Abstract  The acute toxicity of TNT, RDX, LAP (1.6 TNT/1.0 RDX), and/or LAP(I) (photolyzed LAP: 0.032 TNT/1.0 RDX, 10% undegraded RDX) was determined in mammalian species. In male and female rats, respectively, the acute oral LD50s were: TNT, 1320 and 794 mg/kg; RDX, 71 and about 70 mg/kg; and LAP, 574 and 594 mg/kg or lower, depending on particle size. In male and female mice, respectively, the LD50s were: TNT, 660 mg/kg (both sexes); RDX, < 75 and 86 mg/ kg; and LAP947 and 1131 mg/kg. LAP(I) was examined in mice only; the acute oral LD50s in males and females were: 585 and 684 mg/kg, respectively. LAP and LAP(I) produced conjunctivitis, iritis, and/or corneal opacity in rabbit eyes; the irritation was not totally reversed in unwashed eyes after 7 days and longer. In in vitro microbial assays using microsomal activation (Ames Test), TNT was mutagenic. LAP was also mutagenic, and photolysis increased its mutagenicity. In contrast, in vivo cytogenetics studies on rat bone marrow extracts failed to detect an effect of either TNT or LAP on somatic cells. The effects of repeated oral administration of TNT and of LAP were determined in 90-day studies in dogs, rats, and mice. Observations common to the three species treated with either test material were depressed body weight and/or weight gain and food intake, mild to moderate hemolytic anemia, enlarged spleens.

Abstract  Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a widely used munitions compound, and hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), its N-nitroso product of anaerobic microbial nitroreduction, are contaminants of military sites. Previous studies have shown MNX to be the most acutely toxic among the nitroreduced degradation products of RDX and to cause mild anemia at high dose. The present study compares hematotoxicity with acute oral exposure to MNX with parent RDX. Both RDX and MNX caused a modest decrease in blood hemoglobin and ~50% loss of granulocytes (NOAELs=47 mg/kg) in female Sprague-Dawley rats observed 14 days post-exposure. We explored the possibility that blood cell loss observed after 14 days was delayed in onset because of toxicity to bone marrow (BM) progenitors. RDX and MNX decreased granulocyte/macrophage-colony forming cells (GM-CFCs) at 14, but not 7, days (NOAELs=24 mg/kg). The earliest observed time at which MNX decreased GM-CFCs was 10 days post-exposure. RDX and MNX likewise decreased BM burst-forming units-erythroid (BFU-Es) at 14, but not 7, days. Granulocyte-erythrocyte-monocyte-megakaryocyte (GEMM)-CFCs were unaffected by RDX and MNX at 7 days suggesting precursor depletion did not account for GM-CFC and BFU-E loss. MNX added to the culture media was without effect on GM-CFC formation indicating no direct inhibition. Flow cytometry showed no differential loss of BM multilineage progenitors (Thy1.1(+)) or erythroid (CD71(+)) precursors with MNX suggesting myeloid and erythroid lineages were comparably affected. Collectively, these data indicate that acute exposure to both RDX and MNX caused delayed suppression of myelo- and erythropoiesis with subsequent decrease of peripheral granulocytes and erythrocytes.

Abstract  The object of this report is to present the results of a study of the toxic effects of cyclomethylenetrinitramine on the brain after chronic administration to male rats. In 1973 the Department of Pharmacology and Toxicology of the University of Maryland School of Pharmacy contracted with Office of Naval Research to screen several parameters of central nervous system function for possible effects from three months' exposures to cyclomethylenetrinitramine.

Abstract  This study was conducted to evaluate the dermal toxicity of the munitions compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX; CAS Reg. No. 121-82-4) in New Zealand Albino rabbits after a single application of 2 g/kg in carboxymethylcellulose (1%). Toxicoogical endpoints included body weight measurements, observations of clinical signs and mortality. Although two males died during the 14 day observation period, gross necropsy and microscopic examination found Tyzzar's Disease as the cause of death. A slight, transient body weight loss was evident for most of the surviving animals, and no other signs of toxicity were observed. To ensure the integrity of the results, the study was repeated only on male rabbits of the same strain but from a different supplier. This repeat study resulted in no more mortality. The results of acute dermal toxicity of RDX, 2g/kg in carboxymethylcellulose on single application to rabbit skin show a slight transient body weight loss, no clinical signs of toxicity, and found no mortality in male and female rabbits up to a 14-day observation period.

Abstract  1. PURPOSE. This study was conducted to assess the feasibility of using exhaled breath condensate as a non-invasive sampling method for measuring biomarkers ofRDX exposure in Yorkshire pigs. A secondary objective was to assess the absorption and distribution of a single oral dose ofRDX throughout the body. 2. CONCLUSION. Breath sampling of juvenile swine was considered technically feasible for this kind of study while simultaneous sampling of blood from the ear permitted monitoring of RDX absorption over time. This model can be used again for this kind of study. 3. RECOMMENDATION. Use this model to continue studies on breath analysis of swine with modifications and more effective trapping of breath.

Abstract  A study of the toxicology of the explosives cyclotrimethylenetrinitramine (RDX) and cyclotetramethylenetetranitramine (HMX) in acetone, cyclohexanone, and pure and technical grade dimethylsulfoxide (DMSO) was initiated to establish whether there is any danger to plant personnel that handle such mixtures. This report contains a review of the existing literature on each explosive and on each solvent. It also describes tests that were conducted to establish the intravenous toxicity of the explosives in DMSO, the skin effects, the pharmacological effects, the sensitization potential and the ocular effects of the explosives in each solvent. In mice, the intravenous LD50 for RDX in DMSO is 18.7 mg/kg and for HDX in DMSO in 28.9 mg/kg. In guinea pigs, the intravenous LD50 for RDX in DMSO is 25.1 mg/kg and for HDX in DMSO is 28.2 mg/kg. The LD50’s of RDX and HMX in other solvents were not established. RDX and HMX in the three solvents did not penetrate the skin, as evidenced by the lack of physiological responses in dogs and unchanged blood component values in rabbits. From the intravenous studies in dogs, it was shown that acetone and cyclohexanone alone exert a depressant effect on the cardiovascular system. Cyclohexanone also causes changes in the electroencephalogram pattern and produces a semicomatose to comatose condition. DMSO had relatively little effect. Therefore, the majority of these studies were done with the explosives in DMSO. It was found that the immediate effects of RDX and HDX differ, RDX affecting the CNS immediately and HDX producing a circulatory collapse initially, with delayed CNS disturbances. Topically and intradermally applied RDX and HDX in the three solvents did not produce usually any greater skin damage than the solvents alone, but there were several exceptions. Repeated topical applications caused dermatitis without fissures, eschars, or scabs, but intradermal injection caused severe skin damage. Topical or intradermal application of the solvents or of RDX and HMX in the solvents 3 days a week for 3 weeks, followed in 2 weeks by topical or intradermal challenge, gave no evidence of sensitixzation. Ocular administration showed that RDX and HMX are no more damaging than the solvents alone, but the solvents themselves cause cataracts in guinea pigs. From these studies, it is evident that strict precautions should be taken to avoid skin and ocular contact with HMX and RDX in the solvents studied.

Abstract  Dose-effect and time course relationships were determined for the effects of the explosive cyclotrimethylenetrinitramine (RDX) on seizure susceptibility. Male Long Evans rats treated with 0-60 mg/kg RDX po were monitored for spontaneous seizures during an 8-hr interval between dosing and audiogenic (AG) seizure testing. Blood samples for analyzing plasma RDX concentrations were obtained immediately thereafter. Spontaneous and AG seizures were observed at dosages as low as 10-12.5 mg/kg, with significant seizure incidence induced by dosages of 25.0 mg/kg (5.34 micrograms RDX/ml plasma) and 50.0 mg/kg (8.28 micrograms RDX/ml plasma), respectively. Spontaneous seizure incidence peaked at 2 hr for all RDX treatment groups, then decreased (12.5 and 25.0 mg/kg) or remained elevated (50.0 mg/kg) for the remaining 6 hr. In contrast, AG seizures (37.5 mg/kg) could be elicited only at 8 and 16 hr, despite significant elevation of plasma RDX concentrations at 2 and 4 hr. Because limbic system involvement was suggested by spontaneous seizure characteristics, the rate of amygdaloid kindling was measured following daily treatment with 6.0 mg/kg. This dosage significantly accelerated kindling development without inducing spontaneous seizures or producing an accumulation of RDX in plasma. These data provide preliminary evidence that limbic structures may participate in RDX-induced seizure susceptibility.

Abstract  C-4 (cyclonite) explosive ingestions are rarely reported in the literature. We report the case of a canine ingestion of cyclonite that resulted in seizures unresponsive to conventional treatment. Case Report: A 3-year-old, otherwise healthy, male Rottweiler ingested approximately 1 cubic cm of C-4 explosive during an exhibition exercise. The owner reported vomiting after 30 minutes and generalized seizure-like activity 4 hours after ingestion. The dog was brought to a health care center where 8 further generalized seizures occurred over 10 hours. Treatment consisted of several doses of benzodiazepines and barbiturates in addition to supportive care. After the eighth seizure, the dog was placed on a continuous intravenous infusion of propofol, which was continued until 60 hours after ingestion. A granular odorous material was retrieved rectally after several high warm saline enemas. The dog made a complete recovery and was released after 72 hours. Conclusion: C-4 (cyclonite) ingestion is rarely reported in the literature. Seizures that occur after exposure may be prolonged and recalcitrant to conventional therapy warranting aggressive treatment.

Abstract  RDX is found in soil and ground water in and surrounding training ranges, creating potential hazards to human health. Oral RDX over-exposure causes seizure in rats and humans, the mechanism of which is unknown. In this study rats were dosed orally at 75 mg/kg RDX to induce seizure. The brain concentration of RDX was determined in samples taken from rats euthanized at the time of seizure onset: brain acetylchohnesterase was also measured. Also, RDX was screened for affinity to a library of brain receptors to determine if RDX affected any seizure-related targets. Brain concentrations of RDX were greater than 8 microg/g wet wt. in the animals that seized. RDX was found to bind exclusively to the convulsant site on the GABAa receptor with an IC 50 of 22 microM. The mechanism of RDX-induced seizure is likely due to dis-inhibition of excitatory neurons by blockage of the GABA-mediated inhibitory chloride current. This valuable information contributes mode of action insights that can be used in the physiologically-based pharmacokinetic modeling to extrapolate rat data to human.