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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
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:
other: OECD Guideline 414 (Pre-Natal 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
Justification for study design:
No Data Available

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 species / strain selection:
No Data Available
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Keari Inc.
- Age at study initiation: Females: 10 to 15 weeks
Males: 12 to 17 weeks.
- Weight at study initiation: Not documented
- Fasting period before study: Not documented
- Housing: Not documented
- Diet (e.g. ad libitum): Solid food purchased form Japan Kurea
- Water (e.g. ad libitum): Tap water
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1°C
- Humidity (%): 50 ± 10%
- Air changes (per hr): Not documented
- Photoperiod (hrs dark / hrs light): 12 hours light/dark

IN-LIFE DATES: From: To: Not documented

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
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.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
10 days
Frequency of treatment:
Once daily from days 6 to 15 of pregnancy
Details on study schedule:
No Data Available
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 100, 500, 1000 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
20 rats per dose
Control animals:
yes, concurrent no treatment
Details on study design:
No Data Available
Positive control:
No Data Available

Examinations

Parental animals: Observations and 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.
Oestrous cyclicity (parental animals):
No Data Available
Sperm parameters (parental animals):
No Data Available
Litter observations:
At term (on the 20th day of pregnancy) the fetuses were killed and examined to ascertaine the intrauterine death, external, internal and skeletal malformations.
Postmortem examinations (parental animals):
No Data Available
Postmortem examinations (offspring):
At term (on the 20th day of pregnancy) the fetuses were killed and examined to ascertaine the intrauterine death, external, internal and skeletal malformations.
Statistics:
No Data Available
Reproductive indices:
No Data Available
Offspring viability indices:
No Data Available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No significant changes in maternal parameters were observed in the all groups.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No significant changes in maternal parameters were observed in the all groups.
Body weight and weight changes:
effects observed, non-treatment-related
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 during pregnancy in the test chemical-treated groups did not differ from the control group.
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
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No significant changes in maternal parameters were observed in the all groups.

Effect levels (P0)

Dose descriptor:
NOAEL
Remarks:
Maternal developmental/reproduction
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
Intrauterine deaths did not show any significant increases in the fetuses treated by the test chemicals.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In both sexes of the 1,000 mg/kg group, body weight of the fetuses was significantly decreased. However, the fetal body weight was significantly increased at 10 and 100 mg/kg and therefore alterations in fetal body weight were inconclusive and not dose related.
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
Sexual maturation:
not specified
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
External malformations did not show any significant increases in the fetuses treated by BA. In the fetuses of 1,000 mg/kg group, internal and skeletal variations, such as dilation of the renal pelvis, wavy ribs, dumbbell shape of thoracic vertebra body, absence and splitting of thoracic vertebra body and lumber ribs, increased significantly. Internal and skeletal variations were not considered adverse effects.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality
body weight and weight gain
gross pathology
Remarks on result:
other: No adverse effect was observed.

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no
Treatment related:
no

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 did not alter the normal growth and development of offspring and, consequently the developmental NOAEL was 1000 mg/kg for the F1 generation.
Executive summary:

A prenatal developmental toxicity study was performed to investigate the toxic effect of the test chemical on foetus 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. 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 chemical did not alter the normal growth and development of offspring and, consequently the developmental NOAEL was 1000 mg/kg for the F1 generation.