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Key value for chemical safety assessment

Additional information

In vitro

2 -butoxyethanol (2BE) is not mutagenic in bacteria, not withstanding a significant response according to one report in S. typhimurium TA97a. This was not substantiated by another study specifically designed to investigate this finding.

Two of three mammalian cell mutation assays did not indicate any mutagenic activity for 2BE. The single positive result was obtained in an assay using a very high concentration (20 mM) that was poorly reported and not considered reliable.

No evidence for chromosomal aberration induction has been found in a number of mammalian cell culture studies with 2BE.

Four studies are available that assess the potential for induction of sister-chromatid exchanges (SCEs). It was concluded in a reliable study that there was no significant induction by 2 -butoxyethanol at concentrations up to 3.5 mg/ml in the absence of S9 mix and 5.0 mg/ml in the presence of rat liver S9 mix, although a trend test was significant (thereby judged to be an equivocal result) in the absence of S9 mix in one of two trials; the other being clearly negative. A second study also did not show an increase in SCE frequency at concentrations up to 0.25 %. However, another study reported a small induction of SCEs in V79 cells and a forth study found a significant increase in SCEs in cultured human lymphocytes, both in the absence of S9 mix. Both studies used lower concentrations that the two reporting negative results and both had shortcomings so are not regarded as key determinants for this end point. Furthermore, the significant SCE results could be artefacts due to cell cycle delay.

There have been reports of cell transformation, but the results have been inconsistent and not repeated across studies. There is also some indication of inhibition of gap-junctional intercellular communication in a single study with 2BE and its two major metabolites, atlhough interpretation of this result was unclear. A single assay for UDS induction used a technique that is now considered to be invalid if a significant response is obtained.

A single study is available on aeuploidy and this reported weak aneugenic effects in a study without metabolic activation. No effects were seen in the same study when the metabolic butoxyacetic acid (BAA) was examined. Evidence for slight micronuclei formation was found in a long exposure in vitro study with 2BE. These appeared to be as a result of aneuploidy, rather than chromosomal breakage.

The balance of evidence suggests that mutagenicity is not an important property of 2 -butoxyethanol

In vivo

There is no evidence for micronucleus induction in bone marrow cells or interaction with DNA in several organs of rats. The possibility of non-disjunction occurring and not being detected in these assays appears to be remote, because BAA produced no evidence of aneugenicity in vitro. BAA is rapidly formed in vivo and is by far the most prevalent blood metabolite of 2BE, so exposure of possible target cells to either 2BE or butoxyacetaldehyde (a transient intermediate metabolite) at high concentrations is brief. In a pigA assay using both acute and sub-acute oral gavage dosing in rats, whilst clear adverse effects were seen on haemolysis from doses of 100mg/kg upwards, the ratio of mutant to normal reticulocytes (with the mutant pigA mutant phenotype) was not affected. It was also noted that the blood parameters had all just about reverted to within normal historical ranges within 7 days of treatment ceasing.

The clear balance of evidence suggests that does not pose a significant mutagenic potential in vivo.


Short description of key information:
IN VITRO
Bacterial mutagenicity
- negative (with and without metabolic activation.) (KEY STUDY) TA97, TA98, TA100, TA1535, TA1537
- negative (with and without metabolic activation.) TA98, TA100, TA102
- positive (with and without metabolic activation.) TA97a
- negative (with and without metabolic activation.) TA97a, TA100, WP2uvrA

Chromosome abberation
- negative (with and without metabolic activation) CHO cells (KEY STUDY)
- negative (without metabolic activation) V79 cells ((tested separately: BAL positive, BAA negative)
- negative (without metabolic activation) human lymphocytes
- negative (without metabolic activation) human lymphocytes

Gene mutation, mammalian cells
- negative (without metabolic activation) AS52 cells grt locus. (BAL tested separately and negative)
- negative (without and without metabolic activation) CHO cells hgprt locus
- positive (without metabolic activation) V79 cells hprt locus (BAL tested separately and positive)

Sister chromatid exchange
- negative (with and without metabolic activation) CHO cells
- negative (with and without metabolic activation) CHO cells
- ambiguous (without metabolic activation) V79 cells (tested separately: BAL ambiguous, BAA negative)
- ambiguous (without metabolic activation) human lymphocyte cells

Cell transformation
- negative (without metabolic activation) SHE cells
- negative (without metabolic activation) SHE cells (tested separately: BAL negative, BAA negative)
- positive (without metabolic activation) SHE cells

Gap junction inhibition
- unclear (without metabolic activation) V79 cells (tested separately: BAL negative, BAA negative)

Aneuploidy
- ambiguous (without metabolic activation) V79 cells (tested separately: BAL ambiguous, BAA negative)

Micronucleii
- ambiguous (without metabolic activation) V79 cells (tested separately: BAL ambiguous, BAA positive)

IN VIVO
Negative (Micronucleus test, F344 rat)
Negative (Micronucleus test, B6C3F1 mouse)
Negative (Micronucleus test, CD1 mouse)

Negative (PigA assay)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

No clear evidence of mutagenicity. In particular, the in vivo data is clearly negative from a number of studies.