A mixture of: 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea; 3-cyclohexyl-1-(4-(4-(3-octadecylureido)benzyl)phenyl)urea; 3,3'-dioctadecyl-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

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

The water solubility of MDI/CHA/ODA is very low (<1 mg/L) and the particles of the powder are relatively large (MMAD: 212 µm). 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/ODA will show a high systemic exposure after oral administration. The absorption will furthermore be lowered by the relatively large molecular weight (618 g/mol) of this substance limiting the passage through biological membranes. Its highly lipophilic character (logPow = 13.5) indicates that uptake by micellular solubilisation may be of particular importance. For risk assessment purposes the oral absorption of MDI/CHA/ODA 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/ODA 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/ODA particles < 100μm, which have a potential to be inhaled, are present. Particles will predominantly settle in the nasopharyngeal region (particles with aerodynamic diameter > 1-5 μm), while those reaching thetracheobronchial or pulmonary region will be limited (no particles < 1 μm and 1% < 5 μm).The low water solubility of MDI/CHA/ODA indicates a potential for accumulation, while its lypophilic character (logPow = 13.5) indicates the potential for absorption directly across the respiratory tract epithelium. For risk assessment purposes the inhalation absorption of MDI/CHA/ODA is set at 100% as a worst case assumption.

MDI/CHA/ODA being a solid with a relatively high molecular weight has no real potential for dermal absorption. Furthermore, its low water solubility and highly lipophilic character do not facilitate dermal absorption. As the criteria for 10% dermal absorption as given in the TGD (2) (MW > 500 and logPow > 4) are met, 10% dermal absorption of MDI/CHA/ODA is proposed for risk assessment purposes. 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/ODA after dermal and inhalatory absorption.