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EC number: 223-517-5 | CAS number: 3937-56-2
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2006-01-18 to 2006-05-10
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- DL-hexane-1,2-diol
- EC Number:
- 230-029-6
- EC Name:
- DL-hexane-1,2-diol
- Cas Number:
- 6920-22-5
- IUPAC Name:
- hexane-1,2-diol
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Chemical name: 1,2-hexanediol
- CAS no.: 6920-22-5
- EC-no.: 230-029-6
- Source and lot/batch No.of test material: Symirise GmbH & Co. Ltd / lot 2
- Purity: 99.7%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- Age: not given, but based on weight range ~7-9 weeks of age
Weight at dosing: F: 194-292 g
Source: Charles River U.K. Ltd, Margate, Kent, UK
Acclimation period: 4 days
Diet: Certified Rodent diet PMI 5002, BCM IPS Ltd, UK, ad libitum
Water: Municipal water supply, ad libitum
Housing: 4-5/cage of the same sex, then housed individually upon assignment to the study
Temperature: 19-23°C
Humidity: 40-70%
Air changes: 15 changes/hour
Photoperiod: 12 hours light/dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability data (generated under CA 7.8.2/01) confirmed the test article formulations to be stable for at least 14 days. Analysis of weekly formulations show concentrations to be within ±% of nominal
concentration. - Details on mating procedure:
- refer to details on study design
- Duration of treatment / exposure:
- 14 days / oral
- Frequency of treatment:
- daily
- Duration of test:
- 15 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 30 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- No. of animals per sex per dose:
- 24/gp
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Four groups of 96 pregnant female SD rats received the test article via oral gavage at concentrations of 0, 30, 100, 300 mg/kg bw/d from day 5 of gestation to day 19 post-partum (pp) using a dose volume of 5 mL/kg. On day 20 of gestation, dams were subjected to caesarean section and macroscopic examination. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).
Examinations
- Maternal examinations:
- Clinical signs of toxicity: observed once daily, in the morning throughout gestation and, additionally 1 h after dosing throughout the dosing period
Mortality: twice daily during the normal working week and once daily at weekends
Bodyweight: weighed on Day 3, Days 5 to 8, Day 11, Day 14, Day 17 and Day 20 of gestation
Food consumption: recorded for discrete periods throughout the study on Day 3 to 5, Day 5 to 8, Day 8 to 11, Day 11 to 14, Day 14 to 17 and Day 17 to 20 of gestation
Necropsy: On day 20 of gestation, dams were subjected to caesarean section and macroscopic examination. - Ovaries and uterine content:
- The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined. Pregnancy status, no. of copora lutea, gravid uterus weight, number position and type of intra-uterine implantation were recorded as well as placental weight.
- Fetal examinations:
- Number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as foetuses examined for external anomalies. Foetuses were transferred to 90% industrial methylated spirits (IMS) in distilled water and examined for visceral anomalies under a low power binocular microscope. The remaining foetuses were identified using colour coded wires and placed in 70% IMS in distilled water. The foetuses were eviscerated, processed and the skeletons stained with alizarin red. The foetuses were examined for skeletal development and anomalies.
- Statistics:
- Bodyweight, bodyweight change and food consumption: Bartlett' s test for homogeneity of variance and one way analysis of variance, followed by Dunnet's multiple comparison test or, if unequal variances were observed, an alternative multiple comparison test.
Litter data and litter, placental and foetal weights: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control value against treated values - Indices:
- Percentage pre-implantation loss was calculated as:
(no. of corpora lutea - no. of implantations) / no.of copora lutea x 100
Percentage post-implantation loss was calculated as:
(no. of implantations - no. of live foetuses) / no.of implantations x 100 - Historical control data:
- no historical control data provided
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No test article related effects were observed.
- Mortality:
- no mortality observed
- Description (incidence):
- All animals survived to the scheduled necropsy
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test article related effects were observed.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No test article related effects were observed.
- 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):
- No test article related effects (refer to Table CA 7.8.2/02-1)
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related macroscopic abnormalities were seen at post mortem examination for animals that were killed at the end of the study.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Details on results:
- no evidence of maternal toxicity up to the maximum dose level, deemed to be a maximum tolerated dose based on the dose range finder reported under CA 7.8.2/01
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- No test article related effects were observed (refer to Table CA 7.8.2/02-2)
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No test article related effects were observed (refer to Table CA 7.8.2/02-3)
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Litters were unaffected by maternal treatment (refer to Table CA 7.8.2/02-3)
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Early and late resorptions were unaffected by maternal treatment (refer to Table CA 7.8.2/02-3)
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- The mean number of live young were unaffected by maternal treatment up to a maximum dose of 300 mg/kg bw/day (refer to Table CA 7.8.2/02-3)
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- No test article related effect observed (refer to Table CA 7.8.2/02-2)
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- No test article related effect observed (refer to Table CA 7.8.2/02-2)
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- The administration of SYM05/841129 at dose levels up to 300 mg/kg bw/d (deemed to a maximum tolerated dose) caused resulted in no maternal toxicity
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 300 mg/kg bw/day
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Placental and foetal weights at were unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The mean number of live young were unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratio were unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Litter size and weights at all dose levels were essentially similar to control and were considered to have been unaffected by maternal treatment (refer to Table CA 7.8.2/02-3)
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- Post natal surivial was unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)
- External malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, distribution nor incidence of foetal findings observed during extemal examination at necropsy indicated any adverse effect of maternal treatment on foetal growth or development at 30, 100 or 300 mg/kg/day.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, distribution nor incidence of foetal findings observed during skeletal examinations indicated any adverse effect of maternal treatment on foetal growth or development at 30, 100 or 300 mg/kg/day (refer to Table CA 7.8.2/02-4 and Table CA 7.8.2/02-5).
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, distribution nor incidence of foetal findings observed during detailed visceral examinations indicated any adverse effect of maternal treatment on foetal growth or development at 30, 100 or 300 mg/kg/day (refer to Table CA 7.8.2/02-6)
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- No effects were observed on foetal growth or development in the offspring of animals treated with up to 300 mg/kg bw/day
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects were observed on foetal growth or development
- Remarks on result:
- other:
Fetal abnormalities
- Abnormalities:
- no effects observed
- Description (incidence and severity):
- No effects were observed on foetal growth or development
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Lowest effective dose / conc.:
- 300 mg/kg bw/day
Any other information on results incl. tables
Table
CA 7.8.2/02-1:
Bodyweight during gestation and gravid uterus weight at termination (±sd)
Parameter |
Dose level (mg/kg bw/d) |
|||
0 |
30 |
100 |
300 |
|
GD 3 |
250 ±26 |
252 ±20 |
248 ±19 |
249 ±22 |
GD 5 |
262 ±25 |
263 ±21 |
263 ±20 |
263 ±23 |
GD 6 |
266 ±26 |
267 ±21 |
267 ±22 |
266 ±23 |
GD 7 |
270 ±28 |
272 ±23 |
273 ±22 |
271 ±23 |
GD 8 |
275 ±28 |
277 ±21 |
278 ±21 |
276 ±23 |
GD 11 |
294 ±31 |
298 ±24 |
299 ±25 |
297 ±26 |
GD 14 |
312 ±33 |
318 ±26 |
320 ±28 |
315 ±27 |
GD 17 |
344±39 |
349 ±31 |
351 ±34 |
344 ±30 |
GD 20 |
387 ±46 |
396 ±35 |
396 ±40 |
388 ±34 |
Gravid uterus weight (g) |
78.87 ±1906 |
79.31 ±10.59 |
79.02 ±14.55 |
74.63 ±16.29 |
Adjusted terminal bwt (g) |
308 ±33 |
316 ±30 |
317 ±32 |
313 ±27 |
Table
CA 7.8.2/02-2:
Summary of female performance
Parameter |
Dose level (mg/kg bw/d) |
|||
0 |
30 |
100 |
300 |
|
Initial group size |
24 |
24 |
24 |
24 |
No. not pregnant |
0 |
0 |
0 |
0 |
No. pregnant |
24 |
24 |
24 |
24 |
No. killedin extremis |
0 |
0 |
0 |
0 |
With live young at day 20 |
24 |
24 |
24 |
24 |
Table
CA 7.8.2/02-3:
Litter data on day 20 of gestation – group mean values (±sd)
Parameter |
Dose level (mg/kg bw/d) |
|||
0 |
30 |
100 |
300 |
|
Number of Corpora Lutea |
15.6 ±3.1 |
15.3 ±1.6 |
16.0 ±3.1 |
14.9 ±2.5 |
No. of live implants [m; f; total] |
5.8 ±2.6; |
6.1 ±1.9; |
6.3 ±2.5; |
5.8 ±2.3; |
% male foetuses |
46.23 ±12.76 |
49.31 ±12.94 |
50.00 ±17.84 |
50.29 ±18.19 |
No. of embryonic/foetal deaths [early; late; total] |
0.3 ±0.6; |
0.5 ±1.1; |
0.3 ±0.4; |
0.3 ±0.8; |
Implantation loss % [pre; post] |
17.8 ±14.9 |
16.3 ±9.1; |
19.2 ±14.1; |
19.6 ±3.0; |
Mean foetal weight (g) [M; F] |
4.14 ±0.36; |
4.20 ±0.23; |
4.24 ±0.34; |
4.10 ±0.23; |
Mean foetal weight (g) |
3.99 ±0.30 |
4.09 ±0.22 |
4.10 ±0.30 |
3.99 ±0.21 |
Mean placental weight (g) |
0.63 ±0.28 |
0.57 ±0.05 |
0.57 ±0.07 |
0.56 ±0.05 |
Total litter weight (g) |
48.81 ±12.24 |
50.18 ±6.67 |
50.45 ±7.69 |
46.49 ±11.15 |
Total placental weight (g) |
7.15 ±1.63 |
6.96 ±1.06 |
7.06 ±1.46 |
6.51 ±1.42 |
Table
CA 7.8.2/02-4:
Foetal skeletal development – group incidence
Parameter |
Dose level (mg/kg bw/d) |
||||
0 |
30 |
100 |
300 |
||
No. of foetuses / litters examined |
|||||
141/24 |
140/24 |
142/24 |
132/24 |
||
Number of ribs |
3/3 |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
Number of fully ossified sternebrae |
<4 |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
0/0 [-%] |
Number of post lumbar vertebral centra |
<7 |
3/3 [1.8%] |
1/1 [0.6%] |
2/2 [1.5%] |
2/2 [1.2%] |
Number of post lumbar vertebral arches |
<5 |
13/9 [8.1%] |
9/6 [6.8%] |
14/8 [10.1%] |
12/8 [8.2%] |
Number of metacarpals |
<6 |
1/1 [1.0%] |
0/0 [-%] |
0/0 [-%] |
1/1 [0.4% |
Number of metatarsals |
6 |
4/2 [7.3%] |
0/0 [-%] |
1/1 [0.7%] |
1/1 [0.7%] |
Fontanelle |
Sm |
6/3 [3.4%] |
6/4 [3.8%] |
8/4 [6.1%] |
5.4 [4.1%] |
Table
CA 7.8.2/02-5:
Foetal skeletal findings – group incidence
Parameter |
Dose level (mg/kg bw/d) |
|||
0 |
30 |
100 |
300 |
|
No. of foetuses / litters examined |
||||
141/24 |
140/24 |
142/24 |
132/24 |
|
HEAD/NECK |
||||
- Incomplete ossification of one cranial bone |
39/19 [25.3%] |
34/15 [23.9%] |
33/15 [22.1%] |
33/19 [27.0%] |
- Incomplete ossification of more than one cranial bone |
27/17 [18.9%] |
23/13 [19.2%] |
36/15 [25.6%] |
17/8 [14.1%] |
- Irregular ossification of one cranial bone |
20/13 [13.5%] |
15/9 [11.4%] |
18/11 [12.3%] |
25/16 [17.5%] |
- Incomplete ossification of one facial bone |
1/1 [0.5%] |
1/1 [0.8%] |
1/1 [0.5%] |
1/1 [0.7%] |
- Incomplete ossification of more than one facial bone |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [0.8%] |
- No ossification of hyoid |
23/12 [17.7%] |
15/11 [10.1%] |
27/13 [17.9%] |
23/13 [17.1%] |
- Incomplete ossification of hyoid |
1/1 [0.5%] |
0/0 [-%] |
1/1 [0.6%] |
0/0 [-%] |
- Hyoid bipartite |
1/1 [0.7%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
-Irregular ossification of more than one cranial bone |
1/1 [0.5%] |
4/3 [2.95%] |
5/4 [3.4%] |
2/1 [1.0%] |
- No ossification of more than one cranial bone |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [3.0%] |
STERNEBRAE (1-4) |
||||
- 5thsternebra not ossified |
0/0 [-%] |
0/0 [-%] |
1/1 [0.8%] |
0/0 [-%] |
- Incomplete ossification of one sternebra |
0/0 [-%] |
1/1 [0.6%] |
0/0 [-%] |
2/2 [1.3%] |
- No ossification of one sternebra |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
1/1 [0.7%] |
- No ossification of more than one sternebrae |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
- No ossification of vertebrae or ribs below 3rdthoracic |
0/0 [-%] |
0/0 [-%] |
0/1/1 [0.7%] |
0/0 [-%] |
- Incomplete ossification of more than one sternebrae |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [5.9%] |
RIBS |
||||
-All ribs rudimentary |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
- Bilateral/unilateral wavy 13thrib(s) |
2/2 [1.1%] |
2/2 [1.4%] |
5/4 [3.3%] |
2/1 [1.2%] |
- Bilateral/unilateral short 13thrib(s) |
2/2 [1.1%] |
4/3 [3.3%] |
3/2 [2.0%] |
6/6 [4.2%] |
- Bilateral/unilateral wavy rib(s)) |
2/2 [1.1%] |
1/1 [0.7%] |
0/0 [-%] |
0/0 [-%] |
- Bilateral/unilateral thickened rib(s) |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
0/0 [-%] |
- Bilateral/unilateral rudimentary 14thrib(s) |
0/0 [-%] |
0/0 [-%] |
1/1 [0.8%] |
0/0 [-%] |
VERTEBRAE |
||||
-One thoracic vertebral centre semi-bipartite |
16/11 [10.9%] |
11/9 [7.9%] |
11/9 [8.5%] |
12/8 [7.6%] |
- More than onr thoracic vertebral centre semi-bipartite |
1/1 [0.7%] |
1/1 [1.0%] |
4/2 [3.8%] |
9/5 [7.9%] |
- One thoracic vertebral centre bipartite |
2/2 [1.1%] |
4./3 [3.3%] |
4/3 [2.2%]
|
7/6 [5.0] |
- More than one thoracic vertebral centre bipartite |
1/1 [0.7%] |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
- One lumbar vertebral centre semi-bipartite |
0/0 [-%] |
0/0 [-%] |
1/1 [1.0%] |
2/1 [1.4%] |
OTHER |
||||
- Pubisnot ossified |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
- Ilia and ischia close together |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
- Upwards pelvic shift |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
TOTAL |
91/21 [64.5%] |
79/22 [56.4%] |
99/24 [70.4%] |
93/24 [69.7%] |
Table
CA 7.8.2/02-6:
Foetal visceral findings – group incidence
Parameter |
Dose level (mg/kg bw/d) |
|||
0 |
30 |
100 |
300 |
|
No. of foetuses / litters examined |
||||
154/24 |
156/24 |
155/24 |
148/24 |
|
- 3rdventricle dilated |
4/4 [2.3%] |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
- eye lens - ovoid |
4/4 [2.2%] |
2/2 [1.2%] |
2/2 [1.2%] |
1/1 [0.7%] |
- Small cleft in palate proximal to mouth |
0/0 [-%] |
0/0 [-%] |
1/1 [0.6%] |
0/0 [-%] |
- undescended lobe(s) of thymus |
6/5 [7.6%] |
3/3 [1.7%] |
5/5 [2.9%] |
2/2 [1.5%] |
- thyroid small |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
- small lobe of thyroid |
1/1 [0.5%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
- pericardial oedema |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [0.5%] |
- blood in pericardial sac |
0/0 [-%] |
1/1 [0.6%] |
0/0 [-%] |
0/0 [-%] |
- partial persistant truncus arteriosas |
1/1 [0.5%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
- high interventricular septal defect |
1/1 [0.5%] |
0/0 [-%] |
0/0 [-%] |
1/1 [1.0%] |
- No brachiocephalic trunk — common carotid and subclavian exit from aorta |
1/1 [0.5%] |
0/0 [-%] |
0/0 [-%] |
1/1 [1.0%] |
-Retro oesophageal subclavian artery |
0/0 [-%] |
0/0 [-%] |
1/1 [0.6%] |
0/0 [-%] |
- Heart malrotated |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [1.0%] |
- Area of haemorrhage an diaphragm |
0/0 [-%] |
0/0 [-%] |
1/1 [0.7%] |
0/0 [-%] |
- Small inguinal hernia — small protrusion in abdominal wall |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
1/1 [0.6%] |
- Blood in abdomen |
0/0 [-%] |
0/0 [-%] |
1/1 [0.6%] |
1/1 [0.6%] |
- Small renal papilla |
13/11 [7.9%] |
15/8 [9.5%] |
16/11 [10.1%] |
1/1 [0.6%] |
- increased renal pelvic cavitation |
0/0 [-%] |
4/3 [2.4%] |
2/1 [0.9%] |
10/5 [6.7%] |
- No development of renal papilla |
1/1 [0.5%] |
3/2 [1.9%] |
0/0 [-%] |
6/5 [4.5%] |
- Adrenal dark |
1/1 [0.5%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
- extra lobulation of median lobe of liver |
1/1 [0.5%] |
3/2 [1.9%] |
0/0 [-%] |
0/0 [-%] |
- dilated ureter |
7/7 [8.1%] |
11/7 [7.1%] |
7/5 [4.1%] |
8/5 [5.6%] |
- kinked ureter |
7/6 [7.6%] |
9/6 [5.4%] |
11/6 [6.5%] |
7/4 [4.9] |
- dilated lateral ventricle |
1/1 [0.5%] |
0/0 [-%] |
0/0 [-%] |
0/0 [-%] |
TOTAL |
25/15 [18.6%] |
23/10 [14.6%] |
26/15 [16.2%] |
19/13 [13.0%] |
Applicant's summary and conclusion
- Conclusions:
- The daily administration of SYM05/841129 during the period of organogenesis, at dose levels up to 300 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 300 mg/kg bw/d (deemed to be the maximum tolerated dose), the maximum dose tested.
The NOAEL for developmental toxicity was set at 300 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 300 mg/kg bw/d (a dosedeemed to be the maximum tolerated dose for maternal animals). - Executive summary:
SYM05/841129 was daily administered by oral gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/d, to groups of 24 time-mated SD rats from day 5 to day 19 of gestation (GD) inclusive. The dose levels were selected based on a dose range finding study, reported under CA 7.8.2/01. The maximum dose (300 mg/kg bw/d) was deemed to be a maximum tolerated dose On day 20 of gestation all rats were subjected to a caesarean section and macroscopic examination of the organs in the thoracic and abdominal cavities. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).
Treatment at dosages up to 300 mg/kg bw/d was well tolerated by the pregnant females and was not associated with any effects on clinical condition, bodyweight, bodyweight change, food intake or necropsy observations.
There were no effects at dosages up to 300 mg/kg/day on embryofoetal survival, growth and development.
The daily administration of SYM05/841129 during the period of organogenesis, at dose levels up to 300 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 300 mg/kg bw/d (deemed to be the maximum tolerated dose), the maximum dose tested.
The NOAEL for developmental toxicity was set at 300 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 300 mg/kg bw/d (a dosedeemed to be the maximum tolerated dose for maternal animals).
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