Morpholinium sulphamate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2013-05-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Morpholinium sulphamate

EC Number:

258-061-6

EC Name:

Morpholinium sulphamate

Cas Number:

52636-67-6

Molecular formula:

C4H9NO.H3NO3S

IUPAC Name:

morpholin-4-ium sulfamate

Test material form:

solid

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. This characteristic combined with a log Pow value between -1 and 0 and a high water solubility allow dissolution of Morpholinium sulphamate in the gastro-intestinal fluids and contact with the mucosal surface. However, diffusion through biological membranes might be limited by the ionic properties of the substance. Due to its low pKa value (1.0) sulphamidic acid is estimated to be absorbed in the acidic milieu of the stomach (~ pH 1.4 to 4.5). Based on its pKs value (8.4) morpholine might be absorbed in the small intestine due to the present basic milieu (~ pH 5 to 8). Passage through aqueous pores or carriage through the epithelial barrier by the bulk passage of water is assumed to be an alternative pathway of absorption for small, water soluble substances like the test substance. Oral administration of morpholinium sulphamate revealed no adverse effects. However, increased mean concentrations of serum bile acids in female animals and decreased activated partial thromboplastin time and prothrombin time in male animals at 1000 mg/kg bw/day might be associated with the bioavailability of the test item. This assumption is in line with experimental data of Tanaka et al. (1978) who have shown bioavailability of 14C labelled morpholine after oral administration in rats.
Inhalation exposure of vapour was considered to be not relevant as morpholinium sulphamate is manufactured in an aqueous solution (50 %, w/v) and evaporation of the dissociated test substance can be excluded. However, the substance might reach the respiratory tract in form of mist and might dissolve in the mucous. As passive diffusion of ionic substance through the respiratory tract epithelium is limited carriage through aqueous pores is assumed to be an entry route to systemic circulation.
Dermal penetration of morpholinium sulphamate is estimated to be low due to its high water solubility (> 900 g/L) and low log Pow value (< 0). It is general accepted that if a compound’s water solubility is higher than 10 g/L and the log Pow value is below 0 absorption can be anticipated to be low. The ionic properties of morpholinium sulphamate in aqueous solution further limit uptake through the skin. No enhanced dermal penetration is expected as morpholinium sulphamate has no skin irritation properties.

Details on distribution in tissues:

Assuming that morpholinium sulphamate is absorbed into the organism following oral intake, it may be widely distributed via the blood stream due to its hydrophilic properties and in turn the extracellular concentration may be higher than the intracellular one. In a toxicokinetic study with 14C labelled morpholine palmitate (Tanaka et al., 1978) the highest tissue concentration of morpholine after oral administration was found in the muscle and in the intestine. Intravenous administration of radio labelled morpholine (Stee et al., 1981) revealed a high tissue concentration in the kidney.
Particularly, due to the high water solubility and low log Pow value a long biological half-life in tissues is not expected. This assumption is supported by experimental data of Tanaka et al. (1978) and Sohn et al. (1982). 90 % of the original dose was found in the urine after 3 days and 0.08 to 0.14 % was found in the faeces after oral administration of morpholine salts (200 mg/kg bw) on rats (Tanaka et al., 1978). After intraperitoneal administration of 125 mg/kg bw 14C Morpholine (Sohn et al., 1982) the blood plasma half-lives in the rat, hamster and guinea pig were 115, 120 and 300 min, respectively. In all three species, approximately 80 % of the radioactivity was excreted in the urine in 24 hours.

Details on excretion:

Based on the high water solubility, morpholinium sulphamate is expected to be excreted via urine. This assumption is supported by Tanaka et al. (1978), Sohn et al. (1982) and van Stee et al. (1981) who have shown that 90 to 99% of administered morpholine was renal excreted. Less than 1 % was found in faeces.

Metabolite characterisation studies

Details on metabolites:

Generally, the function of xenobiotic metabolism is to increase water solubility of highly lipophilic substances to facilitate their excretion from the organism. As morpholinium sulphamate is already a small, highly water soluble molecule, no metabolic conversion is expected. This assumption is in line with excretion data of morpholine published by Sohn et al. (1982). While non-metabolized 14C Morpholine constituted up to 99 % of the urinary radioactivity in the rat and hamster, a significant portion of the dose (approximately 20 %) appeared as N-methylmorpholine-N-oxide in the urine of guinea pigs after i.p. administration of morpholine. As no or only minor metabolite formation is expected for morpholinium sulphamate, there is no indication for metabolic activation of the test substance.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Taken together, physico-chemical properties and experimental data indicate bioavailability of morpholinium sulphamate via oral route and to a less extent via inhalation route. Dermal uptake is estimated to be low.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient and experimental data absorption via oral route and to a less extent via inhalation route is likely to occur. However, bioavailability after dermal exposure is low. Extracellular concentration is likely to be higher than intracellular due to the hydrophilicity of morpholinium sulphamate. As morpholinium sulphamate is already a small, highly water soluble molecule, no metabolic conversion is expected. Based on the molecular weight and the high water solubility morpholinium sulphamate is excreted via the urine. Bioaccumulation of the test substance is not likely to occur based on their physico-chemical properties.