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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: data reliablity constrained by design as a limit test

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Isooctyl acrylate
EC Number:
249-707-8
EC Name:
Isooctyl acrylate
Cas Number:
29590-42-9
Molecular formula:
C11H20O2
IUPAC Name:
6-methylheptyl acrylate
Details on test material:
- Name of test material (as cited in study report): C-236
- Impurities (identity and concentrations): NA
- Composition of test material, percentage of components: NA
- Isomers compositon: NA
- Purity test date: NA
- Lot/batch no.: 4-81
- Expiration date of the lot/batch: NA
- Stability under test conditions: Stable
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
Sex: Female
TEST ANIMALS
- Source: Charles river Breeding Laboratories, Inc. Kingston, MY
- Age at study initiation:
5 weeks at receipt
9 weeks for acclimitization and to reach sexual maturity

- Diet (e.g. ad libitum): adlibitum,
Purina Rodent Laboratory Chow
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 9 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 deg
- Humidity (%): 57%
- Air changes (per hr): Not available
- Photoperiod (hrs dark / hrs light):12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test material was diluted to the appropriate dosing volume in corn oil vehicle by magnetic stirring. The prepared dilutions were well shaked before use and the animals were dosed while solutions werer mixed on a magnetic stirrer.

Fresh solutuions were prepared weekly.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1000 mg/kg
- Concentration (if solution): NA
- Constant volume or concentration used: Yes and Yes


VEHICLE
- Justification for use and choice of vehicle (if other than water):

Corn oil was used as the test compound is not soluble in water
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]: co-housed

- If cohoused:
Animals were placed in breeding cages for a maximum of three weeks. Females were rotated after the tenth day of mating.

- M/F ratio per cage: One male per two females

- Length of cohabitation: 3 weeks maximum

-Females were rotated after the 10th day of mating.

- Further matings after two unsuccessful attempts: [no / yes (explain)] N.A.


- Verification of same strain and source of both sexes: [yes / no (explain)] Yes

- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy

Mating was confirmed by presence of a vaginal plug or daily examination of vaginal smears for the presence of sperm.
Duration of treatment / exposure:
The test compound (C-236) was administered to a group of 22 pregnant rats at a single dose level (1000 mg/kg) from days 6 to 15 of gestation. A separate groups served as a vehicle (corn oil) control.
Frequency of treatment:
Daily
Duration of test:
Days 6 to 15 of gestation

Details on study schedule : Age at mating of the mated animals in the study: ca 9] weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
analytical conc.
No. of animals per sex per dose:
22
Details on study design:
- Limit test at 1000 mg/kg

Examinations

Maternal examinations:
All animals were obseved once daily and records made of martalizty, moribundity, and clinical signs

- Cage side observations checked in table were included. Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were taken on days 0, 6, 9, 12, 15,and 20 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food and water consumption were recorded for Days 6-8, 9-11, 12-14, 15-17 and 18-20 of gestation.

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

Food and water consumption were recorded for Days 6-8, 9-11, 12-14, 15-17 and 18-20 of gestation.

- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
On day 20 of gestations, females were sacrificed by carbon dioxide asphyziation and the fetuses were taken by cesarean section. Following gross examination of each dam, the number of corpora lutea per ovary and the number and placement of implantation sites, early and late resorptions, and live and dead fetuses in each uterine horn were recorded. Fetuses were removed from the placenta, individually identified, examinied externally, weighed and sexed and measured. Gravid and nongravid uterine weights (with ovaries attached) were recorded at cesarean section.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: 2/3rds
- Soft tissue examinations: Yes 2/3rds
- Skeletal examinations: Yes: 2/3rds
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
Statistics:
Box's test, ANOVA Dunnett's T-Test, Chi-square test, Fishers "Exact" test
Historical control data:
Not applicable

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal toxicity was noted.
Symptoms consisted on effect of body weight, clinical signs and gross pathology. Apparent effects on food and water water consumption were also noted.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Any visceral or sketelat effects noted were correlated with the maternal toxicity.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 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
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations

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:
no
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
The test materials toxicity at 1000 mg/kg/day from days 6 to days 15 of gestation were largely attributed to maternal toxicity. As this was a limit study, no definitive dose-response relationship was established.
Executive summary:

Pregnant female rats were exposed to IOA (C-236) at 1000 mg/kg from days 6 to days 15 gestation in a limit test. Clear signs of maternal toxicity were noted as evidenced by effects of body weight, clinical signs and gross pathology. Apparent effects on food and water consumption were also noted. No definitive indication of teratogenic effects were noted in the fetuses. Any effects observed in the developing fetuses were believed attributable to the maternal toxicity. The developmental No Observed Adverse Effect Level (NOAEL) for IOA was 1000 mg/kg/day.