Registration Dossier
Registration Dossier
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EC number: 201-877-4 | CAS number: 89-04-3
Developmental toxicity / teratogenicity
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:
- 2 017
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Adopted 22nd January 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Trioctyl benzene-1,2,4-tricarboxylate
- EC Number:
- 201-877-4
- EC Name:
- Trioctyl benzene-1,2,4-tricarboxylate
- Cas Number:
- 89-04-3
- Molecular formula:
- C33H54O6
- IUPAC Name:
- 1,2,4-trioctyl benzene-1,2,4-tricarboxylate
- Test material form:
- liquid
Constituent 1
- 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 or test system 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.
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Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
