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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
three-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The SIDS rating for this study is "Very Good but lacking some of the measurements called for in the current OECD Guideline" Only the SIDS summary for this study was available for review (data provided was limited)
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 CD albino
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
F0 group consisted of 10 males and 20 females cohabited for 14 days. F1a group was discarded and the F0 group remated. Twenty to 24 apparently normal offspring (F1b) of each sex were randomly selected in approx. equal numbers from each group and mated 1 / 1 with rats from the same group. The same procedure was followed with the F2 group. The F3b group was sacrificed after weaning and the overt physical and reproductive parameters called for in the FDA Guideline were evaluated.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Females were dosed during pregnancy and between matings. Males were dosed until successful delivery of each “b” generation (the "a" generations were discarded).
Frequency of treatment:
Females were dosed during pregnancy and between matings. Males were dosed until successful delivery of each “b” generation (the "a" generations were discarded).
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:
24 animals per sex per dose
Details on study design:
F0 group consisted of 10 males and 20 females cohabited for 14 days. F1a group was discarded and the F0 group remated. Twenty to 24 apparently normal offspring (F1b) of each sex were randomly selected in approx. equal numbers from each group and mated 1 / 1 with rats from the same group. The same procedure was followed with the F2 group. The F3b group was sacrificed after weaning and the overt physical and reproductive parameters called for in the FDA Guideline were evaluated.

The F3b group was sacrificed after weaning and the overt physical and reproductive parameters called for in the FDA Guideline, were evaluated. Prostate weights of male progeny were not determined. Sperm morphology, motility and histopathologic effects were not determined for the F1 andF2 generations. As usual, rats in each cage were examined daily.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Control analyses were carried out over eight-day periods to measure evaporation of NG from the diet under cage conditions during the week. GC also was used for these analyses, but with a 63Ni detector. This information was used to calculate actual dosage received by the rats. Feeders were topped off with fresh diet on the fourth day of each week, and diet in each feeder was replaced totally every seven days. The feed for the control rats contained 10 % (w/w) of diet that had been dried to 0.1 % water content.
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
No data
Postmortem examinations (parental animals):
No data
Postmortem examinations (offspring):
No data
Statistics:
Mean or mean ± standard error
Reproductive indices:
No data
Offspring viability indices:
No data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased feed consumption in females (F1b gestation)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
decreased feed consumption in females (F1b gestation)
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
46 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: not specified
Remarks on result:
other: All generations
Dose descriptor:
LOAEL
Effect level:
452 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: decreased feed intake in dams during F1b gestation resulted in decreased litter size and birth weights
Dose descriptor:
NOAEL
Effect level:
39 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased body weight
Sexual maturation:
effects observed, treatment-related
Description (incidence and severity):
aspermatogenesis in F2a males
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Results: F2 generation

Effect levels (F2)

Dose descriptor:
LOAEL
Generation:
F2a
Effect level:
408 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: aspermatogenesis leading to infertility

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

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