Abstract  Acute oral LD50's and standard errors were 119.0 +/- 4.6, 118.7 +/- 4.5, and 118.1 +/- 2.8 mg/kg in male, female and combined sexes of rats. The corresponding mouse LD50's were 97.2 +/- 8.7, 58.9 +/- 26.8, and 80.3 +/- 9.6 mg/kg, respectively. There were no statistically significant sex differences in either species. Toxic signs, including gasping, labored breathing and convulsions, indicated neurotoxicity.

Abstract  Male LACA mice were administered 3H-RDX orally or intravenously at dosages of 203.5 x 10(3)Bq(5.5[mu]Ci) per mouse and 112.85 x 10(3)Bq (3.05[mu]Ci contains 0.55mg RCX) per mouse. After administration, mice were sacrificed at different times. Tissues such as organs, blood, urine and feces were collected for testing. The test results demonstrated that 3H-RDX can be rapidly distributed through the blood to other tissues regardless of administration method. For oral administration, T1/2Ka = 5 min and T1/2 = 50.4 min. For intravenous administration, T1/2 = 9 min. In the case of intravenous administration, the order of 3H-RDX levels observed as a function of organ was: lung > heart > liver > kidney > brain > spleen > testicle > fat > muscle; in the case of oral administration, the order of 3H-RDX peak levels observed was: liver > kidney > muscle > lung > spleen > heart > brain > testicle > fat. It was also demonstrated that for both administration methods the radioactivity decreased significantly in 12-24 hours. Seven days after oral administration, the radioactivity in different organs dropped almost to background levels; after intravenous administration, mice immediately suffered from seizures, shock, etc, and recovered after 1.5 min. The RDX concentration in blood and brain tissue at the time was 1.57g/ml and 0.82g/g, respectively. When administered orally, the speed of 3H-RDX excretion via the urine was faster than via feces, at a ratio of 1.3:1. The total amount excreted via both urine and feces on day 1 was 64.82% of the total administered amount. The results suggest that 3H-RDX is widely distributed in mice and excreted via urine and feces. No significant 3H-RDX accumulation was observed in the tissues that were tested. Hexogen (RDX), i.e., cyclotrimethylene trinitramine, is a type of high explosive that is more powerful than TNT. It has been extensively used in the armament industry of our country. Hexogen is in the form of a white powder. The melting point is 203 oC. It is slightly soluble in water, not soluble in ether and carbon tetrachloride, and soluble in dimethylsulfoxide, acetone, cyclohexanone, hot aniline, phenol, and nitrobenzene[1]. It was earlier reported by Sanderman [2] that the oral LD50 for non-fasting rats was 200 mg/kg and 50-100 mg/kg for fasting rats. Most of the RDX was excreted in its original form via feces within three weeks, and only 1-2% was excreted via urine. It was reported by Skhlyanskaya [3] that the oral LD50 for mice is 500 mg/kg. If a dose of 20 mg/kg was orally administered for 30 consecutive days, mice gradually grew weaker and possibly died, however without demonstrating any nervous system symptoms. It was reported by Von Ottingen [5] that the oral LD50 for rats is 200 mg/kg; no intoxication was observed if a dose of 15mg/kg was fed daily to rats for 3 months. Schneider [4] recently reported the distribution and metabolism of RDX in rats and piglets and demonstrated that RDX was distributed evenly in animals and had no accumulating organs. Sun [6] also proved that RDX has no significant accumulation in rats, however, significant degeneration of nerve cells and a series of pathological changes in lung, heart, liver, gastrointestinal and testicular tissue occurred in fatally intoxicated animals. In order to further explore the effects of RDX on the body and clarify how RDX is absorbed, distributed and excreted, a study was conducted using oral and intravenous administration of 3H-RDX in mice.

Abstract  The neurobehavioral effects of Hexogen were investigated in 60 exposed workers (with a control group consisting of 32 people) using a neurobehavioral test battery consisting of memory retention, simple reaction time, choice reaction time, letter cancellation and block design. The physical examination results exhibited no significant differences (P > 0.05). Memory quotient and block design scores of the exposed group were significantly lower than those of the control group (P < 0.01). The total behavioral test score was in good linear correlation with the symptom score and exposure index (R = 0.5232, P < 0.01), suggesting that long-term low-level exposure (X = 0.407 ± 0.382 mg/m3) to Hexogen affects the behavioral functions of exposed individuals.

Abstract  We hypothesized that CYP3A N -dealkylation of alachlor is a key determinant in hepatocyte cytotoxicity and that such metabolism has relevance to human hepatotoxicity. Results show that highly N -dealkylated chloroacetanilides alachlor and acetochlor were potent cytotoxicants compared to negligible N -dealkylated metolachlor to Sprague-Dawley (SD) rat hepatocytes (NRH). Higher cytotoxicity of N -dealkylated alachlor metabolite CDEPA in NRH suggests that N -dealkylation is a bioactivation process. Sensitization to alachlor cytotoxicity in hepatocytes from dexamethasone-pretreated rats (DRH), and lower alachlor cytotoxicity with a potent CYP3A inhibitor (clotrimazole) correlated with the rate of CDEPA formation supports a critical role of CYP3A N -dealkylation. In contrast, alachlor cytotoxicity in cryopreserved human hepatocytes is inversely correlated with CYP3A4 indicating its involvement in detoxication. Further, comparable cytotoxicity of alachlor, acetochlor, and metolachlor suggests species-specific mechanisms of toxicity for these chloroacetanilides with a greater relative risk of adverse effects from metolachlor in humans than predicted from rat studies. RDX (hexahydro-1,3,5-trinitro-1,3,5-trazine) is widely used munitions compound and now contaminate soil and ground water at artillery training and manufacturing sites. RDX is anaerobically degraded to mono di and tri N -nitroso products MNX, DNX and TNX, respectively. MNX is the most potent of three degradation products in-terms of LD 50 and anemia. We hypothesized that transformation of RDX to MNX decreases hematotoxicity. Results are obtained from studies conducted using female SD rats indicate that 14-day acute oral exposure to RDX and MNX resulted in anemia (NOAEL 47 mg/kg). RDX was more potent than MNX in decreasing peripheral blood leukocytes and bone marrow cellularity. RDX and MNX were found to decrease Burst Forming Units-Erythroblasts (BFU-E, NOAEL 12 mg/kg) and Granulocyte Macrophage-Colony Forming Units (CFU-GM, NOAEL < 12 mg/kg) 14 days after exposure. Stimulation of the Colony Forming Units-Granulocyte, Erythrocyte, Monocyte, Macrophage (CFU-GEMM) at lower doses and no effects with CFU-GM and BFU-E were observed after 7-day acute exposure. Flow cytometry analysis revealed no change in cell surface expression CD71 and Thy1.1 markers. In conclusion, reduction of RDX to MNX is a detoxification process and may affect growth of a relatively proximal committed stem cell population in hematopoiesis.

Abstract  The genotoxicity of energetic compounds that commonly occur in contaminated soils at military training sites has not been rigorously tested. The Salmonella and Muta T Mouse in vitro mutagenicity assays were employed to examine the mutagenic activity of selected energetic compounds including TNT, tetryl, RDX, and HMX, as well as explosives-contaminated soil samples. Salmonella analyses employed strains TA98 (frameshift), TA100 (base-pair substitution), and the metabolically enhanced YG 1041, with and without exogenous metabolic activation (S9). Results indicate that TNT is a direct-acting mutagen, eliciting significant responses without S9. Strains TA98, TA100, and YG1041 yielded mutagenic potencies of 0.87±0.03, 1.72±0.08, and 1.32±0.06 revertants/IJg TNT, respectively. In contrast, tetryl elicited significant responses both with and without S9, exhibiting mutagenic activity in all strains. Potencies ranged from 1.27±0.13 to 14.98±1.67 revertants/IJg tetryl. Testing of soil samples yielded significant responses in strains TA98 and YG1 041, with and without S9. Mutagenic potencies ranged from 3.48±0.13 to 16.20±0.97 revertants/mg soil equivalent. Responses obtained using the Muta ™Mouse assay in FE 1 cells indicate that TNT can induce lacZ mutations, with and without S9. In contrast, there is little evidence to support the mutagenic activity of tetryl or RDX. HMX appears to be toxic to FE1 cells. Testing of soil samples in the Muta™Mouse assay is currently underway. Analysis of other energetic compounds and contaminated soil samples is warranted in order to reliably estimate mutagenic hazard.

Abstract  A teratology study in rats was performed to define the effects of trinitro-RDX on the developing fetus, oral dosage levels of 2, 6, and 20 mg rat/kg/day were administered to pregnant female rats critical period of organogenesis. Fetuses derived from RDX-treated dams had significantly lower body weights and lengths when compared to control fetuses. It was recommended that human females of childbearing age be protected from exposure to trinitro-RDX by means of appropriate industrial hygiene practices. It was further recommended that additional developmental toxicity studies be performed.

Abstract  Objective: To understand the distribution and concn. of occupational hazard in small and middle test workplaces of explosive industry, and provide the scientific basis of phys. health for explosive industry workers. Methods: According to national stds. of GBZ 159-2004 and GBZ/T 192.1-2007, occupational hazard factors in the workplaces were sampled to det. Results: The concns. of 14 kinds of chems. and dust fluctuation range was large, the exceeding rate of detd. points for CTWA of ethylacetate and aluminum was 4.0%, for CMC of nitroglycerin 7.7%, for CSTEL of trinitrotoluene, ethylacetate and toluene-2,4 diisocyanate (TDI) 39.4%, and for std.-gauge multiple 3.3%. Conclusion: Occupational hazard factors are TNT, RDX, HMX, Et acetate, nitroglycerin and other chems. and dust in the explosive industry, and the fluctuating range of the concn. is relatively large. The workers contact with toxic substances is relatively short, but short term concn. was relatively high. The testing results show that explosive industry workers who contact with toxic substances should strengthen their personal protection.

Abstract  Given the potent carcinogenic effects of most N-nitroso compds., the reductive transformation of the common explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) to a group of N-nitroso derivs., 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 environment have caused concerns among the general public. Questions are arising about whether the same transformations also occur in mammals and, if true, to what extent. This study investigated the N-nitroso derivs. prodn. in the deer mice GI tract following RDX administration. The findings verified that such transformations do occur in the mammalian GI tract at notable levels: the av. MNX concns. in deer mice stomach were 85 ng/g and 1,318 ng/g for exposure to 10 mg/kg and 100 mg/kg diet, resp. DNX in stomach were 217 and 498 ng/g for 10 mg/kg and 100 mg/kg dietary exposure, resp. Changes in other toxic endpoints including body wt. gains, food consumptions, organ wts. and behaviors were also reported.

Abstract  Composition C-4 is a putty-like explosive material that is widely used in Vietnam by US forces. It is found in Claymore mines and in standard demolition kits. Detonation is usually accomplished with a blasting cap. The main chemical component of Composition C-4 is RDX, which has been used as an explosive since World War I. The chemical structure of RDX is cyclotrimethylenetrinitramine, which is similar to TNT. Although insoluble in water, in 80 per cent ethanol RDX is broken down to its constitutent parts of methylamine, nitrous acid, ammonia, and formaldehyde. Composition C-4 also contains small amounts of polyisobutylene, motor oil and sebacate.

Abstract  Translation of article appearing in Farmakologiia i Toksikologiia.

Abstract  Genotoxicity is a specialized case of biological effects in which the toxicological endpoint is an alteration of the information content, structure, or segregation of DNA in an organism. Genotoxicants have been defined as compounds that covalently bind and/or cause gene mutations or chromosomal changes in in vitro or in vivo systems, as opposed to nongenotoxic carcinogens that act via altering enzyme levels or inducing cell proliferation. Typical in vitro assays for genotoxicity include microbial reversion assays (e.g., Salmonella assay), mammalian cell-based assays (e.g., chromosomal aberration), as well as measures of interactions at the DNA level (adduct formation, strand breakage). In vivo assays share many of the endpoints monitored in vitro, such as adducts, strand breakage, chromosomal aberrations, micronuclei formation, and mutations (e.g., alterations in the hypoxanthine guanine phosphoribosyl transferase [HGPRT or HPRT] gene sequence), and endpoints that cannot be monitored in vitro such as the formation of neoplastic lesions and increases in cancer incidence. Data for genotoxicity of explosives are limited as compared to those available for common environmental contaminants (e.g., benzo[a]pyrene). This chapter will present both in vitro and in vivo mutagenicity methodologies including microorganism assays, mammalian cell-based assays, plant assays, and available carcinogenicity data, as well as a short discussion on structure–activity relationships for mutagenicity of nitroaromatics. © 2009 by Taylor & Francis Group, LLC.

Abstract  Energetics is a class of compounds that includes explosives, pyrotechnics, and propellants. The predominant manufacturing and use of these substances is specific to the military, particularly in regard to training. Consequently, environmental contamination from the use of energetic compounds within the U.S. Department of Defense is widespread. Causes include practices associated with manufacturing, loading, and packing operations; testing/firing ranges; and demilitarization of outdated supplies. Explosives, such as 2,4,6-trinitritoluene (TNT) and 1,3,5-trinitrohexahydro-1,3,5-triazine (RDX), are considerably more prevalent in environmental media given the nature of their use and source for contamination (e.g., through unexploded ordnance and production). © 2009 by Taylor & Francis Group, LLC.

Abstract  We determined the influence of sample storage time on the percutaneous absorption of C-14 labeled hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine (RDX), 2, 6-dinitrotoluene (26DNT) and 2, 4, 6-trinitrotoluene (TNT) from two' soil types, Yolo having 1.9% carbon and Tinker having 9.5% carbon content. RDX soil samples stored at -20C for 27 months and 62 months were compared to freshly spiked soil samples. Similarly, 26DNT samples stored 35-36 months and TNT samples stored 18 months were compared to freshly spiked samples. Approximately 10 ug/cm2 of radio labeled compound was applied in 10 mg/ cm2 of soil to freshly excised pig skin pretreated with artifical sweat (5 ul) and mounted in skin penetration-evaporation chambers, Radiolabel recovered from the dermis and tissue culture media (receptor fluid) was summed to determine percent absorption from the soils. For each compound, percent absorptions of label were highest from Yolo soil. Storage did not significantly alter percutaneous absorption values for RDX, as values were all less than 1%, regardless of soil type or age. Similarly, 26DNT absorption was 1-2% for Tinker soil and 16-18% for Yolo soil, regardless of soil age. TNT absorption was approximately 0.5% from Tinker soil and 3-4% from Yolo soil for fresh and stored samples. HPLC analysis of26DNT in receptor fluid at maximum flux indicated no metabolism or breakdown. For TNT, extensive conversion to monoarnino derivaties and other metabolites was observed. The absorption of 26DNT from low carbon soil was reduced from 16-J 8% to near zero without sweat pretreatment, indicating that skin surface moisture was a critical variable in determining topical bioavailability.

Abstract  Live fire military training involves the detonation of explosive warheads on training ranges. The purpose of this experiment is to evaluate the hydrogeological changes to the vadose zone caused by military training with high explosive ammunition. In particular, this study investigates artillery ammunition which penetrates underground prior to exploding, either by design or by defective fuze mechanisms. A 105 mm artillery round was detonated 2.6 m underground, and hydraulic conductivity measurements were taken before and after the explosion. A total of 114 hydraulic conductivity measurements were obtained within a radius of 3m from the detonation point, at four different depths and at three different time periods separated by 18months. This data was used to produce a three dimensional numerical model of the soil affected by the exploding artillery round. This model was then used to investigate potential changes to aquifer recharge and contaminant transport caused by the detonating round. The results indicate that an exploding artillery round can strongly affect the hydraulic conductivity in the vadose zone, increasing it locally by over an order of magnitude. These variations, however, appear to cause relatively small changes to both local groundwater recharge and contaminant transport.

Abstract  The soil and groundwater of former ordnance plants and their dumping sites have often been highly contaminated with the explosive 2,4,6-trinitrotoluene (2,4,6-TNT) leading to a potential hazard for humans and the environment. Further hazards can arise from metabolites of transformation, by-products of the manufacturing process, or incomplete combustion. This work examines the toxicity of polar nitro compounds relative to their parent compound 2,4,6-TNT using four different ecotoxicological bioassays (algae growth inhibition test, daphnids immobilization test, luminescence inhibition test, and cell growth inhibition test), three genotoxicological assays (umu test, NM2009 test, and SOS Chromotest), and the Ames fluctuation test for detection of mutagenicity. For this study, substances typical for certain steps of degradation/transformation of 2,4,6-TNT were chosen for investigation. This work determines that the parent compounds 2,4,6-TNT and 1,3,5-trinitrobenzene are the most toxic substances followed by 3,5-dinitrophenol, 3,5-dinitroaniline and 4-amino-2-nitrotoluene. Less toxic are the direct degradation products of 2,4,6-TNT like 2,4-dinitrotoluene, 2,6-dinitrotoluene, 2-amino-4,6-dinitrotoluene, and 4-amino-2,6-dinitrotoluene. A weak toxic potential was observed for 2,4,6-trinitrobenzoic acid, 2,4-diamino-6-nitrotoluene, 2,4-dinitrotoluene-5-sulfonic acid, and 2,6-diamino-4-nitrotoluene. Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine and hexahydro-1,3,5-trinitro-1,3,5-triazine show no hint of acute toxicity. Based on the results of this study, we recommend expanding future monitoring programs of not only the parent substances but also potential metabolites based on conditions at the contaminated sites and to use bioassays as tools for estimating the toxicological potential directly by testing environmental samples. Site-specific protocols should be developed. If hazardous substances are found in relevant concentrations, action should be taken to prevent potential risks for humans and the environment. Analyses can then be used to prioritise reliable estimates of risk.

Abstract  Dermal exposure of RDX and other nitroaromatics is a major concern for the military. There is no information on dermal absorption of RDX in humans for risk assessment. We studied dermal absorption of RDX in human skin in vitro in flow-through diffusion cells. RDX (38.46 microg/0.5 microCi) in acetone (10 microl) was applied to the skin and collected as diffused receptor fluid for every 6 hr up to 24 hrs. The unabsorbed RDX was washed with soap water and water with cotton swabs, and radioactivity present in washings was determined. The RDX absorbed or penetrated in the skin was also determined by separating stratum corneum, epidermis and dermis at the end of the experiments.

Abstract  Trimethylenetrinitroamine or <> or <> is an explosive obtained by treating urotropine with nitric acid. Workmen employed in the last phases of the production of this explosive, and especially in the drying and sieving, are exposed to the inhalation of powdered material. Several of them have shown a symptomatology consisting in generalised epileptic fits accompanied by loss of consciousness, absence of reflexes, biting of the tongue, salivation, enuresis and involuntary discharge of semen. The fits started suddenly, sometimes preceded by periods of sleelessness and nervous irritability; they were followed by deep coma lasting for several hours and often ending in vomiting and subsequent amnesia.Out of some 20 workmen exposed to the dust of T4, 17 had convulsive fits or attacks of loss of consciousness, either isolated or repeated. This fact cannot, therefore, be considered as casual but seems to be connected with the inhalation of T4 powder. The workmen mainly affected by fits were those given to excessive drinking and eating, but there have been cases of persons so affected who were absolutely free from disease or vice. The authors believe that the epileptic fits are due to cortical angiospastic crises caused by absorption of T4.