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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Toxicology of Cyclotrimethylenetrinitramine distribution and metabolism in the rat and the miniature swine

Author:

SCHNEIDER NR, BRADLEY SL, ANDERSEN ME

Year:

1977

Bibliographic source:

Toxicology and applied pharmacology, 39, pp 531-541

Materials and methods

Objective of study:

distribution

metabolism

Test guideline

Qualifier:

no guideline followed

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

RDX

IUPAC Name:

RDX

Test material form:

solid: crystalline

Details on test material:

RDX, stored wetted with 50% alcohol, was air-dried, weighed, and administered either as a slurry in isotonic saline or dissolved in DMSO.
Randomly RDX [14C] (>97% purity; specific gravity: 4.25 mCi/mmol), dissolved in acetone, was added to unlabeled RDX.
The RDX solution was evaporated to dryness and reconstituted with DMSO, yielding a solution with 50 mg of RDX/mL and 4-7 µCi of 14C/mL.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

other: intraperitoneal, oral and intravenous administration

Vehicle:

DMSO

Duration and frequency of treatment / exposure:

No data available

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Intraperitoneal administration:
10 rats dosed ip with 500 mg RDX/kg had severe, clonic-tonic convulsions and 8 rats died within 6 hr. The two rats not killed by RDX were sacrificed after 3.5 and 6.5 hr. The times to first seizure and death were 23.8 +/- 6.9 min and 171 +/- 37.4 min, respectively; the number of convulsions per rat was 10 +/- 1.6. The interpolated plasma RDX concentration at first seizure was 5.2 +/- 0.4 µg/mL. Tissue were removed at death or sacrifice for RDX analysis.
Plasma urine samples were collected at 10 min intervals for 2 hr from two rats dosed ip with 50 mg/kg. Plasma RDX concentrations increased to 1.05 +/- 0.05 µg/mL at 90 min and then reached a plateau; at 2 hr the concentration of RDX was 1.09 +/- 0.04 µg/mL.
Urine RDX concentrations, 2.8 +/- 0.4 µg/mL at 2 hr.

Oral administration:
Groups of 10 rats each were sacrificed at specific times up to 24 hr after being dosed by gavage with 100 mg/kg, and plasma and tissue RDX concentrations were determined.

Intravenous administration:
Ten rats were injected iv via femoral vein catheter with 0.125 mL of a solution of 10 mg RDX/ mL in DMSO, representing a dosage of 5-6 mg/kg. Plasma RDX cocentration at 30 sec was 4.4 +/- 0.35 µg/mL and decreased to 1.9 +/- 0.17 µg/mL at 6 hr. The plasma disappearance was biphasic. The distribution phase t1/2 was 6.32 +/- 0.18 min, the elimination phase was 10.1 +/- 0.32 hr, and the volume of distribution was 2.18 L/kg.
Convulsions occurred within seconds after starting the injection and ceased within 1 min after completion of the injection.

Details on excretion:

All 10 rats dosed by gavage with 50 mg/kg RDX/kg, using a more finely powdered RDX than was used in the previous experiments, convulsed, within 2 hr of dosing and two died. Urine, plasma, and fecal RDX were monitored for 14 days in the surviving rats. The daily fecal dry mass from these rats decreased to 25% of normal for the first 2 days after dosing, but returned to normal by Day 4, and the total fecal excretion of RDX in the first 6 days was 0.69 +/- 0.05%. Total urinary excretion of RDX during the first 6 days was 2.37 +/- 0.15% and appreciable amounts of RDX were not excreted in either the urine or the feces after the first week.

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

10 rats were dosed by gavage with 50 mg of [14C]RDX /kg. The value of tissue radioactivity at 24 hr were divided by the specific activity of the RDX to yield values of a theoretical RDX concentration, which assumed the radioactivity to be totally associated with RDX. These data were compared with data of actual tissue RDX concentrations from rats dosed by gavage with 100 mg of RDX/kg. Even though this comparison is between groups of rats dosed with different amounts of RDX, the difference between radioactivity and the concentration of RDX is, if anything, underestimated. The urine RDX of rats dosed with [14C]RDX was, for instance, 2.61 +/- 0.25 µg/mL, which would account for only 3.6% of the total urinary radioactivity.

To complete the investigation of RDX metabolism, three groups of 10 rats each were dosed by gavage with 50 mg of [14C]RDX/kg: the first group was used for urine collection, the second group was used for 14CO2 collection, and the last was used for preparation of whole-body homogenates at 96 hr after dosing. The excretion of radioactivity after 4 days was 9.5 +/- 0.3%; carcass residual RDX was 0.3 +/- 0.05 µg/g, only 0.6% of the original dose. Fecal radioactivity did not exceed 3% of the total administered.

Total recovery of radioactivity at 4 days was approximately 90%:
- 3% in feces,
- 10% in carcass,
- 34% in urine,
- 43% as 14CO2

Any other information on results incl. tables

In the rat, the distribution of RDX was essentially unaffected by route of administration or by dosage. The volume of distribution, 2.2 L/kg and the tissue/plasma ratios during the first 24 hr indicate that RDX does accumulate to some extent in all tissues examined.

However, RDX was not preferentially found in lipid-rich tissues of the central nervous system. In fact, the kidney consistently contained the highest concentration of RDX, but this concentration was at most only two to three-times the RDX content of the heart or brain.

While the RDX concentration in most tissues was fairly stable between 2 and 24 hr following oral administration, liver concentration varied widely, and the liver contained greater amounts of radioactivity than expected based on its RDX content, indicating the presence of RDX metabolites in this organ.

In these experiments, RDX was either given as a saline slurry or dissolved in DMSO. Rats dosed by gavage with 100 mg RDX/kg using a coarse, granular preparation of RDX did not convulse, but 10 rats dosed with 50 mg/kg using a finely powdered preparation all convulsed and two died. Approximately 20% of the rats in the metabolism studies died after being dosed by gavage with 50 mg of [14C]RDX/kg in DMSO solution. The acute LD50 of RDX was dependent on the physical form of the RDDX and on the method used to suspend or dissolved it.

Regarding these present experiments, the oral toxicity of the more finely powdered RDX, whose saline slurry was more stable, was equivalent to the oral toxicity of DMSO solutions of RDX. Both had LD50 values of about 100 mg/kg. The LD50 of the coarse, granular RDX was approximately 300 mg/kg. Differences in toxicity of these preparations were mirrored by the plasma RDX concentrations reached in rats dosed with different particle size RDX. Plasma RDX at 24 hr after a dose of 100 mg of coarse, granular RDX/kg was 3.04 µg/mL, while it reached 4.7 µg/mL after dose of only 50 mg of finely powdered RDX /kg.

Conclusions as to the distribution of RDX and its uptake and elimination kinetics are, however, equivalent regardless of how the RDX was prepared for dosing. Plasma RDX concentrations reached a dose-dependant plateau within several hours, maintained it for 24 hr and then declined over the next 2 days. Although qualitative comparisons between experiments with different RDX preparations should not be affected, quantitative comparisons between such experiments should be avoided if possible.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
According to the results obtained in this study, a large majority of RDX was totally recovered after 4 days in rats after gavage and the RDX metabolites were mainly localised in liver and in urine 24 hours after po dosing.
The authors suggest that it exist a dose-dependent particle size of RDX in the acute oral toxicity.