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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:
14 Jun - 16 Jul 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2022
Report date:
2022

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted 2018
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid
EC Number:
940-877-5
Cas Number:
2241455-89-8
Molecular formula:
C9H12N2O4
IUPAC Name:
Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS srl, San Pietro al Natisone (UD), Italy and supplied by Envigo Holland
- Age at study initiation: 11 weeks (males), 7-9 weeks (females)
- Weight at study initiation: at least 313.3-352.2 g (males) 180.5-218.5 g (females)
- Housing: before and after mating, the animals were housed no more than 5 of one sex to a cage clear polysulfone cages measuring 59.5×38×20 cm (Tecniplast Gazzada S.a.r.l., Buguggiate, Varese); nesting material was provided inside suitable bedding bags. In addition, suitable nesting material (Scobis 0 Mucedola) was provided as necessary. Nesting material was changed at least 2 times a week. During the mating period, one male rat was housed with one female rat in clear polysulfone cages measuring 42.5×26.6×18 cm (Tecniplast Gazzada S.a.r.l., Buguggiate, Varese) with a stainless steel mesh lid and floor.
- Diet: laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via G. Galilei 4, 20019 Settimo Milanese (MI), Italy), ad libitum
- Water: ad libitum
- Acclimation period: 4 weeks

DETAILS OF FOOD AND WATER QUALITY:
There was no information available to indicate that any non-nutrient substance likely to influence the effect of the test item was present in the drinking water or the diet. Records of analysis of water, diet and bedding material are kept on file at ERBC.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 14 June 2021 To: 16 July 2021

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required amount of DMPSA was suspended in the vehicle using the following procedure:
– the required amount of test item was weighed
– the required amount of vehicle was added
– the mixture was shaken by hand
– the mixture was treated with a Silverson for 2-3 minutes
– the resulting suspension was left under magnetic stirring, at room temperature, for at least 1 hour prior to dosing or analysis.
The formulation was prepared daily from the start of the study up to June 28, thereafter weekly (concentrations of 25, 75, 250 mg/mL) up to July 12 and finally for three days, according to stability data obtained from ERBC Study No. A4260 and from the pre-formulation analysis performed during the course of this study. Concentrations were calculated and expressed in terms of test item as supplied.

VEHICLE
- Justification for use and choice of vehicle: corn oil, no justification provided
- Concentration in vehicle: 25, 75 and 250 mg/mL
- Amount of vehicle: 4 mL/kg bw/day

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical method was validated in ERBC Study no. A4260 in the range from 20 to 200 mg/mL and it was extended up to 250 mg/mL in the present study. Linearity, accuracy and precision were within the limits stated in the validation protocol (r > 0.99; accuracy 85-115%; precision CV < 10%).
A 28 hour stability and an 8 day (9 day only for 250 mg/mL) stability at room temperature were verifed in the range from 20 to 250 mg/mL.
The proposed preparation procedure for the test item was checked in the range from 20 to 250 mg/mL by chemical analysis (concentration and homogeneity) in ERBC Study nos. A4260 and X1780 to confrm that the method was suitable. Final results for all levels were within the acceptability limits stated in ERBC SOPs for concentration (85-115%) and homogeneity (CV < 10%).
Samples of the preparations made during Week 1 and the last week of treatment were analysed to check the homogeneity and concentration. Results of the analyses were within the acceptability limits stated in ERBC SOPs for suspensions (85-115% for concentration and CV < 10% for homogeneity).


Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight, until a positive identifcation of mating was made.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Day 6 through Day 19 post coitum.
Frequency of treatment:
daily, 7 days/week
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected in consultation with the Sponsor, based on the results obtained in a previous oral toxicity study in rats (OECD 422) and preliminary non-GLP study (ERBC Study No. E0590), in which no adverse effects were noted at all dose levels (100, 300 and 1000 mg/kg bw/day).
- Rationale for animal assignment: Animals were allocated to the groups by computerised stratifed randomisation to give approximately equal initial group mean body weights.
- Fasting period before blood sampling for rat dam thyroid hormones: not specified
- Time of day for rat dam blood sampling: in the morning of the day of necropsy

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, mortality was checked two times per day

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: on Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum.

FOOD CONSUMPTION : Yes
- Food consumption was measured on Days 3, 6, 9, 12, 15, 18 and 20 post coitum starting from Day 0 post coitum.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: brain, thyroids

OTHER: Immunoanalysis - Thyroid hormone determination (T3, T4 and TSH) (delegated phase)
- Time schedule: on Day 20 post coitum
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
- Uteri or individual uterine horns without visible implantations were immersed in a 20% solution of ammonium sulphide to reveal evidence of embryonic death at very early stages of implantation.
- Other:
– Number, sex and weight of all live foetuses
– Number and sex of dead foetuses (foetuses at term without spontaneous movements and breathing)
– Number of intra-uterine deaths
– Gross evaluation of placentae
Blood sampling:
- Plasma: No
- Serum: Yes
- Volume collected: approximately 0.8 mL
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
- Anogenital distance of all live rodent pups: Yes
Statistics:
For continuous variables the signifcance of the differences amongst group means was assessed by analysis of variance (one-way Anova).
Inter-group differences were assessed by Dunnett’s test or a modifed t test, depending on the homogeneity of data (verifed by Bartlett’s test).
Statistical analysis of non-continuous variables was carried out by means of the KruskalWallis test and intergroup differences between the control and treated groups assessed by a non-parametric version of the Williams test.
Indices:
Pre-implantation loss was calculated as a percentage from the formula:
Pre impl.Loss% = no.of corpora lutea−no.of implantations / no.of corpora lutea × 100

Post-implantation loss was calculated as a percentage from the formula:
Post impl.Loss% = no.of implantations −no.of live foetuses / no.of implantations × 100

Total implantation loss was calculated as a percentage from the formula:
Total impl.Loss% = no.of corpora lutea−no.of live foetuses / no.of corpora lutea × 100
Historical control data:
T3, T4, TSH Historical control data for Sprague Dawley rat in serum (2020-2021) was provided in tables (Please refer to "Any other information on materials and methods incl. tables" section).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
A scab was observed on the nose of a female from the control group on Day 20 post coitum.
On Day 6 of the gestation phase, tooth cut and salivation were observed each respectively in one mid-dose female and in one high dose animal.
These fndings were not considered related to the treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No animal died during the study.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The statistically signifcant reduction in body weight gain recorded on Day 9 post coitum in the high dose group compared to the control group was considered incidental since it was limited only on Day 9 post coitum. (Please refer to Table 1 in the "any other inforamtion on results incl. tables" section)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No changes in food consumption were noted in all treated groups, when compared to controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
no effects observed
Description (incidence and severity):
There was no effect on thyroid hormone determination.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related organ weight changes (brain and thyroid gland) at the end of the treatment period. Any variations were considered to be within the range of expected spontaneous changes in rats of the same age and unrelated to treatment.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related macroscopic observations at the end of the treatment period. Any macroscopic observations were within the range of occasionally observed and expected spontaneous changes in rats of the same age and therefore considered unrelated to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related microscopic observations in the thyroid gland at the end of the treatment period. Any microscopic observations had a comparable incidence in control and treated groups and/or are characteristically seen in untreated rats of the same age and were considered incidental and unrelated to treatment.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
There was no effect on thyroid hormone determination.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Early or late resorptions:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Dead fetuses:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
The number of females with live foetuses on gestation Day 20 was 24 in each of the control, low and high dose groups and 25 in the mid-dose group.
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
A total of 3 females were found not pregnant at necropsy: 1 each in the control, low and high dose groups. (non-treatment related and non adverse, no dose-response relationship, individual finding)
Other effects:
no effects observed
Description (incidence and severity):
Gravid uterus weight: No differences were detected in terminal body weight, uterus weight and absolute weight gain (terminal body weight minus gravid uterus weight, minus body weight at Day 0 post coitum) between control and treated groups.

Corpora lutea: no effects observed (Please refer to Table 2 in the "any other information on results incl. tables" section)

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no treatment-related effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Changes in sex ratio:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
(Please refer to Table 2 in the "any other information on results incl. tables" section)
Anogenital distance of all rodent fetuses:
no effects observed
Description (incidence and severity):
No treatment-related differences were noted in the mean values of the anogenital distance of foetuses of both sexes maternally exposed at all dose levels compared to the control group. (Please refer to Table 2 in the "any other information on results incl. tables" section)
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
A total of 6 foetuses were small (body weight below 2.7 g) at the external examination: 1 in the control group, 2 in the low dose group from 2 different litters, and 3 in the high dose group from 2 different litters.
Cleft palate was noted in 1 foetus of the control group. This fnding was confrmed as visceral malformation at the visceral examination of foetuses.
Anomalies, as hindlimb with abnormal shape and a rudimentary tail, were observed in one foetus of the control group and one foetus of the low dose group, respectively.
No other fndings were recorded in all groups. All observations are considered incidental, due to a missing dose-relationship and the occurence in the control group. (Please refer to Table 3 in the "any other information on results incl. tables" section)
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No malformation was observed at skeletal examination of foetuses. Anomalies and variations were noted both in control and treated groups with a similar incidence, suggesting no treatment-related adverse effect of the test item. (Please refer to Table 4 in the "any other information on results incl. tables" section)
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Cleft palate, observed at the external examination in 1 foetus of the control group, was confrmed at the foetal visceral examination.
Anomalies and variations were noted in control and treated groups with a similar incidence, suggesting no treatment-related adverse effect of the test item. (Please refer to Table 5 in the "any other information on results incl. tables" section)
Other effects:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Body weight gain per day (g) of pregnant females – group mean

Dose group (mg/kg bw/day)

Number

Day of gestation

3

6

9

12

15

18

20

Control

24

4.012±

1.337 

3.227±

1.445

3.019±

1.344

4.298±

1.321

  5.857±

1.636

13.584±

2.610

15.198± 3.274

100

24

4.339±

0.961

3.412±

0.944

2.970±

1.324

4.362±

0.965

5.388±

1.741

14.477±

1.777

15.140±

2.774

300

25

3.674±

2.666

2.960±

1.479

3.790±

2.940

4.297±

1.385

6.038±

1.745

13.639±

2.662

14.528±

3.574

1000

24

3.806±

1.093

3.509±

1.120

2.110*±

1.552

4.925±

1.557

6.019±

1.562 

14.427±

2.683

15.432±

2.566

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

Data shown as mean± standard deviation

 

Table 2: Litter data and sex ratios – group mean

Dose group (mg/kg bw/day)

Control

100

300

1000

Number

24

24

25

24

Corpora lutea

15.17±

2.12

13.92±

2.54

14.36±

3.32 

14.33±

2.06

Implantations

14.25±

2.19

13.33±

2.04

13.56±

3.27

13.79±

1.98

Uterine deaths early

0.63±

2.24

0.08±

0.28

0.28±

0.61

0.29±

0.75

Uterine deaths late

0.04±

0.20

0.04±

0.20

0.00±

0.00

0.08±

0.41

Uterine deaths total

0.67±

2.26

0.13±

0.34

0.28±

0.61

0.38±

0.82

Viable total

13.58±

3.05

13.21±

2.00

13.28±

3.39

13.42±

2.08

Viable males

6.50±

1.82 

6.67±

2.30

6.96±

2.61

6.75±

1.94

Viable females

7.08±

2.19

6.54±

1.98

 6.32±

2.43

6.67±

2.14

% males

48.19±

9.33

49.89±

15.03

52.37±

13.46

50.58±

13.70

Pre-Implantation loss %

6.05±

7.55  

3.54±

5.85

5.58±

8.51 

3.63±

6.04

Post-Implantation loss %

4.56±

15.10

0.88±

2.38

2.31±

5.23

2.74±

5.70

Implantation loss % total

10.55±

15.43

4.40±

6.06

 7.71±

10.14 

6.28±

7.86

Litter weigth (g)

49.38±

11.02

48.02±

7.27

48.25±

11.73

50.33±

8.24

Mean foetal weight males

3.76±

0.23

3.77±

0.17

3.74±

0.22

3.84±

0.19

Mean foetal weight females

3.56±

0.21

3.51±

0.19

3.57±

0.25

3.66±

0.22

Weight combined (g)

3.65±0.21

3.64±1.67

3.66±0.23

3.75±

0.19

* = mean value of group is significantly different from control

Data shown as mean± standard deviation

 

Table 3: External examination of fetuses

Dose group (mg/kg bw/day)

Organ, Category, Observation

Number of fetuses affected

%

Control

Forelimb AN Abnormal shape

1

0.31

Head MA Cleft palate

1

0.31

Whole foetus No abnormalities detected

323

99.08

Whole foetus AN Small

1

0.31

100

Tail AN Rudimentary

1

0.32

Whole foetus No abnormalities detected

314

99.05

Whole foetus AN Small

2

0.63

300

Whole foetus No abnormalities detected

332

100.00

1000

Whole foetus No abnormalities detected

319

99.07

Whole foetus AN Small

 

3

3

VA = Variation, AN = Anomaly, MA = Malformation

 

Table 4: Skeletal examination of fetuses

Dose group (mg/kg bw/day)

Organ, Category, Observation

Number of fetuses affected

%

Control

Forepaw(s) AN Metacarpal(s) no ossification

34

20.24

Ribs VA Rudimentary

4

2.38

Ribs VA Short

14

8.33

Ribs VA 14 ribs

2

1.19

Skull VA Interparietal incomplete ossification

8

4.76

Skull VA Supraoccipital incomplete ossification

44

26.19

Sternebrae AN No ossification

2

1.19

Sternebrae AN Asymmetrical ossification

5

2.98

Sternebrae VA Incomplete ossification

32

19.05

Sternebrae VA No ossification

7

4.17

Sternebrae VA Incomplete ossification

16

9.52

Thoracic vertebrae AN Centrum bipartite

2

1.19

Thoracic vertebrae VA Centrum incomplete ossification

7

4.17

Thoracic vertebrae VA Centrum dumb-bell shaped

2

1.19

100

Forepaw(s) AN Metacarpal(s) no ossification 4th

29

17.68

Ribs VA Rudimentary 14th

4

2.44

Ribs VA Short 14th

12

7.32

Ribs VA 14 ribs

1

0.61

Sacral vertebrae AN Arch(es) incomplete ossification

1

0.61

Skull VA Interparietal incomplete ossification

7

4.27

Skull VA Supraoccipital incomplete ossification

34

20.73

Sternebrae AN Bipartite 5th

1

0.61

Sternebrae AN Asymmetrical ossification

4

2.44

Sternebrae AN Asymmetrical ossification 5th

2

1.22

Sternebrae AN No ossification

1

0.61

Sternebrae VA Incomplete ossification 5th

22

13.41

Sternebrae VA Incomplete ossification 6th

33

20.12

Sternebrae VA No ossification 5th

3

1.83

Sternebrae VA Incomplete ossification

1

0.61

Thoracic vertebrae AN Centrum bipartite

1

0.61

Thoracic vertebrae VA Centrum dumb-bell shaped

5

3.05

Thoracic vertebrae VA Centrum incomplete ossification

4

2.44

300

Forepaw(s) AN Metacarpal(s) no ossification 4th

31

17.82

Ribs VA Rudimentary 14th

4

2.30

Ribs VA Short 14th

13

7.47

Skull VA Interparietal incomplete ossification

3

1.72

Skull VA Supraoccipital incomplete ossification

43

24.71

Sternebrae AN Asymmetrical ossification 5th

2

1.15

Sternebrae AN Asymmetrical ossification

3

1.72

Sternebrae VA No ossification 5th

3

1.72

Sternebrae VA Incomplete ossification 6th

34

19.54

Sternebrae VA Incomplete ossification 5th

26

14.94

Thoracic vertebrae VA Centrum dumb-bell shaped

1

0.57

Thoracic vertebrae VA Centrum incomplete ossification

8

4.60

1000

Forepaw(s) AN Metacarpal(s) no oss. 4th

25

14.97

Lumbar vertebrae AN Centrum bipartite and asymmetrical ossification

1

0.60

Ribs VA Rudimentary 14th

6

3.59

Ribs VA Short 14th

15

8.98

Skull VA Supraoccipital incomplete ossification

26

15.57

Skull VA Interparietal incomplete ossification

5

2.99

Sternebrae AN Asymmetrical ossification

5

2.99

Sternebrae AN No ossification 6th

1

0.60

Sternebrae AN Asymmetrical ossification 5th

3

1.80

Sternebrae VA Incomplete ossification

2

1.20

Sternebrae VA Incomplete ossification 5th

23

13.77

Sternebrae VA Incomplete ossification 6th

17

10.18

Sternebrae VA No ossification 5th

1

0.60

Thoracic vertebrae AN Centrum bipartite and asymmetrical

2

1.20

Thoracic vertebrae AN Centrum bipartite

2

1.20

Thoracic vertebrae VA Centrum incomplete ossification

10

5.99

Thoracic vertebrae VA Centrum dumb-bell shaped

2

1.20

VA = Variation, AN = Anomaly, MA = Malformation

 

Table 5: Visceral Examination of foetuses

Dose group (mg/kg bw/day)

Organ, Category, Observation

Number of fetuses affected

%

Control

Abdomen VA Haemorrhagic

5

3.16

Abdomen VA Umbilical vein left sided

2

1,27

Great vessels VA Innominate artery short

1

0.63

Head MA Cleft palate

1

0.63

Heart AN Atrium enlarged slight

2

1.27

Kidneys AN Ectopic

1

0.63

Kidneys VA Pelvic dilatation slight

3

1.90

Testis AN Displaced

10

6.33

Ureter VA Enlarged slight

13

8.23

100

Abdomen VA Umbilical vein left sided

3

1.96

Kidneys AN Pelvic dilatation moderate

2

1.31

Kidneys VA Pelvic dilatation slight

1

0.65

Testis AN Displaced

10

6.54

Ureter AN Enlarged moderate

3

1.96

Ureter VA Enlarged slight

8

5.23

300

Abdomen VA Umbilical vein left sided

4

2.56

Abdomen VA Haemorrhagic

5

3.21

Heart AN Atrium enlarged slight

1

0.64

Kidneys VA Pelvic dilatation slight

1

0.64

Testis AN Displaced

4

2.56

Ureter VA Enlarged slight

5

3.21

1000

Abdomen VA Umbilical vein left sided

1

0.65

Abdomen VA Haemorrhagic

5

3.25

Heart AN Atrium enlarged slight

4

2.60

Kidneys AN Ectopic

1

0.65

Kidneys VA Pelvic dilatation slight

1

0.65

Testis AN Displaced

11

7.14

Ureter VA Enlarged slight

5

3.25

VA = Variation, AN = Anomaly, MA = Malformation

 

Applicant's summary and conclusion

Conclusions:
Based on the results obtained in this prenatal developmental toxicity study in rats, the NOAEL for maternal and developmental toxicity can be set at 1000 mg/kg bw/day.