Registration Dossier

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
The repeated dose 28-day oral toxicity study in rats (OECD TG 407) and 90-day repeated dose toxicity studies (OECD TG 408 and OECD TG 411) provide information on histopathological changes of reproductive organs, estrous cycle and spermatogenesis for the first generation. However they do not provide information on functional fertility or other aspects of reproductive toxicity. Information from the pre-natal developmental toxicity study (OECD TG 414) in rats regarding sexual function and fertility is limited to the maintenance of the pregnancy from implantation up to close to the parturition. More information is required regarding hazardous properties due to pre/peri/postnatal exposure manifested during the postnatal development including sexual maturation and histopathological integrity of the reproductive organs at adulthood. An extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension), is planned to fulfill this endpoint.

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- OTNE

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Please refer to justification on study design

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS:

- Premating exposure duration for parental (P0) animals: minimally 2-week pre-mating (in accordance with OECD TG 443).
- Basis for dose level selection: the dose levels will be based on toxic effects observed in previous in vivo studies (in accordance with OECD TG 443). The highest dose will be chosen with the aim to induce some systemic toxicity, but not death or severe suffering of the animals.
- Exclusion of extension of Cohort 1B: The conditions to include the extension of Cohort 1B are currently not met.
- Termination time for F2: not applicable, as cohort 1B will not be extended
- Exclusion of developmental neurotoxicity Cohorts 2A and 2B: The available in vivo dataset for OTNE does not indicate specific concerns on neurotoxicity after repeated exposure (for details please refer to in Chapter 7.9.1 of this dossier wich contains an evaluation of neurotoxicity findings in the available 28-day and 90-day repeated dose toxicity studies for OTNE). The structural analogue AETT suggested by ECHA does not give a cause for concern due to the difference of metabolic pathways of OTNE and AETT, as the neurotoxic metabolite of AETT, a gamma-diketone, is not generated during the metabolisation of OTNE (Cammer, 1980).
- Exclusion of developmental immunotoxicity Cohort 3: No triggers described in Column 2 of Section 8.7.3., Annex X and further elaborated in ECHA Guidance on Information Requirements and Chemical Safety Assessment R.7a, chapter R.7.6 (version 4.1, October 2015). have been identified for the inclusion of Cohort 3 (developmental immunotoxicity).
- Route of administration: Oral, as this is a relevant and possible route of human exposure and a suitable route of administration as specified in OECD TG 443.



Results and discussion

Applicant's summary and conclusion