Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

The mutagenicity of tetraglyme was derived from experimental studies and analogue approaches using triglyme, diglyme, monoglyme, as source chemicals.

The analogue approach is justified based on the following:

The analogue approach using triglyme, diglyme and monoglyme as source chemicals is justified:

a.   The target chemical belongs to the homologues series of glymes, where there is an incremental increase in the number of CH2CH2O units. Therefore, it can be assumed that target and other glyme members (mono-, di-, and triglyme) share the same toxic mode action.

b.   The findings in repeated dose toxicity studies are comparable for target and source chemicals: the target is the male reproductive organ. Further, findings in thymus and altered hematological values are indicative of altered blood system.

c.    The findings in reproductive performance are comparable: No live pubs and/or reduced number of pubs were the common finding.

d.   The findings in developmental toxicity studies are comparable: the most notable findings were paw skeletal malformations. These findings were observed also at dose levels not associated with apparent maternal toxicity.

Four Ames tests are available on tetraglyme and its source (triglyme, diglyme and monoglyme) chemicals. No mutagenicity could be derived in all four studies.

Diglyme and monoglyme were examined in the UDS tests similar to current OECD Guideline 482. No induction of unscheduled DNA-synthesis is observed for the these test items.

Monoglyme was evaluated for potential mutagenic activity with a Chinese Hamster Ovary (CHO) mutation test. The result indicated that monoglyme was not mutagenic with and without metabolic activation.

Monoglyme was tested the SCE assay in CHO cells. The result suggested a possible clastogenic (chromosome breaking )effect of this chemical in mamallian cells.

Diglyme was tested in the chromosome aberration test in rats. Rodents were exposed to the test compound atmospheres for 7 h/d for either 1 or 5 days. The result showed that the test item did not produce a detectable significant aberration of the bone marrow metaphase chromosomes of rats.

Monoglyme was tested in the chromosome aberration test in hamsters. The test item was diluted with water and dosed at 2000 mg/kg bodyweight to male and female hamsters. The result indicated that monoglyme did not produce a detectable significant aberration of the bone marrow metaphase chromosomes of hamsters.

Diglyme was tested in a dominant-lethal assay in rats and found to be positive. However, the test result is considered to be of limited relevance due to the possibility that the observed effect may not truly reflect the genotoxicity but rather reproduction organ toxicity.

Monoglyme was tested in a Mamalian Micronucleus test in mice. Animals treated with monoglyme up to 2000 mg/kg bw/d (2 applications, one daily) did not show any clinical sign. The number of micronuclei containing polychromatic erythrocytes and normocytes were not influenced by the treatment with monoglyme. Based on the result, it was stated that during the study monoglyme did not induce micronuclei as determined by the micronucleus test in the bone marrow cells of the mouse.

It can be concluded from the data available for tetraglyme and its structural analogues that no mutagenicity and genotoxicity are caused by tetraglyme and therefore classification for this end point is not warranted.


Justification for selection of genetic toxicity endpoint
The genotoxicity of tetraglyme should be assessed by read-across and by weight of evidence approaches. The provided studies are considered to be all useful for the weight of evidence approach.

Short description of key information:
- Ames test: negative (4 studies, each on tetraglyme, triglyme, diglyme and monoglyme)
- in vitro UDS assay: negative (3 studies, two on monoglyme and one on diglyme)
- in vitro mammalian cell gene mutation assay: negative (one study on monoglyme)
- in vitro SCE assay: positive (one study on monoglyme)
- in vivo micronucleus test in mice: negative (one study on monoglyme)
- in vivo chromosome aberration test: negative (2 studies, each on diglyme and monoglyme)
- in vivo rodent dominant lethal test: positive ( one study on diglyme; limited relevance)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

It can be concluded from the available data for tetraglyme and its structural analogues that no mutagenicity and genotoxicity are caused by tetraglyme and therefore classification for this end point is not warranted.