4-ethylmorpholine

Endpoint summary

Description of key information

For NEM, 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-ethylmorpholine (CAS 100-74-3), named NEM hereafter, is a liquid with a low molecular weight (115.17 g/mol), a very high water solubility (303 g/l), a moderate log Kow (0.14) and a low volatility (vapour pressure of 0.112 kPa at 25°C). Its pKa is 7.67. The substance is found to be eye irritant.

The backbone of NEM is a morpholine group which is a heterocycle containing both an ether and a tertiary amine functional group. Besides morpholine, NEM contains additionally an N-substituted ethyl group. Due to the presence of the amine group, NEM is considered a base and potentially ionisable.

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 NEM.

Absorption

Oral/GI absorption:

Since NEM is a small (MW <200) and very watersoluble molecule (solubility 303g/L), the substance will readily dissolve into the gastrointestinal (GI) fluids and subsequently pass through the aqueous pores or will be carried through the epithelial barrier by the bulk passage of water (passive diffusion). Based on its molecular weight and the moderate log Kow, absorption by passive diffusion will be favoured. The pH in the small intestine is 6 – 7.4, this means that based on the pKa value, there is a majority of ionised NEM present at this pH. Since it is generally thought that ionized substances do not readily diffuse across biological membranes, diffusion can be hampered to some extent.

A 28-day repeated oral toxicity study (Hoechst, 1996) has been performed with NEM in which no macroscopic changes were observed at any of the tested doses. The histophatological evaluation revealed microgranuloma in the male liver at the highest dose (800 mg/kg b.w) as well as hyperthrophy of the centrilobullar hepatocytes in the liver and vacuolation of the epithelium in the distal and henle’s loop in the kidneys from both males and females at the highest dose. This indicates that absorption after oral exposure has occurred. In consequence, NEM is 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 NEM as an ionized substance. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

Respiratory absorption:

Given the low vapour pressure of 0.112 kPa, NEM is not considered to be a volatile substance and the availability for inhalation as a vapour is limited. If the substance ends up in the respiratory tract, NEM would readily diffuse/dissolve into the mucus lining the tract. Due to the moderate logKow value, NEM has the potential to be absorbed directly across the respiratory tract epithelium through passive diffusion. The respiratory absorption factor is set to 100%.

Dermal absorption:

NEM is a liquid substance and therefore the product is taken up by the skin more readily in comparison to dry products. NEM has a slightly positive log Kow (0.14) which involves some lipophilicity and consequently some penetration into the lipid-rich stratum corneum. From the stratum corneum, NEM can be partitioned into the epidermis since the substance is very soluble in water. As NEM is a corrosive substance, absorption/penetration will be enhanced.

In an acute dermal toxicity study (Mallory V, 1991), rabbits were exposed to NEM. Fur was clipped from the dorsal area of the trunk of the test animals and a square gauze patch was used to cover the dosed area and wrapped with rubber dam and elastic bandage to retard evaporation. The exposure time was 24 hours. During the study decreased activity was observed and necrosis of the skin at application sites was observed. The acute LD50 in males and females was determined to be 1980.4 mg/kg (males 1924.0 mg/kg, females 2031.2 mg/kg). Necropsy of the animals dying on study revealed irritation of underlying muscle at the application site. No visible lesions were observed in any animal at terminal necropsy. These observations may indicate some absorption of the test substance. The dermal absorption factor is set to 100% (default), based on a molecular weight < 500 and a log Kow in the range of -1 to 4 (ECHA guidance on IR&CSA, R.7c). However, it is also generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor for NEM is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

Distribution:

The high water solubility and low molecular weight predict that the substance will distribute widely through the body due to diffusion through aqueous channels and pores. Based on the slightly positive log Kow value (lipophilic character), the substance may distribute into cells and hence the intracellular concentration may be higher than the extracellular concentration particularly in fatty tissues.

Accumulation:

Based on the moderate log Kow and the high water solubility, NEM will not easily accumulate in the body (lung, adipose tissue, stratum corneum).

Metabolism:

Once absorbed, NEM might undergo phase I biotransformation (including aliphatic and aromatic hydroxylation) followed by conjugation reactions (phase II) including glucuronidation and sulfation.

Excretion:

Given the high water solubility and low molecular weight, NEM and its metabolites will be mainly excreted via the urine. Most of the product will be filtered out of the blood by the kidneys, though a small amount many end up in the urine through passive diffusion and possible re-absorption into the systemic circulation across the tubular epithelium.