Registration Dossier

Administrative data

Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Type of information:
experimental study planned
Justification for type of information:
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out
m-phenylene di(acetate) [CAS no. 108-58-7]

- Name of the substance for which the testing proposal will be used [if different from tested substance]
Not applicable; test shall be conducted with m-phenylene di(acetate) [CAS no. 108-58-7]

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
According to REACH regulation Annex VIII and IX Column 2 chapter 8.4 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.
Annex VIII; Column 2 chapter 8.4: “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”.
Annex IX Column 2 chapter 8.4: “[i]f 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 most recent ECHA position document on in vivo genotoxicity testing indicates: “When there is a positive result from an in vitro gene mutation study in bacteria (Ames test, OECD TG 471) or from an in vitro gene mutation study in mammalian cells (OECD TG 476 for tests using the Hprt and xprt genes; OECD TG 490 for tests using the thymidine kinase gene), adequate somatic cell in vivo tests to investigate gene mutations are TGR (OECD TG 488), comet assay (OECD TG 489) or, if justified, Unscheduled DNA Synthesis (UDS) test with mammalian liver cells in vivo (OECD TG 486)…Consequently, a testing proposal must be submitted for in vivo tests intended to meet the information requirements of the REACH Regulation. Following examination of such a testing proposal, ECHA has to approve the test in its evaluation decision before it can be undertaken.” (Cited from ECHA position document “Three recently approved in vivo genotoxicity test guidelines (Revised in February 2018; https://echa.europa.eu/documents/10162/21650280/oecd_test_guidelines_genotoxicity_en.pdf)

Due to the positive results of the HPRT assay according to OECD Guideline 490 (In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene) and the negative result in the Ames test according to OECD Guideline 471 (Bacterial Reverse Mutation Assay Test) and the negative OECD TG 487 test (In vitro Mammalian Cell Micronucleus Test), the conduction of an in-vivo Comet assay is proposed to evaluate potential mutagenic activity in vivo.
As discussed in IUCLID chapter 7.1, Toxicokinetics, based on the high water solubility and the favorable octanol-water partition coefficient an absorption following ingestion is likely and signs of systemic toxicity are seen at very high doses (acute oral toxicity > 2000 mg/kg bw, repeated dose toxicity at 500/1000 mg/kg bw).
The test shall be conducted according to OECD TG 489 on rat and by the oral route (gavage). The following systemic and local organs shall be analysed: liver, glandular stomach, duodenum/jejunum and bone marrow.

- Available GLP studies
There is no in vivo genotoxicity study conducted according to GLP available

- Available non-GLP studies
There is no in vivo genotoxicity study available

- Historical human data
No data available

- (Q)SAR
There is no QSAR model available which is accepted by ECHA for the endpoint in vivo genotoxicity in case of a positive in vitro genotoxicity study.

- In vitro methods
According to REACH regulation Annex VIII Column 2 chapter 8.4 appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VII.
Due to the positive results of the HPRT assay according to OECD Guideline 490 (In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene) and the negative result in the Ames test according to OECD Guideline 471 (Bacterial Reverse Mutation Assay Test) and the negative OECD TG 487 test (In vitro Mammalian Cell Micronucleus Test), the conduction of an in-vivo Comet assay is proposed to evaluate potential mutagenic activity in vivo.

- Weight of evidence
According to REACH regulation Annex VIII Column 2 chapter 8.4 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.
The data from the available in vitro genotoxicity assays is not sufficient for a weight of evidence consideration according to the ECHA’s REACH guidance documents.

- Grouping and read-across
Based on the chemical structure and the physicochemical characteristics of m-phenylene di(acetate) no grouping or read-across approach was identified to fill the default information for an in vivo mutagenicity study according to Annex VIII column 2 chapter 8.4.

- Substance-tailored exposure driven testing [if applicable]
Not applicable

- Approaches in addition to above [if applicable]
Not applicable

- Other reasons [if applicable]
According to REACH regulation Annex VIII Column 2 chapter 8.4 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.

The most recent ECHA position document on in vivo genotoxicity testing indicates: “When there is a positive result from an in vitro gene mutation study in bacteria (Ames test, OECD TG 471) or from an in vitro gene mutation study in mammalian cells (OECD TG 476 for tests using the Hprt and xprt genes; OECD TG 490 for tests using the thymidine kinase gene), adequate somatic cell in vivo tests to investigate gene mutations are TGR (OECD TG 488), comet assay (OECD TG 489) or, if justified, Unscheduled DNA Synthesis (UDS) test with mammalian liver cells in vivo (OECD TG 486)…Consequently, a testing proposal must be submitted for in vivo tests intended to meet the information requirements of the REACH Regulation. Following examination of such a testing proposal, ECHA has to approve the test in its evaluation decision before it can be undertaken.” (Cited from ECHA position document “Three recently approved in vivo genotoxicity test guidelines (Revised in February 2018; https://echa.europa.eu/documents/10162/21650280/oecd_test_guidelines_genotoxicity_en.pdf)


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 REACH regulation Annex VIII and IX Column 2 chapter 8.4 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.
Annex VIII; Column 2 chapter 8.4: “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”.
Annex IX Column 2 chapter 8.4: “[i]f 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”.


FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed
Due to the positive results of the HPRT assay according to OECD Guideline 490 (In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene) and the negative result in the Ames test according to OECD Guideline 471 (Bacterial Reverse Mutation Assay Test) and the negative OECD TG 487 assay (In vitro Mammalian Cell Micronucleus Test), the conduction of an in-vivo Comet assay According to OECD TG 489 is proposed to evaluate potential mutagenic activity in vivo.
As discussed in IUCLID chapter 7.1, based on the high water solubility and the favorable octanol-water partition coefficient an absorption following ingestion is likely and signs of systemic toxicity are seen at very high doses (acute oral toxicity > 2000 mg/kg bw, repeated dose toxicity at 500/1000 mg/kg bw).
The test shall be conducted according to OECD TG 489 on rat and by the oral route (gavage). The following systemic and local organs shall be analysed: liver, glandular stomach, duodenum/jejunum and bone marrow.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion