Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
No data are available on effects after repeated dose exposure, or on effects on reproduction and development. This is related to the fact that based on data on analogue 1,4-H6XDI it is concluded that no suitable solvent or vehicle can be found to perform the study. The attempts for 1,4-H6XDI are reported in Charles River report 514834, attached in section 7.5.1. The included data indicate that 1,4-H6XDI self-reacts and/or reacts with hydrolysis/degradation products in aqueous media, forming a complex mixture of random, high molecular weight products. An attempt was made to perform a repeated dose study with undiluted substance (i.e. without the use of a vehicle), however it was concluded that this was not feasible due to irritating/corrosive effects in the stomach (report attached below). Since the test item was administered undiluted, it was assumed that similar effects on the stomach wall will be induced also at lower dose levels, possibly more restricted. However, accumulation of these local effects may occur at continuation of treatment and may result in similar severe toxicity in the animals as apparent in the current study but at a later stage. Therefore, it was considered unethical to administer the undiluted test item to animals in a repeated dose study. Moreover, the undiluted test item cannot be administered accurately at dose levels below 25 mg/kg, because dose volumes will be less than 5 µl per animal.
As adverse local effects were also seen after inhalation exposure and after dermal exposure in experiments with 1,3-H6XDI, performance of a repeated dose study via dermal or respiratory route was not considered ethical for the same reason as performing the repeated dose study via the oral route.
Finally, exposure via feed was considered, however it was considered not technically feasible to verify the dose levels via analytics. Due to the reactivity of the substance, it is expected to react with protein moieties in the feed. If such processes take place, the rats will be exposed to various forms of the reacted substance which will exclude unbiased conclusion on the NOAEL on the substance itself.

The results of a dose range finding study (based on which it is concluded that a repeated dose study with the undiluted substance is not possible) with 1,4-H6XDI and the results of the attempt to develop an analytical method for 1,4-H6XDI are attached in Section 7.5.1. The considerations to read across the data are included in the read across document, attached in Section 13.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion