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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:
29 Oct 2007 to 22 Nov 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Jan 2001
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
Aug 1998
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
Apr 2004
Qualifier:
according to guideline
Guideline:
other: JMAFF, 12 - Nousan 8147, Teratology (2-1-18)
Version / remarks:
Nov 2000
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
632-619-2
EC Number:
632-619-2
Cas Number:
881685-58-1
Molecular formula:
C20 H23 F2 N3 O
IUPAC Name:
632-619-2

Test animals

Species:
rat
Strain:
Wistar
Remarks:
HanRcc: WIST(SPF Quality)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 11 weeks (day 0 post coitum):
- Weight at study initiation: 192 - 231 g (day 0 post coitum):
- Housing: Animals were housed individually in Makrolon cages (type-3) with wire mesh tops and standardised granulated softwood bedding.
- Diet: Pelleted standard rat/mouse maintenance diet, ad libitum
- Water: Community tap water in water bottles, ad libitum.
- Acclimation period: Minimum 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
Humidity (%): 30 - 70
Air changes (per hr): 10 - 15
Photoperiod: 12 hours light/12 hours dark
Music: background music played at a centrally defined low volume for at
least 8 hours during the light period

IN-LIFE DATES: From: 17 Oct 2007 To: 22 Nov 2007

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% w/v aqueous CMC high viscosity
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet: once a week.
- Mixing appropriate amounts with vehicle: The test item was weighed into a plastic tray on a tared precision balance. The test item was then transferred into a mortar and ground with a pestle. Then the vehicle was added (w/v) in portions to suspend the test item and clean the mortar. The preparation was transferred into a glass beaker and homogenised using an ultra-turrax before subdividing. The test item formulation was prepared once a week. The preparation was subdivided into separate aliquots for dosing each day. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
- Storage temperature of food: Dose formulations were stored refrigerated (2 - 8 °C)

VEHICLE
- Concentration in vehicle: 2, 7.5 and 20 mg/mL
- Amount of vehicle: 10 mL/kg body weight
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
STABILITY OF TEST SUBSTANCE FORMULATIONS
Samples for determination of concentration, homogeneity and stability (7 days) of the dose formulations were taken during the first week of the administration period. Additionally, samples for determination of concentration were taken during the last week of the administration period. For homogeneity, three samples of approximately 2 g were taken from the top, middle and bottom of each formulation and transferred into amber glass vials. For content and stability, samples were taken from the middle only. The samples were frozen (-25 °C to -15 °C) pending analysis. Analysis was performed using a method provided by the Sponsor (capillary GC).
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: yes, in special automatic mating cages i.e. with synchronised timing to initiate the nightly mating period.
- M/F ratio per cage: 1/1
- Length of cohabitation: nightly mating period until evidence of copulation was observed
- Proof of pregnancy: A copulation plug was observed, and/or the daily vaginal smear was sperm positive, referred to as day 0 of gestation.
Duration of treatment / exposure:
Day 4 to 20 p.c.
Frequency of treatment:
Daily
Duration of test:
Untill Day 21 p.c.
Doses / concentrationsopen allclose all
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
Low dose. Group 2
Dose / conc.:
75 mg/kg bw/day (actual dose received)
Remarks:
Mid dose. Group 3
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Remarks:
High dose. Group 4
No. of animals per sex per dose:
24
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The dose levels were selected based on results of a previous dose range finding toxicity study in Han Wistar rats, using dose levels of 0, 60, 125, and 250 mg/kg/day.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS:
- Time schedule: Once daily, during acclimatisation and up to day of necropsy

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: Twice daily for viability / mortality

BODY WEIGHT:
- Time schedule for examinations: daily from day 0 until day 21 post coitum.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Food consumption was recorded at following intervals: Days 0 - 4, 4 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18 and 18 - 21 post coitum.

POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day: on day 21 post coitum, the scheduled necropsy, females were sacrificed by CO2 asphyxiation and the foetuses removed by Caesarean section. The necropsy was carried out in random manner.
- Organs examined: Post mortem examination, including gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, position of foetuses in the uterus and the number of corpora lutea was performed and the data recorded. The uteri (and contents) of all females with live foetuses were weighed during necropsy on day 21 post coitum to enable the calculation of the corrected body weight gain.
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
- Head examinations: Yes: half per litter

Foetuses were removed from the uterus, sexed, weighed individually, examined for gross external abnormalities, sacrificed by a subcutaneous injection of sodium pentobarbital and allocated to one of the following procedures:
- Microdissection technique (sectioning/dissection technique). At least one half of the foetuses from each litter were fixed in Bouin's fixative (one foetus per container). They were examined by a combination of serial sections of the head and microdissection of the thorax and abdomen. This included detailed examination of the major blood vessels and sectioning of the heart and kidneys. After examination, the tissue was preserved in a solution of glycerine/ethanol (one foetus per container). Descriptions of any abnormalities and variations were recorded.
- The remaining foetuses were eviscerated and with the exception of over the paws, the skin was removed and discarded. Carcasses were processed through solutions of ethanol, glacial acetic acid with Alcian blue (for cartilage staining), potassium hydroxide with Alizarin red S (for clearing and staining ossified bone) and aqueous glycerine for preservation and storage. The skeletons were examined and all abnormalities and variations were recorded. The specimens were preserved individually in plastic bags. If no implantation sites were evident, the uterus was placed in an aqueous solution of ammonium sulphide to accentuate possible haemorrhagic areas of implantation sites.
Foetuses with abnormalities were photographed

Statistics:
The following statistical methods were used to analyse maternal, reproduction and skeletal examination data:
- Means and standard deviations of various data were calculated and included in the report.
- All statistical tests were two-sided.
- Statistical significance between groups was evaluated by Analysis of Variance (ANOVA). In the case where variances were non-homogeneous, appropriate transformations were applied (e.g. log, square root, or double arcsine) to stabilise the variances before the ANOVA. The Dunnett many-one t-test was then used to compare each group to control based on the error mean square in the
ANOVA.
- Fisher's exact test was applied if the variables could be dichotomisd without loss of information.
- For statistical tests on foetal data, comparisons were made between groups for number of foetuses affected and number of litters affected, for completeness. The litter was considered the proper unit of measurement for overall study evaluation.
Indices:
- From the on-line recorded reproduction data, the following parameters were calculated: Pre- and post-implantation losses, embryonic and foetal deaths, live and dead foetuses, foetuses with abnormalities and/or variations, foetal sex ratios and foetal body weights.
- For reproduction data, group mean values were calculated both on a litter basis and on a percentage per group basis.
- Mean foetal weights were calculated from the individual weights on a per litter basis.
Historical control data:
Historic Control Data are provided for all reproductive and foetal findings observed in the current study. These historic control data were taken from 6 studies in the same strain of rat, evaluated by similar foetal examination criteria, in this laboratory between 2006 and 2007.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 200 mg/kg/day, ventral recumbency and sedation were noted in all 24 dams between day 4 to day 9 p.c. Starting again on day 13 p.c., ventral recumbency was noted in a small number of females in this group up to day 18 p.c. Sedation and ruffled fur were noted in a few dams up day 21 p.c., the end of treatment
There were no clinical signs or symptoms noted at 20 and 75 mg/kg/day.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All female animals survived until scheduled necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 75 and 200 mg/kg/day, mean body weight was statistically significantly reduced compared to controls from day 7 and day 5, respectively, through the end of study. Mean body weight gain in these groups was also statistically significantly reduced starting on day 6 and 5, respectively, again until the end of study. When corrected for gravid uterine weights, females at 200 mg/kg/day lost an average of 6 g of body weight during treatment compared to a body weight gain in controls of approximately 34 g. At 75 mg/kg/day, body weight gain corrected for gravid uterine weight was decreased approximately 41% when compared with controls.
At 20 mg/kg/day, mean body weight and mean body weight gain were not influenced by treatment with the test item.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption at 75 and 200 mg/kg/day was statistically significantly reduced for the total treatment period (days 4 to 21 p.c.).
Mean food consumption at 20 mg/kg/day was considered to be unaffected by treatment
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:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related findings were noted in any dam at scheduled necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related effects on pre-implantation loss and post-implantation loss
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related effects on the number of living foetuses.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related effects on implantation rate.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
General systemic toxicity
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
Key result
Dose descriptor:
NOAEL
Remarks:
Maternal developmental toxicity
Effect level:
> 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Calculated on litter basis, the mean body weight of foetuses was statistically significantly lower at 75 and 200 mg/kg/day.
There were no effects on mean foetal body weight at 20 mg/kg/day.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratios were considered to be not influenced by treatment with the test substance.
Changes in litter size and weights:
no effects observed
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Variations were noted in all groups. These variations were known to be common in this strain of rat, and/or were within the range of the historical reference data. Thus, they were considered as not related to the treatment with the test substance.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
- Skeletal examination: There were no treatment-related differences in the incidence of bone and cartilage abnormalities. The sporadic incidences noted (vertebra absent, cervical vertebral arch short, misshapen and / or reduced thoracolumbar vertebrae [thoracolumbar scoliosis]) were without dose-relationship and therefore considered to be of incidental nature. There were no treatment-related statistical differences in the incidence of bone and cartilage variations. The incidences of the variation “costal cartilages asymmetrically aligned at sternum” were slightly higher in the dosed groups compared to the control group, but were within the range of the historical reference data (based on litter) and thus considered to be of incidental nature. The other incidences of bone and cartilage variations were noted mostly without dose relationship, and were therefore considered to be of incidental nature.
- Bone examinations - ossification stage / supernumerary ribs: Skeletal examination (ossification stage) of foetuses did not reveal any direct test substance-related findings. Due to the statistically significantly reduced body weight of the foetuses at 75 and 200 mg/kg/day, the increased incidence of non-ossified or incompletely ossified bones were considered to be delayed development, and related to the maternal toxicity observed. At 200 mg/kg/day, statistically significantly higher incidences of a number of variations such as non-ossified vertebral bodies, incompletely ossified proximal phalanges, talus, and metatarsalia were observed. At 75 mg/kg/day, only the incidence of non-ossified cervical vertebral body 3 was statistically increased on a litter basis. All other incidences were similar in the test item treated groups and the control group and / or were within the range of historical reference data.
- Cartilage examinations: The noted incidence in common cartilage variations was dose-independent, not statistically significant in all but one finding on a litter basis, and therefore considered to be of incidental nature.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
During the visceral examination of foetuses, abnormalities were noted in 5 foetuses. Abnormalities observed included thoracic and abdominal situs inversus, heart interventricular septal defect, and diaphragmatic hernia. As they were noted without dose-relationship, they were considered to be of incidental nature.
Variations were noted in all groups. These variations were known to be common in this strain of rat, and/or were within the range of the historical reference data. Thus, they were considered as not related to the treatment with the test item.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
Developmental toxicity
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: skeletal defects
Description (incidence and severity):
Poor ossification

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
75 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

Dose verification

The identity of the test substance was confirmed by the retention times of syn-isomer and anti-isomer which were similar to those measured in the working standards. The test item concentration in all samples was found to be within 86.4% and 102.9% of the nominal content. In addition, the homogenous distribution of the test item in 0.5% aqueous carboxymethylcellulose solution was demonstrated. The dosing formulations were considered to be stable for at least 7 days in the refrigerator

Table 1 Mortality and clinical signs or observations

 

Test substance (mg/kg/day)

Observation

0 (control)

20

75

200

Number of females

24

24

24

24

Ventral recumbency

0

0

0

24

Sedation

0

0

0

24

Ruffled fur

0

0

0

6

Number of animals with signs

0

0

0

24

 No clinical signs or observations

24

24

24

0

Table 2 Intergroup comparison of maternal body weight (g)

 

Dose level test substance (mg/kg/day)

Maternal body weight

0 (control)

20

75

200

Day 0 (Pre-dosing)

212

211

211

208

Day 4 (Pre-dosing)

226

224

225

223

Day 5

229

226

227

218**

Day 7

236

231

226**

212**

Day 10

249

243

239**

221**

Day 12

257

252

247*

228**

Day 15

272

267

261**

240**

Day 20

330

323

315*

275**

Day 21

341

333

325*

282**

Maternal body weight gain on day 21

114.6

108.6

99.8*

59.5**

Weight gain on day 21 corrected for gravid uterus weight (g)

34.2

26.0

20.2**

-5.7**

*/**: Dunnett-Test based on pooled variance significant at 5 % (*) or 1 % (**) level

Table 3 Intergroup comparison of food consumption(g/rat/day)

 

 

Dose level test substance (mg/kg/day)

Food consumption

0 (control)

20

75

200

Pre-dosing:

Days 0 - 4

21.9

21.7

21.9

22.1

During dosing

Days 4 - 6

22.9

23.4

19.4**

13.7**

 

Days 6 - 9

22.9

21.5

19.4**

13.5**

 

Days 9 - 12

24.7

23.8

22.2**

17.1**

 

Days 12 - 15

24.6

23.5

22.3**

17.7**

 

Days 15 - 18

26.3

25.3

24.0**

17.6**

 

Days 18 - 21

25.2

24.6

22.3**

16.7**

*/**: Dunnett-Test based on pooled variance significant at 5 % (*) or 1 % (**) level

Table 4 Caesarean section observations for all pregnant females

Observation

Test substance (mg/kg/day)

 

0 (control)

60

125

250

Animals Assigned (Mated)

24

24

24

24

Animals Pregnant

23

23

24

24

Nonpregnant

1

1

0

0

Corpora Lutea/Dam

14.4

14.8

14.4

14.2

Implantations/Dam

13.7

13.9

13.9

13.2

Gravid Uterus Weight (g)

80.4

82.6

79.6

65.2

Total Litters (viable)

23

23

24

24

Foetuses/Dam

12.4

13.1

13.1

12.2

Number of Intra-uterine deaths (litters affected)

29 (15)

18 (12)

18 (13)

25 (14)

Early deaths (Number of litters affected)

26 (13)

16 (11)

16 (11)

25 (14)

Late deaths (Number of litters affected)

3 (3)

2 (2)

2 (2)

0

Mean Foetal Weight (g)

4.8

4.7

4.5*

4.0**

         Males (g)

5.0

4.8

4.7*

4.1**

         Females (g)

4.7

4.6

4.4*

3.9**

Sex Ratio (% Males per litter)

47.9

51.8

46.3

47.9

Pre-implantation Loss (%)

4.8

6.2

3.5

7.0

Post-implantation Loss (%)

9.2

5.9

5.4

7.9

  * / ** : Dunnett-Test based on pooled variance significant at level 5% (*) or 1% (**)

Table 5 External/visceral examinations

 

test substance (mg/kg/day)

 

0 (control)

20

75

200

Number of foetuses (litters)

150 (23)

156 (23)

163 (24)

151 (24)

Number of abnormal foetuses (litters)

0

1 (1)

3 (3)

1 (1)

Number of foetuses with variations (litters)

52 (21)

55 (22)

63 (23)

76 (23)

Table 6 Skeletal examinations - bone and cartilage abnormalities and variations

 

test substance (mg/kg/day)

 

0 (control)

20

75

200

Number of foetuses (litters)

136 (23)

145* (23)

152* (24)

141 (24)

Number of abnormal foetuses (litters)

1 (1)

0

2 (2)

0

Number of foetuses with variations (litters)

23 (12)

31 (18)

38 (17)

34 (18)

Costal cartilages asymmetrically aligned at sternum foetuses (litters)

1 (1)

3 (3)

6 (5)

7 (5)

* One less fetus at cartilage examination.

Table 7 Bone examinations - ossification stage / supernumerary ribs

 

test substance (mg/kg/day)

Selected findings

0 (control)

60

125

250

Number of litters examined

23

23

24

24

Non ossified:
cervical vertebral body 1
cervical vertebral body 2
cervical vertebral body 3


7
3
3


13
7
6


12
9
10#


17##
19##
13##

Non ossified:
toe 2 proximal phalanx, left
toe 3 proximal phalanx left
toe 4 proximal phalanx left
toe 5 proximal phalanx left
toe 5 proximal phalanx right


3
3
3
10
10


5
5
5
12
10


5
3
3
14
11


10#
10#
10#
21##
18#

# / ##: Fisher's Exact Test significant at level 5% (#) or 1% (##)

Applicant's summary and conclusion

Conclusions:
The NOAEL for maternal toxicity was 20 mg/kg/day beased on reduced body weight food consumptions and clinical signs. The NOAEL for developmental toxicity was considered to be 20 mg/kg/day as a result of reduced body weight and ossification.
Executive summary:

The purpose of this OECD TG 414 study in compliance with GLP was to assess the effects of test substance on the pregnant rat and the embryonic and foetal development when administered orally, by gavage, once daily to mated female rats from day 4 through to day 20 post coitum. Each group consisted of 24 mated female rats. The test substance was administered at dose levels of: 0 (vehicle control, 20, 75 and 200 mg/kg/day, for respectively Group 1, 2, 3 and 4. A standard dose volume of 10 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (0.5 % w/v aqueous CMC high viscosity). All females were sacrificed on day 21 post coitum and the foetuses were removed by Caesarean section. Examination of dams and foetuses was performed in accordance with international recommendations.

All female animals survived until scheduled necropsy. Ventral recumbency and sedation were noted in 24/24 dams, and ruffled fur in 6/24 dams at 200 mg/kg/day. There were no findings in dams at 20 or 75 mg/kg/day. Mean food consumption at 75 and 200 mg/kg/day was statistically significantly reduced. Mean body weight and mean body weight gain was statistically significantly reduced starting on day 7and day 6 at 75 mg/kg/day and on day 5 post coitum at 200 mg/kg/day. There were no treatment-related effects on pre-implantation loss, implantation rate, post-implantation loss, or the number of living foetuses. No treatment related findings were noted in any dam at scheduled necropsy. At scheduled caesarean section, no abnormal live foetus was noted at external examination at 0, 20, 75, and 200 mg/kg/day, respectively.

Sex ratios were considered not to be influenced by treatment with the test item. Mean foetal body weight was statistically significantly reduced at 75 and 200 mg/kg/day.

As the abnormalities in foetuses of test item-treated dams were noted without dose-relationship, they were considered to be of incidental nature. There were no treatment-related visceral variations. There were no treatment related bone and cartilage abnormalities noted.

Skeletal examination (ossification stage) of foetuses did not reveal any direct test item-related findings. Due to the statistically significantly reduced foetal body weight at 75 and 200 mg/kg/day, the increased incidence of non-ossified or incompletely ossified bones were considered to be delayed development, and probably related to the maternal toxicity observed.

There were no treatment-related increases in the incidences of cartilage variations in any dose group when compared with controls. In this prenatal developmental toxicity study the doses of 20, 75, and 200 mg/kg/day were administered to pregnant Han Wistar rats.

Maternal toxicity was noted at 75 and 200 mg/kg/day with statistically significantly decreased food consumption and corresponding statistically significantly decreased body weight gain. Clinical signs were only noted at 200 mg/kg/day. At 75 and 200 mg/kg/day, the only treatment related foetal effects noted were decreased body weight and delayed ossification. These effects were considered to be secondary to the maternal toxicity observed at these dose levels.

In conclusion, there was no evidence of maternal and foetal toxicity at 20 mg/kg/day, which was established as a no observed adverse effect level (NOAEL).