Registration Dossier
Registration Dossier
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EC number: 231-820-9 | CAS number: 7757-82-6
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Literature data
Data source
Reference
- Reference Type:
- publication
- Title:
- Morphine-induced fetal malformations. 3. Possible mechanisms of action.
- Author:
- Arcuri, P. and Gautieri, F. J.
- Year:
- 1 973
- Bibliographic source:
- Pharmaceut. Sci. 62(10): 1626-1634.
Materials and methods
- Principles of method if other than guideline:
- In the study, which was aimed at documenting teratogenic effects of morhine sulfate, atropine sulfate and physostigmine sulfate, sodium sulfate served as anion control, with sodium chloride as negative control.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Sodium sulphate
- EC Number:
- 231-820-9
- EC Name:
- Sodium sulphate
- Cas Number:
- 7757-82-6
- Molecular formula:
- H2O4S.2Na
- IUPAC Name:
- disodium sulfate
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- CF-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 25-30 g
Administration / exposure
- Route of administration:
- subcutaneous
- Vehicle:
- water
- Details on exposure:
- Injectable solutions of sodium sulfate (10 mg/ml) was prepared fresh weekly by dissolving the drugs in distilled water.
- Frequency of treatment:
- Day 8 or 9 of gestation, single dose
Doses / concentrations
- Remarks:
- Doses / Concentrations:
60 mg/kg bw
Basis:
nominal conc.
Examinations
- Maternal examinations:
- Day 8 or 9 of gestation were described termination of pregnancy, removal of fetuses, gross inspection, and preparation of the excised fetuses for both skeletal and soft tissue examination.
A second aspect of this study involved the actions upon the placental vasculature as determined by transport of a 22Na. .
Five minutes after the subcutaneous administration of the respective the isotope, 0.1 ml delivering 3 µc., was injected intravenously into a tail vein of the mouse. By reporting the activity of the samples as a percentage of the concentration of isotope in maternal blood, each animal served as its own control. - Fetal examinations:
- Day 8 or 9 of gestation were prepared the excised fetuses for both skeletal and soft tissue examination.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
No clinical abnormalities, differeces in maternal weight ratio, uterine left/righ horn fetal ratio and resorption ration were observed.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEC
- Effect level:
- >= 60 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEC
- Effect level:
- >= 60 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Fetal body weight changes:
- not specified
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No fetal weight differences, sex ratio, skeletal abnormalities, soft tissue abnormalities, more specifically exencephaly, cryptorchid test and axial skeletal fusions were observed.
Effect levels (fetuses)
- Remarks on result:
- not measured/tested
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Mean Values of Test Groups Receiving Single Injections (Treatment on Day 8)
| Treatment | Maternal Weight ration S/T | Fetal Ratio. Right Horn/Left Harn | Resorotion Ration Right Horn/Left Harn | X fetal Weight, g | Sex Ratio, M/F | Soft tissue abnormalities | Skeletral abnormalities |
| Control (untreated) | 25.5/48.0 | 6.2/3.7* | 0.17/0.33 | 1.07 | 4.0/5.8 | 0.0 | 1.5 |
| Saline, 0.3 ml | 26.8/51.0 | 5.8/6.2 | 0.33/0.50 | 1.13 | 6.5/5.5 | 0.17 | 1.3 |
| Sodium sulphate | 26.8/44.7* | 4.5*/4.0 | 0.00/0.50 | 1.11 | 5.3/3.2 | 0.00 | 6.0* |
*Statistically significant in comparison with saline control. p < 0.05.
Mean Values of Test Groups Receiving Single Injections (Treatment on Day 9)
| Treatment | Maternal Weight ration S/T | Fetal Ratio. Right Horn/Left Harn | Resorotion Ration Right Horn/Left Harn | X fetal Weight, g | Sex Ratio, M/F | Soft tissue abnormalities | Skeletral abnormalities |
| Saline, 0.3 ml | 25.2/49.7 | 6.2/4.0 | 0.50/0.33 | 1.20 | 5.7/4.5 | 0.0 | 0.8 |
| Sodium sulphate | 27.0*/46.7* | 4.8/5.7* | 0.00/0.33 | 1.10* | 6.5/4.0 | 0.00 | 7.8 |
*Statistically significant in comparison with saline control. p < 0.05.
Occurrence of Exencephaly, Axial Skeletal Fusions, and Cryptorchid Testes with Treatment on Day 8
| Treatment | Exencephaly | Cryptorchid Testes | Axial Skeletral Fusions | |||||||||
| Litters | Foetous | Litters | Foetous | Litters | Foetous | |||||||
| Normal | Abnormalities | Normal | Abnormal | Normal | Abnormal | Normal | Abnormal | Normal | Abnormal | Normal | Abnormal | |
| Control (untreated) | 6 | 0 | 59 | 0 | 6 | 0 | 12 | 0 | 6 | 0 | 28 | 0 |
| Saline, 0.3 ml | 6 | 0 | 72 | 0 | 6 | 0 | 24 | 0 | 6 | 0 | 34 | 0 |
| Sodium sulphate | 6 | 0 | 51 | 0 | 6 | 0 | 13 | 0 | 6 | 0 | 25 | 0 |
Occurrence of Exencephaly, Axial Skeletal Fusions, and Cryptorchid Testes with Treatment on Day 9
| Treatment | Exencephaly | Cryptorchid Testes | Axial Skeletral Fusions | |||||||||
| Litters | Foetous | Litters | Foetous | Litters | Foetous | |||||||
| Normal | Abnormalities | Normal | Abnormal | Normal | Abnormal | Normal | Abnormal | Normal | Abnormal | Normal | Abnormal | |
| Saline, 0.3 ml | 6 | 0 | 61 | 0 | 6 | 0 | 16 | 0 | 6 | 0 | 30 | 0 |
| Sodium sulphate | 6 | 0 | 63 | 0 | 6 | 0 | 15 | 0 | 6 | 0 | 32 | 0 |
Applicant's summary and conclusion
- Conclusions:
- Clinical observations, maternal weight ratio, uterine left/righ horn fetal ratio and resorption ration do not revealed abnormalities; no fetal weight and sex ratio differences, skeletal abnormalities, soft tissue abnormalities, more specifically exencephaly, cryptorchid test and axial skeletal fusions were observed.
- Executive summary:
The study was aimed at documenting teratogenic effects of morhine sulfate, atropine sulfate and physostigmine sulfate, sodium sulfate served as anion control.
Test was conducted in the 8 -9 day period of gestation at 60 mg/kg
Results
Clinical observations, maternal weight ratio, uterine left/righ horn fetal ratio and resorption ration do not revealed abnormalities; no fetal weight and sex ratio differences, skeletal abnormalities, soft tissue abnormalities, more specifically exencephaly, cryptorchid test and axial skeletal fusions were observed.
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