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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:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from a secondary literature

Data source

Reference
Reference Type:
publication
Title:
Teratological Studies on the test chemical in Pregnant Rats.
Author:
Ishiguro et al
Year:
1993
Bibliographic source:
Kagoshima Univ, 1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Equivalent or similar to OECD Guideline 414 (Pre-Natal Developmental Toxicity Study)
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Benzyl acetate
EC Number:
205-399-7
EC Name:
Benzyl acetate
Cas Number:
140-11-4
Molecular formula:
C9H10O2
IUPAC Name:
Acetic acid, phenylmethyl ester
Test material form:
not specified
Details on test material:
Name: Benzyl acetate
CAS No.: 140-11-4
Molecular Formula: C9-H10-O2
Molecular Weight: 150.176
SMILES: c1(COC(C)=O)ccccc1

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
No Data Available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with olive oil to achieve concentration levels of 1000, 500, 100, 10 and 0 mg/ml

VEHICLE
- Justification for use and choice of vehicle (if other than water): olive oil
- Concentration in vehicle: Not documented
- Amount of vehicle (if gavage): Not documented
- Lot/batch no. (if required): VDR7446
- Purity: Not documented
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available.
Details on mating procedure:
On confirmation of the oestrous cycle of the females, 12-17 week old male rats were introduced and the males and females were co-housed from 5pm until the next morning when the presence of sperm in the vagina was considered to be successful mating. This was considered to be day zero of pregnancy. Based on their weight, pregnant rats were separated into 6 groups and relocated to separate cages.
Duration of treatment / exposure:
10 days
Frequency of treatment:
Daily from gestation day 6 to 15
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 100, 500, 1000 mg/kg bw/day
No. of animals per sex per dose:
20 rats/dose
Control animals:
yes, concurrent no treatment
Details on study design:
No Data Available

Examinations

Maternal examinations:
Parent examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Every 2 days
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, examined every 2 days.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes - Sacrifice on gestation day 20
- Organs examined: No Data Available
OTHER: The implantation in the womb, corpus lutea quantity, the implantation quantity, the resorption embryo count and the living or dead foetuses. The weight of the placenta was measured.
Ovaries and uterine content:The ovaries and uterine content was examined after termination.
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes - Number of early resorptions: No data - Number of late resorptions: No data - Other:
Fetal examinations
- External examinations: Yes: all living foetuses - Soft tissue examinations: Yes: half per litter - Skeletal examinations: Yes: - Head examinations: No data
Statistics
One way layout dispersion method if equal dispersion detected. The Kruskal-Wallis method was used to verify significance in the case of equal dispersion. The multi-comparison verification method of Scheffe and Dunnett was used to verify the significance of subjected groups. An X2 verification method was also performed to determine the frequency of of the bone changes, internal organs of the foetuses and the gender comparison of the surviving foetuses.
Ovaries and uterine content:
Yes. The number of implantation and corpora lutea, live/dead fetuses, resorptions, implantation ratio, sex ratio, or placenta weigh were recorded.
Fetal examinations:
Yes, on GD 20th foetuses were examined for intrauterine death, and internal, external and skeletal malformations.
Statistics:
Yes. Results were analyzed using Bartlett's test, test method of Kruskal-Wallis, Dunnett's multiple comparison testing method or Scheffe's multiple comparison testing method.
Indices:
No data available.
Historical control data:
No data available.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were observed.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No mortality was observed.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
A slightly decreasing in maternal body weight gain was noted in the 1,000 mg/kg group, but not significantly.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption did not differ between treated and control groups.
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:
no effects observed
Description (incidence and severity):
No treatment related adverse effect was observed.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related adverse effect was observed.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The number of implantations did not differ in treated and control rats.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
The number of resorptions did not differ in treated and control rats.
Early or late resorptions:
no effects observed
Description (incidence and severity):
The number of resorptions did not differ in treated and control rats.
Dead fetuses:
no effects observed
Description (incidence and severity):
The number of live/dead fetuses did not differ in treated and control rats.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
no effects observed
Description (incidence and severity):
The placenta weight did not differ in treated and control rats.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Remarks:
Maternal general toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
mortality
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Remarks:
Maternal developmental
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
dead fetuses
early or late resorptions
pre and post implantation loss
total litter losses by resorption
Remarks on result:
other: No maternal developmental toxicity was observed.

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
The fetal body weight was significantly decreased at 1000 mg/kg, but significantly increased at 10 and 100 mg/kg.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The number of live/dead fetuses were comparable in treated and control groups.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratio of fetuses was comparable in treated and control groups.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No increase in incidence of external malformations were seen at any dose level.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
The only skeletal malformation (fused ribs) was seen in one foetus of the high-dose group, which did not increase the incidence of skeletal malformations compared to controls. The authors suggested that the skeletal malformations were related to the significant decrease in fetal body weight. Skeletal variations (i.e., wavy ribs, dumbbell shaped vertebrae, absence/splitting of thoracic vertebrae, presence of lumbar ribs and degree of ossification) were statistically increased at 1000 mg/kg.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
There was a statistically significant increase in the combined incidence of organ variations (i.e., slight dilatation of the lateral ventricle and renal pelvis, and presence of levo-umbilical artery) in animals from the 500 and 1000 mg/kg dose groups.
Other effects:
not specified

Effect levels (fetuses)

Dose descriptor:
NOAEL
Remarks:
Developmental
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Remarks on result:
other: No adverse developmental effect was observed.

Applicant's summary and conclusion

Conclusions:
The oral administration of the test chemical up to 1000 mg/kg was not maternally toxic as no adverse effect on parameters examined were observed. The prenatal exposure to 1000 mg/kg of the test chemical substance did not alter the normal growth and development of offspring and, consequently the developmental NOAEL was 1000 mg/kg for both maternal and F1 generations.
Executive summary:

A prenatal developmental toxicity study was performed to investigate the toxic effect of the test chemical on fetus organogenesis and development. Groups of 20 pregnant Wistar rats were administered 0, 10, 100, 500, or 1,000 mg/kg bw/day by gavage during gestation days 6-15 (GD 6-15). On day 20 of gestation, pregnancies were terminated, and the fetuses were examined for intrauterine death, and internal, external and skeletal malformations. Maternal parameters included mortality, body weight, food consumption, and clinical and gross examinations. No maternal toxic effects on parameters examined were observed as no death and alterations of body weight, food consumption was reported, and clinical and gross examinations did not reveal any effect attributable to test chemical administration. Examination of the uterus content revealed that the number of implantation and corpora lutea, live/dead fetuses, or resorptions, implantation ratio, sex ratio, or placenta weigh did not differ in treated and control rats.The fetal body weight was significantly decreased at 1000 mg/kg and significantly increased at low and middle doses, thus these alterations were inconclusive and showed no dose-dependence.There was a statistically significant increase in the combined incidence of organ variations (i.e., slight dilatation of the lateral ventricle and renal pelvis, and presence of levo-umbilical artery) in animals from the 500 and 1000 mg/kg dose groups. The only skeletal malformation (fused ribs) was seen in one fetus of the high-dose group, which did not increase the incidence of skeletal malformations compared to controls. The authors suggested that the skeletal malformations were related to the significant decrease in fetal body weight. Skeletal variations (i.e., wavy ribs, dumbbell shaped vertebrae, absence/splitting of thoracic vertebrae, presence of lumbar ribs and degree of ossification) were statistically increased at 1000 mg/kg. However, skeletal variations are minor structural changes which have little or no detrimental effect on the animal and often are transient changes. No increase in intrauterine death or external variations was noted at any dose level.In conclusion, the oral administration of the test chemical up to 1000 mg/kg was not maternally toxic evidenced by the absence of alterations of parameters examined. In addition, the prenatal exposure to 1000 mg/kg of the test substance did not alter the normal growth and development of offspring and, consequently the developmental NOAEL was 1000 mg/kg for the F1 generation.