Registration Dossier

Administrative data

Endpoint:
genetic toxicity in vivo, other
Remarks:
Combined gene mutation (comet assay) and micronucleus assay
Type of information:
experimental study planned
Study period:
according to decision by ECHA
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
N, N, N’, N’-tetrakis(2, 3-epoxypropyl)-m-xylene-a, a’-diamine
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 studies available covering genetic toxicity information requirements.
- Available non-GLP studies: There is one well performed Ames test available, in which a weak positive response was observed in three of the tester strains in presence of metabolic activation. Since this data is insufficient for C&L, the need for additional information is triggered (ECHA Guidance in Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance).
- Historical human data: There are no historical human data available on genetic toxicity for the substance.
- (Q)SAR: At present there is no valid (Q)SAR model available which can fulfill the data requirements for vivo genetic toxicity of substances. (ECHA Guidance in Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance)
- In vitro methods: Because of the (weak) positive gene mutation test in bacteria, independent on the outcome of in vitro assays (in vitro micronucleus, chromosome aberration and in vitro mammalian cell gene mutation test) in vivo testing has to be performed for at least mutagenicity (ECHA Guidance in Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance). Therefore, the in vitro alternatives are not of added value for the assessment of the mutagenic potential of the substance nor form an alternative for the in vivo tests. An in vitro micronucleus test is only of limited value since a positive response will trigger an additional in vivo study as well. The proposed simultaneous assessment of mutagenicity (Comet assay) and clastogenicity (micronucleus test) in vivo is therefore the most efficient strategy in terms of animal use.
- Weight of evidence: There are no data available which are sufficient for a weight of evidence approach.
- Grouping and read-across: No substances or a category of substances are known which apply for read across addressing the genetic toxicity of the substance.
- Substance-tailored exposure driven testing: not applicable
- Approaches in addition to above: not applicable
- Other reasons: not 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:
- According to Column 2 Annex VII Further mutagenicity studies shall be considered in case of a positive result in the in vitro gene mutation study in bacteria.
According to Column 1 Annex VIII there are two data requirements: 1. In vitro cytogenicity study in mammalian cells or in vitro micronucleus study. 2. In vitro gene mutation study in mammalian cells, if a negative result in Annex VII and Annex VIII, 1.
- According to Column 2 Annex VIII: Appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VIII.
- According to column 2 Annex IX: If there is a positive result in any of the in vitro genotoxicity studies in Annex VII or VIII and there are no results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study shall be proposed by the registrant.
The points outlined above apply for the test substance and make in vivo testing unavoidable. Thus, in order to fulfill the information requirements a combined in vivo Comet assay (OECDE 489) and micronucleus test (OECD 474) is proposed.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
An in vivo test in mice is proposed in which the OECD guidelines 474 and 489 are combined, in order to fully cover the information requirements on mutagenic and clastogenic properties of the substance in one study, in order to reduce the use of test animals to a minimum.

Data source

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Qualifier:
according to
Guideline:
OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)

Test material

Reference
Name:
Unnamed

Results and discussion

Applicant's summary and conclusion