Toxicokinetic and mass balance of morpholine in rats

Abstract

1. Morpholine (MOR) has a broad spectrum of use and represents high risk of human exposure. Ingested MOR can undergo endogenous N-nitrosation in the presence of nitrosating agents forming N-nitrosomorpholine (NMOR), classified as possible human carcinogen by the International Agency for Research on Cancer.

2. In this study, we evaluated the MOR toxicokinetics in six groups of male Sprague-Dawley rats orally exposed to 14C-radiolabelled MOR and NaNO2. The major urinary metabolite of MOR, N-nitrosohydroxyethylglycine (NHEG), was measured through HPLC as an index of endogenous N-nitrosation. Mass balance and toxicokinetic profile of MOR were determined by measuring radioactivity in blood/plasma and excreta.

3. MOR reached maximum blood concentration 30 minutes after administration. Elimination rate was rapid (70% in 8h). Most of the radioactivity was excreted in the urine (80.9 ± 0.5%) and unchanged 14C-MOR was the main compound excreted in the urine (84% of the dose recovered). 5.8% of MOR is not absorbed and/or was not recovered.

4. Endogenous nitrosation of MOR was demonstrated by the detection of NHEG. The maximum conversion rate found was 13.3 ± 1.2% and seems to be impacted by the MOR/NaNO2 ratio.

5. These results help refining our knowledge of the endogenous production of NMOR, a possible human carcinogen.

Keywords:

• Toxicokinetic
• morpholine
• endogenous
• N-nitrosation
• N-nitrosomorpholine
• oral exposure

Disclosure statement

The authors AP, SK, SR, MB, SA, PAC are employed by Electricité de France (EDF).

Additional information

Funding

This work was supported by Electricité de France (EDF).