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  Incorporation of RDX in the diets of rats at levels of 1.0, 3.1, and 10 mg/kg over a two-year period did not lead to appearance of important evidence of toxicity.

Abstract  This report summarizes the results of a series of experiments designed to determine in rats the behavioral effects of acute and subchronic exposure to RDX. The behavioral endpoints included measures of sensory (acoustic startle), motor (landing footspread, figure-eight maze activity) and cognitive (flavor-aversion conditioning, acquisition and performance of schedule-controlled behavior) capacity. Since the behavioral evaluations were to be carried out using newly assembled equipment in a newly constructed laboratory, several preliminary behavioral experiments were executed to insure that the equipment and test conditions were appropriate. Additional pilot experiments determined the appropriate conditions for measuring RDX levels in blood and brain, and the time course of RDX levels in blood and in brain. Phase I involved determining the acute effects of RDX. The results of these experiments showed that RDX produced a multitude of behavioral effects. Phase II involved determining the subchronic effects of RDX.

Abstract  1,2,5-trinitro-1,3,5-triazine, commonly known as RDX, is a military explosive that has been extensively used by the U.S. Military since the late 1930's and has been reported to cause convulsions in military field personnel and munition workers during use and manufacture. In addition, military bases across the United States have been contaminated due to the testing and disposal of RDX. Thus, human exposure is possible both during remediation processes and through groundwater contamination. This report outlines a progressive series of three oral toxicity studies on RDX that were designed to identify effect levels, define target organs, support regulatory actions, and provide risk assessment information. Male and femal Fischer 344 rats were dosed 7 days a week for a period of 13 weeks at dosages of 0, 4, 8, 10, 12, and 15 mg/kg/day. The RDX was suspended in a solution of 1% Methylcellulose/0.2% Tween 80 in distilled water. Male and female dose dependent mortality, as well as other measured parameters, was observed at dosages of 8 mg/kg/day and above. The No Observed Adverse Effect Level for this study was 4 mg/kg/day, based on mortality.

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  A study was carried out in 42 rhesus monkeys to evaluate the toxicity of RDX and TNT when given orally, once daily, seven days per week for 13 weeks (90 days). Dosages of RDX were 10, 1 and 0.1 mg/kg/day and for TNT were 1, 0.1 and 0.02 mg/kg/day. Five monkeys on the highest dose of RDX showed 12 instances of CNS disturbance, usually involving tonic convulsions. One of these monkeys were euthanatized; the others recovered and survived the study. Except for frequent episodes of emesis, predominantly in the high dosage RDX group, no other clinical signs of toxicologic significance were observed. Laboratory testing revealed only scattered changes of no toxicologic significance. Histopathologic examination showed some increases in numbers of degenerate or necrotic megakaryocytes in bone marrow sections and increased amounts of iron-positive material in liver cord cytoplasm, both occurring in the high dosage groups of both RDX and TNT. The toxicologic importance of these two findings is uncertain.

Abstract  Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) has been widely used as an explosive in U.S. army munitions formulations since World War II. Two-year carcinogenicity studies revealed RDX to be noncarcinogenic in two strains of rats, but a 2-year carcinogenicity study in B6C3F1 mice revealed an increased incidence of hepatocellular neoplasms in females. Based on results of the study in B6C3F1 mice, RDX has been classified as a possible carcinogen. The authors reevaluated the archived histological sections from the B6C3F1 mouse study, using current histopathologic diagnostic criteria and interpretations. The earlier evaluation showed a statistically significant increase in the incidence of hepatocellular adenoma/carcinoma in female mice from the three highest dose groups (7, 35, and 175/100 mg/kg/day). The revaluation yielded a slightly lower incidence at each of the dose levels in female mice. The reduced number of hepatocellular neoplasms was largely due to reclassification of hepatocellular adenomas as foci of cytoplasmic alteration, in compliance with current diagnostic criteria. The reevaluation was reviewed by a pathology working group (PWG), which arrived at a consensus classification of each lesion. Based on the consensus diagnoses of the PWG, only one female group (35 mg/kg/day) showed a significant increase when compared to controls. The incidence of hepatocellular neoplasms for all groups, including the 35 mg/kg/day group, was within the reported incidence range for spontaneous hepatocellular neoplasms in female B6C3F1 mice. The increased incidence of hepatocellular neoplasms in female mice given RDX at 35 mg/kg/day was interpreted as equivocal evidence of a carcinogenic effect.

Abstract  Dogs given daily dosages of RDX of 0.1, 1 or 10 mg/kg/day for 90 days developed no signs of toxicity other than temporary episodes of emesis to which a tolerance apparently developed. One medium level animal died for reasons unrelated to the study. Dogs given daily dosages of TNT of 0.02, 0.1 or 1 mg/kg/ day for 90 days developed no signs of toxicity other than temporary episodes of emesis to which tolerance apparently developed. Laboratory diagnostic procedures and both gross and microscopic postmortem examinations revealed no important differences from controls.

Abstract  This study was conducted to evaluate the toxicity of the munitions compounds 2,4,6-trinitrotoluene (TNT; CAS Reg. No. 118-96-7) and hexahydro-1,3, 5-trinitro-1,3,5-triazine (RDX; CAS Reg. No. 121-82-4), and their potential toxic interactions in Fischer 344 rats when administered in the diet for at least 13 weeks. The data derived were also to be used to select dose levels for comprehensive chronic toxicity/carcinogenicity studies. Groups of 10 rats per sex received TNT at doses of 1, 5, 25, 125 or 300 mg/kg/day; RDX at doses of 10, 30, 100, 300 or 600 mg/kg/day; and the following combinations of these compounds: TNT 5/RDX 30 mg/kg/day, TNT 5/RDX 300 mg/kg/day, TNT 125/RDX 30 mg/ kg/day, TNT 125 RDX 100 mg/kg/day, and TNT 125/RDX 300 mg/kg/day. Thirty rats per sex served as controls. Toxicologic endpoints included clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, and gross and tissue morphology. An appropriate 10% reduction in body weight gain was seen for males receiving TNT 5 or 25 mg/kg/day, and for females administered TNT 125 mg/kg/day. Other toxic effects following the administration of TNT 25 mg/kg/day or greater included reduced food intake, hypercholesterolemia and anemia (reduced hemoglobin, hematocrit and erythrocyte counts). Splenomegaly with congestion and hemosiderosis of the red pulp, hepatomegaly with hepatocellular hypertrophy, testicular atrophy with degeneration of the seminiferous tubular epithelium and slight increases in kidney weights with deposition of pigment were also seen for rats receiving TNT 125 or 300 mg/kg/ day. Elevated methemoglobin levels and cerebellar lesions were observed only at the TNT 300 mg/kg/day dose level.

Abstract  Groups of Fischer 344 rats received hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in the diet for up to 13 weeks at doses of 0, 1, 10, 30, 100, 300 or 600 mg/kg/day. Toxicological responses included slight reductions of food intake and body weight gain, hyperreactivity to approach, decreased serum triglyceride levels, marginal leukocytosis and mortality.

Abstract  The PWG was convened to review selected H & E-stained liver sections from a two-year chronic study of hexahydro-1,3,5-trinitro-1,3.5-triazine (RDX) administered in the diet. The following is a summary of review findings. - A number of liver lesions were downgraded from tumor to non-tumor status. As a result of these changes there are four less hepatocellular tumors in Group 3, two less hepatocellular tumors in Group 4, and two less hepatocellular tumors in Group 5. - A number of lesions were downgraded from malignant to benign status. As a result of these changes there are three less hepatocellular carcinomas in Group 2, three less hepatocellular carcinomas in Group 4, and one less hepatocellular carcinomas in Group 5. - Two new non-tumor diagnoses were added. As a result of these changes there are two additional non-tumor hepatocellular lesions in Group 2. - The PWG review altered the numerical incidence of hepatocellular lesions in all dose groups except the controls. The general incidence pattern persisted in Groups 1 through 4, but the previously noted linear increase in liver tumor incidence in all treated groups was no longer evident in Group 5.

Abstract  The potential toxic interactions in F344 rats of the munitions compounds trinitrotoluene (TNT) and hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) were examined following their coadministration in the diet. Groups of 10 rats per sex received TNT at doses of 5 or 125 mg/kg/day, RDX at doses of 30, 100, or 300 mg/kg/day, and combinations thereof for 13 weeks. Thirty rats per sex served as controls. Toxicologic endpoints included clinical observations, body weight, food consumption, hematology, clinical chemistry, organ weights, and tissue morphology. The major toxic effects following the dietary administration of TNT to rats included anemia, hypercholesterolemia, and hepatomegaly, splenomegaly, and testicular atrophy with their accompanying histologic lesions. RDX intoxication in rats included hypotri-glyceridemia, behavioral changes, and mortality. Most of the toxic effects of these chemicals were partially antagonized following their coadministration.

Abstract  This study was conducted to evaluate the toxicity of the munitions compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX: CAS Reg. No. 121-82-4) in B6C3F1 mice when administered in their diet for up to 24 months. RDX purity was established to be 89.2-98.7% with the main contaminant of HMX. Groups of 85 mice per sex received RDX at doses of 0, 1.5, 7.0, 35.0 or 100.0 mg/kg/day. This last dose was reduced from 175 mg/kg/day in Test Week 11 due to high mortality. Ten mice/sex/dose were killed following 6 and 12 months on test with surviving animals killed after 24 months of treatment. Toxicologic endpoints included clinical signs, body weights, food consumption, hematology, clinical chemistry, ophthalmology, organ weights, and gross and tissue morphology. The major toxic effects observed (during the administration of RDX to B6C3FI mice for up to 24 months included hepatotoxicity, possible CNS involvement, and testicular degeneration. In addition, hepatocellular adenomas and/or carcinomas were more prevalent for RDX-treated females than for corresponding controls. Whether serum cholesterol levels and/or the incidence of hepatocellular tumors were increased at the 7 mg/kg/day dose level is equivocal. The no-effect level under the conditions of the present study is 1.5 mg/kg/day.

Abstract  Levine et al. (1983) is a three-volume study report. Click on the links under Relationship(s) to get to the HERO entry with additional details for each volume.