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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: scientifically acceptable and well reported

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
25 inseminated Wistar rats per group were orally administered daily doses of 0, 300, 300, and 1000 mg kg bw on days 6-15 of pregnancy. Dams were examined regarding body weight, appearance and behaviour. on day 20 of gestation dams were killed and the foetuses delivered by caesarean section were examined for morphological changes.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
content: 99.8%

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
Males were mated with 2 femals each overnight. day 0 of gestation was the day sperm was observed in the vaginal smear the morning after mating.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: chremophor/water 0.5%
Details on exposure:
test substance was orally applicated as 0.5% aqueous cremophor emulsion
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
content, homogenicity and stability of the formulation were examined
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
day 6 to day 15 of gestation
Frequency of treatment:
daily
Duration of test:
On day 20 of pregnancy foetuses were delivered by C-section.
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
Doses were sheduled from experiences of other studies with this test substance.

Examinations

Maternal examinations:
dams were examined regarding body weight, appearance and behaviour.
Ovaries and uterine content:
The uterine content was examined after termination: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
Statistics:
According Wicoxon and chi²-test.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Indigestions and rough fur.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
At 1000 mg/kg bw four animals died.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At doses of 1000 mg/kg bw body weight gain was decreased.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
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:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Doses of 1000 mg/kg bw seriously impaired body weight gain of the the maternal animals and clear signs of an intoxication were evident. Four animals of this dose group died.

Maternal developmental toxicity

Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
Number of fetuses were lower in dams dosed with 1000 mg/kg bw/d.
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
Number of fetuses were lower in dams dosed with 1000 mg/kg bw/d.
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Number of fetuses were lower in dams dosed with 1000 mg/kg bw/d.
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Number of fetuses were lower in dams dosed with 1000 mg/kg bw/d.
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
Number of fetuses were lower in dams dosed with 1000 mg/kg bw/d.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related deaths (mortality: 4/25).
Description (incidence and severity):
At 1000 mg/kg bw/d, there were signs of maternal toxicity (body weight gain reduced during the whole gestation; treatment-related deaths (mortality: 4/25)). Signs of embryotoxicity were reduced number and decreased weights of the fetuses at the high dose level.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Body weight gain of dams was decreased in the dose group of 1000 mg/kg bw/d.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: Body weight gain of dams was decreased in the dose group of 1000 mg/kg bw/d.

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain of dams was decreased in the dose group of 1000 mg/kg bw/d.

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Description (incidence and severity):
Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes

Any other information on results incl. tables

In all dose groups, no indications of teratogenesis was observed.
At 1000 mg/kg bw/d, there were signs of maternal toxicity (body weight gain reduced during the whole gestation; treatment-related deaths (mortality: 4/25)). Signs of embryotoxicity were reduced number and decreased weights of the fetuses at the high dose level
.

Doses up to 300 mg/kg bw/g were tolerated without any signs of maternal toxicity and without toxic signs on embryonal and foetal development.

Applicant's summary and conclusion

Conclusions:
Body weight and number of fetuses were lower in dams dosed with 1000 mg/kg bw/d. Evidence of teratogenic effects were not found in this dose group.
Executive summary:

Method: 25 inseminated Wistar rats per group were orally administered daily doses of 0, 100, 300, and 1000 mg kg bw on days 6-15 of pregancy. dams were examined regarding body weight, appearance and behaviour. On day 20 of gestation dams were killed and the foetuses delivered by caesarean section were examined for morphological changes.

Result: NOEL = 300 mg/kg bw/day for maternal and embryonal/foetal toxicity

Reference: Renhof (Bayer AG), 1986