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Updated: Jul 23, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Toxicokinetic and mass balance of morpholine in rats

Aleksandra Piotrowski1, Saïd Kinani2, Fabrice Nesslany3

  • 1EDF - Industrial Toxicology Division at EDF, General Direction of Safety and Health, Paris, France.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|July 11, 2023
PubMed

Insights

Morpholine (MOR) exposure poses risks, as it can form the carcinogen N-nitrosomorpholine (NMOR) in the body. This study tracked MOR

Area of Science:

  • Toxicology
  • Pharmacokinetics
  • Carcinogenesis

Background:

  • Morpholine (MOR) is widely used, leading to significant human exposure risks.
  • Ingested MOR can form N-nitrosomorpholine (NMOR), a potential human carcinogen, via endogenous nitrosation.
  • Understanding MOR toxicokinetics is crucial for assessing NMOR-related health risks.

Purpose of the Study:

  • To investigate the toxicokinetics of morpholine (MOR) following oral administration in rats.
  • To assess the extent of endogenous N-nitrosation of MOR by measuring its metabolite, N-nitrosohydroxyethylglycine (NHEG).
  • To determine the mass balance and excretion profile of radiolabeled MOR.

Main Methods:

  • Oral administration of 14C-radiolabeled MOR and sodium nitrite (NaNO2) to Sprague-Dawley rats.
  • Quantification of radioactivity in blood, plasma, urine, and feces to establish mass balance and toxicokinetic profiles.
  • Measurement of N-nitrosohydroxyethylglycine (NHEG) in urine using High-Performance Liquid Chromatography (HPLC) as a biomarker of endogenous nitrosation.

Main Results:

  • MOR rapidly reached peak blood concentrations within 30 minutes and was quickly eliminated (70% in 8 hours).
  • The majority of radioactivity was excreted in urine (80.9%), primarily as unchanged MOR (84% of recovered dose).
  • Endogenous nitrosation of MOR was confirmed by NHEG detection, with a maximum conversion rate of 13.3%, influenced by the MOR/NaNO2 ratio.

Conclusions:

  • MOR exhibits rapid absorption and elimination in rats, with urinary excretion of unchanged MOR being the predominant pathway.
  • The study confirms endogenous nitrosation of MOR, demonstrating the formation of NHEG and indicating a conversion rate dependent on reactant concentrations.
  • These findings contribute to a better understanding of endogenous N-nitrosomorpholine production, relevant to human carcinogen risk assessment.
Keywords:
N-nitrosationN-nitrosomorpholineToxicokineticendogenousmorpholineoral exposure

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