Hydrocarbons, C4

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

other: EU Risk Assessment

Adequacy of study:

other information

Reliability:

other:

Data source

Reference

Reference 1

Reference Type:

other: EU Risk Assessment

Title:

European Union Risk Assessment Report 1,3-BUTADIENE, CAS No: 106-99-0, EINECS No:203-450-8

Author:

[ECB] European Chemicals Bureau

Year:

2002

Reference 2

Reference Type:

review article or handbook

Title:

Overview of reproductive and developmental toxicity studies of 1,3-butadiene in rodents.

Author:

Morrissey, R.E. et al.

Year:

1990

Bibliographic source:

Environ Health Persp. 86; 79-84.

Reference 3

Reference Type:

study report

Title:

Unnamed

Year:

1987

Reference 4

Reference Type:

other company data

Title:

Unnamed

Year:

1981

Materials and methods

Principles of method if other than guideline:

EU Risk Assessment on the major component of C4 Hydrocarbons: 1,3-Butadiene

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Buta-1,3-diene

EC Number:

203-450-8

EC Name:

Buta-1,3-diene

Cas Number:

106-99-0

Molecular formula:

C4H6

IUPAC Name:

buta-1,3-diene

Details on test material:

- Name of test material (as cited in study report): 1,3-butadiene
- CAS number: 106-99-0
- EINECS number: 203-450-8

Test animals

Species:

other: rat and mouse

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

LOAEC

Remarks:

rat

Effect level:

1 000 ppm (nominal)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEC

Remarks:

mouse

Effect level:

200 ppm (nominal)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

1

Dose descriptor:

LOAEC

Remarks:

mouse

Effect level:

200 ppm (nominal)

Basis for effect level:

other: fetotoxicity

2

Dose descriptor:

LOAEC

Remarks:

mouse

Effect level:

200 ppm (nominal)

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The developmental toxicity of butadiene has been investigated in mice and rats by the NTP. An overview of the studies is provided

by Morissey et al. (1990).

Groups of 31-33 pregnant Swiss CD-1 mice and 30 pregnant Sprague-Dawley rats were exposed to 0, 40, 200 or 1,000 ppm butadiene for 6 hours/day on days 6-15 of gestation (Hackett et al., 1987a,b). Mice were sacrificed on day 18 of gestation and rats on day 20. Implantation sites were recorded. Live fetuses were weighed and gross, visceral and skeletal examination made.

Maternal toxicity was elicited at the highest exposure level in rats, observed as a statistically significant, 31% reduction in bodyweight gain during gestation. Exposure to butadiene had no effect on developmental parameters at any exposure concentration. In the mouse study, a statistically significant reduction in maternal bodyweight gain during gestation was seen at 200 ppm (14% reduction) and 1,000 ppm (20% reduction). Fetal weight was statistically significantly lower at 200 ppm (16% less than control) and 1,000 ppm (22% less than control). There were no statistically significant increases in percentage resorptions or malformations per litter although

there was a slight, statistically significant increase in minor skeletal abnormalities at 200 and/or 1,000 ppm, indicative of growth retardation (supernumerary ribs, reduced sternebral ossification and misaligned, scrambled or cleft sternebrae).

These studies demonstrate that butadiene is not a developmental toxicant to the rat following inhalation exposure. However, in the mouse, butadiene appears to have a minor effect on development, with retardation in fetal bodyweight and skeletal development seen at 200 and 1,000 ppm, concentrations which also produced evidence of maternal toxicity.

In a study conducted on behalf of the IISRP, female rats were exposed to 0, 200, 1,000 or 8,000 ppm for 6 hours/day on days 6-15 of gestation and sacrificed on day 20 (Irvine, 1981). There were 40 negative controls, 24 females in each test group and 26 females in a positive control group dosed with aspirin. There was a statistically significant concentration-related reduction (14-45%) in maternal bodyweight gain at all exposure levels. There was a marginal concentration-related lowering of fetal weight and size (crown/rump length) which reached statistical significance at 8,000 ppm (mean fetal weight 6% less than control; crown/rump length

5% less than control). It was noted that the values of these parameters were low in all groups, compared with historical controls. Statistically significantly increased incidences of marked and severe forms of wavy ribs, irregular rib ossification and incomplete ossification were noted at 8,000 ppm. These effects are considered to be indicative of delayed development. There was a statistically significantly increased incidence of bipartite thoracic centra in all exposure groups. An appropriate response was seen in the positive control group. This study demonstrates that butadiene has a minor effect on fetal development at concentrations which are toxic to the dam.