Metabolite Profiling of [¹⁴C]hexahydro-1, 3, 5-trinitro-1,3,5-triazine (RDX) in Yucatan Miniature Pigs

Abstract

The study reported herein examined the metabolism of 14C-labeled hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) resulting from a single oral gavage of 5 ml/kg to male and female Yucatan miniature pigs (43 mg/kg, 56 microCi/kg in 0.5% carboxymethylcellulose in water). Blood, urine, and feces were collected at selected times of 1, 6, 12, and 24 h postdose. At 24 h postdose, liver samples were collected. Blood, plasma, liver, and excreta were analyzed for total RDX-derived radioactivity and metabolites were identified. Urine was the major route of elimination of 14C-RDX-derived radioactivity in both males and females. Relatively low levels of radioactivity were found in gastrointestinal contents and in feces, suggesting nearly complete absorption of 14C-RDX following an oral dose. Analysis of urine by liquid chromatography-mass spectrometry (LC/MS) identified quantifiable levels of two ring-cleavage metabolites, 4-nitro-2,4-diazabutanal and 4-nitro-2,4-diaza-butanamide, as well as parent RDX. The 4-nitro-2,4-diazabutanal, was seen in earlier studies of aerobic metabolism of RDX. The 4-nitro-2,4-diaza-butanamide, an amide, was not previously reported but was tentatively identified in this study. Analysis by a more sensitive method (LC/MS/MS) also showed trace amounts of the RDX metabolites 1-nitroso-3,5-dinitro-1,3,5-triazacyclohexane (MNX) (in both male and female urine) and 1-nitro-3,5-dinitroso-1,3,5-triazacyclohexane (DNX) (in male urine). Analysis of plasma by LC/MS/MS also revealed quantifiable levels of RDX and trace levels of MNX, DNX, and 1,3,5-trinitroso-1,3,5-triazacyclohexane (TNX). None of the liver extracts showed quantifiable levels of RDX or any identifiable metabolites. Most of the radioactivity was in the form of water-soluble high-molecular-weight compounds. RDX when given orally to pigs was rapidly metabolized by loss of two nitro groups followed by ring cleavage.

Toxic effects of cyclonite (C‐4) plastic explosive ingestion in a dog

“…A study performed in pigs fed 43 mg/kg of RDX found 2 other metabolites in the urine; 1‐nitrosos‐3, 5‐dinitro‐13,5 triazacyclohexane (MNX) and 1‐nitro‐3, 5 dinitroso‐1,3,5‐triazacyclohexane (DNX). It is unknown at this time if these metabolites cause renal damage 7 …”

“…It is unknown at this time if these metabolites cause renal damage. 7 Working dogs, especially those that are exposed to explosive materials are at risk of ingesting C-4. During the training period, the explosive may not be completely packaged in order for the scent to be as potent as possible.…”

Development of a Relative Source Contribution Factor for Drinking Water Criteria: The Case of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

“…The major route of elimination was through urine in Yucatan miniature pigs. The analysis of liver samples by HPLC showed no parent compound RDX and no metabolites were detected (Major et al 2007).…”

Evaluation of natural and nitramine binding energies to 3-D models of the S1S2 domains in the N-methyl-D-aspartate receptor

“…The widespread use of RDX and HMX after World War II has resulted in their presence in at least 16 of the 1397 hazardous waste sites on the National Priorities List [24], and they are found as pollutants in soil [25,26] and the air [27] around or near munitions manufacturing sites. In mammals, the clinical outcome of oral administration of RDX is the rapid onset of seizures (skeletal muscle convulsions) and increased salivation in humans [28], rats [29][30][31], mice [32], pigs [33], northern bobwhite quail [34], and western fence lizards [35]. Recently, evidence that RDX binds to the γ-aminobutyric acid type A receptor (GABA A R) instead of the NMDAR was presented [36].…”