Bis(2-ethylhexyl) maleate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was evaluated under the OECD SIDS program and scored as reliability 2a: Reliable with restriction; acceptable, well-documented publication which meets basic scientific standard

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Teratology and multigeneration reproduction studies with maleic anhydride in rats

Author:

Short RD, Johannsen FR, Levinskas G J, Rodwell DE, Schardein JL

Year:

1986

Bibliographic source:

Fundam. Appl. Toxicol. 7: 359-366

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:

Maleic anhydride

EC Number:

203-571-6

EC Name:

Maleic anhydride

Cas Number:

108-31-6

Molecular formula:

C4H2O3

IUPAC Name:

furan-2,5-dione

Constituent 2

Reference substance name:

2,5-Furandione

IUPAC Name:

2,5-Furandione

Test material form:

other: briquettes

Details on test material:

- Name of test material (as cited in study report): Maleic anhydride
- Molecular formula (if other than submission substance): C4H2O3
- Molecular weight (if other than submission substance): 98.06 g/mol
- Smiles notation (if other than submission substance): O=C1OC(=O)C=C1
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig. 1
- Physical state: white solid (briquette)
- Analytical purity: >99%

Test animals

Species:

rat

Strain:

CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: approximately 12 weeks
- Housing: Besides mating and lactation, animals were housed individually.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Animals were acclimated to for at least 10 days

ENVIRONMENTAL CONDITIONS
Animals were maintained in environmentally controlled rooms with a photoperiod of 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Ground maleic anhydride was suspended in corn oil. A 1% (w/v) concentration ws used to administer all doses.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

From day 6 to day 15 from gestation

Frequency of treatment:

Daily during day 6 and day 15 from gestation

Duration of test:

Animals were sacrificed on day 20 of gestation

No. of animals per sex per dose:

25 females/dose group

Control animals:

yes, concurrent vehicle

Details on study design:

Doses were selected based on the results of a pilot study

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

Fetuses were weighed and examined for external abnormalities, skeletal abnormalities, and abnormalities in the soft tissue.

Statistics:

Analysis of variance followed by Dunnett's test for adult body weights
Mann-Whitney U test for fetal body weights
chi square of Fisher's exact test for litters with anomalies
Level of significance: p<0.05

Historical control data:

not reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
The general appearance and behavior of rats were not altered by treatment. One adult died in each of the experimental groups, but the overall survival in these groups was 96%. Dams in the experimental groups either failed to gain weight or lost weight between day 6 and day 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.
Dams from all test groups produced normal-sized litters, and there was no evidence of postimplantation loss.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

> 140 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Fetal body weights were slightly reduced for all test groups, compared with the control groups.However, the reductions were statistically significant only in the low- and high-dose groups. But this is not considered to be compound-related, because fetal weights for control and all treated groups were slightly greater than the values for historical controls. Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation. The fetal variations were comparable both in type and frequency in the control and treated groups.

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Effect level:

> 140 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

> 140 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Maleic anhydride is not teratogenic under the conditions of the present test.