Registration Dossier

Administrative data

Endpoint:
in vivo mammalian somatic cell study: gene mutation
Type of information:
experimental study planned
Study period:
experimental study planned (testing proposal)
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Reaction mass of N-butylphthalimide and N-sec-butylphthalimide and N-propylphthalimide

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 for this substance covering the endpoint of gene mutation in vivo
- Available non-GLP studies: There are no non-GLP studies available for this substance covering the endpoint of gene mutation in vivo
- Historical human data: There are no historical human data available on gene mutation for the substance.
- (Q)SAR: There is no valid (Q)SAR model available to address gene mutation in vivo and which outcome would be reliable enough to rule out the concern raised from an In Vitro Mammalian Chromosome Aberration Test (ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance).
All three components of Reaction mass of N-butylphthalimide and N-sec-butylphthalimide and N-propylphthalimide are included in the annex III list:
N-butylphthalimide CAS 1515-72-6: Suspected carcinogen: ISS Carcinogenicity model in VEGA (Q)SAR platform predicts that the chemical is Carcinogen (moderate reliability)
N-sec-butylphthalimide CAS 10108-61-9: Suspected carcinogen: ISS Carcinogenicity model in VEGA (Q)SAR platform predicts that the chemical is Carcinogen (moderate reliability)
N-propylphthalimide CAS 5323-50-2: Suspected carcinogen: ISS Carcinogenicity model in VEGA (Q)SAR platform predicts that the chemical is Carcinogen (moderate reliability)

- In vitro methods:
• An in vitro bacterial reverse mutation assay (AMES test OECD 471) was conducted under GLP with the test item and did not indicate a potential for gene mutation on the bacterial strains tested (preliminary results, study in progress).
• An In Vitro Mammalian Chromosome Aberration Test (OECD 473) was conducted under GLP. The test item Reaction mass of N-butylphthalimide and N-propylphthalimide and N-sec-butylphthalimide tested up to cytotoxic concentrations, with and without mammalian metabolic activation system, induced structural chromosome aberrations and endoreduplication in Chinese Hamster lung cells. Thus, the test item is considered clastogenic in this system (preliminary results, study in progress).
- Weight of evidence: There is no data available which is sufficient for a weight of evidence approach.
- Grouping and read-across: There is no data available on the three substances that are the components of the test item and there are no substances which apply for read across addressing gene mutation in vivo in this case.

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:

Based on ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R 7a and according to the requirements of Annexes IX and X, if there is a positive result in any of the in vitro studies from Annex VII or VIII and there are no appropriate results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study should be proposed to ascertain if this potential can be expressed in vivo.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
Details on study design / methodology proposed:

Based on the available in vitro data, an alkaline in vivo Comet assay (OECD 489) is proposed to assess the mutagenic properties of the test substance in vivo.
The test substance is proposed to be administered orally by gavage to rats. Doses will be based on data available for acute oral toxicity study (OECD 423) and a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422). Organs proposed to be evaluated are the stomach and the liver, as the site of first contact after oral administration and the site of metabolism, respectively. Moreover, these were the organs that presented adverse effects on the acute oral toxicity study. The test item will be administered at least on two consecutive days. The tissues are proposed to be evaluated after 2-6 h after the last administration. Since the available data did not demonstrate relevant differences between males and females, the use of males only is proposed.

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)
Version / remarks:
29 July 2016

Results and discussion

Applicant's summary and conclusion