Merginol 901

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).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic information

The target substance can be divided into a mono-, di- and triadduct. With increasing size of the adduct, the physico-chemical properties vary, and thus the absorption potential decreases. The triadduct is not expected to be absorbed at all. After uptake, the mono- and diadduct are considered to be metabolized by phase I and II enzymes, leading to an excretion of the degradation/conjugation products mainly via bile.

1.    Chemical and physico-chemical description of the substance

The substance to be registered is a reaction product of fatty acids (C16-18 (even numbered) and C18-unsaturated) with methanol and trimethylolpropane (TMP). It can be described with the CAS # 188831-96-1 (CAS name: Fatty acids, C16-18 (even numbered, C18 unsaturated), epoxidized, Me esters, polymers with trimethylolpropane). The reaction process starts with a fatty acid methyl ester. Due to the high percentage of oleic acid in the fatty acid composition, the main product at this stage is oleic acid methyl ester. Besides, methyl esters of saturated fatty acids are present, but would not further react because they lack a double-bond. In the second and third production step, this unsaturated double-bond is epoxidized and ring-opened with TMP. Due to the remaining hydroxyl groups of the TMP component, the monoadduct can further react with a second or even third epoxidized oleic acid methyl ester to form a di- or triadduct. In the following, the three major components of the target substance – mono-, di- and triadduct with oleic acid – are discussed.

Description of the physico-chemical properties:

- physical state (20°C): liquid

- vapour pressure (20°C): 0.0000019 Pa

- molecular weight: appr. 450 (monoadduct), 770 Da (diadduct), 1070 (triadduct)

- log Kow: 5.67 (monoadduct), 12.16 (diadduct), 18.65 (triadduct)

- water solubility: 72-618 mg/L at 20 °C (experimental data with 1 or 10 g/L weighted sample)

- Boiling point: substance decomposes at about 200°C

The substance is characterized by a lipophilic nature, a low volatility and relatively low water solubility. It is assumed that mainly the monoadduct contributes to the water solubility, as the di- and triadduct have an extremely high log Kow.

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 toxicokinetic behaviour can be evaluated.

2.1 Absorption:

The amount that is expected to be absorbed decreases in general with an increase in molecular weight / log Kow. Taking this into account, the uptake by each possible route of exposure is considered to be negligible for the triadduct, which has a high molecular weight of >1000 Da and a log Kow of 18.65. The potential for absorption is little better for the diadduct: though smaller in the molecular weight (appr. 770 Da), it still has a high log Kow (12.16) and consequently a very low water solubility. The water solubility of the target substance was measured in an experiment, and resulted in a value of 72-618 mg/L (for 1 or 10 g/L added). It was concluded that the mono-adduct is primarily responsible for the water solubility. Altogether, the proportion of mono-, di- and triadduct present in the target substance is expected to strongly shift towards the monoadduct in the body, as the absorption potential of the di- and triadduct is very limited.

With regard to absorption after inhalation, the target substance has a low vapour pressure of 0.0000019 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 Kow, the relatively low water solubility and the rather high molecular weight. Theoretically, a systemic uptake of the mono-/diadduct could take place after micellular solubilisation.

In the gastro-intestinal tract, the highly lipophilic substance with limited water solubility and a relatively high molecular weight (appr. 450-1070 Da) is unlikely to be absorbed by passive diffusion. An uptake due to micellular solubilisation could be expected for the monoadduct and partly for the diadduct. Altogether, an oral absorption of 75% is assumed for the target substance.

With a molecular weight of 770 and 1070 Da and a log Kow of 12.16 or 18.65, the di- and triadduct are unlikely to be absorbed dermally. Even the size and the lipophilicity of the monoadduct (450 Da, log Kow = 5.67) is not favorable for a dermal uptake. It is expected that the monoadduct enters the stratum corneum, but the transfer to the epidermis (and thus the bioavailability after dermal contact) will be limited. The QSAR program DERMWIN predicts a kp of 0.0384 cm/hr for the monoadduct, which represents a moderate uptake. On the basis of this prediction, it is assumed that 50% of the monoadduct will be absorbed after dermal exposure. Taking into account the percentage of mono-, di- and triadduct, a dermal absorption of 5 % is assumed for the target substance.

2.2 Metabolism and Excretion:

Once absorbed, a metabolic reaction could in principle take place: at the epoxide- / the ether site or involving the free hydroxy group(s) of the target substance.

A metabolic reaction at the ether site is unlikely, as ethers are considered to be relatively physiologically stable.

The hydroxy groups are good substrates for conjugation by metabolic Phase II enzymes (e.g. glutathione transferase). This reaction improves their water solubility and enables the excretion via bile or urine. In consideration of the high molecular weight (>500 Da after conjugation), an excretion via bile is more likely.

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 target substance, methanol as well fatty acid ether with trimethylolpropane is formed.

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 employs 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) .

The fatty acid ether with TMP formed after ester cleavage could in theory be further metabolized like dietary fatty acids, at least up to the site where TMP is bound. In this oxidation process, carbon dioxide and water are formed. However, the fatty acid ether with TMP could well be water-soluble enough to be excreted via bile, especially if the free hydroxyl groups are further conjugated by metabolic phase II enzymes.

In consideration of the limited uptake and the enzymatic processes in place for metabolic degradation, the target substance is not expected to have a bioaccumulation potential.