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Key value for chemical safety assessment

Additional information

1,2 -Butadiene is not expected to be genotoxic. As described in Section 7.1 (Toxicokinetics endpoint summary) the presence of the adjacent double bonds is likely to preclude the formation of an epoxide (Krause and Hashmi, 2004) unlike its isomer 1,3-butadiene where the double bonds are separated by a single bond and is genotoxic via its epoxide metabolites (IARC 1992).

1,2-Butadiene has been tested in bacterial mutation assays (Ames tests) where it was not mutagenic in the presence and absence of metabolic activation (Harlan, 2008a). Positive control compounds gave the expected results demonstrating that the studies were robust. A chromosome aberration (in vitro cytogenetic – IVC) assay on 1,2 -butadiene in human lymphocytes was also negative in the presence and absence of metabolic activation whilst positive control compounds gave the expected results. This guideline study demonstrated that 1,2 -butadiene was not clastogenic (Harlan, 2008b).

An in vitro gene mutation study on 1,2 -butadiene in mammalian cells has been conducted. 1,2-Butadiene was non-mutagenic in L5178Y TK +/- mouse lymphoma cells in the absence of metabolic activation whilst it was considered to be weakly positive in the presence of 2% metabolic activation. The weak evidence of gene mutation is only indicated by increases in large colony mutants. The increases in mutant colonies observed were equally due to increases in small and large colonies. The increase in small colony mutants is suggestive of a cytogenetic event. Any gene mutation effect is therefore small and of likely questionable significance. Overall, the increases were small, were only seen at very high test material atmosphere concentrations and did not reproducibly meet the criteria for a positive of exceeding the Global Evaluation Factor across all three experiments carried out.

1,2 -Butadiene is therefore not concluded to be genotoxic in vitro, and no further in vivo data are proposed. The rationale for this is:

The Ames test for bacterial gene mutation was negative.

The IVC assay for cytogenetic activity was negative.

The L5178Y assay for gene mutation activity has provided a only weak positive response which, importantly, was not supported by the results of the IVC assay, which is designed to look in detail for cytogenetic activity. Considering all of the available data for the test material, the small increases seen in the L5178Y assay are not considered to indicate a significant genotoxic effect of the material in vitro. 

The weight of evidence across the three core assays is for no reproducible genotoxic activity. In vivo follow up experiments are therefore not proposed.

There are no genetic toxicity data on 1,2 -butadiene in humans.

 

Additional References

IARC (1992). IARC monographs on the evaluation of carcinogenetic risks to humans. Vol. 54. IARC, Lyon, France pp. 137-285.


Short description of key information:
The available data indicate that 1,2-butadiene is not genotoxic. In vitro assays for bacterial mutation and chromosome aberration were negative in the presence and absence of metabolic activation. 1,2-Butadiene was non-mutagenic in L5178Y mouse lymphoma cells in the absence of metabolic activation whilst it was weakly positive in the presence of 2% metabolic activation. The weight of evidence across the three core assays is for no reproducible genotoxic activity.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

1,2 -Butadiene has low potential for genotoxicity and therefore does not warrant classification under Dir 67/548/EEC or GHS/CLP.