4-morpholinecarbaldehyde

Endpoint summary

Description of key information

Absorption by the oral, dermal and inhalation routes is expected. Moreover distribution through extracellular body fluids is likely. Excretion will most likely occur rapidly via the urine. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

In line with Chapter R.7c (ECHA, 2012) the main toxicokinetic properties of N-formylmorpholine are assessed on the basis of its physicochemical properties and with regards to the results of the standard toxicity studies conduted with this substance. Specific toxicokinetics or dermal absorption studies are not available for N-formylmorpholine.

N-formylmorpholine (CAS No. 4394-85-8) is a colorless to yellowish solid or liquid that is odourless. It has a molecular weight of 115.13 g/mol and an absolute density of 1.1429 g/cm³ at 20 °C. The substance has a melting point of 20-21 °C and a boiling point of 244 °C at 1.013 hPa. N-formylmorpholine is fully water soluble and has a log Pow of -1.32 at 25 °C. The vapour pressure was estimated to be < 0.2 mbar at 25 °C.

Absorption:

Oral absorption:

Based on low molecular weight, the negative log Pow and a high water solubility, N-formylmorpholine is likely to be absorbed in the GI tract. The vast amount of N-formylmorpholine will be absorbed in the small intestine as the predominant site of absorption within the GI tract. The log Pow of N-formylmorpholine closely below -1 and 4 indicates that it will diffuse well across plasma membranes. In addition, gastro-intestinal absorption of N-formylmorpholine is considered to occur via passive diffusion through aqueous pores or carriage with the bulk passage of water, which is favoured for small (molecular weight < 200 g/mol), water soluble substances. Overall, considerable gastrointestinal absorption is expected for N-formylmorpholine based on its physicochemical properties. However, the available toxicity studies show only very low systemic toxicity of N-formylmorpholine.

In an acute oral toxicity study (BASF, 1967; XVII83), no mortalities occurred during the test up to the high dose level of 7314 mg/kg bw and no abnormalities were found at necropsy after 7 days. The clinical signs of toxicity were limited to a slightly disturbed general condition associated with ruffled fur.

Absorption after inhalation:

N-formylmorpholine exhibits a low volatility (vapour pressure of < 0.2 mbar) and a high boiling point (> 244 °C). Therefore, only a minimal amount of the substance is available for inhalation. However, if vapour or airborne particles reach the alveolar region of the lung, a complete absorpton is assumed.

Dermal absorption:

As N-formylmorpholine is a solid or liquid with a melting point of 20-21 °C and a high water solubility, a molecular weight well below 500 and a log Pow of -1.32, dermal absorption is likely. Its log Pow value suggests that N-formylmorpholine is not likely to cross the stratum corneum, but N-formylmorpholine was identified as a skin sensitiser in a LLNA (Harlan CCR, 2011; 58V0173/97X001). Therefore, a dermal absorption was demonstrated in vivo.

Based on the results of the above mentioned toxicity studies and based on phys./chem. properties, N-formylmorpholine is considered to be bioavailable.

Generic absorption rates:

Based on the above information the generic values of 50 % for oral absorption and dermal as well as 100 % for absorption via inhalation were derived.

Distribution and metabolism:

Based on the physicochemical properties (molecular weight: 115.13 g/mol, log Pow: -1.32, high water solubility), N-formylmorpholine is likely to be widely distributed systemically throughout the extracellular compartments of the body after absorption.

Particularly due to the high water solubility and the negative log Pow value below -1, a long biological half-life in tissues can not be expected. Thus, N-formylmorpholine has a low bioaccumulation potential.

The metabolism is determined by physicochemical factors like electronic and steric effects within the molecule and/or by the presence of functional groups. Phase II conjugation reactions like glucuronidation or sulfatation might occur subsequent to Phase I reaction, e.g. after introduction of a OH-group via Cytochrome P450 mediated oxidation. Generally, metabolism will render the molecule more polar and harmless, leading to faster excretion. No conversion into a metabolite that is more toxic than the parent compound is expected as no increases in toxicity were noted in the presence of a metabolic activation system during the in vitro mutagenicity tests (BASF AG 1985, 40/1110180/84; CCR, 1997, 32M0173/979023; BASF SE, 2011; 50110173/9711001).

Therefore, a clear indication is given that the formation of reactive metabolites is unlikely.

Excretion:

The high water solubility and the low molecular weight (< 150 g/mol) indicate that renal excretion is the most relevant route for systemically available N-formylmorpholine. The log Pow indicates no or a low potential for accumulation in the tissues.