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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: SIDS rating is "Very Good", this study record is based uponreview of the SIDS summary.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: FDA Guidelines (1966)
Deviations:
not specified
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Glycerol trinitrate
EC Number:
200-240-8
EC Name:
Glycerol trinitrate
Cas Number:
55-63-0
Molecular formula:
C3H5N3O9
IUPAC Name:
propane-1,2,3-triyl trinitrate

Test animals

Species:
rat
Strain:
other: Charles River albino

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Sexually mature virgin females were mated with experienced young adult male rats. The dams' F1c litter was used for this study. The dams were placed on test or control diets for gestation days 6-15, including, and were sacrificed (CO2 inhalation) on gestation day 20.
Details on mating procedure:
Females were examined by vaginal lavage in late afternoon and, if signs of proestrus were present, were then placed with the experienced male overnight in the ratio of two females/male. The next morning, the females were examined for the presence of sperm or a vaginal plug. During pregnancy, the dams were observed daily.
Duration of treatment / exposure:
24 hours/day (continuous) for days 6-15 of gestation
Frequency of treatment:
24 hours/day (continuous) for days 6-15 of gestation
Duration of test:
24 hours/day (continuous) for days 6-15 of gestation
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.01 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.1 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1.0 %
Basis:
nominal in diet
No. of animals per sex per dose:
21-22 females per dose
Control animals:
yes

Examinations

Maternal examinations:
Corpora lutea, as well as numbers and positions of live, dead, and resorbed fetuses were determined at necropsy. Fetuses were then removed from the uterus, weighed, and examined for any external anomalies. Half the fetuses from each litter were then fixed in Bouin's fluid, manually sectioned, and examined for soft tissue /internal organ anomalies by Wilson's method (Wilson, 1965). The remaining fetuses were fixed in 70% ethanol followed by 1% potassium hydroxide and then stained with alizarin red (Staples and Schnell, 1964). This was followed by differential decolorization and examination for skeletal anomalies.

Additional parameters measured included no. mated, no. of sperm positive, no of pregnancies, maternal weight, liver weights, Implants/dam (i.e., viable fetuses, dead fetuses, early resorptions and late resorptions), live litters, fetal weight, soft tissue anomalies, diaphragmatic hernia, skeletal anomalies (i.e., Yyoid bone, unossified, Sternabrae unossified).
Fetal examinations:
Corpora lutea, as well as numbers and positions of live, dead, and resorbed fetuses were determined at necropsy. Fetuses were then removed from the uterus, weighed, and examined for any external anomalies. Half the fetuses from each litter were then fixed in Bouin's fluid, manually sectioned, and examined for soft tissue /internal organ anomalies by Wilson's method (Wilson, 1965). The remaining fetuses were fixed in 70% ethanol followed by 1% potassium hydroxide and then stained with alizarin red (Staples and Schnell, 1964). This was followed by differential decolorization and examination for skeletal anomalies.

Additional parameters measured included no. mated, no. of sperm positive, no of pregnancies, maternal weight, liver weights, Implants/dam (i.e., viable fetuses, dead fetuses, early resorptions and late resorptions), live litters, fetal weight, soft tissue anomalies, diaphragmatic hernia, skeletal anomalies (i.e., Yyoid bone, unossified, Sternabrae unossified).
Statistics:
Mean or mean ± standard error

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
The weights of the high-dose females at termination and their weight changes (excluding the uterus and contents) were significantly less than those of the control group and less than those of the two groups tested at lower doses. In addition, their liver weights were significantly increased relative to their corrected body weight and increased relative to those of the two lower dose test groups. Diaphragmatic hernias occurred only in the high dose group and were believed, by the investigators, to be due to the test material. Their incidence was not significant (two-sample rank test), but they occurred in 4/19 of the high dose litters from this study.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
6 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
6 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
The incidences of unossified and incompletely ossified hyoid bones also were significantly increased compared to the controls and were increased compared to the two lower dose test groups. However, sternabrae, centra and skull bones were not similarly affected. The investigators believe that these diaphragmatic hernias may have been at least partially responsible for the poor reproductive performance of the group dosed at the1.0 % (w/w) dietary level in the three-generation reproduction test.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

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