Subchronic and Chronic Toxicity Studies of 2,4-Dinitrotoluene. Part I. Beagle Dogs

Abstract

Subchronic and chronic toxicities of 2,4-dinitrotoluene (2,4-DNT) were studied in beagle dogs. The major adverse effect of 2,4-DNT in dogs was a neuropathy, characterized by incoordination and paralysis. There were vacuolation, endothelial proliferation, and gliosis of the cerebellums of some affected dogs. These effects were seen in 1 dog given 1.5 mg/kg per day for 2 years, in all dogs given 10 mg/kg per day within 6 months, and in all dogs given 25 mg/kg per day within 2 months. There was great variation between individuals in onset and severity of adverse effects. Some dogs progressed to a complete paralysis, leading to death. Methemoglobin and its sequelae were common, but not life threatening. Heinz bodies were a useful indicator of this effect. Less important adverse effects seen included testicular degeneration and biliary tract hyperplasia. No changes were found in tumor incidence, immunoglobin E and cytogenetic assays, and other routine hematologic and clinical laboratory tests.

Dose-related Effects Following Oral Exposure of 2,4-Dinitrotoluene on the Western Fence Lizard, Sceloporus occidentalis

“…The control and the lowest two dose groups (9 and 15 mg/kg 2,4-DNT) had 100% survival, unlike 25, 42, and 70 mg/kg/d, where the mean survival was 54.9 d (standard error [SE] Ϯ 0.4), 51.4 d (SE Ϯ 0.4), and 39.6 d (SE Ϯ 0.6), respectively. The means comparison generated from the survival analysis revealed a significant decrease in survival between the bottom three dose groups (0, 9, and 15 mg/kg/d) and the top three dose groups (25,42, and 70 mg/kg 2,4-DNT); however, as expected, no significant differences between 0, 9, and 15 mg/kg 2,4-DNT were detected. Although 0, 9, and 15 mg/kg/d 2,4-DNT dose groups were similar in survival, significant differences became apparent in body weight analysis.…”

“…Kidneys are a target organ for 2,4-DNT toxicity. Following exposure to 2,4-DNT, renal effects have been reported in birds, mice, rats, dogs, and possibly humans [22][23][24][25][26][27]. In the present study, lizards exposed to 15 mg/kg/d 2,4-DNT had significantly heavier kidneys than controls, suggesting effects from 2,4-DNT exposure on renal function.…”

Dose-related effects following oral exposure of 2,4-dinitrotoluene on the western fence lizard, Sceloporus occidentalis

“…Kidneys are a target organ for 2,4‐DNT toxicity. Following exposure to 2,4‐DNT, renal effects have been reported in birds, mice, rats, dogs, and possibly humans [22–27]. In the present study, lizards exposed to 15 mg/kg/d 2,4‐DNT had significantly heavier kidneys than controls, suggesting effects from 2,4‐DNT exposure on renal function.…”

Wildlife Toxicity Assessment for 2,4-Dinitrotoluene and 2,6-Dinitrotoluene

“…The most relevant chronic studies were those conducted by Ellis et al (1979 and [34,39], Lee et al (1985) [30], and Hong et al (1985) [32] in dogs, rats, and mice, respectively. Effects from chronic 2,4-DNT exposures were consistent with those of subchronic exposures and included decreased survival, decreased body weights and food consumption, anemia, hepatocellular dysplasia, kidney tumors in mice, serious neuromuscular effects in dogs, ovarian atrophy in female mice, and decreased spermatogenesis and testicular atrophy in male mice.…”

“…For 2,4-DNT, the neuromuscular effect in dogs [34,39] was chosen as the basis for TRV development. The severe [34,39] paralysis and incoordination induced by 2,4-DNT occurred at relatively low concentrations (LOAEL was 1.5 mg/kg/day; NOAEL was 0.2 mg/kg/day) and in some cases, precluded dogs from eating and drinking normally. In less severe cases, hind leg, lip, and tongue control were hampered.…”