2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one

Endpoint summary

Description of key information

Investigation of toxicokinetic properties was conducted as a desk study based upon the key and supporting informtion provided in this dossier, and using scientifically accepted methods.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Chemistry

The test material (279 Da) is a solid of low water solubility (17.9 mg/g). The material has a particle size of 9.6 – 40.9 µm and melts from 74.6 °C onward. A vapour pressure of 0.002 Pa indicates a very low volatility. The log Pow is 3.09.

Absorption

In acute oral and dermal toxicity studies, rats were administered to the test substance. Mortality was observed in all treatment groups after oral administration in a dose dependent manner. Animals suffered i.a. from sedation, diarrhoea, skin erythema and transient alopecia. Gross necropsy was without findings. Single dermal application caused ruffled fur and ventral body position, gross lesions were not observed. The NOAEL in male and female rats in a subacute oral repeated dose study is 100 mg/kg bw due to mortalities in the high dose group, decreased body weight, gross lesions on skin and congestion in parenchymatous organs. Administration of the substance over a subchronic period resulted in decreased body weight, adverse ophthalmoscopic findings, increased organ weight (liver, kidney) and hemosiderosis in spleen. The NOAEL after subchronic oral administration is therefore considered to be 75 mg/kg bw. In regard to the results of the acute and longterm studies and considering the low molecular weight uptake of the substance from the gastro-intestinal system is most likely. The test substance cannot undergo pH-dependent hydrolysis in the stomach, thus, the unchanged (parent) substance is taken up into the system. Furthermore, in a combined 1-generation / developmental toxicity study significant teratogenic effects were observed at 40 mg/kg bw and above. Considering the toxicity on the fetal and new-born rats, it is expected that the test item and/or its metabolites pass also the placenta barrier.

The test material has a particle size of 9.6 – 40.9 µm and is therefore scarcely inhalable. The vapour pressure is 0.002 Pa indicating low volatility even at high temperatures (manufacturing).

According to the model of Fitzpatrick [1], the test item is slightly skin permeable. However, single dermal application of high doses of the test substance did not result in mortality or clinical signs. A singificant penetration of the test material through intact skin is not expected.

Metabolism

The substance is photo-labile and undergoes degradation with radical formation under light exposure.It can be assumed that the intact substance circulates in the blood. At locations that are easily penetrated by light (eyes, legs of rats) photo-cleavage resulting in radical formation may occur. These radicals are expected to be responsible for the toxicity on eyes and the acanthosis. The absorbed parent compound is most likely subject to hepatic metabolic degradation i.a. S-demethylation, keto-hydroxylation and morpholine ring cleavage. In addition, metabolic transformation may also involve ring opening of the morpholine moiety catalyzed by cytochrome-P450-dependent monooxygenases.

Excretion 

Experimental data on Moclobemide show that the material is excreted via the urine after extensive metabolic transformation. The metabolic pathways include mainly oxidative attack of the morpholine moiety; the metabolites in turn were excreted as conjugates of glucuronic and / or sulfuric acid [1]. Accumulation in the body is therefore not expected.

[1] Modelling skin permeability in risk assessment––the future, D. Fitzpatrick et al, Chemosphere 55 (2004) 1309–1314