Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: theoretical approach
Adequacy of study:
key study
Study period:
2009-03-16
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is based on expert judgment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Objective of study:
other: toxicokinetic assessment
GLP compliance:
no
Remarks:
not applicable

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Y-513
- Purity test date: no data
- Lot/batch No.: F-1570
- Expiration date of the lot/batch: 19 February 2013
- Stability under test conditions: stable
- Storage condition of test material: At room temperature in the dark

Results and discussion

Preliminary studies:
See below

Any other information on results incl. tables

The water solubility of the powder Y-513 is very low (<0.36 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 Y-513 will show a high systemic exposure after oral administration. The absorption will furthermore be lowered by the relatively large molecular weight (657.55g/mol, component A; 723.58 - 2194.71, component B) of this substance limiting the passage through biological membranes. The presence of a sulphonate group in component B will also impair absorption as ionised substances do not easily pass the GI wall. Although the particles of the powder are not fairly large (MMAD 30.615 µm), the number of particles in the nanometer size range is low and uptake by pinocytosis therefore low. Its highly lipophilic character (logPow > 6.5) indicates that uptake by micellular solubilisation may be of particular importance. For risk assessment purposes the oral absorption of Y-513 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 and reduction of the azo-bond to produce two primary amines may take place. Absorbed Y-513 might undergo aromatic hydroxylation and conjugation (1). Significant distribution of the substance throughout the body is not expected based on its relatively high molecular weight and low water solubility. Because of the reduced molecular weight after the potential cleaving of the amide-bond and azo-bond, the conjugates might either be excreted via the bile or the urine.

Based on the particle size of Y-513 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), although those reaching the tracheobronchial or pulmonary region are also present (2% < 1 μm and 16% < 5 μm).The low water solubility of Y-513 indicates a potential for accumulation, while its lypophilic character (logPow > 6.5) indicates the potential for absorption directly across the respiratory tract epithelium. For risk assessment purposes the inhalation absorption of Y-513 is set at 100% as a worst case assumption.

Y-513 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 Y-513 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 Y-513 after dermal and inhalatory absorption.

REFERENCES

1. A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics., McGraw-Hill,New York, 2001

2. ECB EU Technical Guidance Document on Risk Assessment, 2003

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
For risk assessment purposes the following absorption factors were derived:
oral absorption factor: 10%
dermal absorption factor: 10%
inhalation absorption factor: 100%