Morpholinium toluene-4-sulphonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable publication which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Excretion and Distribution of Morpholine Salts in Rats.

Author:

Tanaka A, Tokieda T, Nambaru S, Osawa M & Yamaha T

Year:

1978

Bibliographic source:

J. Food Hygienic Soc. 19: 329-334.

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Elimination, distribution and metabolism of Morpholine salts in rats were investigated by means of chemical analysis and/or radioassay . Gas-liquid chromatography was used for chemical analysis of Morpholine in the rat urine and faeces. The analytical results of the excreta accorded with those made by the tracer technique.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Morpholine

EC Number:

203-815-1

EC Name:

Morpholine

Cas Number:

110-91-8

Molecular formula:

C4H9NO

IUPAC Name:

morpholine

Details on test material:

Morpholine (purity >99 %), Morpholine-hydrochloride und -palmitate
Labelled Morpholine was diluted with nonradioactive Morpholine to the specific activity of 10200 dpm/mg.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: young adult (based on body weight)
- Weight at study initiation: 200 to 350 g
- Metabolism cages: yes
- Diet: standard diet (CE-2, Japan CLEA, Tokyo, Japan), ad libitum (fasted overnight in the case of peroral administration)
- Water: ad libitum

Administration / exposure

Route of administration:

other: oral and intravenous

Vehicle:

not specified

Details on exposure:

Please refer to "Doses / concentrations"

Duration and frequency of treatment / exposure:

single treatment

Doses / concentrations

Remarks:

Doses / Concentrations:
Radioassay
14C-Morpholine: 200 mg/kg bw (oral); 150 mg/kg bw (intravenous injection)
14C-Morpholine palmitate: 400 mg/kg bw (oral)

Chemical Assay
Morpholine-HCI: 500 mg/kg bw (oral); 250 mg/kg bw (intravenous injection)

No. of animals per sex per dose / concentration:

3 animals

Control animals:

not specified

Positive control reference chemical:

Not indicated

Details on study design:

A rationale for dose selection was not provided.

Details on dosing and sampling:

Elimination study:
Rats were given an oral dose of 200 mg/kg bw of 14C-Morpholine or were treated intravenously at 150 mg/kg bw. 14C-Morpholine palmitate was administered by gavage at 400 mg/kg bw. Morpholine-HCl was dosed as a 5% aqueous solution, and palmitate as a dimethyl sulfoxide solution. Urine and faeces were collected every 24 hours. A water wash of the cages at the end of the experiment was combined with the final day urine. Dose levels of Morpholine-HCI were 500 mg/kg bw for oral administration and 250 mg/kg bw for intravenous injection.

Distribution study:
After dosing wih 14C-Morpholine HCl, the animals were killed at 2, 6 and 12 hour intervals. Organs and tissues were removed, dried in air, powdered and weighed. Portions of the samples were oxidized to carbon dioxide for measuring radioactivity in a scintillator. Only the intestine was solubilized in a 0.5 N sodium hydroxide solution under gentle reflux and an aliquot of the solution was mixed with a dioxane scintillator for counting. The organ-affinity was compared with regard to the level of radioactivity content in terms of RSA (relative specific activity).

Metabolic studies:
The collected urine was extracted with ether or isopropyl ether, and an aliquot of the concentrate was spotted onto thin-layer films, and subsequently developed with several solvents to detect urinary metabolites.

Statistics:

Mean values and standard deviations were calculated.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

The distribution of 14C-labeled Morpholine following oral administration (200 mg/kg bw) or i.v. injection (150 mg/kg bw) to 3 animals per group was investigated. The highest level was found in the muscles and intestines.

Details on excretion:

The analytical method by GLC was sufficient to determine free Morpholine in biological fluids. Morpholine salts were rapidly excreted by rats after peroral or intravenous administration. The urinary excretion accounted for most of the dose and a small fraction was found in the faeces. The elimination patterns were essentially similar for Morpholine-HCl and –palmitate. Morpholine was excreted almost unchanged in the rat urine. Ninety percent of the original dose was found in the urine after 3 days and 0.08 to 0.14 % was found in the faeces.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Thin-layer chromatography of concentrated urine revealed only the existence of 14C-Morpholine which indicated the same Rf values as those of the authentic sample in some solvents. It became clear that Morpholine was mainly excreted unchanged in the urine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Morpholine exhibited a very low bioaccumulation potential. Morpholine appeared to be an inert substance in the body.

Executive summary:

In this toxicokinetic study provided by Tanaka et al. (1977), elimination, distribution and metabolism of Morpholine salts in rats were investigated by means of chemical analysis and/or radioassay. Gas-liquid chromatography was used for chemical analysis of Morpholine in the rat urine and faeces. The distribution of 14C-labeled Morpholine via oral administration (200 mg/kg bw) or i.v. injection (150 mg/kg bw) to 3 male animals per group was investigated. The analytical results of the excreta accorded with those made by the tracer technique. When rats were given Morpholine-HCl or -palmitate, about 90% of the dose was excreted in the urine over a period of 3 days and the remaining in the faeces (0.08 to 0.14 %). Morpholine was largely excreted unchanged in the urine: Ninety percent of the original dose was found in the urine after 3 days. The lowest affinity was found for adipose regardless of routes of administration. The elimination of Morpholine from organs, tissues and blood was generally rapid and specific organ-affinity was not observed in other organs except the intestine. The highest level was found in the muscle and intestine.

This toxicokinetic study in the rat is as classified acceptable.