Guerbet alcohols, C24-26, branched and cyclic

Endpoint summary

Additional information

No experimental data on toxicokinetics, absorption, distribution, metabolism and excretion (ADME) are available for the UVCB substance “Guerbet alcohols, C24-26, branched and linear”. In order to assess its toxicokinetic behavior the physical-chemical properties and the available toxicity data are evaluated.

Absorption

In general, absorption of a substance is possible when the substance is able to cross biological membranes. The absorption potential of a substance is mainly determined by its physicochemical properties. In case where non transport mechanisms are involved, this process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight. In this regard, substances which are sufficiently soluble in water, with molecular weights (MW) below 500 g/mol and Log P values between -1 and 4 are favorable for absorption. Generally, the absorption of substances which are surfactants or irritants may be enhanced, because of damage to cell membranes.

“Guerbet alcohols, C24-26, branched and linear” was found to be slightly irritating to the skin and eyes in rabbits in in vivo studies according to OECD Guideline 404 and 405. Thus, the possibility of an enhanced absorption due to damaged cell membranes is somewhat increased.

Oral absorption

“Guerbet alcohols, C24-26, branched and linear” has a molecular weight of ≥ 354.65 ≤ 382.71, which indicates a potential for oral absorption. However, due to its high log P value of > 6 and its very low water solubility of far below 0.5 mg/L, absorption may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

In an acute oral toxicity study in rats according to OECD 423 (acute toxic class method), no signs of toxicity were observed following administration of 2000 mg/kg bw of “Guerbet alcohols, C24-26, branched and linear”. Additionally, no treatment-related adverse effects in rats were observed in a Repeated Dose 90-day Oral Toxicity Study according to OECD 408 after treatment of up to 1000 mg/kg bw/day of “Guerbet alcohols, C24-26, branched and linear”. These results indicate either a relative non-toxicity of the substance or support the assumption that the absorption via gastrointestinal tract is limited.

Based on physical chemical parameters and the available data, a low oral absorption rate can be estimated for “Guerbet alcohols, C24-26, branched and linear”, predominantly due to the insolubility of the substance in water and its high log P value.

Dermal absorption

In order to cross the skin, a substance must first penetrate into the stratum corneum and may subsequently reach the viable epidermis and the dermis where the vascular network is located. The penetration of a substance into deeper skin layers and reaching the systemic circulation enables the substance to become systemically available.

Molecular weight and the lipophilicity (log P) are decisive parameters influencing dermal absorption. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the lower layers of the epidermis are most resistant to penetration by highly lipophilic compounds. A molecular weight of less than 100 favors dermal uptake, whereas substances with a molecular weight of above 500 may be too large. Furthermore, the substance must be sufficiently soluble in water to partition form the stratum corneum into deeper layers of the epidermis. If water solubility is below 1 mg/L dermal uptake is likely to be low.

“Guerbet alcohols, C24-26, branched and linear” is a liquid. Therefore, it is potentially taken up more readily than dry particulates. The evaporation after skin contact does not need to be regarded due the substance’ high boiling point and low vapour pressure; hence it can be assumed that it will remain on the skin until mechanical removal. With a molecular weight of ≥ 354.65 ≤ 382.71 dermal absorption is generally possible. Nevertheless, due to a high Log P value of > 6 and the fact that the substance is virtually insoluble in water, the rate transfer between the stratum corneum and the viable epidermis and the uptake into the stratum corneum itself is expected to be low. However, skin penetration might be enhanced due to the substance' slight irritating potential to skin and eyes.

Nevertheless, an available acute dermal toxicity study according to OECD 402 revealed no toxic effect of “Guerbet alcohols, C24-26, branched and linear” in rats following dermal exposure over a 24 hour period at a level of 2000 mg/kg. This result indicates either a relative non-toxicity of “Guerbet alcohols, C24-26, branched and linear” or supports the assumption that the absorption via skin is limited based on physical chemical properties.

Absorption by inhalation

Absorption by inhalation is known to be favorable for small water-soluble substances with high volatility. Substances with low volatility have a vapor pressure of less than 0.5 kPa or a boiling point above 150 °C.

“Guerbet alcohols, C24-26, branched and linear” is a liquid with a low vapor pressure of 0.007 kPa at 20°C and a boiling point of > 370°C at 101 kPa and therefore not considered to be available for inhalation.

Distribution and accumulative potential

Taking into account the high lipophilicity (Log P value > 6) and the poor water solubility (< 0.5 mg/L), the absolute systemic bioavailability of absorbed “Guerbet alcohols, C24-26, branched and linear” is rather low.

Due to its lipophilic properties, absorbed “Guerbet alcohols, C24-26, branched and linear” can bind to plasma proteins; therefore, a theoretical bioaccumulation in fatty tissue cannot totally be excluded. Nevertheless, as the substance is expected to be extensively metabolized, tissue retention is unlikely.

With regard to skin contact, the highly lipophilic substance might penetrate, albeit slowly, the lipid rich stratum corneum, but is not well absorbed systemically. As the stratum corneum is sloughed off, the persistence is clearly limited.

Metabolism

As first step of the biotransformation of resorbed “Guerbet alcohols, C24-26, branched and linear” mainly the oxidation of the alcohol to the corresponding carboxylic acid by phase I enzymes is expected. The carboxylic acid is then expected to be glucoronised by the phase II enzymes UDP-glucuronosyltransferases to the ester glucuronides and excreted. Only minor parts of Guerbet alcohols, C24-26, branched and linear is expected to be metabolized and excreted as alcohol glucuronides.

Excretion

In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile). Substances that are excreted in the urine tend to be water-soluble and of low molecular weight (below 300), whereas substances that are excreted in the bile tend to have higher molecular weight.

Based on the chemical structure of ”Guerbet alcohols, C24-26, branched and linear”, the molecular weight close to 400 and its low water insolubility, the substance is expected to be rather eliminated via the bile in the faeces than in the urine. Also for the Phase 2 conjugated metabolites of the substance, elimination via the bile is expected.