4-methylmorpholine

Endpoint summary

Description of key information

For the test substance, no study is available for the determination of toxicokinetics, metabolism and distribution. Therefore, a qualitative assessment is performed on the basis of the physico-chemical properties of the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

N-methylmorpholine (CAS 109-02-4), named NMM hereafter, is a liquid with a high water solubility (miscible), a moderate log Kow (-0.32) and a moderate vapour pressure (2.27 kPa at 20°C). Its pKa is 7.72. The substance is found to be corrosive to the skin.

The backbone of NMM is the morpholine group which contains a cyclic ether, a tertiary aliphatic amine and heterocyclic fragments. Besides morpholine, NMM contain additionally an N-substituted methyl group.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of NMM.

 

Absorption

Oral/GI absorption:

Following its high water solubility, NMM will readily dissolve into the gastrointestinal fluids and subsequently will pass through aqueous pores or will be carried through the epithelial barrier by the bulk passage of water.

Based on its molecular weight which is <200 (101 g/mole) and the moderate log Kow, absorption by passive diffusion will be favoured.

It is generally thought that ionised substances do not readily diffuse across biological membranes. The intestine is where absorption after oral administration normally takes place. The pKa of NMM suggests that this substance will be at nearly 50% in its ionised form and hence diffusion can be hampered in some extent.

In an acute oral toxicity study (Mallory VT, 1990), clinical signs observed included decreased activity, piloerection, salivation, abnormal gait, abnormal stance, ptosis, chromodacryorrhea, dyspnea and convulsions. Necropsy of the animals sacrificed during the study revealed distended and/or fluid filled stomachs and intestines, dark liver, dark pitted, mottled and/or pale kidneys and fluid filled uterine horns. Terminal necropsy of the remaining animals revealed mottled kidneys. Similar effects have been observed in the acute dermal toxicity study (Mallory VT, 1990). These observations may indicate significant absorption of the test substance.

No data are available from repeated toxicity studies by oral administration with NMM. However a 28-day repeated oral toxicity study (Hoechst, 1996) has been performed with N-ethylmorpholine (NEM), a very similar substance to which read-across is proposed (see supporting information in the Read Across document). No macroscopic changes were observed in this study at any of the tested doses. Histopathological evaluation revealed microgranuloma in male liver at the highest dose (800 mg/kg bw) as well as hyperthrophy of centrilobular hepatocytes in liver and vacuolation of the epithelium in distal and Henle’s loop in kidneys in both, males and females at the highest dose. This indicates that absorption after oral exposure has occurred. In consequence, NMM is also considered to be substantially absorbed after oral exposure.

In the gastro-intestinal tract hardly any degradation of the substance is to be expected.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of NMM as an ionized substance. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

 

Respiratory absorption:

Given the vapour pressure of 2.27 kPa, NMM is not considered to be a highly volatile substance and the availability for inhalation as a vapour is limited.

Once in the respiratory tract, the very hydrophilic substance may be retained within the mucus, and subsequently absorption may occur. Absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log Kow value.

Di Pasquale (1979) investigated inhalation toxicity of NMM after repeated whole body exposure for 14 days (1 or 7 hours per day, 5 days per week). Sprague Dawley male and female rats were exposed to 0 (control), 100 or 1000 ppm (equivalent to 0, 414 or 4140 mg/m³; 15 males and 15 females/dose). Gross signs of irritation, transient cloudiness of the eye, and possibly elevations in atypical lymphocyte differential counts were the only detectable manifestations of exposure. 

Based on the above considerations, the inhalatory absorption factor is set to 100%, as a worst case assumption.

 

Dermal absorption:

In view of its high water solubility and moderate log Kow, penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited although its physical form (liquid) favours dermal absorption. As NMM is a corrosive substance, absorption/penetration will be enhanced.

In an acute dermal toxicity study (Mallory VT, 1990), NMM was tested at 3000 mg/kg in rabbits. Necropsy of the animals sacrificed during the study revealed pale and/or mottled liver, pale and/or mottled kidneys, dark red and mottled lungs, oral and/or nasal discharge, and severe irritation of the underlying muscle at the application site. Similar effects have been observed in the acute dermal toxicity study (Mallory VT, 1990). These observations may indicate significant absorption of the test substance.

Generally default values of 10% and 100% are used for dermal absorption, based on molecular weight and log Kow value (ECHA guidance on IR&CSA, R.7c). It is generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor for NMM is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

 

Distribution:

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like the test substance, will diffuse through aqueous channels and pores. The high water solubility and low molecular weight predict that the substance will distribute widely through the body.

Based on the log Kow < 0 and the high water solubility, the substance will not likely distribute into cells through the membrane and hence the intracellular concentration is not expected to be higher than the extracellular concentration.

 

Accumulation:

In view of the moderate log Kow and the high water solubility, the test substance is not expected to accumulate in the body (lung, adipose tissue, stratum corneum). Based on the liquid form of the test substance, no accumulation is expected within the lungs. 

 

Metabolism:

Once absorbed, extensive hydroxylation (aliphatic carbons) may occur to increase the solubility of the substance and oxidative deamination (tertiary amines), followed by rapid sulfation or glucuronidation is expected. 

 

Excretion:

The water soluble conjugated metabolites from Phase II biotransformation will be excreted from the systemic circulation through the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium.