Absorption, distribution, and biotransformation of hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine in B6C3F1 mice (Mus musculus)

Abstract

Absorption, distribution, and biotransformation are 3 critical aspects affecting toxicant action in animals. In the present study, B6C3F1 mice (Mus musculus) were exposed for 28 d to contaminated feed that contained 1 of 5 different hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) concentrations: 0 mg/kg, 0.5 mg/kg, 5 mg/kg, 50 mg/kg, and 500 mg/kg. The authors quantified RDX and its reductive transformation products hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) in the stomach, intestine, plasma, liver, and brain of these mice. Average RDX concentrations followed a dose-dependent pattern for all matrices tested. No controls had concentrations above limits of detection. Average RDX concentrations in tissues of exposed mice ranged from 11.1 ng/mL to 182 ng/mL, 25.6 ng/g to 3319 ng/g, 123 ng/g to 233 ng/g, 144 ng/g to 35 900 ng/g, and 51.1 ng/g to 2697 ng/g in the plasma, brain, liver, stomach, and intestine, respectively. A considerable amount of RDX was present in the brain, especially in the highest-exposure group. This is consistent with the widely observed central nervous system effects caused by γ-aminobutyric acid inhibition associated with RDX exposure. N-nitroso metabolites of RDX were also present in tested tissues in a dose-dependent pattern. Average MNX concentrations in the stomachs of mice exposed to RDX ranged from nondetectable in control exposures to 490 ng/g in the highest-exposure groups. In the brain, MNX accumulated at a maximum average concentration of 165.1 ng/g, suggesting the potential formation of MNX from RDX within the brain. At higher exposures, DNX and TNX were present in the stomach, plasma, and brain of mice. The presence of RDX metabolites at notable amounts in different tissues suggests that RDX can transform into its N-nitroso metabolites in vivo by an undefined mechanism.

Wildlife Toxicity Assessment for 1,3,5-Trinitrohexahydro-1,3,5-Triazine (RDX)

“…Bhushan et al [16], used rabbit liver cytochrome P450 in vitro. In vivo metabolism of RDX has been shown in both deer mice (Peromyscus maniculatus) [19] and a laboratory mouse strain (B6C3F1) [20], with nitroso-derivatives found at low concentrations (relative to RDX) in the stomach and brain and other organs, but none of these studies measured the ring cleavage products NDAB or MEDINA. In addition, two novel metabolites, 4-nitro-2, 4-diazabutenal (NDAB) and MEDINA, were produced under aerobic or anaerobic conditions, respectively.…”