Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remarks'
Remarks:
The reliability of this qualitative judgement is limited as it is predominantly based on available phys/chem data which are not always clearly defined for an UVCB substance. No experimental data on toxicokinetics are available.

Data source

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
This qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics follows the recommendations of ECHA (ECHA Endpoint specific guidance, Chapter R.7c; section R.7.12.2.1).
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
Name: Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. residues
Physical state: liquid
Appearance: brown liquid

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Mechanisms by which substances can be absorbed in the gastro-intestinal (GI) tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. As the test substance is miscible with water and has a mean molecular weight below 200, this passive diffusion will be the predominant mechanism for absorption in the GI tract. In addition, moderate octanol/water partition coefficient (logPow) values (between -1 and 4) are favourable for absorption by passive diffusion; as logPow values of 0.565 and <0.3 were obtained, uptake of several components in the test substance might be hampered. Ionized substances do not readily diffuse across biological membranes and the pKa is an important parameter to indicate ionization at a GI relevant pH. For UVCB substances this parameter can however not easily be defined. Following pKa values of individual components in the test substance it can be concluded that some ionization at the biologically relevant pH range might occur, thus hampering the uptake of these individual components. Following the above it can be concluded that the test substance will show a relatively high systemic exposure after oral administration. For risk assessment purposes, 50 to 100% oral absorption of the test substance is proposed. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

The test substance being a water soluble liquid will readily dissolve into the mucus lining the respiratory tract. Lipophilic substances (log P >0) would then have the potential to be absorbed directly across the respiratory tract epithelium. Hydrophilic substances might be absorbed through aqueous pores (for substances with molecular weights below around 200 as the test substance) or be retained in the mucus and transported out of the respiratory tract, subsequently swallowed and becoming available for oral absorption. In view of its low, but partly unbounded logPow value (0.565 and <0.3) both processes will be relevant for the test substance components. For risk assessment purposes the inhalation absorption of the test substance is set at 100%.

The test substance is a water soluble liquid and as such readily available for absorption through the skin. As the test substance is miscible with water and has a relatively low logPo/w (0.565 and <0.3) it may contain components which are too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake might thus be slowed. With a molecular mass below 500 and logPow in the range [-1, 4], the data meet the criteria for 100% dermal absorption as given in the ECHA Endpoint Specific Guidance 7.c for the implementation of REACH (R.7.12 ¿Guidance on Toxicokinetics¿). The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor of 100%.

The above absorption factors should be treated with care as one of the driving parameters, the octanol/water partition coefficient, refers to pH 12. At biological relevant pH it is expected that a significant amount of the substance will be in its ionized form and thus in general being more water soluble. It is thus anticipated that the test substance has a more hydrophilic character than is concluded from the octanol/water partition coefficient determined at pH 12.
Details on distribution in tissues:
Once absorbed, the water soluble test substance is expected to widely distribute through the body. Following its logPow (0.565 and <0.3) the test substance may contain components which are too hydrophilic to distribute into cells, as well as components which will distribute into cells resulting in an intracellular concentration higher than the extracellular concentration.
Details on excretion:
The test substance is expected to undergo Phase I and Phase II metabolic reactions. Based on the high water solubility and relatively low molecular weight, the test substance and its conjugation products are expected to be mainly excreted in the urine.

Metabolite characterisation studies

Metabolites identified:
not specified

Any other information on results incl. tables

As the test substance is an UVCB substance, not all physico/chemical properties are clearly defined but reflect the properties of a group of substances. The toxicokinetic assessment is thus indicative only as single substances within the UVCB might have significant different physico/chemical properties.

Applicant's summary and conclusion

Conclusions:
A qualitative judgement on the toxicokinetic behaviour was performed based on physico-chemical characteristics. The test substance is expected to be well absorbed via the oral, dermal and inhaltion route. Absorption factors of 50-100% for oral and 100% for inhalation and dermal absorption are proposed. These absorption factors should be treated with care as one of the driving physico/chemical parameters (Pow) refers to a pH (12) outside the biologically relevant range. The substance is anticipated to be widely distributed through the body, metabolised and excreted mainly in the urine.