Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2017-05-09 to 2017-06-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Adopted 22nd January 2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Polynt Lot No. 3606217009
- Expiration date of the lot/batch: 09 Jan 2018

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient conditions
- Stability under test conditions: Stable
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: None

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: None

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS srl, San Pietro al Natisone, Italy
- Age at study initiation: circa 13 weeks
- Weight at study initiation: 203 - 259 g
- Fasting period before study: None
- Housing: Group caged except during mating
- Diet (e.g. ad libitum): Commercial laboratory rodent dient, ad-libitum
- Water (e.g. ad libitum): Municipal drinking water, ad-libitum
- Acclimation period: circa 4 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 deg C
- Humidity (%): 40 - 70 %
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2017-05-09 To: 2017-06-11

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:

- VEHICLE
- Justification for use and choice of vehicle (if other than water): Commonly used vehicle for non-water miscible materials
- Concentration in vehicle: 0, 25, 75 and 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The formulation procedure was checked in the range from 1 to 250 mg/mL by chemical analysis for concentration and homogeneity to confirmthat the method was suitable.
Samples of the formulations prepared during Weeks 1 and 3 of the dosing phase were analysed to check the homogeneity and concentration.
Details on mating procedure:
- Impregnation procedure: Cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: Until mating verified
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as Day 0 of pregnancy
- Any other deviations from standard protocol: No
Duration of treatment / exposure:
From Day to Day 19 post coitum (13 days)
Frequency of treatment:
Daily
Duration of test:
20 days post coitum
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Vehicle control
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24 mated females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on data from screening studies
- Rationale for animal assignment: Random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 9, 12, 15 and 20 post coitum

FOOD CONSUMPTION: Yes
- Food consumption determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - At intervals over Days 0-6, 6-9, 9-12, 12-15 and 15-20

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
- Organs examined: Detailed examination with particular attention to ovaries and uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
For continuous variables the significance of the differences amongst group means was assessed by Dunnett's test or a modified t test, depending on the homogeneity of data.
Statistical analysis of non-continuous variables was carried out by means of the Kruskal-Wallis test and intergroup differences between the control and treated groups assessed by a non-parametric version of the Williams test.
Indices:
Pre-implantation loss
Post-implantation loss
Total implantation loss
Sex ratio

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significantly reduced body weight and body weight gain in animals dosed at 1000 mg/kg bw/day
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food consumption in animals dosed at 1000 mg/kg bw/day
Gross pathological findings:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Lack of treatment related effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Lack of treatment related effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Body weight (g) of dams - Group mean data

 

 

 

Gestation day:

Treatment

 

0

6

9

12

15

20

 

(n)

23

23

23

23

23

23

Control

Mean

233.12

257.83

266.89

278.76

297.89

373.46

 

SD

10.52

10.80

11.61

10.89

14.68

25.64

 

(n)

23

23

23

23

23

23

100 mg/kg

Mean

235.71

258.33

268.14

279.27

295.16

372.80

 

SD

12.70

11.49

11.68

11.01

11.88

12.55

 

(n)

22

22

22

22

22

22

300 mg/kg

Mean

234.61

257.08

266.14

276.12

294.56

371.29

 

SD

11.62

11.97

110.8

12.01

12.87

19.92

 

(n)

23

23

23

23

23

23

1000 mg/kg

Mean

231.91

255.48

262.70

272.62

288.40*

355.69*($)

 

SD

11.81

11.68

11.07

11.73

13.63

23.18

  

 

Food consumption (g/animal/day) of dams - Group mean data

 

 

 

Gestation day:

Treatment

 

6

9

12

15

20

 

(n)

9

9

9

9

9

Control

Mean

20.21

18.90

20.13

20.79

22.99

 

SD

1.72

1.10

2.12

2.59

1.47

 

(n)

8

8

8

8

8

100 mg/kg

Mean

19.82

19.22

18.55

18.52

22.02

 

SD

0.87

2.05

0.72

1.37

2.55

 

(n)

9

9

9

9

9

300 mg/kg

Mean

20.59

19.51

19.20

19.33

23.39

 

SD

1.80

2.05

1.52

1.46

1.11

 

(n)

10

10

10

10

10

1000 mg/kg

Mean

20.35

17.28

17.37*($)

18.37*

22.35

 

SD

0.97

2.17

2.50

1.97

3.11

 

 

Uterus weight (g) of dams - Group mean data

 

 

 

Terminal body weight

Absolute weight gain

Gravid uterus weight

Treatment

 

(g)

(g)

(g)

 

(n)

23

23

23

Control

Mean

371.23

62.94

75.15

 

SD

25.84

10.06

18.48

 

(n)

23

23

23

100 mg/kg

Mean

370.42

55.76

78.96

 

SD

11.78

8.31

7.97

 

(n)

22

22

22

300 mg/kg

Mean

370.59

57.96

78.01

 

SD

15.73

11.70

11.76

 

(n)

23

23

23

1000 mg/kg

Mean

352.09*

44.83*

75.33

 

SD

22.26

11.47

13.47

 

 

Macroscopic findings in dams - Group incidence

 

 

Treatment:

Control

100 mg/kg

300 mg/kg

1000 mg/kg

 

Number in group:

24

24

24

24

Finding

Number examined:

10

10

10

10

Uterus

Not pregnant

1

1

2

1

 

Unilateral implantation

1

0

0

0

 

 

 

 

 

 

No abnormalities

 

22

23

22

23

 

 

Litter data - Group mean data

 

 

 

Corpora

Implantations

Uterine deaths

Viable foetuses

%

Implantation loss

Litter weight

Treatment

 

Lutea

 

Early

Late

Total

Male

Female

males

Pre-

Post-

Total

(g)

 

(n)

23

23

23

23

23

22

23

22

23

23

23

23

Control

Mean

13.78

13.70

0.52

0.00

13.17

6.00

7.17

43.43

0.48

3.69

4.17

48.05

 

SD

3.67

3.59

0.73

0.00

3.52

2.54

2.37

15.61

2.31

5.06

5.22

13.47

 

(n)

23

23

23

23

23

23

23

23

23

23

23

23

100 mg/kg

Mean

15.04

14.70

0.74

0.00

13.96

7.13

6.83

51.74

2.07

4.83

6.84

51.55

 

SD

2.01

1.89

1.48

0.00

2.06

2.24

2.44

14.64

5.92

9.01

10.32

8.05

 

(n)

22

22

22

22

22

22

22

22

22

22

22

22

300 mg/kg

Mean

14.86

14.45

1.18

0.00

13.27

6.64

6.64

49.03

2.14

8.05

10.15

50.47

 

SD

2.62

2.06

1.62

0.00

2.39

2.15

1.59

13.53

6.01

11.29

11.59

8.88

 

(n)

23

23

23

23

23

23

23

23

23

23

23

23

1000 mg/kg

Mean

14.26

13.83

0.65

0.00

13.17

6.91

6.26

51.67

2.58

4.87

7.38

49.46

 

SD

2.75

2.50

1.11

0.00

2.81

2.79

2.05

14.03

6.66

8.70

10.33

9.71

 

 

 

External examination of foetuses - Group incidence

 

 

 

 

 

Number of foetuses

 

Number of litters

Treatment

Organ

Category

Observation

Observed

Affected

%

 

Observed

Affected

%

 

Whole foetus

 

No abnormalities observed

303

298

98.35

 

23

-

-

 

 

AN

Small

303

5

1.65

 

23

4

17.39

100 mg/kg

Whole foetus

 

No abnormalities observed

321

321

100.00

 

23

23

100.00

300 mg/kg

Whole foetus

 

No abnormalities observed

292

291

99.66

 

22

-

-

 

 

AN

Small

292

1.00

0.34

 

22

1

4.55

1000 mg/kg

Whole foetus

 

No abnormalities observed

303

303

100.00

 

23

23

100.00

 


 

Skeletal examination of foetuses - Group incidence

 

 

 

 

 

Number of foetuses

 

Number of dams

Treatment

Organ

Category

Observation

Observed

Affected

%

 

Observed

Affected

%

Control

Forepaw(s)

AN

Metacarpal(s) no ossification 4th

157

16

10.19

 

23

9

39.13

 

Hindpaw(s)

AN

Metatarsal(s) no ossification 4th

157

1

0.64

 

23

1

4.35

 

Lumbar vertebrae

AN

Centrum dumbbell shaped

157

1

0.64

 

23

1

4.35

 

Lumbar vertebrae

VA

Centrum incomplete ossification

157

1

0.64

 

23

1

4.35

 

Pelvic girdle

AN

Pubis incomplete ossification

157

2

1.27

 

23

2

8.70

 

Ribs

VA

Rudimentary 14th

157

26

16.56

 

23

15

65.22

 

Ribs

VA

Short 14th

157

1

0.64

 

23

1

4.35

 

Sacral vertebrae

AN

Arch(es) incomplete ossification

157

1

0.64

 

23

1

4.35

 

Sacral vertebrae

AN

Arch(es) no ossification

157

1

0.64

 

23

1

4.35

 

Skull

AN

General incomplete ossification

157

1

0.64

 

23

1

4.35

 

Skull

AN

Temporal incomplete ossification

157

27

17.20

 

23

15

65.22

 

Skull

AN

Palatine incomplete ossification

157

1

0.64

 

23

1

4.35

 

Skull

VA

Interparietal incomplete ossification

157

1

0.64

 

23

1

4.35

 

Skull

VA

Supraoccipital incomplete ossification

157

1

0.64

 

23

1

4.35

 

Sternebrae

AN

No ossification 6th

157

1

0.64

 

23

1

4.35

 

Sternebrae

AN

Bipartite 5th

157

1

0.64

 

23

1

4.35

 

Sternebrae

AN

Asymmetrical ossification

157

3

1.91

 

23

3

13.04

 

Sternebrae

AN

Rudimentary 5th

157

1

0.64

 

23

1

4.35

 

Sternebrae

AN

Bipartite

157

2

1.27

 

23

1

4.35

 

Sternebrae

AN

Asymmetrical ossification 5th

157

2

1.27

 

23

2

8.70

 

Sternebrae

VA

Incomplete ossification 6th

157

17

10.83

 

23

10

43.48

 

Sternebrae

VA

No ossification 5th

157

4

2.55

 

23

3

13.04

 

Sternebrae

VA

Incomplete ossification 5th

157

15

9.55

 

23

10

43.48

 

Sternebrae

VA

Incomplete ossification

157

6

3.82

 

23

4

17.39

 

Thoracic vertebrae

AN

Centrum no ossification

157

1

0.64

 

23

1

4.35

 

Thoracic vertebrae

AN

Centrum bipartite

157

1

0.64

 

23

1

4.35

 

Thoracic vertebrae

AN

Centrum asymmetrical ossification

157

1

0.64

 

23

1

4.35

 

Thoracic vertebrae

VA

Centrum incomplete ossification

157

10

6.37

 

23

7

30.43

 

Whole foetus

 

No abnormalities detected

157

86

54.78

 

-

-

-

100 mg/kg

Forepaw(s)

AN

Metacarpal(s) no ossification 4th

156

12

7.69

 

23

7

30.43

 

Hindpaw(s)

AN

Metatarsal(s) no ossification 4th

156

2

1.28

 

23

2

8.70

 

Lumbar vertebrae

VA

Centrum incomplete ossification

156

1

0.64

 

23

1

4.35

 

Pelvic girdle

AN

Ischium incomplete ossification

156

1

0.64

 

23

1

4.35

 

Pelvic girdle

MA

Pubis no ossification

156

1

0.64

 

23

1

4.35

 

Ribs

VA

14 ribs

156

2

1.28

 

23

1

4.35

 

Ribs

VA

Rudimentary 14th

156

26

16.67

 

23

14

60.87

 

Skull

AN

Temporal incomplete ossification

156

18

11.54

 

23

10

43.48

 

Skull

AN

Palatine incomplete ossification

156

1

0.64

 

23

1

4.35

 

Skull

VA

Supraoccipital incomplete ossification

156

2

1.28

 

23

2

8.70

 

Sternebrae

AN

Asymmetrical ossification 5th

156

4

2.56

 

23

4

17.39

 

Sternebrae

AN

Asymmetrical ossification

156

3

1.92

 

23

2

8.70

 

Sternebrae

AN

No ossification

156

3

1.92

 

23

3

13.04

 

Sternebrae

AN

No ossification 6th

156

1

0.64

 

23

1

4.35

 

Sternebrae

AN

Rudimentary 5th

156

3

1.92

 

23

2

8.70

 

Sternebrae

VA

Incomplete ossification 6th

156

26

16.67

 

23

11

47.83

 

Sternebrae

VA

No ossification 5th

156

5

3.21

 

23

5

21.74

 

Sternebrae

VA

Incomplete ossification

156

4

2.56

 

23

4

17.39

 

Sternebrae

VA

Incomplete ossification 5th

156

12

7.69

 

23

7

30.43

 

Thoracic vertebrae

AN

Centrum no ossification

156

1

0.64

 

23

1

4.35

 

Thoracic vertebrae

VA

Centrum incomplete ossification

156

4

2.56

 

23

4

17.39

 

Thoracic vertebrae

VA

Centrum asymmetrical dumb-bell shaped

156

1

0.64

 

23

1

4.35

 

Thoracic vertebrae

VA

Centrum dumb-bell shaped

156

4

2.56

 

23

4

17.39

 

Whole foetus

 

No abnormalities detected

156

50

32.05

 

-

-

-

300 mg/kg

Forepaw(s)

AN

Metacarpal(s) no ossification 4th

151

9

5.96

 

22

4

18.18

 

Ribs

VA

14 ribs

151

6

3.97

 

22

1

4.55

 

Ribs

VA

Short 14th

151

1

0.66

 

22

1

4.55

 

Ribs

VA

Rudimentary 14th

151

33

21.85

 

22

15

68.18

 

Skull

AN

Temporal incomplete ossification

151

13

8.61

 

22

10

45.45

 

Skull

VA

Supraoccipital incomplete ossification

151

1

0.66

 

22

1

4.55

 

Sternebrae

AN

Bipartite 5th

151

1

0.66

 

22

1

4.55

 

Sternebrae

AN

Asymmetrical ossification

151

2

1.32

 

22

1

4.55

 

Sternebrae

AN

No ossification

151

1

0.66

 

22

1

4.55

 

Sternebrae

AN

Asymmetrical ossification 5th

151

2

1.32

 

22

2

9.09

 

Sternebrae

VA

No ossification 5th

151

4

2.65

 

22

3

13.64

 

Sternebrae

VA

Incomplete ossification

151

3

1.99

 

22

2

9.09

 

Sternebrae

VA

Incomplete ossification 5th

151

15

9.93

 

22

8

36.36

 

Sternebrae

VA

Incomplete ossification 6th

151

12

7.95

 

22

7

31.82

 

Thoracic vertebrae

VA

Centrum dumb-bell shaped

151

6

3.97

 

22

4

18.18

 

Thoracic vertebrae

VA

Centrum incomplete ossification

151

5

3.31

 

22

3

13.64

 

Thoracic vertebrae

VA

Centrum asymmetrical dumb-bell shaped

151

2

1.32

 

22

2

0.09

 

Whole foetus

 

No abnormalities detected

151

86

56.95

 

-

-

 

1000 mg/kg

Forepaw(s)

AN

Metacarpal(s) no ossification 4th

154

4

2.60

 

23

3

13.04

 

Pelvic girdle

AN

Pubis incomplete ossification

154

1

0.65

 

23

1

4.35

 

Ribs

VA

Rudimentary 14th

154

18

11.69

 

23

10

43.48

 

Ribs

VA

14 ribs

154

1

0.65

 

23

1

4.35

 

Ribs

VA

Short 14th

154

3

1.95

 

23

3

13.04

 

Skull

AN

Temporal incomplete ossification

154

17

11.04

 

23

11

47.83

 

Sternebrae

AN

Asymmetrical ossification

154

2

1.30

 

23

2

8.70

 

Sternebrae

AN

Asymmetrical ossification 5th

154

8

5.19

 

23

6

26.09

 

Sternebrae

VA

Incomplete ossification 5th

154

8

5.19

 

23

6

26.09

 

Sternebrae

VA

Incomplete ossification 6th

154

8

5.19

 

23

4

17.39

 

Thoracic vertebrae

AN

Centrum bipartite

154

1

0.65

 

23

1

4.35

 

Thoracic vertebrae

VA

Centrum incomplete ossification

154

2

1.30

 

23

2

8.70

 

Thoracic vertebrae

VA

Centrum dumb-bell shaped

154

3

1.95

 

23

3

13.04

 

Whole foetus

 

No abnormalities detected

154

99

64.29

 

-

-

-

 

 

Visceral examination of foetuses - Group incidence

 

 

 

 

 

Number of foetuses

 

Number of dams

Treatment

Organ

Category

Observation

Observed

Affected

%

 

Observed

Affected

%

Control

Abdomen

VA

Haemorrhagic

146

2

1.37

 

23

2

8.70

 

Brain

AN

Ventricles enlarged moderate

146

1

0.68

 

23

1

4.35

 

Brain

VA

Ventricles enlarged slight

146

2

1.37

 

23

2

8.70

 

Great vessels

VA

Innominate artery longer

146

3

2.05

 

23

2

8.70

 

Heart

AN

Atrium enlarged

146

8

5.48

 

23

5

21.74

 

Heart

AN

Ventricle enlarged

146

1

0.68

 

23

2

8.70

 

Heart

AN

Pericardial fluid

146

6

4.11

 

23

4

17.39

 

Heart

VA

Ventricle enlarged

146

1

0.68

 

23

2

8.70

 

Kidneys

AN

Ectopic

146

13

8.90

 

23

8

34.78

 

Kidneys

AN

Pelvic dilatation moderate

146

1

0.68

 

23

1

4.35

 

Kidneys

VA

Pelvic dilatation slight

146

5

3.42

 

23

4

17.39

 

Testis

AN

Displaced

146

9

6.16

 

23

5

21.74

 

Ureter

AN

Enlarged moderate

146

11

7.53

 

23

10

43.48

 

Ureter

AN

Kinked moderate

146

2

1.37

 

23

2

8.70

 

Ureter

VA

Kinked slight

146

9

6.16

 

23

8

34.78

 

Ureter

VA

Enlarged slight

146

27

18.49

 

23

16

69.57

 

Whole foetus

 

No abnormalities detected

146

85

58.22

 

-

-

-

100 mg/kg

Abdomen

VA

Haemorrhagic

156

6

3.85

 

23

3

13.04

 

Great vessels

VA

Innominate artery longer

156

1

0.64

 

23

1

4.35

 

Heart

AN

Atrium enlarged

156

19

12.18

 

23

9

39.13

 

Heart

AN

Pericardial fluid

156

18

11.54

 

23

7

30.43

 

Heart

VA

Ventricle enlarged

156

2

1.28

 

23

2

8.70

 

Kidneys

AN

Ectopic

156

22

14.10

 

23

10

43.48

 

Kidneys

AN

Pelvic dilatation moderate

156

1

0.64

 

23

1

4.35

 

Kidneys

VA

Pelvic dilatation slight

156

2

1.28

 

23

2

8.70

 

Testis

AN

Displaced

156

19

12.18

 

23

10

43.48

 

Ureter

AN

Kinked moderate

156

2

1.28

 

23

2

8.70

 

Ureter

AN

Enlarged moderate

156

10

6.41

 

23

6

26.09

 

Ureter

VA

Kinked slight

156

19

12.18

 

23

12

52.17

 

Ureter

VA

Enlarged slight

156

26

16.67

 

23

17

73.91

 

Whole foetus

AN

Generalised oedema slight

156

1

0.64

 

23

1

4.35

 

Whole foetus

 

No abnormalities detected

156

69

44.23

 

-

-

-

300 mg/kg

Abdomen

VA

Haemorrhagic

140

2

1.43

 

22

2

9.09

 

Great vessels

VA

Innominate artery short

140

1

0.71

 

22

1

4.55

 

Heart

AN

Ventricle enlarged

140

1

0.71

 

22

5

22.73

 

Heart

AN

Pericardial fluid

140

10

7.14

 

22

7

31.82

 

Heart

AN

Atrium enlarged

140

12

8.57

 

22

8

36.36

 

Heart

VA

Ventricle enlarged

140

4

2.86

 

22

5

22.73

 

Kidneys

AN

Pelvic dilatation moderate

140

2

1.43

 

22

2

9.09

 

Kidneys

AN

Ectopic

140

14

10.00

 

22

9

40.91

 

Kidneys

VA

Pelvic dilatation slight

140

2

1.43

 

22

2

9.09

 

Testis

AN

Displaced

140

5

3.57

 

22

4

18.18

 

Thoracic cavity

AN

Haemorrhage

140

2

1.43

 

22

2

9.09

 

Ureter

AN

Enlarged moderate

140

11

7.86

 

22

9

40.91

 

Ureter

AN

Kinked moderate

140

4

2.86

 

22

3

13.64

 

Ureter

MA

Kinked extreme

140

1

0.71

 

22

1

4.55

 

Ureter

VA

Enlarged slight

140

32

22.86

 

22

14

63.64

 

Ureter

VA

Kinked slight

140

15

10.71

 

22

10

45.45

 

Whole foetus

AN

Generalised oedema slight

140

1

0.71

 

22

1

4.55

 

Whole foetus

 

No abnormalities detected

140

68

48.57

 

-

-

-

1000 mg/kg

Abdomen

VA

Haemorrhagic

147

11

7.48

 

23

6

26.09

 

Great vessels

AN

Innominate artery absent

147

1

0.68

 

23

1

4.35

 

Great vessels

MA

Absence of aortic arch

147

1

0.68

 

23

1

4.35

 

Great vessels

VA

Innominate artery short

147

2

1.36

 

23

2

8.70

 

Heart

AN

Pericardial fluid

147

11

7.48

 

23

8

34.78

 

Heart

AN

Atrium enlarged

147

7

4.76

 

23

5

21.74

 

Kidneys

AN

Ectopic

147

12

8.16

 

23

8

34.78

 

Kidneys

VA

Pelvic dilatation slight

147

5

3.40

 

23

5

21.74

 

Testis

AN

Displaced

147

4

2.72

 

23

4

17.39

 

Thoracic cavity

AN

Haemorrhage

147

1

0.68

 

23

1

4.35

 

Ureter

AN

Kinked moderate

147

1

0.68

 

23

1

4.35

 

Ureter

AN

Enlarged moderate

147

10

6.80

 

23

7

30.43

 

Ureter

MA

Kinked extreme

147

1

0.68

 

23

1

4.35

 

Ureter

MA

Enlarged extreme

147

1

0.68

 

23

1

4.35

 

Ureter

VA

Kinked slight

147

8

5.44

 

23

7

30.43

 

Ureter

VA

Enlarged slight

147

16

10.88

 

23

12

52.17

 

Whole foetus

 

No abnormalities detected

147

96

65.31

 

-

-

-

 

Key to tables

* = mean value of group is significantly different from control at p < 0.05

** = mean value of group is significantly different from control at p < 0.01

($) = Modified t test if group variances are inhomogeneous ($)

AN = Anomoly

VA = Variation

MA = Malformation

Applicant's summary and conclusion

Conclusions:
Developmental toxicity has been examined in rats at dose levels of 100, 300 or 1000 mg/kg bw/day administered during teh period of organogenesis.
No exposure related developmental toxic effects were observed and, as a result, the highest dose investigated, 1000 mg/kg bw/day, was considered to be the No Observed Adverse Effect Level (NOAEL) for embryo-foetal effects.
Executive summary:

Developmental toxicity has been examined in rats using methods described in OECD test guideline No. 414. The substance was administered during the period of organogenesis at levels of 100, 300 or 1000 mg/kg bw/day.

No exposure related developmental toxic effects were observed and, as a result, the highest dose investigated, 1000 mg/kg bw/day, was considered to be the No Observed Adverse Effect Level (NOAEL) for embryo-foetal effects.