Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
Before evaluating the present testing proposal, the registrant kindly asks ECHA to consider waiving possibilities according to section 1 of REACH Annex XI due to animal welfare.
In the available OECD 422, animals are dosed before and after gestation, so exposure during the relevant gestation days (organogenesis) as described in the OECD 414 study is secured. Dead pups and pups killed at day 13 post-partum, are carefully examined externally for gross abnormalities, pup weight, litter size and thyroid function is further determined in the OECD 422. In the present OECD 422, there were not any effects on the pups, no gross abnormalities were noted, up to the limit dose of 1000 mg/kg. Hence, it is highly unlikely that the substance is a developmental toxicant, and so, testing should be omitted due to animal welfare according to section 1 of REACH Annex XI (use of existing data).

NON-CONFIDENTIAL NAME OF SUBSTANCE: 1,1'-(methylenedi-4,1-phenylene)bis(1H-pyrrole-2,5-dione)
- Name of the substance on which testing is proposed to be carried out: 1,1'-(methylenedi-4,1-phenylene)bis(1H-pyrrole-2,5-dione)

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 is a developmental / reproductive screening study according to OECD TG 422 under GLP available. As stated above, in this study pregnant rats were dosed also within the stages of pregnancy which are critical for organ development. No substance-related effects have been observed, all NOAELs for general toxicity, reproductive and developmental toxicity were found to be 1000 mg/kg bw, the limit dose.
- Available non-GLP studies: None related to developmental toxicity (or reproductive toxicity)
- Historical human/control data: not available
- (Q)SAR: not available
- In vitro methods: not available / not suitable
- Weight of evidence: Only OECD 422 study available
- Grouping and read-across: No possible alternative structures available
- Substance-tailored exposure driven testing [if applicable]: not applicable/available
- Approaches in addition to above [if applicable]: not applicable
- Other reasons [if applicable]: 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:
Currently, the available data in strict terms is not totally adequate to assess the potential developmental toxicity of the registered substance. There is neither a developmental toxicity study of any kind in any species available, nor human data.
However, according to REACH Annex IX, the following is required:
Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414), unless either:…
— the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure.
As there is not any toxic effect observed in the available OECD 422 study up to 1000 mg/kg, this waiving possibility could be an option, but cannot be definitively confirmed by the strict terms of the REACH regulation.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]: none additional

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1'-(methylenedi-p-phenylene)bismaleimide
EC Number:
237-163-4
EC Name:
1,1'-(methylenedi-p-phenylene)bismaleimide
Cas Number:
13676-54-5
Molecular formula:
C21H14N2O4
IUPAC Name:
1,1'-(methylenedi-4,1-phenylene)bis(1H-pyrrole-2,5-dione)

Test animals

Species:
rat

Results and discussion

Applicant's summary and conclusion