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Administrative data

Link to relevant study record(s)

Description of key information

High oral and inhalation absorption is assumed. Dermal absorption is suspected to be low, but was conservatively assumed to be half of the oral/inhalation absorption. A wide distribution throughout the body is likely. An accumulation potential is not expected. Metabolism might play a minor role. Renal excretion is considered as most relevant.

Key value for chemical safety assessment

Additional information

Phys-chem properties relevant for toxicokinetic assessment

The non-aromatic O-heterocyclic compound 4-acetylmorpholine (CAS-No. 1696-20-4, MW 129.16 g/mol) is a colourless to yellowish, slightly odoured organic liquid. 4-Acetylmorpholine is completely water soluble and has a partition coefficient Log Pow of -0.81 (24°C). 4-acetylmorpholine has a vapor pressure of 0.022 hPa at 20°C. Exposure to 4-acetylmorpholine may occur through inhalation and dermal contact at workplaces where 4-acetylmorpholine is produced or used.

Toxicokinetic Analysis of 4 -acetylmorpholine

Oral absorption

Administered orally it can be assumed that the test item is well absorbed in the gastrointestinal (GI) tract after dissolving in GI fluids due to its low molecular weight, the high water solubility, the low Log Pow of -0.81 and the absence of ionisable groups in the 4-acetylmorpholine molecule at pH values of small intestine. These substance characteristics favour the absorption via passive diffusion, e.g. by passage through aqueous pores or carriage through the epithelial barrier with the bulk passage of water. The systemic effects seen after oral administration demonstrate that the test item is absorbed from the GI tract.

Dermal absorption

As 4-acetylmorpholine is a liquid which completely dissolves in water and has a Log Pow of -0.81, it can be assumed that dermal absorption is significantly lower than oral absorption. This is also indicated by a very low percutaneous permeability coefficient Kp of 0.0000855 cm/hr (calculated with Epi Suite, Dermwin). Conservatively, dermal absorption is assumed to be 50% of the oral absorption.

Respiratory absorption

The test item is a liquid exhibiting low volatility due to a low vapor pressure (< 0.5 kPa) and a high boiling point (> 150°C). Therefore only a minimal amount of the substance is available for inhalation. Based on the aforementioned physico-chemical properties (see “oral absorption”), an absorption rate similar to the oral absorption is expected.

Distribution and metabolism

Since the 4-acetylmorpholine molecule is relative small, completely water soluble and has a negative Log Pow value, a wide distribution throughout the body is likely to occur after absorption. Based on the physico-chemical characteristics, particularly the high water solubility and Log Pow value below 0, long biological half-life of 4-acetylmorpholine in tissues can not be expected, thus it has no accumulation potential. The metabolism itself is determined by physico-chemical factors like electronic and steric effects within the molecule (Karcher W & Devillers J, 1990). Since 4 -acetylmorpholine is already highly water soluble, metabolism might play a minor role. This is supported by metabolism data on morpholine, which showed that Morpholine is eliminated mainly in a non-metabolized form in the urine of the rat, mouse, hamster and rabbit (Griffiths, 1968; Tanaka et al., 1978; Van Stee et al., 1981; Sohn et al., 1982).

Excretion

The high water solubility and low molecular weight (< 400) indicate that renal excretion is the most relevant route of systemically available 4-acetylmorpholine.

References

Karcher W & Devillers J (eds.) (1990): Practical Applications of Quantitative Structure-Activity Relationships (QSAR) in Environmental Chemistry and Toxicology.Chemical and Environmental Science Series, Vol. 1.

Griffiths MH (1968). The metabolism of N-triphenylmethylmorpholine in the dog and rat. Biochem. J., 108: 731-740.

Tanaka A et al. (1978). Excretion and Distribution of Morpholine Salts in Rats. J. Food Hygienic Soc. 19: 329-334.

Van Stee EW, Wynns PC and Moorman MP (1981). Distribution and disposition of Morpholine in the rabbit. Toxicology 20: 53-60.

Sohn OS et al.(1982). Metabolism and Disposition of Morpholine in the Rat, Hamster and Guinea Pig. Toxicol. Appl. Pharmacol. 64: 486-491.