Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Theoretical assessment taking all currently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: 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
Deviations:
not applicable
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): L579
- Substance type: white powder

Results and discussion

Main ADME results
Type:
absorption
Results:
For risk assessment purposes: oral absorption 10%, inhalation absorption 100% and dermal absorption 10%

Any other information on results incl. tables

TOXICOKINETIC ASSESSMENT

L579 is considered to be insoluble in water. In general a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract. Thus, the water insolubility can be considered a potentially rate-limiting factor for the absorption of the compound. The low molecular weight of this substance is favourable for absorption (3). After oral administration, it is unlikely that L579 will show a high systemic exposure (1). In the presence of food and bile salts some systemic exposure might be possible. For risk assessment purposes the oral absorption of L579 is set at 10% as a worst case assumption.

Once absorbed, distribution of L579 throughout the body will be limited due to its water insolubility (3).

Based on the particle size of L579 (98.21% < 10 μm), particles < 100 μm which have a potential to be inhaled, are present. Particles with an aerodynamic diameter below 50 μm may reach the thoracic regions, whereas particles with an aerodynamic diameter below 15 μm may reach the alveolar region of the respiratory tract. The water insolubility of L579 indicates that L579 will not dissolve into the mucus lining of the respiratory tract and the deposits in the nasopharyngeal region will likely to be coughed or sneezed out of the body, or swallowed. As most of the particles have a size < 10 μm (98.21%), the fraction that will reach the alveolar region of the respiratory tract will be available for absorption. For risk assessment purposes the inhalation absorption of L579 is set at 100%.

L579 being a solid which is considered to be insoluble in water has no real potential for dermal absorption. Its molecular weight above 100 does not favour dermal absorption. Based on these physical/chemical properties of L579, dermal absorption is considered to be low. Although the criteria for 10% dermal absorption as given in the REACH guidance (2) (MW > 500 and log Pow < -1 or > 4) are not met as data on log Pow are not available for inorganic substances, 100% dermal absorption is considered not relevant for L579 as it is generally accepted that dermal absorption does not exceed oral absorption. For risk assessment purposes therefore, 10% dermal absorption of L579 as default value is considered to be appropriate.

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of L579 after 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. McGraw-Hill, New York, 2001.

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%