6 . 4 

24 

2 9 . 8 

58. 4 

4 1 . 8 

6 . 8 

23 

17. 8 

70. 0 

39. 8 

10. 2 

Day 16-2 1 

dos e (mg/kg ; 

grou p 1 grou p 2 group 3 grou p 4 

0 300 100 0 300 0 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

52.1 

91.6 

66.0 

11. 9 

24 

56.1 

98.2 

70.0 

10.3 

24 

35.7 

100.9 

67.8 

14.2 

23 

23.4 

95.6 

63.3 

16.5 
TERATOLOGY STUDY IN RATS 72 

GU Project No. 840862 Test Article: TK 12443 

Day 0-21 

dose (mg/kg; 

Day 6-21 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.si gn. 

21 

133.3 

227.4 

171.0 

23.0 

24 

144.5 

234.0 

173.9 

22.5 

24 

134.8 

242.0 

171.1 

24.7 

23 

95.0 

255.6 

166.0 

32.2 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

103.5 

184.3 

138.3 

20.3 

24 

115.4 

185.8 

142.0 

18.8 

24 

106.0 

191.6 

140.1 

20.9 

23 

67.8 

207.3 

133.2 

27.7 
TERATOLOGY STUDY IN RATS 7 3 

GU Project No. 840862 Test Article: TK 12443 

Day 6-16 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

49.9 

92.9 

72.3 

10.1 

24 

57.1 

100.0 

71.9 

10.0 

24 

60.1 

98.6 

72.3 

9.5 

23 

44.4 

111.7 

69.9 

14.1 
TERATOLOGY STUDY IN RATS 74 

GU Project No. 840862 Test Article: TK 12443 

9.1.3. "Corrected" body weights 

Analysis of "corrected" Body weight 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min . 

max. 

mean 

+ S.D. 

stat. sign. 

21 

220 

289 

252 

19.6 

24 

221 

304 

261 

20.4 

24 

224 

315 

258 

21.2 

23 

222 

304 

260 

21.9 

Analysis of "corrected" body weight gain 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

21 24 24 23 

-7.0 1.0 6.0 9.8 

58.1 68.4 75.3 86.0 

25.6 33.7 29.4 30.4 

16.7 17.1 15.1 18.1 

N 

min. 

max. 

mean 

+S.D. 

stat. sign 
TERATOLOGY STUDY IN RATS 75 

GU Project No. 840862 Test Article: TK 12443 

Analysis of "corrected" body weight diff. % 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat. si gn. 

21 

-3.0 

25.2 

11.3 

7.3 

24 

0.4 

32.2 

14.9 

7.7 

24 

2.5 

31.4 

12.8 

6.3 

23 

4.1 

39.7 

13.3 

8.0 

Analysis of gravid uterus weight 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

81 

135 

113 

12.2 

24 

65 

129 

108 

14.8 

24 

80 

139 

111 

14. 9 

23 

12 

155 

103 ~ 

33.1 
TERATOLOGY STUDY IN RATS 76 

GU Project No. 840862 Test Article: TK 12443 

9.1.4. Food Consumption 

Analysis of Food consumption 

Day 0-6 

group 1 group 2 group 3 

dose (mg/kg) 0 300 1000 

group 4 

3000 

m m . 

max. 

mean 

+S.D. 

stat.sign. 

24 

18. 2 

20.3 

19.1 

1.0 

. 24 

18.8 

21.1 

19.4 

0. 8 

24 

18.7 

20.8 

19.5 

0.8 

24 

18.2 

20.4 

19.7 

0.8 

Day 6-11 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min . 

max. 

mean 

+ S.D . 

stat . s i g n . 

24 

20. 6 

24. 0 

22. 1 

1 . 5 

24 

21. 6 

24. 7 

22. 8 

1 . 0 

24 

21. 4 

24. 2 

23. 0 

1 . 1 

24 

22. 5 

25. 1 

23. 9 

1 . 0 

* 
TERATOLOGY STUDY IN RATS 77 

GU Project No. 840862 Test Article: TK 12443 

Day 11-16 

dos e (mg/kg) 

grou p 1 grou p 2 group 3 grou p 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign 

24 

23. 2 

27.0 

25.1 

1.2 

24 

24 . 0 

27. 3 

26. 0 

1 . 2 

24 

24. 8 

27. 1 

26. 0 

0 . 8 

24 

24.3 

27.9 

26.3 

1.2 

Day 16-21 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign 

24 

20.8 

27.2 

23. 1 

2.1 

24 

23.6 

27.1 

25.8 

1.4 

24 

22.0 

26.7 

24.5 

1.6 

24 

24.4 

25.7 

25.1 

0.6 
TERATOLOGY STUDY IN RATS 7! 

GU Project No. 840862 Test Article: TK 12443 

Day 0-21 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

. 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

24 

20. 6 

24. 4 

22. 3 

1 . 3 

24 

21. 8 

2 4 . 9 

23. 3 

1.0 

24 

22. 1 

24. 5 

23. 1 

1 . 0 

24 

22. 6 

24. 3 

23. 6 

0 . 7 

Day 6-21 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

24 

21. 5 

26.1 

23.6 

1.5 

24 

23.0 

26.4 

24.9 

l.l' 

24 

23.5 

26.0 

24. 5 

1.0 

24 

24.3 

26.0 

25.1 

0.7 
TERATOLOGY STUDY IN RATS 7 9 

GU Project No. 840862 Test Article: TK 12443 

Day 6-16 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S . D. 

stat. sign. 

24 

21.9 

25.5 

23.6 

1.3 

24 

22.8 

26.0 

24.4 

1.0 

24 

23.1 

25.6 

24.5 

0.9 

24 

23.7. 

26.5 

25.1 

1.0 

* 
TERATOLOGY STUDY IN RATS 80 

GU Project No. 840862 Test Article: TK 12443 

9.1.5. Uterine data 

Corpora lutea total 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat: si gn. 

21 

12 

22 

16.1 

2.15 

24 

11 

20 

16.0 

2.33 

24 

13 

20 

16.9 

1.57 

23 

8 

23 

16.9 

2.81 

Implantations total 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. si gn. 

21 

11 

18 

15.3 

1.83 

24 

10 

19 

15.2 

2.19 

24 

13 

19 

16.0 

1.56 

23 

1 

19 

14.3 

3.90 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article: TK 12443 

Resorptions early total 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. si gn. 

21 

0 

2 

0.48 

0.60 

24 

0 

3 

0. 88 

0.90 

24 

0 

5 

0.96 

1.37 

23 

0 

7 

0.87 

1.46 

Resorptions late total 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

0 

1 

0.05 

0.22 

24 24 • 

0 

1 

0.04 

0.20 

23 

0 

1 

0.09 

0.29 
TERATOLOGY STUDY IN RATS 82 

GU Project No. 840862 Test Article: TK 12443 

Resorptions total 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

0 

2 

0.52 

0.68 

24 

0 

3 

0.88 

0.90 

24 

0 

5 

1.00 

1.35 

23 

0 

7 

0.96 

1.46 

Dead fetuses total 

dose (mg/kg; 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. si gn. 

21 

0 

2 

0.11 

0.19 

24 24 

0 

1 

0.05 

0.20 

23 

0 

1 

0.04 

0.21 
TERATOLOGY STUDY IN RATS 83 

GU Project No. 840862 Test Article: TK 12443 

Live Fetuses total 

dose (mg/kg; 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign, 

21 

10 

17 

14.81 

1.81 

14 

2 

24 

7 

18 

33 

63 

14 

2 

24 

11 

19 

96 

.10 

23 

10 

19 

13.30 

4.44 

Live Fetuses male 

dose (mg/kg; 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

4 

10 

6.8 

.73 

24 

4 

11 

6.9 

2.09 

24 

3 

13 

6.9 

2.31 

23 

0 

12 

6.7 

2.99 
TERATOLOGY STUDY IN RATS 84 

GU Project No. 840862 Test Article: TK 12443 

Live Fetuses female 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S. D. 

stat.sign. 

21 

5 

12 

8.0 

2.16 

24 

2 

12 

4.5 

2.86 

24 

4 

12 

8.1 

2.04 

23 

0 

11 

6.6 

2.71 

Sex-ratio per litter 

dos e (mg/kg) 

grou p 1 grou p 2 group 3 grou p 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+S.D. 

stat.sign. 

21 

0.25 

0.67 

0.46 

0.11 

24 

0.29 

0.75 

0.49 

0.15 

24 

0. 21 

0.76 

0.46 

0.12 

23 

0.00 

1.00 

0.50 

0.20 
TERATOLOGY STUDY IN RATS 85 

GU Project No. 840862 Test Article: TK 12443 

Litter weight 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. si gn. 

21 

58.6 

96.6 

81.8 

9.0 

24 

43.9 

95.3 

78.4 

11.8 

24 

48.1 

103.7 

79.9 

12.3 

23 

5.7 

111.1 

72.6 

24 .8 

Body weight male (per litter) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat.sign. 

21 

5.1 

6.2 

5.7 

0.32 

24 

5.0 

6.5 

5.7 

0.36 

24 

2.9 

6.1 

5.5 

0.61 

22 

2.8 

7.0 

5.6 

0.78 
TERATOLOGY STUDY IN RATS 86 

GU Project No. 840862 Test Article: TK 12443 

Day Body weight female (per litter) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 21 24 24 22 

min. 4.9 4.7 3.1 4.3 

max. 5.9 5.9 5.7 6.8 

mean 5.4 5.3 5.2 5.4 

+S.D. 0.27 0.30 0.51 0.56 " 

stat.sign. 

Body weight total (per litter) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D . 

stat . si gn. 

2 1 

5 . 0 

6 . 0 

5 . 5 

0.2 8 

24 

4 . 9 

6 . 3 

5 . 5 

0.3 4 

24 

3 . 0 

5 . 8 

5 . 4 

0.5 5 

23 

2 . 8 

6 . 8 

5 . 5 

0.7 7 
TERATOLOGY STUDY IN RATS 57 

GU Project No. 840862 Test Article: TK 12443 

Body weight male (per group) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. sign. 

142 

3.6 

6.5 

5.7 

0.42 

165 

4.2 

6.7 

5.7 

0.47 

165 

2.1 

6.5 

5.5 

0.72 

* 

155 

2.6 

7.1 

5.6 

0.60 

Body weight female (per group) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+ S.D. 

stat. sign 

169 

3.6 

6.3 

5.4 

0.37 

179 

2.6 

6.4 

5.3 

0.44 

194 

2.8 

6.0 

5.2 

0.54 

151 

3.9 

6.8 

5.4 

0.51 
TERATOLOGY STUDY IN RATS 88 

GU Project No. 840862 Test Article: TK 12443 

Body weight total (per group) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

N 

min. 

max. 

mean 

+S . D. 

stat.sign. 

3 1 1 

3 . 6 

6 . 5 

5 . 5 

0.4 3 

344 

2 . 6 

6 . 7 

5 . 5 

0.5 0 

359 

2 . 1 

6 . 5 

5 . 3 

0.6 4 

306 

2 . 6 

7 . 1 

5 . 5 

0.5 7 
TERATOLOGY STUDY IN RATS 89 

GU Project No. 840862 Test Article: TK 12443 

9.1.6. Fetal skeletal findings 

External fetal malformations 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 311 344 359 324 

Number of 

affected fetuses 1 0 0 1 

o 

stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 1 0 0 1 

stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 90 

GU Project No. 840862 Test Article: TK 12443 

Fetal skeletal anomalies 

dose (mg/kg) 

group 1 group 2 group 3 group 4 

0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 4 

o 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 4 

o 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of Cerv.Vert.(1) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 

Number of 

affected fetuses 161 187 192 

o 

stat.sign.(chi ) 

Total number of 

litters 21 24 24 

Number of 

affected litters 21 24 24 

Stat.sign.(chi ) 

216 

145 

+ 

24 

23 
TERATOLOGY STUDY IN RATS 91 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Cerv.Vert.(2) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 187 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 21 

stat.sign.(chi ) 

230 

202 

24 

24 

239 

213 

24 

24 

216 

183 

24 

24 

Skeletal maturation: oss. of Cerv.Vert.(3) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

Stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

210 

68 

21 

19 

230 

75 

24 

19 

239 

92 

+ + 

24 

20 

216 

55 

24 

stat.sign.(chi ^2, 
TERATOLOGY STUDY IN RATS 92 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Cerv.Vert.(4) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 

Number of 

affected fetuses 37 50 67 

stat. sign, (chi'^) + + 

Total number of 

litters 21 24 24 

Number of 

affected litters 17 17 18 

9 Stat.sign.(chi ) 

216 

35 

24 

14 

Skeletal maturation: oss. of Cerv.Vert.(5) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

210 

23 

21 

13 

230 

36 

24 

14 

239 

48 

24 

14 

216 

21 

24 

12 

stat.sign.(chi . 2, 
TERATOLOGY STUDY IN RATS 93 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Cerv.Vert.(6) absent 

group 1 group 2 group 3 group ' 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

Stat. sign, (chi'^) 

210 

17 

21 

11 

230 

19 

24 

239 

25 

24 

216 

17 

24 

10 

Skeletal maturation: oss. of Cerv.Vert.(7) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
.,iJSj^:. 

TERATOLOGY STUDY IN RATS 94 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Sternebra (2) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of Sternebra (5) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 9 5 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Calcanei(L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 

Number of 

affected fetuses 178 191 184 

9 

stat.sign.(chi ) 

Total number of 

litters 21 24 24 

Number of 

affected litters 21 24 24 

9 

stat.Sign.(chi ) 

216 

156 

++ 

24 

23 

Skeletal maturation: oss. of Calcanei (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 

stat.sign.(chi ) 

Total number of 

litters , 21 

Number of 

affected litters 2 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 96 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Calcanei (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affecte d fetuse s 9 10 10 8 

9 Stat.sign.(ch i ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 8 6 9 7 

9 

stat.sign.(chi ) 

Skeletal maturation: oss. of Calcanei (total) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses • 210 230 239 216 

Number of 

affected fetuses 189 207 198 173 

9 stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 21 24 24 23 

9 stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 97 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Metatarsal 1 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 Stat.sign.(chi ) 

210 

21 

230 

10 

24 

239 

17 

+ 

24 

216 

11 

24 

Skeletal maturation: oss. of Metatarsal 1 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 98 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Metatarsal 1 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of Metatarsal 1 (total) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 

Number of 

affected fetuses 7 14 20 

9 stat.Sign.(chi ) + 

Total number of 

litters 21 24 24 

Number of 

affected litters 6 7 9 

stat.sign.(chi^) 

216 

12 

24 
TERATOLOGY STUDY IN RATS 99 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Rib 13 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of Rib 13 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

stat.sign.(chi^) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 100 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Rib 13 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of Rib 13 (total) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 3 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 3 

stat.sign.(chi^) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 101 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.dist.phal.nuclei 5 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nucleus 2 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of •" 

affected fetuses 2 

9 Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

9 

stat.sign.(chi ) 

230 

24 

239 

12 

24 

216 

24 
TERATOLOGY STUDY IN RATS 102 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.prox.phal.nuclei 2 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 239 

21 24 24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nuclei 2 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 103 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.prox.phal.nuclei 2 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 3 

9 Stat.sign.(chi^) 

Total number of 

litters 21 

Number of 

affected litters 3 

9 stat.sign.(chi ) 

230 

24 

239 

++ 

24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nucleus 3 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 104 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.prox.phal.nucleus 4 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 239 

21 24 24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nucleus 4 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

Stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 105 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.prox.phal.nucleus 4 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.Sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nucleus 4 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 106 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.prox.phal.nucleus 5 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 4 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 4 

9 

stat.sign.(chi ) 

230 

24 

239 

++ 

24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nucleus 5 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 4 

9 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 4 

9 stat.sign.(chi ) 

230 

24 

239 

10 

24 

216 

10 

24 
TERATOLOGY STUDY IN RATS 107 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of ant.prox.phal.nucleus 5 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

stat.sign.(chi .2, 

210 

21 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of ant.prox.phal.nucleus 5 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 10 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affecte d litter s 

9 stat.sign.(ch i ) 

230 

24 

239 

30 

+ + 

24 

11 

216 

21 

+ 

24 

10 
TERATOLOGY STUDY IN RATS 108 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Metacarpal 5 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affecte d fetuse s 0 0 0 1 

9 

stat.sign.(ch i ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 0 0 0 1 

9 

stat.sign.(chi ) 

Skeletal maturation: oss. of post.prox.phal.nuclei 2 (L+R) absent 

group 1 group 2 group 3 group 4 

• dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 ' 216 

Number of 

affecte d fetuse s 22 38 59 33 

stat.sign.(chi^ ) +++ 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 15 11 14 12 

9 stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 109 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 2 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

stat.sign.(chi . 2. 

210 

21 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of post.prox.phal.nuclei 2 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 11 16 17 16 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 11 11 11 10 

9 

stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 110 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 2 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 39 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 15 

9 

stat.sign.(chi ) 

230 

63 

24 

16 

239 

84 

++ + 

24 

216 

55 

24 

15 

Skeletal maturation: oss. of post.prox.phal.nuclei 3 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 10 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 

9 

stat.sign.(chi ) 

230 

32 

++ 

24 

11 

239 

38 

+++ 

24 

11 

216 

27 

++ 

24 

11 
TERATOLOGY STUDY IN RATS 111 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 3 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 3 

9 

Stat.Sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

• 2 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of post.prox.phal.nuclei 3 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 6 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 6 

9 stat.sign.(chi ) 

230 

24 

239 

12 

24 

10 

216 

24 
TERATOLOGY STUDY IN RATS 112 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 3 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 19 43 52 36 

stat.sign.(chi^) ++ +++ + 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 12 14 14 12 

9 

stat.sign.(chi ) 

Skeletal maturation: oss. of post.prox.phal.nuclei 4 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 11 31 36 28 

stat.sign.(chi^) ++ +++ ++ 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 5 11 10 11 

9 

stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 113 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 4 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: oss. of post.prox.phal.nuclei 4 (R) absent 

group 1 group 2 group- 3 group 4 

dose (mg/kg) 0 300 1000 . 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 6 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 6 

9 

stat.sign.(chi ) 

230 

24 

239 

14 

24 

10 

216 

24 
TERATOLOGY STUDY IN RATS 114 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 4 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 19 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 11 

9 

stat.sign.(chi ) 

230 239 

41 

++ 

24 

13 

54 

'+++ 

24 

14 

216 

34 

+ 

24 

12 

Skeletal maturation: oss. of post.prox.phal.nuclei 5 (L+R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number" of 

affected fetuses 54 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 16 

9 

stat.sign.(chi ) 

230 

76 

24 

19 

239 

98 

++ + 

24 

19 

216 

68 

24 

17 
TERATOLOGY STUDY IN RATS 115 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 5 (L) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 11 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 9 

9 

Stat.sign.(chi ) 

230 

15 

24 

10 

239 

12 

24 

216 

11 

24 

Skeletal maturation: oss. of post.prox.phal.nuclei 5 (R) absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 

21 

11 

23 0 

19 

24 

11 

239 

13 

24 

10 

216 

15 

24 

10 
TERATOLOGY STUDY IN RATS 116 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of post.prox.phal.nuclei 5 (total) 

absent 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 83 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 20 

9 

Stat.sign.(chi ) 

230 

110 

24 

20 

239 

123 

24 

22 

216 

94 

24 

19 

Skeletal maturation: Sternebra 1 poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 

21 

230 

24 

239 

12 

24 

216 

24 
TERATOLOGY STUDY IN RATS 117 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Sternebra 2 poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 5 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of. 

affected litters 5 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

0 

+ 

216 

24 

Skeletal maturation: Sternebra 3 poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 118 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Sternebra 5 poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Sternebra 6 poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

Stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 119 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Calcaneus (L+R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 2 0 1 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 2 0 1 0 

9 

stat.sign.(chi ) 

Skeletal maturation: Calcaneus (R) poorly ossified 

group 1 group 2 . group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 2 2 1 5 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 2 2 1 5 

9 stat.sign.(chi ) 
TERATOLOGY STUDY IN- RATS 120 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Calcaneus (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses ^ 2 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

9 

Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Calcanei (total) poorly ossified 

group 1 group 2 group 3 group. 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 6 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 6 

9 

Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 121 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Metacarpal 5 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 239 

21 24 24 

216 

24 

Skeletal maturation: Ant.prox.phal. nuclei 2 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 

Number of 

affected fetuses 0 6 

9 

Stat.sign.(chi ) + 

Total number of 

litters 21 24 

Number of 

affected litters 0 4 

9 

stat.sign.(chi ) 

239 

24 

0 

+ 

216 

24 
TERATOLOGY STUDY IN RATS 122 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 2 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

. 9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Ant.prox.phal. nuclei 2 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 123 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 2 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 4 11 4 ' 5 

• 2 stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 3 8 4 4 

9 

stat.sign.(chi ) 

Skeletal maturation: Ant.prox.phal. nuclei 3 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 0 0 0 1 

9 

stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 0 0 0 1 

9 Stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 124 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 3 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Ant, prox. phal. nuclei 3 (total) pcx^rly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

stat.sign.(chi^) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 125 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 4 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Ant.prox.phal. nuclei 4 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Nuraber of 

affected fetuses 0 

9 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 126 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 4 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

. 9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Ant.prox.phal. nuclei 4 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

. 9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

U 
TERATOLOGY STUDY IN RATS 127 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 5 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 3 

• 2 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 3 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Ant.prox.phal. nuclei 5 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affec-ted fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 

21 

230 

10 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 128 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Ant.prox.phal. nuclei 5 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 6 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 6 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Ant.prox.phal. nuclei 5 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 11 

9 Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 9 

stat. sign . (clii") 

230 

24 

24 

12 

239 

21 

24 

11 

216 

10 

24 
TERATOLOGY STUDY IN RATS 129 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: oss. of Metatarsal 1 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affecte d fetuse s 2 0 0 0 

9 

stat.Sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 2 0 0 0 

9 stat.sign.(chi ) 

Skeletal maturation: post .prox:. phal. nuclei 2 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 2 11 0 

9 stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 2 11 0 

9 stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 130 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nucleus 2 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 3 

9 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 3 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: post.prox.phal.nuclei 2 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 2 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 2 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 131 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nuclei 2 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 7 5 4 1 

9 

Stat.sign.(chi ) + 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 6 5 4 1 

9 

Stat. sign . (chi •) + 

Skeletal maturation: post.prox.phal.nuclei 3 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216 

Number of 

affected fetuses 1 2 0 1 

9 

stat.sign.(chi ) 

Total number of 

litters '2 1 .2 4 24 24 

Number of 

affected litters 1 2- 0 1 

9 

Stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 132 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nuclei 3 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: post.prox.phal.nuclei 3 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 133 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nuclei 3 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) , 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 Stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 

Skeletal maturation: post.prox.phal.nuclei 4 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

stat.sign.(chi^) 

Total number of 

litters 21 

Number of 

affected litters 0 

stat.sign.(chi") 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 134 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nuclei 4 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

9 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: post.prox.phal.nuclei 4 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 135 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nuclei 4 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 239 216 

21 24 24 24 

Skeletal maturation: post.prox.phal.nuclei 5 (L+R) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 230 239 216 

21 24 24 24 
TERATOLOGY STUDY IN RATS 136 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nuclei 5 (L) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 13 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 11 

9 stat.sign.(chi ) 

230 

24 

239 

24 

3 

+ + 

216 

5 

+ 

24 

5 

+ 

Skeletal maturation: post.prox.phal.nueclei 5 (R) poorly ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 9 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 5 

9 Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 137 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: post.prox.phal.nueclei 5 (total) poorly 

ossified 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 

23 

21 

12 

230 

25 

24 

14 

239 

10 

+ + 

24 

4 

+ 

216 

12 

24 

Skeletal maturation: Short rib 13 (L+R) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 Stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 138 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Short rib 13 (L) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 

21 24 

239 

24 

216 

24 

Skeletal maturation: Short rib 13 (R) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses - 210 

Number of 

affected fetuses 8 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 6 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 139 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Short rib 13 (total) 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

. 9 Stat.sign.(chi ) 

210 

13 

21 

230 

17 

24 

13 

239 

15 

24 

216 

12 

24 

Skeletal maturation: Cervical vertebr. 1 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

16 

24 

10 
TERATOLOGY STUDY IN RATS 140 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Cervical vertebr. 2 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

• 2 stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Thorac.vertebr. 5 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

Stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 141 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Thorac.vertebr. 8 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat. sign . (chi"^) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Thorac.vertebr. 9 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 142 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Thorac.vertebr. 10 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 stat.sign.(chi ) 

210 

21 

230 

24 

239 

5 

+ 

24 

216 

24 

Skeletal maturation: Thorac.vertebr. 11 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

stat.sign.(chi , 2 . 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 143 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Thorac.vertebr. 12 dumbbell-shaped 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 1 

o 

stat. sign, (chi'^) 

Total number of 

litters 21 

Number of 

affected litters 1 

9 

stat.sign.(chi^) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Cerv.vertebr. 1 bipartite 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 10 

9 

Stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 9 

9 

stat.sign.(chi ) 

230 

14 

24 

10 

239 

10 

24 

216 

22 

+ 

24 
TERATOLOGY STUDY IN RATS 144 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Thorac.vertebr. 1 bipcirtite 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.Sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 239 

21 24 24 

216 

24 

Skeletal maturation; Thorac.vertebr. 10 bipartite 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

Stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 

21 

>30 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 145 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Thorac.vertebr. 11 bipartite 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 stat.sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 

stat.sign.(chi ) 

210 230 239 

21 24 24 

216 

24 

Skeletal maturation: Thorac.vertebr. 12 bipartite 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 

Number of 

affected fetuses 

9 

stat.Sign.(chi ) 

Total number of 

litters 

Number of 

affected litters 

9 Stat.sign.(chi ) 

210 

21 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 146 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Thorac.vertebr. 13 bipeirtite 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 

stat.Sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Sternebra 3 oss. incomplete 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

9 stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 147 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Sternebra 4 oss. inccmplete 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 0 

9 

stat.sign.(chi ) 

Total number of 

litters 21 

Number of 

affected litters 0 

- 9 

Stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 

Skeletal maturation: Sternebra 5 oss. incomplete 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 

Number of 

affected fetuses 3 

9 

Stat.sign.(chi^) 

Total number of 

litters 21 

Number of 

affected litters 3 

9 

stat.sign.(chi ) 

230 

24 

239 

24 

216 

24 
TERATOLOGY STUDY IN RATS 14 8 

GU Project No. 840862 Test Article: TK 12443 

Skeletal maturation: Sternebra 6 oss. inccmplete 

group 1 group 2 group 3 group 4 

dose (mg/kg) 0 300 1000 3000 

Total number of 

fetuses 210 230 239 216' 

Number of 

affected fetuses 1 3 2 2 

9 

stat.sign.(chi ) 

Total number of 

litters 21 24 24 24 

Number of 

affected litters 1 2 2 2 

9 

stat.sign.(chi ) 
TERATOLOGY STUDY IN RATS 14 9 

GU Project No. 840862 Test Article: TK 12443 

9.2. Individual Data 

9.2.1. Individual Maternal Clinical Observations 

Individual Maternal Clinical Symptcmis : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 
GU Project No. 

TERATOLOGY STUDY IN RATS 150 

840862 Test Article: TK 12443 

Individual Maternal Clinical Symptoms : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article: 

151 

TK 12443 

Individual Maternal Clinical Symptoms : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article: 

152 

TK 12443 

Individual Maternal Clinical Symptoms : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 
GU Project No. 

TERATOLOGY STUDY IN RATS 153 

840862 Test Article: TK 12443 

Individual Maternal Clinical Symptoms : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 
TERATOLOGY STUDY IN RATS 154 

GU Project No. 840862 Test Article: TK 12443 

Individual Maternal Clinical Symptcxns : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 
TERATOLOGY STUDY IN RATS 155 

GU Project No. 840862 Test Article: TK 12443 

Individual Maternal Clinical Symptcans : dams group 1 : 0 mg/kg 

Dam no Observation Finding 

day p.c. 





















































































































































TERATOLOGY STUDY IN RATS 305 

GU Project No. 840862 Test Article: TK 12443 

9.2.9. Fetal data 

EXPLANATIONS 

The following abbreviationsare used in this section; 

,U undetermined sex 

o.a, ossification still absent 

o.p. ossification poor 

o.i. ossification incomplete 

d-shape 

o.irr. 

bip. 

short, 

fus. : 

O.B. 

(vertebral) center still dumbbell-shaped 

irregular ossification 

bipartite (two apparent 

ossification centers) 

shortend 

fused ossification centers 

no findings 

MET( ) 

MEC( ) 

CAL (L, 

CVC( ) 

THVC( ) 

LVC( ) 

PHAL 

AP( 

R) 

1' 

) 

AD( ) 

Metatarsals (position number) 

Metacarpals (position number) 

Calcaneus (left and right) 

Cervical vertebral centers 

(position number) 

Thoracic vertebral centers 

(position number) 

Lumbar vertebral, centers (position 

number) 

Phalanges 

anterior, proximal (position 

number) 

anterior, distal (position number) 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 

306 

Test Article: TK 12443 

PP( ) 

PD( ) 

STER( ) 

WS 

RIB( ) 

posterior, proximal (position 

number) 

posterior, distal (position 

number) 

Sternebrae (position) 

Wide suture (frontals and 

parietals concerned in this 

respect) 

rib (position number) 

(L) 

(R) 

(L,R) 

left 

right 

left and right 

ER 

FR 

FP 

V 

S 

M 

embryonic resorption 

fetal resorption 

premature birth, random assignment 

of fetus to uterine position 

visceral examination 

skeletal examination 

general malformation, observed at 

external examination 

(M) 

(A) 

Malformatio n 

Anomaly 






















































TERATOLOGY STUDY IN RATS 361 

GU Projec t No. 840862 Test Article : TK 12443 

9.3 . Randomization 

Randomizatio n was achieve d by th e followin g method : 

On severa l consecutiv e days between 12 and 28 mated females ar e weighed 

and numbered according t o thei r body weight ( th e animal vri.th the smallest 

weight is number one ).The ranked animals ar e distribute d among the dose 

groups according t o th e stratificatio n scheme presente d on -the follcwing 

page . This mixture of randcmLzation and stiratif ication allcsws an ecgual weight 

distributio n among th e differen t dose groups. The animals receiv e thei r 

fina l number a t th e time they ar e allocate d t o the respective dose groups. 

Randomizatio n Tabl e 

Weekday I Distributio n among 4 group s 

I grou p 1 grou p 2 grou p 3 grou p 4 

Tue 

Wed 

Thu 

F r i 

0 

1 

2 

3 

1 

2 

3 

0 

2 

3 

0 

1 

3 

0 

1 

2 

Number of mated 

dams each day 

Allocations of weight-ranked dams 

group 1 group 2 group 3 grou p 4 

— — — 1 

12 

13 

14 

15 

16 

17 

18 

19 

20 

21 

3,4,9,10 

3,4,9,10 

13* 

4,7,8,11 

1*,14* 

5,8,9,12 

1*,2*,15* 

2,6,11,15 

2,6,11,15 

17* 

2,7,12,17 

1*,18* 

2,7,12,17 

1*,18*,19* 

1,7,14,20 

5,9,11,17 

1,7,14,20 

5,9,11,17 

21* 

2,5,7,12 

2,5,7,12 

3,5,10,12 

4,6,11,13 

4,7,10,13 

4,7,10,13 

3,8,11,16 

3,8,11,16 

2,6,15,19 

2,6,15,19 

1,3,14,16 

1,3,14,16. 

4,9,10,15 

4,9,10,15 

3,8,13,18 

3,8,13,18 

1,6,8,11 

1,6,8,11 

2,6,9,13 

3,7,10, 14 

5,8,9,12 

5,8,9,12 

5,6,13,14 

5,6,13,14 

4,10,12,16 

4,10,12,16 
TERATOLOGY STUDY IN RATS 362 

GU Project No. 840862 Test Article: TK 12443 

22 

23 

24 

25 

26 

27 

28 

2,7 

5,9 

1*, 

2,7 

5,9 

1*, 

1,9 

5,1 

1,9 

5,1 

25* 

2,1 

6,1 

1*, 

2,1 

6,1 

1*, 

1,1 

5,6 

,16,21 

,14,18 

22* 

,16,21 

,14,18 

22*,23* 

,16,24 

1.14.20 

,16,24 

1,14,20 

0,17,25 

2.15.21 

26* 

0,17,25 

2,17,21 

26*,27* 

0,19,28 

,23,24 

3,8,15,20 4,10,13,19 6,11,12,17 

3,8,15,20 4,10,13,19 6,11,12,17 

2,8,17,23 3,7,18,22 4,6,19,21 

10,12,13,15 

2.8.17.23 3,7,18,22 4,6,19,21 

10,12,13,15 

3.9.18.24 4,8,19,23 5,7,20,22 

11,13,14,16 

3,9,18,24 4,8,19,23 5,7,20,22 

11,13,14,16 

2,9,20,27 3,8,21,26 4,7,22,25 

11,13,16,18 12,14,15,17 

* = These animals were not allocated to any dose group 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article; 

363 

TK 12443 

9.4. Matingtable 

Males: 

Numbers: 

Initial Body Weight: 

Initial Age: 

Females: 

Numbers: 

Tif: RAIf (SPF) albino rats 

01 - 55 ; Delivery from 09.04.1985 

(Batch-No. 38427) 

300 - 350 g 

7 - 8 weeks 

Tif:RAIf (SPF) albino rats 

01 - 24, 25 - 48, 49 - 72, 73 - 96 

Delivery from 05.08.1985 (11579D) 

Group 1 

Female 

number 

001 

002 

003 

004 

005 

006 

007 

008 

009 

010 

Oil 

012 

013 

014 

015 

016 

017 

018 

019 

020 

021 

022 

023 

024 

day 0 pc. 

06.08.85 

06.08.85 

06.08.85 

06.08.85 

06.08.85 

06.08.85 

06.08.85 

06.08.85 

07.08.85 

07.08.85 

07.08.85 

07.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

09.08.85 

09.08.85 

09.08.85 

09.08.85 

Males 

number 

01 

01 

25 

16 

27 

36 

35 

24 

50 

08 

14 

06 

34 

21 

35 

24 

05 

15 

02 

25 

11 

07 

33 

40 

Batch 

• 38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

cxxitrol 

Age 

(weeks) Remarks 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 . 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 
GU Project No. 

TERATOLOGY STUDY IN RATS ' 364 

840862 , Test Article: TK 12443 

Males: 

Numbers: 

Tif: RAIf (SPF) albino rats 

01 - 55 ; Delivery from 09.04.1985 

. (Batch-No. 38427) 

Initial Body Weight: 

Initial Age: 

300 - 350 g 

7 - 8 weeks 

Females: 

Numbers: 

Tif:RAIf (SPF) albino rats 

01 - 24, 25 - 48, 49 - 72, 73 - 96 

Delivery from 05.08.1985 (11579D) 

Group 2 

Femal e 

number 

025 

026 

027 

028 

029 

030 

0 31 

032 

033 

034 

035 

036 

037 

038 

039 

040 

041 

042 

043 

044 

045 

046 

047 

048 

day 0 pc . 

06.08.8 5 

06.08.8 5 

06.08.8 5 

06.08.8 5 

06.08.8 5 

, 06.08.8 5 

06.08.8 5 

06.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

08.08.8 5 

08.08.8 5 

08.08.8 5 

08.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

Male s 

number 

12 

03 

28 

28 

02 

20 

29 

27 

08 

39 

14 

21 

29 

38 

13 

38 

30 

14 

07 

34 

03 

40 

17 

4 1 

Batc h 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

•38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

300 rrgAg 

Age 

(weeks) Remarks 

24-2 5 

24-25 

24-2 5 

24-2 5 

24-25 

24-25 

24-2 5 

24-2 5 

24-2 5 

24-25 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 
TERATOLOGY STUDY IN RATS 365 

GU Project No. 840862 Test Article: TK 12443 

Males: 

Numbers: 

Tif: RAIf (SPF) albino rats 

01 - 55 ; Delivery from 09.04.1985 

(Batch-No. 38427) 

Initial Body Weight; 

Initial Age: 

300 - 350 g 

7 - 8 weeks 

Females: 

Numbers: 

Tif:RAIf (SPF) albino rats 

01 - 24, 25 - 48, 49 - 72, 73 - 96 

Delivery from 05.08.1985 (11579D) 

Group 3 

Femal e 

number 

049 

050 

051 

052 

053 

054 

055 

056 

057 

058 

059 

060 

061 

062 

063 

064 

065 

066 

067 

068 

069 

070 

071 

072 

day 0 pc . 

06.08.8 5 

06.08.8 5 

06.08.8 5 

06.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

07.08.8 5 

08.08.8 5 

08.08.8 5 

08.08.8 5 

08.08.8 5 

08.08.8 5 

08.08.85 -

08.08.8 5 

08.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

09.08.8 5 

Male s 

number 

19 

22 

32 

33 

,19 

26 

47 

25 

31 

11 

18 

23 

04 

18 

17 

43 

12 

07 

31 

42 

08 

13 

21 

16 

Batc h 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

3 84 27 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

1000 ngAg 

Age 

(weeks) Remarks 

24-2 5 

24-2 5 

24-25 

24-2 5 

24-25 

24-2 5 

24-2 5 

24-25 

24-2 5 

24-25 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-2 5 

24-25 

24-2 5 

24-2 5 

24-25 

24-25 

24-2 5 

24-2 5 

24-2 5 

24-2 5 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article: 

366 

TK 12443 

Males: 

Numbers: 

Initial Body Weight; 

Initial Age: 

Females: 

Numbers: 

Tif: RAIf (SPF) albino rats 

01 - 55 ; Delivery from 09.04.1985 

(Batch-No. 38427) 

300 - 350 g 

7 - 8 weeks 

Tif:RAIf (SPF) albin o rat s 

01 - 24, 25 - 48, 49 - 72, 73 - 96 

Deliver y from 05.08.1985 (11579D) 

Group 4 

Female 

number 

073 

074 

075 

076 

077 

078 

079 

080 

081 

082 

083 

084 

085 

086 

087 

088 

089 

090 

091 

092 

093 

094 

095 

096 

day 0 pc. 

06.08.85 

06.08.85 

06.08.85 

06.08.85 

07.08.85 

07.08.85 

07.08.85 

07.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

08.08.85 

09.08.85 

09.08.85 

09.08.85 

09.08.85 

09.08.85 

09.08.85 

09.08.85 

09.08.85 

Males 

number 

18 

04 

' 09 

13 

10 

27 

17 

28 

30 

09 

02 

22 

01 

26 

37 

37 

31 

38 

41 

20 

42 

12 

05 

42 

Batch 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

38427 

Age 

(weeks) 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

. 24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

24-25 

3000 ngAg 

Remarks 
TERATOLOGY STUDY IN RATS 

GU Project No. 840862 Test Article; 

367 

TK 12443 

9.5. Concentration of Test Article in the Vehicle 

The content of TK 12443 in the vehicle was determined with 

samples of all three concentrations prepared on August 22, 

1985. The analysis was performed by the central analytical 

laboratory of . 

The analytical report is filed with the raw data. 

VOLUME 

ml 

2.0 

2.0 

2.0 

NOMINAL 

VALUES 

mg/ml 

•30 

100 

300 

VALUES 

DETERMINED 

mg/ml 

29.5 

93.5 

302.3 

300.2 

RELATION 

% 

98.3 

93.5 

100.8 

100.1 

These values are all within acceptable limits. 
TERATOLOGY STUDY IN RATS 368 

GU Project No. 840862 Test Article: TK 12443 

10. DISTRIBUTION 

This report was distributed to: 

- Plastics and Additives Division 

-

- Qualit y assuranc e departmen t