Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
8th December 2000 - 2nd January 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Draft June 2000
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
Nov. 18, 1987
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
CIT
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, Sulzfeld, Germany
- Age at study initiation: 10-11 weeks old
- Weight at study initiation: a mean body weight of 242 g (range: 198 g to 293 g).
- Housing: individual
- Acclimation period: 5 days
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 20
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air.
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
There was a total of four groups of 25 female rats of the Sprague-Dawley strain, which received the test or control substances once a day by oral administration from day 6 to day 19 post-coitum.
Analytical verification of doses or concentrations:
yes
Remarks:
HPLC analysis
Details on analytical verification of doses or concentrations:
The results of the analyses confirmed the homogeneity and concentrations of the samples of the dosage forms taken on the first day and on the last day of treatment.
Details on mating procedure:
Mating: females were mated at the breeder's facilities. The day of confirmed mating (detection of a vaginal plug) was designated as day 0 post-coitum.
Duration of treatment / exposure:
Each animal was given the dosage forms once a day, at approximately the same time, from day 6 to day 19 post-coitum
Frequency of treatment:
once/day
Duration of test:
day 0 to day 20 post-coitum
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
45 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: The doses used in this study were selected based on the results of a preliminary range finding maternal toxicity study. Groups of 10 mated female Sprague-Dawley rats received the test substance in 0.5% aqueous carboxymethylcellulose at dose levels of 0 (vehicle control group), 50, 100, and 200 mg/kg bw/d. The test substance was administered by gavage on days 6 through 19 of gestation inclusive. The animals were sacrificed on day 20 of gestation, with exception of the high dose dams; these rats were sacrificed on day 10 post coitum due to marked toxicity.
Conclusions of the dose-finding study: The test substance produced slight maternotoxic effects when administered to pregnant rats (days 6 to 19 post coitum) at a dose level of 50 mg/kg bw/d. At 100 mg/kg bw/d, marked maternotoxicity was recorded, with forestomach, stomach and liver as target organs. The 200 mg/kg bw/d dose level was dramatically toxic to the pregnant rats. All surviving dams were sacrificed in a moribund condition before schedule on day 10 post coitum.

- Rationale for animal assignment: the animals were allocated to the groups, according to a stratification procedure, so that the average body weight of each group was similar.

Examinations

Maternal examinations:
Mortality
Each animal was checked for mortality or signs of morbidity:at least twice a day during treatment period, at least once a day on other days.

Clinical symptoms
Each animal was observed for clinical signs (including evidence of abortion/resorption) at approximately the same time.

Food consumption
The quantity of food consumed by each female was recorded for the following intervals: 2-6, 6-9, 9-12, 12-15, 15-18 and 18-20 post-coitum.

Body weight data
The body weight of each female was recorded on days 2, 6, 9, 12, 15, 18 and 20 post-coitum.

After hysterectomy, the females were subjected to a macroscopic post-mortem examination of the principal thoracic and abdominal organs.
A gross evaluation of placentas was also performed.
Ovaries and uterine content:
The weight of the gravid uterus was recorded for each pregnant female at hysterectomy (with at least one live fetus).
The ovaries and uterus of females were examined to determine:
number of corpora lutea,
number and distribution of dead and live fetuses,
number and distribution of early and late resorptions,
number and distribution of implantation sites.
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Examination of the fetuses after dissection from the uterus
Each fetus was submitted to a detailed external examination, which included the observation of all visible structures, surfaces and orifices. Dead fetuses were then discarded. The body weight of each live fetus was recorded. The live fetuses were killed by subcutaneous injection of thiopental sodium.

Soft tissue examination of the fetuses
Approximately half of the live fetuses per litter were fixed with Harrisson's fluid. A detailed soft tissue examination was performed according to a free-hand sectioning technique (Wilson technique) which included the observation of all the organs and structures of the head, neck, thorax and
abdomen.

Skeletal and cartilage examination of the fetuses
The remaining fetuses per litter were fixed in ethyl alcohol. A detailed examination of the skeleton was performed after staining with alizarin red S and alcian blue. This examination included the observation of all the bone structures and cartilage of the head, spine, rib cage, pelvis and limbs.
In particular, cartilage was specifically examined where a bony structure was altered.

Sex of fetuses
The sex of each live fetus was determined at the time of evisceration (after fixation in alcohol) or at the time of the Wilson sectioning.
Statistics:
Mean values were compared by one-way analysis of variance and Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous).
Percentage values were compared by the Fisher exact probability test.
Indices:
The conception rate (%) was calculated as follows:
Number of pregnant females/Number of females mated x 100

The pre-implantation loss was calculated as follows:
Number of corpora lutea - Number of implantation sites/Number of corpora lutea x 100

The post-implantation loss was calculated as follows:
Number of implantation sites - Number of live fetuses/Number of implantation sites x 100

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No substance-related clinical symptoms were observed in the control and the treated groups, the few findings occasionally observed being of no toxicological significance.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no deaths in the control and the treated groups except for one female in the 15 mg/kg/day which was found dead on day 20 of gestation prior to the terminal sacrifice. No clinical signs were observed prior to the death. Food consumption and body weight gain were slightly lower than the group mean values but still within normal range. Foamy content and dilatation of the lungs were recorded at necropsy. The reason for this death is not known but a relation to treatment with the test substance can be ruled out since this single mortality was observed in the mid-dose group
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the period of treatment (day 6 to day 19 post-coitum), the group mean body weight gain was similar in the control and the 5 mg/kg/day groups. In the 15 and 45 mg/kg/day treated groups, the group mean body weight gain was slightly (-8%, not statistically significant) to clearly (-13%, p<0.05) reduced during the period of treatment, with a more marked effect at the beginning (first 3 days of treatment). In these treated groups, the mean values of terminal body weight did not statistically differ from that of the control group, but were lower by -4% and -6%, respectively.
The corrected body weight gain (terminal body weight on day 20 post-coitum minus the weight of gravid uterus minus body weight on day 6 post-coitum) was minimally reduced in the 5 mg/kg/day group (-17%, not statistically significant). This finding was considered to be fortuitous because it was the only effect recorded in this group (no difference in gross body weight gain or food consumption). The corrected body weight gain was slightly (-23%, not significant) to markedly (-44%, p<0.001) reduced in the 15 and 45 mg/kg/day groups respectively. Because this effect was dose-related and correlated with a lower food consumption (in the 45 mg/kg/day group), it was considered to be related to the treatment with the test substance.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
The food consumption was similar in the control and the 5 and 15 mg/kg/day groups. In the 45 mg/kg/day group, there was a notable decrease in food consumption during the treatment period (-7%, not statistically significant), with a more marked effect during the first week of 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
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The mean value of gravid uterus weight was similar in the control and the treated groups, the slight fluctuations recorded correlating with the mean litter size.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
There was no remarkable observation in the 5 and 15 mg/kg/day treated groups. However, in the 45 mg/kg/day treated group, 6/25 females presented paleness, accentuated lobular pattern and/or whitish area on the liver. These necropsy findings might be related to the test substance administration.
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:
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:
not examined
Changes in number of pregnant:
not examined
Description (incidence and severity):
There were no substance-related and /or biological relevant differences between the different test groups in conception rate, in the mean number of corpora lutea and implantation sites or in the pre and post-implantation losses and the number of resorptions. There was only a clearly higher number of live fetuses/dam in the 45 mg/kg/day group: 13.7 fetuses per litter on average, versus 12.6 fetuses per litter in the control group. This difference was considered to be incidental as both values are fully within the historical control range. However, the increased mean number of live fetuses/dam in the highdose group may well account for the slight delays in ossification of the fetal skeletons at this dose-level.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The body weight of the fetuses was similar in the control and the treated groups. Quite large variations were observed between the litters, probably because of a broad range in the time of overnight mating, but the distribution of this range was similar in all the groups.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution was similar in the control and the treated groups.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No malformations were observed at external examination of the fetuses from the control and the 5 and 45 mg/kg/day treated groups. In the 15 mg/kg/day, 1/293 fetuses (= 0.3% of the examined fetuses) from one out of 23 litters (= 4% of the examined litters) displayed a thread-like tail. This external malformation can be also observed occasionally in control fetuses and thus is considered to be of spontaneous occurrence.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There was a low incidence of malformations in each group:
Control group: one fetus (= 0.7% of the examined fetuses) from one out of 22 litters
(= 4.5% of the examined litters) affected
-1/146 fetuses with misshapen 11th pair of ribs.
5 mg/kg/day group: two fetuses (= 1.5% of the examined fetuses) from two out of
19 litters (= 10.5% of the examined litters) affected
-2/133 fetuses with misshapen rib(s) (11th pair),
15 mg/kg/day group: two fetuses (= 1.6% of the examined fetuses) from two out of
18 litters (= 11.1 % of the examined litters) affected
-1/122 fetuses with fused ribs (4th 5th 6th right ribs); this fetus had a slightly lower body weight,
-1/122 fetuses with misshapen ribs (7th to 11th pair).
45 mg/kg/day: four fetuses (= 2.7% of the examined fetuses) from four out of 21 litters (= 19.0% of the examined litters) affected
-3/148 fetuses with misshapen rib (one to five ribs affected, unilaterally),
-1/148 fetuses with misshapen, enlarged 6th sternebra.

Statistical significance was not reached for any of the recorded skeletal malformations, either for fetal incidence, litter incidence or mean percentage of affected fetuses per litter. In addition, there was no clear dose-relationship between the dose-groups: incidence in the mid-dose group is lower than in the low-dose group for misshapen rib; incidence in the mid-dose group is higher than in the low and high-dose groups for fused ribs. Consequently, concerning fetal skeletal malformations, a relationship to treatment with the test substance was ruled out.

In the 5 and 15 mg/kg/day treated groups the incidence and nature of the fetal skeletal variations were similar to those recorded in the control group: the slight differences observed were occasional, not dose-related, and/or not statistically significant.
In addition, the values were within the range of CIT historical control data. The single exception was the incomplete ossification of the frontal bone, which was recorded at a slightly higher incidence in the 15 mg/kg/day group when compared to the contemporary controls and the historical data. However, the difference was slight and the actual control value was already slightly above the highest historical control value. Consequently, this single finding was not considered to be of toxicological significance.
In the 45 mg/kg/day treated group, there was a higher incidence of a number of skeletal variations representing incomplete ossification of skull bones and absence of ossification of 5th sternebra. The differences were greater than those recorded at lower dose-levels, and/or were occasionally outside the range of CIT historical control data. When comparing fetal incidences, statistical significance was reached for three out of five findings. The slightly increased occurrence of delays in ossification at the high dose is, however, not considered to be substance-induced for the following reasons:
-the mean number of live fetuses per litter was distinctly higher in the high-dose
group than in the concurrent control group (13.7 fetuses/dam at 45 mg/kg vs. 12.6 control fetuses/dam - see also § 4.2.2.3). It is very likely, that this is the actual cause
for the transient delays in ossification (although the mean fetal body weights are rather similar in all groups),
-statistical significance for these findings was not reached when comparing the number of affected fetuses on a per litter basis,
-moreover, the overall incidence for fetal skeletal variations was not increased in the high-dose group (93.9%) in comparison to the control group (94.5%).

Special comments on additional skeletal examinations:
A total of 16 litters, accounting for 105 fetuses were also examined for skeletal and cartilage findings. However, since the labeling of the flasks containing the fetuses was accidentally lost, it was not possible to identify which experimental group each litter belonged to. However, a global analysis showed that:
-malformation was confined to a single fetus displaying misshapen ribs (7th to 10th right ribs),
-variations were similar in nature and incidence to that recorded in the properly identified fetuses.
In conclusion, although the skeletal findings recorded in these 105 fetuses cannot be properly attributed to each of the four experimental groups, their incidence and nature did not differ from that observed in the 549 evaluated fetuses and thus do not change the final assessment which is summarized below.

Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The only soft tissue variations recorded were the dilatation of renal pelvis and/or ureter. These common variations were recorded at a similar incidence in the control and treated groups and did not suggest any treatment- or dose-relationship. In addition, the incidence was within the range of CIT historical control data for this strain of rats.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
45 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Skeletal variations

Mean incidence of notable skeletal variations

Dose-level (mg/kg/day)

0

5

15

45

Historical

control range

Interparietal: incomplete ossification

fetal incidence (%)

6.8

12.8

16.4*

29.1***

8.7
(1.5-19.1)

affected fetuses/litter (%)

7.0

12.5

17.7

29.1

Parietal: incomplete ossification

fetal incidence (%)

1.4

3.8

4.9

16.2***

2.7
(0.0-6.9)

affected fetuses/litter (%)

1.6

3.9

5.1

16.2**

Supraoccipital: incompleteossification

fetal incidence (%)

2.7

3.0

2.5

10.1*

4.1
(0.0-17.6)

affected fetuses/litter (%)

3.1

3.0

3.0

9.8

Frontal: incomplete ossification

fetal incidence (%)

6.8

2.3

9.0

13.5

2.2
(0.0-6.3)

affected fetuses/litter (%)

6.3

2.3

8.4

12.2

5th sternebra: unossified

fetal incidence (%)

14.4

12.0

18.9

30.4**

23.7
(9.9-40.5)

affected fetuses/litter (%)

16.0

12.3

17.1

28.6

Total of skeletal variations

fetal incidence (%)

94.5

94.7

91.8

93.9

X

affected fetuses/litter (%)

94.2

94.6

91.2

92.8

*: p<0.05        **: p<0.01       ***: p<0.001 (statistics calculated using absolute values) underlined values: outside CIT historical data.

 

Table 2: HYSTERECTOMY DATA (Summary table)

Dose-level (mg/kg/day)

 

0

5

15

45

Pregnant Females Alive at Term

N

25

24

23

24

with Total Resorptions

N

0

0

0

0

with all DeadFetuses

N

0

0

0

0

with Live Fetuses

N

25

24

23

24

 

 

 

 

 

 

Corpora Lutea

Total

353

363

332

357

No. per animal

Mean

14.1 d

15.1

14.4

14.9

 

S.d.

2.4

2.6

3.0

2.7

 

 

 

 

 

 

Implantation Sites

Total

322

330

299

336

No. per animal

Mean

12.9 d

13.8

13.0

14.0

 

S.d.

2.6

1.8

2.4

2.1

 

 

 

 

 

 

Preimplantation Loss

Total

31 f

33

33

21

 

%

8.8

9.1

9.9

5.9

 

 

 

 

 

 

Fetuses

N

316

321

293

329

No. per animal

Mean

12.6 d

13.4

12.7

13.7

 

S.d.

2.7

2.0

2.3

2.5

Alive

%

100.0

100.0

100.0

100.0

Dead

%

0.0

0.0

0.0

0.0

 

 

 

 

 

 

Live Fetuses

N

316 f

321

293

329

% of implantation sites

 

98.1

97.3

98.0

97.9

No. per animal

Mean

12.6 d

13.4

12.7

13.7

 

S.d.

2.7

2.0

2.3

2.5

 

 

 

 

 

 

Dead Fetuses

N

0 f

0

0

0

% of impantation sites

 

0.0

0.0

0.0

0.0

No. per animal

Mean

0.0

0.0

0.0

0.0

 

S.d.

0.0

0.0

0.0

0.0

 

 

 

 

 

 

Resorptions + Scars

N

6 f

9

6

7

% of impantation sites

 

1.9

2.7

2.0

2.1

No. per animal

Mean

0.2 d

0.4

0.3

0.3

 

S.d.

0.6

0.8

0.6

0.8

 

 

 

 

 

 

Implant Scars

N

0 f

0

0

0

% of impantation sites

 

0.0

0.0

0.0

0.0

No. per animal

Mean

0.0

0.0

0.0

0.0

 

S.d.

0.0

0.0

0.0

0.0

 

 

 

 

 

 

Resorptions: early

N

6 f

9

4

7

% of impantation sites

 

1.9

2.7

1.3

2.1

No. per animal

Mean

0.2 d

0.4

0.2

0.3

 

S.d.

0.6

0.8

0.5

0.8

 

 

 

 

 

 

Resorptions: late

N

0 f

0

2

0

% of impantation sites

 

0.0

0.0

0.7

0.0

No. per animal

Mean

0.0 d

0.0

0.1

0.0

 

S.d.

0.0

0.0

0.3

0.0

 

 

 

 

 

 

Postimplantation Loss

Total

6 f

9

6

7

% of impantation sites

 

1.9

2.7

2.0

2.1

No. per animal

Mean

0.2 d

0.4

0.3

0.3

 

S.d.

0.6

0.8

0.6

0.8

 

 

 

 

 

 

Male Fetuses

N

157 f

147

138

174

 

%

49.7

45.9

47.1

52.9

Female Fetuses

N

159 f

173

155

155

 

%

50.3

54.1

52.9

47.1

 

 

 

 

 

 

Fetal Body Weight (g)

Mean

4.53 d

4.72

4.48

4.49

 

S.d.

0.81

0.88

0.74

0.90

 

 

 

 

 

 

Male Fetuses

Mean

4.65 d

4.84

4.62

4.62

 

S.d.

0.82

0.91

0.79

0.97

 

 

 

 

 

 

Female Fetuses

Mean

4.42 d

4.60

4.37

4.32

 

S.d.

0.84

0.86

0.71

0.85

Statistical key: d=ANOVA + Dunnett-test       f=Fishers exact test

15 mg/kg/day: 1/24 pregnant females died just prior to the hysterectomy

Table 3: SUMMARY OF FETAL EXTERNAL MALFORMATIONS

 

Dose-level (mg/kg/day)

 

0

5

15

45

Litters Evaluated

N

25

24

23

24

Fetuses Evaluated

N

316

321

293

329

Live

N

316

321

293

329

Dead

N

0

0

0

0

 

 

 

 

 

 

Tail

Litter Incidence

N

0

0

1

0

Fetal Incidence

N

0

0

1

0

 

 

 

 

 

 

THREAD-LIKE TAIL

Fetal Incidence

N

0 f

0

1

0

 

%

0.0

0.0

0.3

0.0

Litter Incidence

N

0 f

0

1

0

 

%

0.0

0.0

4.3

0.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.0 d

0.0

0.4

0.0

 

S.d.

0.0

0.0

1.7

0.0

 

 

 

 

 

 

TOTAL FETAL EXTERNAL MALFORMATIONS

Fetal Incidence

N

0 f

0

1

0

 

%

0.0

0.0

0.3

0.0

Litter Incidence

N

0 f

0

1

0

 

%

0.0

0.0

4.3

0.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.0 d

0.0

0.4

0.0

 

S.d.

0.0

0.0

1.7

0.0

 Statistical key: d=ANOVA + Dunnett-test       f=Fishers exact test

 

Table 4: SUMMARY OF FETAL EXTERNAL VARIATIONS

Dose-level (mg/kg/day)

 

0

5

15

45

Litters Evaluated

N

25

24

23

24

Fetuses Evaluated

N

316

321

293

329

Live

N

316

321

293

329

Dead

N

0

0

0

0

 

 

 

 

 

 

TOTAL FETAL EXTERNAL VARIATIONS

Fetal Incidence

N

0 f

0

0

0

 

%

0.0

0.0

0.0

0.0

Litter Incidence

N

0 f

0

0

0

 

%

0.0

0.0

0.0

0.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.0

0.0

0.0

0.0

 

S.d.

0.0

0.0

0.0

0.0

 Statistical key: f=Fishers exact test

Table 5: SUMMARY OF FETAL SOFT TISSUE MALFORMATIONS  

Dose-level (mg/kg/day)

 

0

5

15

45

Litters Evaluated

N

25

24

23

24

Fetuses Evaluated

N

149

155

141

160

 

 

 

 

 

 

TOTAL FETAL SOFT TISSUE MALFORMATIONS

Fetal Incidence

N

0 f

0

0

0

 

%

0.0

0.0

0.0

0.0

Litter Incidence

N

0 f

0

0

0

 

%

0.0

0.0

0.0

0.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.0

0.0

0.0

0.0

 

S.d.

0.0

0.0

0.0

0.0

Statistical key: f=Fishers exact test

Table 6: SUMMARY OF FETAL SOFT TISSUE VARIATIONS

Dose-level (mg/kg/day)

 

0

5

15

45

Litters Evaluated

N

25

24

23

24

Fetuses Evaluated

N

149

155

141

160

 

 

 

 

 

 

KIDNEYS

Litter Incidence

N

7

2

3

2

Fetal Incidence

N

10

2

6

8

 

 

 

 

 

 

DILATED RENAL FELVIS

Fetal Incidence

N

10 f

2

6

8

 

%

6.7

1.3

4.3

5.0

Litter Incidence

N

7 f

2

3

2

 

%

28.0

8.3

13.0

8.3

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

6.1 d

1.4

4.3

5.0

 

S.d.

11.1

4.7

13.4

20.6

 

 

 

 

 

 

URETER

Litter Incidence

N

1

0

2

0

Fetal Incidence

N

2

0

3

0

 

DILATED URETER

Fetal Incidence

N

2 f

0

3

0

 

%

1.3

0.0

2.1

0.0

Litter Incidence

N

1 f

0

2

0

 

%

4.0

0.0

8.7

0.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

1.1 d

0.0

1.7

0.0

 

S.d.

5.7

0.0

5.7

0.0

 

 

 

 

 

 

TOTAL FETAL SOFT TISSUE VARIATIONS

Fetal Incidence

N

10 f

2

6

8

 

%

6.7

1.3

4.3

5.0

Litter Incidence

N

7 f

2

3

2

 

%

28.0

8.3

13.0

8.3

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

6.1 d

1.4

4.3

5.0

 

S.D.

11.1

4.7

13.4

20.6

 Statistical key: d=ANOVA + Dunnett-test       f=Fishers exact test

Table 7: SUMMARY OF FETAL SKELETAL MALFORMATIONS

Dose-level (mg/kg/day)

 

0

5

15

45

Litters Evaluated

N

22

19

18

21

Fetuses Evaluated

N

146

133

122

148

 

 

 

 

 

 

STERNEBRA

Litter Incidence

N

0

0

0

1

Fetal Incidence

N

0

0

0

1

 

 

 

 

 

 

MISSHAPEN STERNEBRA (E)

Fetal Incidence

N

0 f

0

0

1

 

%

0.0

0.0

0.0

0.7

Litter Incidence

N

0 f

0

0

1

 

%

0.0

0.0

0.0

4.8

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.0 d

0.0

0.0

1.0

 

S.d.

0.0

0.0

0.0

4.4

 

 

 

 

 

 

RIB

Litter Incidence

N

1

2

2

3

Fetal Incidence

N

1

2

2

3

 

MISSHAPEN RIB

Fetal Incidence

N

1 f

2

1

3

 

%

0.7

1.5

0.8

2.0

Litter Incidence

N

1 f

2

1

3

 

%

4.5

10.5

5.6

14.3

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.6 d

1.5

0.9

2.4

 

S.d.

3.0

4.7

3.9

6.2

 

 

 

 

 

 

FUSED RIBS

Fetal Incidence

N

0 f

0

1

0

 

%

0.0

0.0

0.8

0.0

Litter Incidence

N

0 f

0

1

0

 

%

0.0

0.0

5.6

0.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.0 d

0.0

0.6

0.0

 

S.D.

0.0

0.0

2.6

0.0

 

TOTAL FETAL SKELETAL MALFORMATIONS

Fetal Incidence

N

1 f

2

2

4

 

%

0.7

1.5

1.6

2.7

Litter Incidence

N

1 f

2

2

4

 

%

4.5

10.5

11.1

19.0

 

 

 

 

 

 

Affected Fetuses/Litter

Mean%

0.6 d

1.5

1.5

3.4

 

S.D.

3.0

4.7

4.6

7.2

Statistical key: d=ANOVA + Dunnett-test       f=Fishers exact test

Applicant's summary and conclusion