Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: assessment based on available information
Adequacy of study:
key study
Study period:
December 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non GLP-assessment report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Objective of study:
other: toxikocinetic assessment
Principles of method if other than guideline:
No guidelines required.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Radiolabelling:
no

Test animals

Species:
other: none

Administration / exposure

Route of administration:
other: oral, dermal and inhalation
Vehicle:
other: not applicable
Details on exposure:
see assessment

Results and discussion

Main ADME results
Type:
other: see conclusions

Applicant's summary and conclusion

Conclusions:
Low bioaccumulation potential
For risk assessment purposes, the oral and dermal absorption for S-10793 are set at 50% while the absorption via inhalation is set at 100%.
Executive summary:

The relatively low molecular weight of S-10793 is favourable for absorption. The good water solubility (> 0.5 g/mL) is also favorable for uptake from the gastro-intestinal tract, as in general a compound needs to be dissolved before it can be taken up (1). The hydrophilic character of S-10793 (log Pow= -1.64) will limit passive diffusion, and the ionization of S-10793 will further impair the uptake, since compounds need to pass the lipid membranes in the gastro-intestinal tract (1). Based on its physical/chemical properties, for risk assessment purposes an oral absorption factor of 50% is proposed for S-10793.

Some distribution of the substance throughout the body is expected based on its relatively low molecular weight, good water solubility and its ionized form. Based on its hydrophilic character, the accumulative potential for S-10793 is considered to be low. Absorbed S-10793 might undergo biotransformation (3). Because of the relatively low molecular weight of S-10793, the biotransformation products will be either excreted via the bile (high molecular weight conjugates) or the urine (small biotransformation products) (2).

In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Based on the information on particle size of S-10793, particles <100 µm which have the potential to be inhaled are present, as particle size ranges from 10 to 1000 microns. For the particles that have the potential to be inhaled, they will be settled in the nasopharyngeal region (larger particles <100 µm), thoracic region (particles <50 µm) or alveolar region (particles <15 µm). Part of the deposits in the nasopharyngeal region will be coughed or sneezed out of the body, or swallowed, while a part will dissolve into the mucus lining of the respiratory tract epithelium. For risk assessment purposes, the inhalation absorption of S-10793 is set at 100% as a worst case assumption.

S-10793 is a substance that is well soluble in water, and therefore has the potential to dissolve in the surface moisture of the skin and partition from the stratum corneum into the epidermis. The hydrophilic character of the substance (log Pow=-1.64) indicates, however, that crossing the lipid rich environment of the stratum corneum will be impaired. However, the data are insufficient to meet the criteria for 10% dermal absorption as given in the endpoint specific guidance for the implementation in REACH (MW > 500, and log Pow< -1 or > 4) (2), and a dermal absorption of S-10793 of 100% should be considered for risk assessment purposes. However, as it is generally accepted that dermal absorption does not exceed oral absorption, 50% dermal absorption is considered to be a more realistic dermal absorption factor.

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of S-10793 after dermal and inhalation absorption.

References: 1). Martinez MN, Amidon GL. Mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620-43. 2). Guidance for the implementation of REACH. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008. 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.