Perhydro-1,3,5-trinitro-1,3,5-triazine

Endpoint summary

Description of key information

Very little is known regarding the toxicokinetics of RDX in humans, but reports of adverse effects following inhalation and oral exposure and measurements of RDX in blood from poisoned individuals indicate that RDX is absorbed through the lungs and the gastrointestinal tract. No information is available regarding the distribution and metabolism of RDX in humans.

A single case study found RDX in the cerebrospinal fluid following oral exposure (Woody et al, 1986), suggesting possible distribution to the nervous system. RDX was almost completely absorbed in miniature pigs after a single oral dose (Major and Reddy, 2007). In rats, mixing RDX with soil considerably reduced absorption compared to administration of neat RDX (Crouse et al, 2008). No preferential accumulation of RDX in specific tissues has been reported in animal studies (Schneider et al, 1977; Schneider et al, 1978).

Several metabolites were identified in the urine from miniature pigs dosed orally with RDX (Major and Reddy, 2007). The urine was the main route of elimination of 14C-RDX-derived radioactivity (Schneider et al, 1977).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption:

The mechanism(s) of absorption of RDX is not known. There are no studies that calculated rates of absorption that could have provided some indication of a possible mechanism of absorption. In rats administered RDX in a capsule, peak blood concentrations were achieved 4–6 hours after dosing (Crouse et al, 2008). In a male miniature pig given a single gavage dose of RDX as a suspension in 0.5% carboxymethylcellulose in water, peak plasma concentration of RDX occurred at approximately 12 hours after dosing, which would suggest a relatively low rate of absorption. Studies with excised human and pig skin showed that mixing RDX with soil significantly reduced dermal absorption relative to RDX neat (Reddy et al, 2008; Reifenrath et al, 2002).

Distribution:

No specific mechanism of distribution was apparent in the available studies. In rats, the distribution of RDX (single doses) seemed unaffected by the route of administration (parenteral vs. oral) or by the dose (Schneider et al, 1977). The concentration of RDX-derived radioactivity in most tissues was fairly stable between 2 and 24 hours after dosing except in the liver, where it fluctuated widely. High concentrations of radioactivity occurred in the liver at 2, 12, and 24 hours after dosing, which led Schneider et al. (1978) to suggest that there might be diurnal variations in the hepatic metabolism of RDX. In 90-day studies, RDX did not accumulate in any of the tissues examined (Schneider et al, 1978).

Metabolism:

The metabolism of RDX has been studied in some detail in miniature pigs (Major and Reddy, 2007) and there is some evidence suggesting that a cytochrome orthologue to the rabbit, CYP2B4, may be involved (Bhushan et al, 2003). The two major metabolites characterized were 4-nitro-2,4-diazabutanal and 4-nitro-2,4-diazabutanamide. Trace amount of MNX, DNX, and TNX were also detected. Some studies have provided some information regarding the role of metabolism in the toxicity of RDX.

In rats, administration of RDX intravenously resulted in convulsive activity within seconds after the injection, which suggested that the convulsions are produced by the parent compound (Schneider et al, 1977). In a 90-day gavage study in monkeys, convulsive events were associated with higher RDX concentrations in plasma (Martin and Hart, 1974), which would also support the idea of the parent compound being responsible for the convulsive activity. More recently, Meyer et al. (2005) reported that MNX and RDX were equipotent in inducing convulsions and lethality in female Sprague-Dawley rats in single-dose gavage studies of 14-day duration; both DNX and TNX were less potent. In a study of age-dependent acute toxicity of RDX in deer mice, Smith et al. (2007) reported that, for all three age brackets tested, RDX was significantly more potent than MNX and TNX.

Excretion:

The urine and exhaled CO2 were the main routes of excretion of 14C-RDX-derived radioactivity in rats following acute- or intermediate-duration exposure to RDX (Schneider et al, 1977; 1978). In the acute studies, only 3% of the administered radioactivity was recovered in the feces over a 4-day period (Schneider et al, 1977). The urine was also the main excretory route of radioactivity in miniature pigs following a single gavage dose of RDX (Major and Reddy, 2007). No information was located regarding how the size of the dose might affect the distribution of metabolic products among excretory pathways.