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Assessment of the Toxicokinetic Behaviour

LCAE category members includes:

9-Octadecenoic acid (9Z)-, decyl ester (CAS-No.3687-46-5),

Fatty acids, C16-18, isotridecyl esters (CAS-No.95912-88-2)

Fatty acids, C16-18, C16-18-alkyl esters (CAS-No. 97404-33-6).

 

The LCAE category members are all long chain alkyl fatty acid esters. The carbon number ranges between C16-C18 for the fatty acid component and between C10-C18 for the primary aliphatic alcohol component. 

9-Octadecenoic acid (9Z)-, decyl ester (molecular weight of 422.74 g/mol) and Fatty acids, C16-18, isotridecyl esters (molecular weight of 438.78- 466.83 g/mol) are liquids which are poorly water soluble (< 0.05 mg/Lat 20 °C). Fatty acids, C16-18, C16-18-alkyl esters (molecular weight of 480.86-536.97 g/mol) is a solid powder which is also poorly water soluble (<1 mg/L).

The log Pow of 12.04 to 16.58 indicates that the substances are very highly lipophilic and therefore may have the ability to pass through biological membranes.

 

Absorption

Several acute oral toxicity studies are available for 9-Octadecenoic acid (9Z)-, decyl ester (CAS-No.3687-46-5). All results showed no evidence of systemic toxicity; at concentrations of >/= of 2 g/kg bw day (Dufour, 1994; Gloxhuber, 1967; Potokar, 1970). This suggests that the test material is of low toxicity, as an absorption through the gastrointestinal tract is in general likely by micellular solubilisation; this mechanism is of importance for highly lipophilic substances such as LCAEs, particularly those who are poorly soluble in water (1mg/L or less).

Since the water solubility of LCAE is <1 mg/L (poorly water soluble) and the logPow is very high, the rate of transfer between the stratum corneum and the epidermis will presumably be very slow or negligible and therefore this will consequently limit absorption across the skin. QSAR based dermal permeability regarding molecular weight, logPow and water solubility, calculated a very low dermal absorption of 4.67e-007-1.22e003cm2/h (DERMWIN v2.00, 2009).

In an acute dermal toxicity study, no signs of systemic toxicity were observed at a limit dose of 2000 mg/kg bw decyl oleate (CAS No 3687 -46 -5), indicating that the test material is either of low toxicity or there is little absorption of the substance (Beerens-Heijnen, 2010). Overall, the dermal uptake of LCAEs in humans is considered as very limited and the dermal exposition is considered negligible for hazard assessment.

LCAEs have very low vapour pressure of < 0.001 Pa at 20°C (QSAR); therefore indicating that inhalation as a vapour (for the liquid LCAEs CAS# 3687 -46 -5 and 95912 -88 -2) will be minimal.

Particle size distribution study for Fatty acids, C16-18, C16-18-alkyl esters (CAS-No. 97404-33-6) has shown 99% of the particles to be greater than 150 µm, thus indicating that absorption via inhalation of the substance will be minimal.

Metabolism 

High molecular weight aliphatic esters are readily hydrolysed to the corresponding alcohol and fatty acid.

Once the fatty acid component has passed the intestinal barrier, the fatty acid will be reformed into triglycerides. The triglycerides are either stored in adipocytes or they are oxidized for energy in the ß-oxidation. During this process, two-carbon molecules are repeatedly cleaved from the fatty acid. This process continues until the entire chain is cleaved into acetyl CoA units. Acetyl-CoA feeds into the citric acid cycle, contributing to the cell's energy supply. The citrate cycle consists of a series of chemical transformations. Two carbon atoms are oxidized to CO2 per cycle, and the resulting energy from these reactions is transferred to other metabolic processes.

The long chain primary aliphatic alcohol component is readily oxidized to the respective aldehyde in a first metabolism step which is followed by a second metabolism step to the respective acid. The acid is either directly conjugated in a phase II reaction with glucuronic acid. Alternatively the carboxylic acid may be completely oxidized to CO2 in the ß-oxidation.

Excretion

As a result from the metabolism of the fatty acid or of the alcohol, one main route of excretion is expected to by expired air as CO2. Another possible route of excretion is expected to be biliary and renal excretion of the conjugated metabolites (ester glucuronide). Additionally it is also possible that the (oxidized) acid will be excreted as such.