(2-ethyl-2-methyl-1,3-dioxolan-4-yl)methyl prop-2-enoate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: gene mutation

Type of information:

experimental study planned

Justification for type of information:

NON-CONFIDENTIAL NAME OF SUBSTANCE: Medol 10
- Name of the substance on which testing is proposed to be carried out: Medol 10
CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION

- Available GLP studies: There are no GLP compliant studies available on in vivo genetic toxicity with the registered substance.
- Available non-GLP studies: There are no non- GLP compliant studies available on in vivo genetic toxicity with the registered substance.
- Historical human/control data: There are no appropriate historical human data available addressing the endpoint in vivo genetic toxicity.
- (Q)SAR: QSAR tools sufficiently addressing the endpoint reproductive toxicity are currently not available.
- In vitro methods: As the substance is being registered at 10-100tpa the following in vitro genetic toxicity studies were conducted: In vitro gene mutation study in bacteria which was concluded as negative and an in vitro cytogenicity/micronucleus study which was concluded as mutagenic to human lymphocytes in vitro. According to ECHA guidance when you have a negative Ames study and a positive micronucleus study, the next step is to submit a testing proposal for Annex IX studies. Therefore we can conclude that the invitro data currently available is not sufficient to conclude on classification and an in vivo study is required.
- Weight of evidence: There are no studies available on in vivo genetic toxicity with the registered substance which could be used in a weight of evidence approach.
- Grouping and read-across: A similar substance is available EC No. 266-380-7, CAS no. 66492-51-1, IUPAC name (5-ethyl-1,3-dioxan-5-yl)-methyl-acrylate. The in vitro genetic toxicity data available on the read across substance is different to the registration substance and therefore it was concluded that the in vivo data available on this substance was not suitable for the read across approach.
- Substance-tailored exposure driven testing [if applicable]: Not applicable
- Approaches in addition to above [if applicable] :Not applicable
- Other reasons [if applicable]

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
An in vivo study is required as the results from the in vitro studies were in conclusive. It is not possible to conclude on genetic toxicity classification without an in vivo study.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
The Combo MN/Comet study(Oral gavage) is the best follow strategy to address the in conclusive results for the following reasons.

The micronucleus portion of the study is qualitatively sensitive to detect micronucleus induction by aneugenic and clastogenic mode of action (MOA) , either of which may be the cause of the dose-related increases in micronuclei observed under all three test conditions of the in vitro MN test. An overall negative in vivo MN result would indicate the incidence of MN shown in the in vitro test is not produced in an in vivo test system. A positive in vivo MN result would potentially require further determination within the study by a FISH work-up to discriminate between aneugenic and clastogenic MOA. In the case of aneugenicity a NOAEL should be determined by evidence of a dose within the study that shows background level of micronuclei. The addition of a safety margin identifies exposure limits to manage safety risks. However, in some instances when a weak MN response results a FISH workup may not reliable because background micronuclei make up a substantial fraction of total micronuclei observed such that a clear cut MOA cannot be determined. In this case the Comet endpoint that detects strand breakage can rule out clastogenicity. Best case is if both in vivo endpoints are negative and in general results from two in vivo endpoints provides a complete big picture data set to evaluate overall genetic toxicology safety assessment.

Materials and methods

Principles of method if other than guideline:

The Combo MN/Comet study(Oral gavage) is the best follow strategy to address the in conclusive results for the following reasons.

The micronucleus portion of the study is qualitatively sensitive to detect micronucleus induction by aneugenic and clastogenic mode of action (MOA) , either of which may be the cause of the dose-related increases in micronuclei observed under all three test conditions of the in vitro MN test. An overall negative in vivo MN result would indicate the incidence of MN shown in the in vitro test is not produced in an in vivo test system. A positive in vivo MN result would potentially require further determination within the study by a FISH work-up to discriminate between aneugenic and clastogenic MOA. In the case of aneugenicity a NOAEL should be determined by evidence of a dose within the study that shows background level of micronuclei. The addition of a safety margin identifies exposure limits to manage safety risks. However, in some instances when a weak MN response results a FISH workup may not reliable because background micronuclei make up a substantial fraction of total micronuclei observed such that a clear cut MOA cannot be determined. In this case the Comet endpoint that detects strand breakage can rule out clastogenicity. Best case is if both in vivo endpoints are negative and in general results from two in vivo endpoints provides a complete big picture data set to evaluate overall genetic toxicology safety assessment.

Test material

Test material information

Constituent 1

Reference substance name:

(2-ethyl-2-methyl-1,3-dioxolan-4-yl)methyl prop-2-enoate

EC Number:

807-159-2

Cas Number:

69701-99-1

Molecular formula:

C10H16O4

IUPAC Name:

(2-ethyl-2-methyl-1,3-dioxolan-4-yl)methyl prop-2-enoate

Test material form:

liquid