6H-Furo[2',3':4,5]oxazolo[3,2-a]pyrimidin-6-one, 2,3,3a,9a-tetrahydro-3-hydroxy-2-(hydroxymethyl)-7-methyl-, (2S,3S,3aR,9aS)-

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: theoretical approach

Adequacy of study:

other information

Study period:

January 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

The compiler evaluated the substance based on available studies.

Objective of study:

other: toxicokinetic assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

The compiler evaluated the substance based on available studies.

GLP compliance:

not specified

Remarks:

not applicable

Radiolabelling:

other: not applicable

Preliminary studies:

See below

Key result

Test no.:

#1

Observation:

not determined

Key result

Test no.:

#1

Toxicokinetic parameters:

other: not applicable

The relatively low molecular weight of Anhydrothymidine (240.2) and high water solubility are favourable for oral absorption. In general, ionisation may impair uptake, since compounds need to pass the lipid membranes in the gastrointestinal wall (1). Since there is no pKa in the logarithm range of 1-12 (calculation), ionisation is not expected. However, log Kow is not favourable for passive diffussion. It is therefore unlikely that Anhydrothymidine will be completely absorbed from the gastrointestinal tract. For risk assessment purposes the oral absorption of Anhydrothymidine is therefore set at 50% as a worst case assumption for route-to-route extrapolation. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Although the relatively small molecular weight is indicative for wide distribution and high water solubility support diffussion through aqueous channels and pores, the log Pow < 0 (-1.97) is not indicative for distribution into cells. The physical/chemical characteristics are not indicative for bioaccumulation.

 

Absorbed Anhydrothymidine might undergo Phase I and Phase II biotransformation (2). Because of the high water solubility and the relatively low molecular weight, Anhydrothymidine will be excreted mainly via urine, and possibly also via the bile.

 

Based on the particle size of Anhydrothymidine, particles with an aerodynamic diameter < 100µm which have the potential to be inhaled, are present (59.71%). Particles with an aerodynamic diameter below 1- 5 µm (0.97% - 7.24%) will settle in the tracheobranchial or pulmonary regions, whereas particles with an aerodynamic diameter above 1 – 5 µm mainly settle in the nasopharyngeal region. The high water solubility of Anhydrothymidine indicates that it will disolve into the mucus lining of the respiratory tract and transported out of the respiratory tract. The log Pow < 0 indicates a low potential for absorption directly across the respiratory tract epithelium. For risk assessment purposes the inhalation absorption of Anhydrothymidine is set at 50% as a worst case assumption.

 

Anhydrothymidine being a water soluble solid with a moderate molecular weight of 240.2 g/mol has the potential for dermal absorption. However, its high water solubility (797 g/l) and log Pow below -1 (-1.97) do not favour dermal absorption. The physical/chemical parameters do not meet the criteria for 10% dermal absorption as given in the TGD (3) (MW > 500 and log Pow < -1), and therefore 100% dermal absorption as default value has to be taken. It is, however, generally accepted that dermal absorption is lower compared to oral absorption. The 100% dermal absorption derived from physical/chemical properties of the substance should therefore be considered a worst case assumption and for risk assessment purposes a lower dermal absorption value might be more appropriate.

 

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

References:

1.Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43.

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

3. 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

Conclusions:

Interpretation of results: bioaccumulation potential cannot be judged based on study results
For risk assessment purposes the following absorption factors were derived:
oral absorption factor: 50%
dermal absorption factor: 100%
inhalation absorption factor: 50%

Description of key information

Interpretation of results: bioaccumulation potential cannot be judged based on study results

For risk assessment purposes the following absorption factors were derived:

oral absorption factor: 50%

dermal absorption factor: 100%

inhalation absorption factor: 50%

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

50