trans-1,4-bis(isocyanatomethyl)cyclohexane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

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 no suitable solvent or vehicle could be found to perform the study. The attempts 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 in section 7.5.1). 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 substance analogue 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) and the results of the attempt to develop an analytical method are attached in section 7.5.1.

Cross-reference

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

short-term repeated dose toxicity: oral

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 no suitable solvent or vehicle could be found to perform the study. The attempts are reported in Charles River report 514834, attached below. 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 substance analogue 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) and the results of the attempt to develop an analytical method are attached.