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Description of key information

For NMMO, 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

Morpholine, 4-methyl-, 4-oxide(or n-methylmorpholine oxide; CAS 7529-22-8; hereafter named NMMO) is a solid substance but it is always marketed as an aqueous solution (mostly as a 50% solution). NMMO is a high water soluble compound (> 100 g/L) with a low log Kow (-1.2) and a moderate vapour pressure (141 Pa). Its pKa is 5.14. NMMO surface tension is 68.9 mN/m at test concentration of 1g/L at 20°C and therefore the substance is not considered to be surface active. The substance was proved not to be skin irritant nor a skin sensitiser.

No toxicokinetic data (animal or human studies) are available on this substance. The information present in this document is mostly based on physico-chemical parameters which allow a qualitative assessment of the toxicokinetic behaviour of NMMO rather than a quantitative assessment.

Absorption

Oral/Gastro Intestinal absorption

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

Based on the moderate log Kow, absorption by passive diffusion will be favoured. Passive diffusion is also considered not to be significantly hindered as its molecular weight is <200 (117 g/mole).

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 NMMO suggests that this substance will be predominantly in its ionised form in the GI tract and hence diffusion can be hampered in some extent.

In an acute oral toxicity study (Mallory, 1981) NMMO was tested via gavage at 7000, 8000, 9000 and 10000 mg/kg male/female Sprague-Dawley rats. Necropsy of animals dosed at 8000, 9000 and 10000 mg/kg and sacrificed during the study, revealed distended fluid-filled stomachs and intestines, mottled lungs, darkened thymuses and darkened lymph nodes. Terminal necropsy revealed no visible lesions in any of the remaining rats. The acute oral LD50 for male and female rats was determined to be 9200 mg/kg,indicating absorption of the test substance.

In a combined repeated dose/reprotox-developmental screening study performed with NMMO (as 50% aqueous solution), males and female rats were exposed to 0,10, 100 and 1000 mg/kg bw/d via oral gavage according to OECD 422 (Martell, 2013). Treatment related effects at the high dose level were observed for body weight, body weight gain and food consumption of male and female rats. Under the experimental conditions of the study, the NOAEL of NMMO (as 50% aqueous solution) was 100 mg/kg bw/ d for males and females. The NOAEL for embryo-fetal toxicity was 100 mg/kg bw/day. These results support the assumption for oral absorption of NMMO.

The oral absorption factor is set to 50%, based on the anticipated hampered diffusion of NMMO 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 141 Pa, NMMO is a low volatile substance and the availability for inhalation as a vapour is limited.

Once in the respiratory tract, NMMO would deposit on the walls of the airways. Deposited substances may be absorbed directly from the respiratory tract or, through the action of clearance mechanisms, may be transported out of the respiratory tract and swallowed. In that last case the substance needs to be considered as contributing to the oral/GI absorption rather than to the inhalation rate.

Although absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log Kow value, NMMO is a highly water-soluble substance and, as suggested by its pKa value, predominantly in its ionised form at physiological pH. Based on this ionization, diffusion can be hampered in some extent.

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 through deeper epidermis layers might be limited although its physical form (liquid) favours dermal absorption.

In an acute dermal toxicity study (Auletta, 1981),New Zealand White male/female rabbits were acutely exposed to 8000 mg/kg bw of NMMO. All animals survived the 4-day post-dose period. The LD50 value of the substance is greater than 8000 mg/kg.

The substance was proved not to be irritant to the skin and not to be a skin sensitiser.

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). The dermal absorption factor is therefore set to 100% (default), based on a molecular weight < 500 and a log Kow in the range of -1 to 4. 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 NMMO is set to 50%. The results of the available toxicity studies using the dermal route do not provide reasons to deviate from this proposed value.

Distribution

The high water solubility, moderate log Kow and low molecular weight predict that the substance will distribute widely through the body.

 

Accumulation

In view of the moderate log Kow and the high water solubility, NMMO will not easily accumulate in the body (lung, adipose tissue, stratum corneum).

Metabolism

Once absorbed, NMMO 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 (amplified by the expected cleavage of the ether bond), NMMO and its metabolites will be mainly excreted via the urine.