Fatty acids, C16-18 and C18-unsatd., Me esters, epoxidized

Endpoint summary

Description of key information

In an in vitro metabolism study, the hydrolysis of oleic acid esterified methanol,  ethylene glycol, glycerol, erythritol, pentaerythritol, adonitol, sorbitol, and sucrose was studied. The hydrolysis was assessed in incubations with various preparations of rat pancreatic juice, including pure lipase. Incubations with sodium taurocholate were included to distinguish lipase from non-specific lipase activity. Lipase did not catalyse the hydrolysis of substances with more than three ester groups. Compounds with four and five ester groups were hydrolysed by the endogenous enzyme non-specific lipase. Compounds containing six or eight ester groups were not hydrolysed by the pancreatic juice(Mattson and Volpenhain 1972).

Additional information

Toxicokinetics

Due to the high lipophilicity, an uptake by micellular solubilisation is expected after oral exposure. On the basis of the application profile of the substance and the physico-chemical properties (low vapour pressure), inhalation as a vapour is negligible. The dermal uptake into the stratum corneum is expected to be efficient, but transfer to the epidermis is limited because of the high lipophilicity. Once absorbed, the substance is expected to be efficiently metabolized by esterases and epoxide hydrolases, as the substance has a high structural resemblance to endogenous substrates of these enzymes. The excretion of the degradation products is via exhalation air (carbon dioxide) or urine (water and Phase II-conjugates of diol fatty acids). A bioaccumulation potential is not expected.

1.    Chemical and physico-chemical description of the substance

The substance to be registered is a reaction product (ester) of fatty acids (C16-18 and C18-unsaturated) with methanol, of which the double bond(s) in the fatty acid chain were subsequently epoxidized. It can be described with the CAS no. 158318-67-3 (CAS name: Fatty acids, C16-18 and C18 -unsatd., Me esters, epoxidized).

Description of the physico-chemical properties:

- physical state (20°C): liquid

- vapour pressure (20°C):1.3 x 10^-6hPa

- molecular weight: appr. 312.5 Da (EPISUITE, v3.12)

- log Kow: >= 6 (23° C)

- water solubility: 8-24 mg/L at 20 °C

- Boiling point: substance decomposes at about 200°C

The substance is characterized by a lipophilic nature, a low volatility and relatively low water solubility.

2.     Toxicokinetic assessment

No experimental data on absorption, metabolism and distribution are available for the substance. Based on the structure and the physico-chemical properties of the substance, the toxivokinetic behaviour can be evaluated.

2.1 Absorption:

In the gastro-intestinal tract, the highly lipophilic substance (log Kow > 6) with limited low water solubility (8-24 mg/L) and a relatively high molecular weight (appr. 312.5 Da) is unlikely to be absorbed by passive diffusion. An uptake due to micellular solubilisation could be expected. The substance to be registered has a low vapour pressure of 1.3 x 10-6 hPa (0.00013 Pa) and decomposes at about 200°C, indicating that inhalation as a vapour will be negligible. If the substance reaches the respiratory tract, passive diffusion is unlikely due to the high log Pow, the relatively low water solubility the rather high molecular weight. Theoretically, a systemic uptake could take place after micellular solubilisation.

With a molecular weight of >300 Da, the substance is relatively large for the dermal absorption. The high lipophilicity (log Kow >6) favours the penetration into the stratum corneum, but limits the transfer between stratum corneum and epidermis. Considering the physico-chemical parameters, an accumulation of the substance in the stratum corneum might occur. As worst case assumption, a dermal uptake of 10% is assumed.

2.2 Metabolism and Excretion:

Once absorbed, a metabolic reaction could in principle take place at the epoxide- or the ester site of the substance. The ester function is likely to be metabolized like dietary fats. As shown by Mattson and Volpenhain, esters of fatty acids and different alcohols (methanol, ethylene glycol, glycerol…) are potential substrates for endogenous lipases in the bile-pancreatic fluid. These enzymes catalyse the hydrolysis to the corresponding alcohol and acid. As cleavage products of the substance to be registered, methanol as well as epoxidized/non-epoxidized fatty acids are formed. The fatty acids without epoxy site are further metabolized like any other dietary fatty acid, undergoing an oxidation to carbon dioxide and water. Epoxidized fatty acids can also be formed endogenously, and some fatty acid epoxides even have a physiological function (e.g. leukotriene A4). Consequently, efficient mechanisms are in place to control the level of epoxides and to further metabolize them. The epoxide function is a typical substrate for epoxide hydrolases, which can be assigned to the Phase I metabolic enzymes. For the conversion of fatty acid epoxides into diol fatty acids, the microsomal epoxide hydrolase mEH_band especially the soluble epoxide hydrolase sEH_TSO play a major role in the human body (reference: e.g. H. Marquardt/S.G. Schäfer, Lehrbuch der Toxikologie. Spektrum Akademischer Verlag, 1997, chapter “Fremstoffmetabolismus” (author: F. Oesch)). These epoxide hydrolases are present in many human organs. However, the major site of metabolism of the fatty acid epoxides is most likely the liver. The resulting diol fatty acids are further processed by metabolic Phase II enzymes, e.g. by glutathione transferase. The glutathione conjugate has an increased water solubility, which enables the excretion via urine.

The mammalian metabolization of methanol is well investigated. It occurs mainly in the liver, where methanol is initially converted to formaldehyde, which is in turn converted to formate. Formate is converted to carbon dioxide and water. In humans and monkeys, the oxidation to formaldehyde is mediated by alcohol dehydrogenases and basically limited to the capacity of those enzymes. In rodents, the oxidation to formaldehyde predominantly employes the catalase-peroxidase pathway which is of less capacity than the ADH-pathway in humans, but on the other hand produces oxygen radicals which may be involved into the developmental effects in rodents which - in contrast to humans - tolerate high methanol levels without signs of CNS or retinal toxicity. The last oxidation step, conversion of formate to carbon dioxide employes formyl-tetrahydrofolate synthetase a co-enzyme, is of comparably low capacity in primates which leads to a low clearance of formate, possibly also from sensitive target tissues (such as CNS and the retina) .