Registration Dossier

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study planned
Study period:
Within 2 years after ECHA consent
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : Dibutyl itaconate

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 the endpoint repeated dose toxicity (90-days) oral route.
- Available non-GLP studies : there are no non-GLP studies available for the endpoint repeated dose toxicity (90-days) oral route.
- Historical human data : there are no historical human data that can be considered for this endpoint repeated dose toxicity (90-days) oral route.
- (Q)SAR : the use of QSARs models for the prediction of repeated dose toxicity in a regulatory context is limited due to the complexity of the systemic interactions and effects involved in repeated dose toxicity studies. This complexity is difficult to predict with computational tools. It is therefore not considered as a possible adaptation to testing.
- In vitro methods : currently, no available alternatives to animal testing are considered adequate to be used on their own for regulatory purposes for detecting toxicity after repeated exposure.
- Weight of evidence : there is no relevant information available that can be used in a WoE to cover the endpoint repeated dose toxicity (90-days) oral route for registration and classification purposes.
- Grouping and read-across : there are currently no structures known (and that also have reliable data on repeated dose toxicity 90-days) that can be used for grouping or read-across, and which is acceptable for registration and classification purposes.

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:
- The specific rules for adaptation from column 1 as given in column 2 are not met as no reliable chronic toxicity study is available, the substance is not classified as R48, a substance does not undergo immediate disintegration and the substance is not unreactive, insoluble and not inhalable and there isn't no evidence of absorption and no evidence of toxicity in a 28-day ‘limit test’.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- An Annex IX dossier requires performance of a 90 day repeated dose study, which will be performed after consent by ECHA. The registrant finds it unjustifiable from aninmal wellfare perspective to perform first a 28 day repeated dose study and then a 90 day study. The 90 day study will be combined with a screening study for development and reproduction toxicity (OECD 421 guideline).
Based on the data available, an oral 90-day repeated dose toxicity study is proposed. Using the oral route of exposure, higher dosing seems to be possible, to make sure that either the limit dose is tested or that the highest dose tested will result in an effect level, and subsequently systemic DNELs can be derived.

Data source

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
other: OECD 421
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage

Results and discussion

Applicant's summary and conclusion