Registration Dossier

Administrative data

basic toxicokinetics in vivo

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
no guideline followed

Results and discussion

Applicant's summary and conclusion

The water solubility of R507-2 is very low (<7 x 10E-5 g/l). Since in general a substances needs to be dissolved before it can be taken up from the gastro intestinal tract, it is unlikely that R507-2 will show a high systemic exposure after oral administration. Although small amount of particles might be taken up by pinocytosis, this absorption will be limited due to the absence of R507-2 particles in the nanometer size range. The absorption will furthermore be reduced by the relatively large molecular weight (553) of this substance limiting passage through biological membranes. In addition, ionization of R507-2 will impair the uptake since the compounds need to pass the lipid membranes in the gastrointestinal wall. The log Pow of R507-2 is not defined, but the solubility in n-octanol is low. Therefore, uptake by micellular solubilisation is considered low. For risk assessment purposes the oral absorption of R507-2 is set at 10%. The result of the toxicity studies do not provide reasons to deviate from this proposed oral absorbtion factor.

In the gastro-intestinal tract the diazo-bond might be reduced to form two primary amines (2). Absorbed R507-2 might undergo further metabolism (incl. aromatic hydroxylation and reduction of azo-bond) followed by conjugation (2). In view of the low water solubility of R507-2 (<7 x 10E-5 g/l) a low potantial for distribution through the human body is anticipated. Distribution into cells will be limited due to high molecular weight (553g/mol) of R507-2. Because of the reduced molecular weight after reduction of the diazo-bond, the conjugates will either be excreted via the bile or the urine.

Based on the particle size of R507-2 <100µm, which have a potential to be inhaled, are present. Particles wil predominantly settle in the nasopharyngeal region (particles with aerodynamic >1-5µm). The low water solubility of R507-2 indicates a potential for clearance by coughing/sneezing (nasopharyngeal region) or via the mucocillary mechanism (tracheobronchial region). Accumulation might occur in the alveolar region where phagocytosis is the main route for absorption and clearance. As the logPow is not defined for this substance, no assessment on the potential for absorption directly across the respiratory tract epithelium is possible. As it is unlikely that R507-2 will be absorbed significantly after inhalation via the lungs, for risk assessment purposes the inhalation absorption of R507-2 is set at 10% as a worst case assumption.

R507-2 being a solid with low water solubility (<1mg/L) has no real potential for dermal absorption. Since the logPow of this substance could not be determined , it can not be assessed whether any anticipated lipophylic character will influence dermal absorption. Although the criteria for 10% dermal absorption of R507-2 is proposed for risk assessment purposes based on its solid form, its low solubility in water and in n-octanol (<1.1 x 10E-3 g/l), and its high molecular weight. 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 R507-2 after dermal and inhalatory absorption.