2,2,2,4,4,4,4-heptakis[(2-ethylhexanoyl)oxy]cyclodimolybdoxan-2-yl 2-ethylhexanoate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline study, published in peer reviewed literature, minor restrictions in design and/or reporting but otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

The Developmental Toxicity of 2-Ethylhexanoic Acid in Wistar Rats

Author:

Pennanen S, Tuovinen K, Huuskonen H, Komulainen H

Year:

1992

Bibliographic source:

Fundamental and Applied Toxicology 19, 505-511 (1992)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexanoic acid

EC Number:

205-743-6

EC Name:

2-ethylhexanoic acid

Cas Number:

149-57-5

Molecular formula:

C8H16O2

IUPAC Name:

2-ethylhexanoic acid

Details on test material:

Purity: 99.5%
Supplier: Merck (Darmstadt, FRD)

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

Virgin female Han:Wistar rats (National Laboratory Animal Center, University of Kuopio, Finland) weighing 200-220 g (12 to 14-weeks old) and male rats of the same strain 360-380 g (16-weeks old) were used for this study. Rats were housed in stainless steel wire mesh cages and kept under a photoperiodic cycle of 12 hr light/12 hr dark in an air-conditioned animal room. Temperature and relative humidity of the room were maintained ay 21 ± 1°C and 55-65% respectively. Animals were housed three per cage before mating and individually during gestation. The animals received commercial rat chow (R3-EWOS, Sodertalje, Sweden) and tap water ad libitum except 2-EHA solution during the experiment.

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

other: 2-EHA was administered as a sodium salt by mixing 2-EHA and NaOH equimolarly in drinking water.

Details on exposure:

Mated females were exposed to 2-EHA on Days 6-19 of gestation via drinking water at doses of 100, 300 and 600 mg/kg bw/day. Control animals received deionised water. Water consumption was recorded for the whole exposure period and the doses were corrected individually according to the most recent body weight taken on days 0, 6, 13 and 20.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Female rats were paired overnight with males and the vaginal smears were checked the next morning for the presence of sperm.

Duration of treatment / exposure:

14-days (days 6-19 of gestation).

Frequency of treatment:

Daily

Duration of test:

20 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300 and 600 mg/kg bw/day
Basis:
nominal in water

No. of animals per sex per dose:

20-21 dams per treatment group
Control: 21 dams
100 mg/kg/day: 21 dams
300 mg/kg/day: 20 dams
600 mg/kg/day: 20 dams

Control animals:

yes, concurrent no treatment

Examinations

Maternal examinations:

- The animals were observed daily for clinical signs.
- Water consumption was recorded for the whole exposure period and the doses were corrected individually according to the most recent bodyweight taken on days 0, 6, 13 and 20
- Food consumption was recorded in the same gestational stage during days 13 to 16 of pregnancy.

Ovaries and uterine content:

The uterine contents and ovaries were examined for the number of corpora lutea, weight of uterus with its contents, number of implantation sites, sex and number of live and dead fetuses, number of early and late resorptions, external abnormalities, and placental weights.

Fetal examinations:

Individual fetal weights, skeletal anomalies and visceral anomalies.

Statistics:

Maternal, fetal, and placental weights, implantations, and living fetuses per litter were analysed by one-way analysis of variance (ANOVA). Comparisons of significant group effects were conducted using the Fisher PLSD test. The fetal bodyweight data were also evaluated using covariate analysis with litter size and sex ratio as covariates. Dose-response relationships for maternal and fetal body weights and affected fetuses and fetuses with skeletal or visceral malformations (group mean of litter percentages) were analysed by the Pearson correlation test. Pre- and postimplantation losses and group mean values of litter percentages of skeletal and visceral anomalies were analysed by the Mann-Whitney U nonparametric test. Other data were analysed by the X2 test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Reduced maternal weight gain at 600 mg/kg/day

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Lower fetal weight at 300 and 600 mg/kg/day
Increased incidences of clubfoot at 300 and 600 mg/hg/day
Increased wavy ribs at all doses, and of extra thoracic ribs at 600 mg/kg/day
Reduced ossification at 600 mg/kg/day
Increased incidences of fetuses with dialation of the lateral ventricles at 600 mg/kg/day.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The maternal NOAEL was 300 mg/kg bw/day and the NOAEL for teratogenicity was 100 mg/kg bw/day. Maternal effects included slightly lower pregnancy rate and reduced body weights. Teratogenic effects included reduced fetal weights and skeletal variations.