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Description of key information

A toxicokinetic assessment is available which describes the percentage absorption after oral, inhalation and dermal exposure to 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]propane-1,3-diyl bis(2-ethylhexanoate) (EC # 230-743-8) (Hatcol 3346) for risk assessment purposes. The assessment is based on physico-chemical properties of Hatcol 3346 and available experimental data (partially read-across).

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

The water solubility of the substance is very low («1 mg/L). Since in general a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract, it seems unlikely that the substance will show a high systemic exposure after oral administration (1). However, its highly lipophilic character (log Po/w > 6) indicates that uptake by micellular solubilisation may be of particular importance. For risk assessment purposes oral absorption is set at 100%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

 

Once absorbed, distribution of the substance throughout the body will be limited by low water solubility. Intracellularcentration of the substance is expected to be higher than extracellular concentration, based on its lipophilic character. The concentration in breast milk may be higher than in blood/plasma. As a lipophilic substance, the substance may concentrate in adipose tissue and depending on the conditions of exposure may accumulate. Daily exposure to the substance may result in a build-up in the body. Once exposure stops, the concentration in the body will decline at a rate determined by the half-life of the substance. the substance may be conjugated and excreted via the bile and may also undergo enterohepatic recycling (circulation of bile from the liver, where it is produced, to the small intestine, where it aids in digestion of fats and other substances, back to the liver) which will prolong its biological half-life (2).

 

the substance has low volatility, i.e., very low vapour pressure (3.06´10-7Pa) and a high boiling point (415°C), and is therefore unlikely to be available for inhalation as a vapour. However, any the substance reaching the respiratory epithelium may be taken up by micellular solubilisation, because of its highly lipophilic character (log Po/w > 6) and low water solubility. For risk assessment purposes the inhalation absorption of the substance is set at 100%.

 

In view of its highly lipophilic character (log Po/w > 6),and the low water solubility («1 mg/L), the rate of transfer of the substance between the stratum corneum and the epidermis will be slow, and uptake into the stratum corneum itself may be slow. Any substance persisting in the stratum corneum may eventually be cleared as the stratum corneum is sloughed off. A dermal absorption of 10% is proposed for risk assessment purposes.

Absorption rates are justified as follows:

Inhalation

No specific studies on inhalation of the substance itself are available.  The substance demonstrated no harmful effects in the toxicity studies, so no conclusions on whether it is absorbed or not can be drawn.  100% inhalation absorption default is assumed in accordance with the guidance.

Dermal

Chapter R.7c: Endpoint specific guidance details as follows:

Substances that can potentially be taken up across the skin include gases and vapours, liquids and particulates. A tiered approach for the estimation of skin absorption has been proposed within a risk assessment framework (EC, 2007): Initially, basic physico-chemical information should be taken into account, i. e. molecular mass and lipophilicity (log P). Following, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen (de Heer et al., 1999).

The substance has the following parameters:

MW range of 640.931;

Water solubility: < 0.4 µg/l.

Log Kow: 6.7.

Taking account of the details within Table R.7.12—3 Interpretation of data regarding dermal absorption, a dermal absorption of 10% is proposed, based on the guidance.

Oral

Chapter R.7c: Endpoint specific guidance details provides various parameters for review when deciding potential oral absorption. Specifically, Table R.7.12—1 Interpretation of data regarding oral/GI absorption provides for various parameters for consideration.

Effects were not noted within the oral dosing studies on the substance, so no conclusions on whether it is absorbed or not can be drawn. However, consideration of Table R.7.12—1 indicates that moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (log P >4), particularly those that are poorly soluble in water (1 mg/l or less) that would otherwise be poorly absorbed. Given that the substance has a water solubility of < 0.4 µg/l. and Log Kow of 6.7, an oral absorption of 100% is proposed for the purposes of assessment as a worst case.