Carbonic acid, ethyl methyl ester

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: Test using close chemical analogue. Study design and performance appear comparable to OECD guideline. Original source reference is not accessible but results are summarised in sufficient detail in secondary sources to allow proper assessment.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Developmental toxicity evaluation of dimethylcarbonate by inhalation in CD-1 mice

Author:

Bevan and Beyer

Year:

1995

Bibliographic source:

International Toxicologist 7(1) 74-P-2

Reference 2

Reference Type:

secondary source

Title:

Office of Environmental Hazard Assessment Final Revised Health Assessment For Dimethyl Carbonate

Author:

Californian Environmental Protection Agency

Year:

2010

Bibliographic source:

OEHHA Assessment, Appendix B (detailed summary of 1995 International Toxicologist paper)

Reference 3

Reference Type:

secondary source

Title:

Non-human toxicity excerpts: peer-reviewed summary of 1995 International Toxicologist paper

Author:

HSDB Database

Year:

2011

Bibliographic source:

US National Library of Medicine Toxicology Data Network

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:

Mouse inhalation teratology study

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl carbonate

EC Number:

210-478-4

EC Name:

Dimethyl carbonate

Cas Number:

616-38-6

Molecular formula:

C3H6O3

IUPAC Name:

dimethyl carbonate

Details on test material:

Dimethyl carbonate

Test animals

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

Mated females

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

air

Details on exposure:

Exposure 6h/day for 10 days

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Not specified

Duration of treatment / exposure:

6h/day

Frequency of treatment:

Daily in days 6-15 of gestation (post-mating)

Duration of test:

Parental females terminated on day 18 of gestation

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 ppm
Basis:
other: control group

Doses / concentrations 2

Remarks:

Doses / Concentrations:
300 ppm
Basis:
other: presumed target concentration (low-dose)

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1000 ppm
Basis:
other: presumed target concentration (mid-dose)

Doses / concentrations 4

Remarks:

Doses / Concentrations:
3000 ppm
Basis:
other: presumed target concentration (high-dose)

No. of animals per sex per dose:

96 mated females/dose

Control animals:

yes

Details on study design:

Foetuses from first 30-32 pregnant females/group taken for foetal examinations

Examinations

Maternal examinations:

Bodyweights recorded on days 0, 15 and 18 post-mating; food intakes recorded

Ovaries and uterine content:

Post-implantation losses determined from counts of resorptions

Fetal examinations:

Weights and sexes noted, inspected for abnormalities (external appearance, visceral and skeletal examination)

Statistics:

Statistical significance of any differences between test and control groups was determined

Indices:

Maternal toxicity assessed by bodyweight gain and food intake. Developmental effects assessed by foetal bodyweights and incidence of malformations

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
At 3000 ppm only, bodyweight gains days 0-15 and 0-18 both significantly reduced compared to controls (p<0.01): over days 0-18, bodyweight gain was 27% lower than controls (based on group mean values).
Food intakes significantly reduced at 1000 and 3000 ppm

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

1 000 ppm

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

1 000 ppm

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Embryo/foetal toxicity at 3000 ppm: post-implantation losses, altered sex ratio with less surviving males. Foetal bodyweights significantly reduced (both sexes p<0.01) and more foetuses <1g weight.
Teratogenicity at 3000 ppm: cases of fused vertebral arches and skullbone malformations, plus skeletal (sternal and rib bone) variations seen at 3000 ppm only.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Externally visible foetal abnormalities at 3000 ppm (significantly different from controls):

140/277 foetuses in 26/29 litters with cleft palate (p<0.01)

24/277 foetuses in 5/29 litters with small ears (p<0.05)

13/277 foetuses in 5/29 litters with abnormal ear position (p<0.05)

5/277 foetuses in 3/29 litters with unperforated anus (p<0.05)

4/277 foetuses in 2/29 litters with absent or undersized digit(s) (p<0.05).

Skeletal abnormalities at 3000 ppm:

- multiple skullbone malformations

- fused vertebral arches.

Skeletal variation at 3000 ppm:

- sternal bones misshaped

- rib bone shape/size variation.

Applicant's summary and conclusion

Conclusions:

Based on the high exposure concentrations required to cause significant embryo or foetal toxicity and foetal abnormalities, and the close association with maternal toxicity (NOAELs being the same for maternal and developmental toxicity), it is concluded that dimethyl carbonate did not show selective developmental toxicity. It is reasonable to assume that ethyl methyl carbonate would show closely similar activity in this type of study.