Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: assessment based on available information
Adequacy of study:
key study
Study period:
nov-dec 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: toxicokinetic assessment
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): FAT 40854/A TE
- Physical state: Reddish-brown 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:
Results:
proposed factor for oral, dermal and inhalation absorption for risk assessment purposes

Any other information on results incl. tables

The hydrophilic character of FAT 40854/A TE (log Pow <-1.8) will limit this passive diffusion and although the water solubility is>500 g/L, the large molecular weight (ca 950 g/mol) will prevent passage through the aqueous pores. Furthermore, the ionization of FAT 40854/A TE will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall (1). It is therefore unlikely that FAT 40854/A TE will be absorbed to a high extent from the gastro-intestinal tract. For risk assessment purposes the oral absorption of FAT 40854/A TE is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor, as red staining of the faeces is observed while reddish discolouration of organs was restricted to the glandular mucosa of the stomach and Peyer’s patches of high dose animals.

Once absorbed, the relatively high molecular weight of FAT40854/A TE is not favourable for wide distribution. Also, the absence of coloured organs in the repeated dose toxicity study is indicative for a low potential for accumulation within the body. Based on the hydrophilic properties (log Pow <-1.8), the extracellular concentration may be higher than the intracellular concentration (1).

There are no data available providing direct information on respiratory absorption. The low vapour pressure <1.5 x 10-3 Pa) indicates that FAT40854/A TE is not available for inhalation as a vapour. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. The particle size distribution for FAT40854/A TE indicates, that the particles of FAT40854/A TE have the potential to be inhaled (<100 µm), of which a significant part may reach the thoracic region (<50 µm) and about 10% may reach the alveolar region (<15 µm) of the respiratory tract. Based on the high water solubility, FAT40854/A TE has the potential to diffuse readily into the mucus lining of the respiratory tract. Log Pow, molecular weight and ionization lower the potential for absorption. Therefore, for risk assessment purposes inhalatory absorption is expected to be less than the standard 100% and is set at 50%.

A solid has to dissolve into the surface moisture of the skin before uptake can begin. Although the water solubility for FAT40854/A TE is high (>500 g/L ), the hydrophilic property (log Pow<-1.8) of FAT40854/A TE is not favourable for penetration into the stratum corneum. According to the criteria given in the REACH guidance (2) 10% dermal absorption will be considered in case MW>500 and log Pow <-1 and >4, otherwise 100% dermal absorption should be used (1). As FAT40854/A TE meets these criteria for restricted dermal absorption, 10% dermal absorption is used for risk assessment purposes.

 

 

 REFERENCES

 

1.    Martinez, 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.,, 2001.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
For risk assessment purposes, the oral and dermal absorption for FAT 40854/A TE is set at 10%, and the absorption via inhalation is set at 50%.
Executive summary:

A toxicokinetic risk assessment for FAT 40854/A TE was made based on available physico-chemical properties of the substance, together with relevant toxicological information. based on all information available, for risk assessment purposes the oral and dermal absorption for FAT 40854 are set at 10%, and the absorption via inhalation is set at 50%. FAT 40854A/TE is considered to have low bioaccumulation potential.