3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea

Endpoint summary

Description of key information

A toxicokinetic assessment was performed based on the available data of the substance. For risk assessment purposes, 10% is used for oral and dermal absorption, 100% for inhalation absorption. 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

The water solubility of MDI/CHA is very low (<1 mg/L).Since in general a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract, it is unlikely that MDI/CHA will show a high systemic exposure after oral administration. The absorption will furthermore be lowered by the relatively large molecular weight (448 g/mol) of this substance limiting the passage through biological membranes. Its lipophilic character indicates that uptake by micellular solubilisation may be of importance. For risk assessment purposes the oral absorption of MDI/CHA is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

In the gastro-intestinal tract the amide-bond might be cleaved by amidases.Absorbed MDI/CHA might undergo aliphatic and aromatic hydroxylation and conjugation (1). Because of the reduced molecular weight after cleaving the amide-bond, the conjugates will either be excreted via the bile or the

urine.

Based on the particle size of MDI/CHA, particles < 100 μm which have a potential to be inhaled, are present. Particles will either settle in the

nasopharyngeal region (particles with aerodynamic diameter > 1-5 μm) or in the tracheobronchial or pulmonary region (particles with aerodynamic diameter < 1-5 μm). The low water solubility of MDI/CHA indicates a potential for accumulation, while its lypophilic character indicates the potential for absorption directly across the respiratory tract epithelium. For risk assessment purposes the inhalation absorption of MDI/CHA is set at 100% as a worst case assumption.

MDI/CHA being a solid with a relatively high molecular weight has no real potential for dermal absorption. Furthermore, its low water solubility and lipophilic character do not facilitate dermal absorption. Although the criteria for 10% dermal absorption as given in the TGD (MW > 500 and logPow > 4) are not met, 10% dermal absorption of MDI/CHA is proposed for risk assessment purposes in view of its solid form, low water solubility and as it is generally accepted that dermal absorption is equal or lower compared to oral absorption for non-irritating substances. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of MDI/CHA after dermal and inhalatory absorption.