Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
October 23, 2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.
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.
GLP compliance:
no
Type:
absorption
Results:
For risk assessment purposes, 50% is used for oral and dermal absorption, 100% for inhalation absorption.
Conclusions:
Interpretation of results (migrated information): other: low bioaccumulation potential based on theoretical assessment.
FDCA has a low bioaccumulation potential based on theoretical assessment.

Description of key information

A toxicokinetic assessment was performed based on the available data of the substance. 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

A substance can enter the body via the gastrointestinal tract, the lungs, and the skin. To determine the absorption rate, the different routes are assessed individually. In general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration. The low molecular weight of FDCA (approximately 156) favors uptake via passive diffusion. FDCA is slightly soluble in water (0.899 g/L), therefore the substance will dissolve into the gastrointestinal fluids to some extent and can potentially be taken up. FDCA contains two ionisable carboxylgroups, and it is therefore expected to ionize as soon as it dissolves in the fluids of the gastro-intestinal tract. It is generally assumed that ionized substances do not readily diffuse across biological membranes, although the absorption of ionic substances (i.e. acids and bases) is influenced by the varying pH of the GI tract. This is also reflected in the Pow, which varies at different pH values: at pH 1.9, a log Pow of 0.56 was measured, which decreases to -1.43 at neutral pH. This indicates that the Pow will vary at different sites of the gastrointestinal tract. At neutral pH, the substance will be more hydrophilic, which will hamper passive diffusion. At lower pH, the log Pow is expected to be moderate which is favourable for absorption by passive diffusion. Although its low molecular weight and moderate Pow at low pH favour passive absorption, its hydrophilicity at neutral pH, its low water solubility, the size of the particles and the ionic dissociation are expected to hamper optimal uptake, therefore, for risk assessment purposes oral absorption of FDCA is set at 50%. The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor. Once absorbed, wide distribution of the substance throughout the body is expected to be limited based on its low water solubility. Absorbed FDCA is most likely excreted via urine. Based on its moderate to low partition coefficient -1.43 to 0.56), it is very unlikely that FDCA will accumulate in adipose tissue. The low vapour pressure (5.6*10-10 Pa at 25°C) indicates that it is not likely that FDCA will reach the nasopharyncheal region or subsequently the tracheo/bronchial/pulmonary region via inhalation of vapour. The mean particle size is above 100 μm, with 50% below 439 μm and 10% of the particles smaller than 164 μm. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. For FDCA, this fraction is about 4.66%. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (for FDCA these fractions were found to be approximately 1.9% and 0.4% respectively). However, once FDCA reaches the tracheobronchial region, it is likely to dissolve within the mucus lining the respiratory tract and to get absorbed. Based on the above data, for risk assessment purposes the inhalation absorption of FDCA is set at 100%.

FDCA is a powder. When it comes in contact with the skin without additional water, uptake will be limited. However, it may dissolve into the surface moisture of the skin. The first layer of the skin, the stratum corneum, is a barrier for hydrophilic compounds. FDCA has a moderate to low log Pow. Since the pH of the skin is in the acidic range (between pH 4.0 to 7.0), which means that the Pow of the substance will be above 0 and is likely to be sufficiently lipophilic to cross the stratum corneum. However, as for oral absorption also for skin absorption the ionisable structure might negatively influence adsorption. According to the criteria given in the REACH Guidance, 10% dermal absorption will be considered in case MW >500 andlog Pow <-1 or >4, otherwise 100% dermal absorption should be used. As the physical/chemical properties of FDCA do not meet the criteria for limited dermal absorption (MW 156 and log Pow between -1.43 and 0.56 at physiological pH range), for risk assessment purposes dermal absorption should be set at 100%. However, as it is generally accepted that dermal absorption does not exceed oral absorption, 50% dermal absorption of FDCA is considered a more realistic dermal absorption factor for risk assessment purposes. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.