Nitrotriazolone (1,2,4-triazol-5-one; NTO), an insensitive, energetic material used in explosive formulations, induced testicular toxicity and oligospermia in repeated-dose oral toxicity tests in rats. To evaluate whether NTO produces additional reproductive and developmental effects, a modified extended one-generation reproductive toxicity test was conducted. Rats were provided ad libitum access to NTO in drinking water at 0-, 144-, 720-, or 3600-mg/L NTO. Treatment of the parental generation began 2 (females) and 4 (males) wk premating and continued until weaning of litters. Direct dosing of offspring (F1) occurred from weaning through puberty. Pups were counted and weighed on postnatal day (PND) 0/1. Anogenital distance (AGD) was measured on PND 4 and males were examined for presence of nipples on PND 13. F1 offspring were examined daily for attainment of puberty. NTO did not markedly affect measures of fertility, including mating indices, gestation index, litter size, and sex ratio. Seminiferous tubule degeneration or atrophy was observed in P1 and F1 3600-mg/L NTO males. F1 males in the 3600 mg/L group exhibited reduced reproductive organ mass (testes, epididymides, and accessory sex organs). Nipple retention was increased in NTO exposed F1 males compared to controls. Attainment of puberty was delayed by 2.6 d in the 3600-mg/L NTO-exposed males relative to controls. Comparison of the effects of NTO with those of antiandrogens suggests absence of malformations of the genital tract in NTO-exposed males. This study supports previous findings indicating that NTO is a testicular toxicant with male developmental effects that may be secondary to testicular toxicity.
The explosive 3-nitro-1,2,4-triazol-5-one (NTO) is an insensitive formulation developed to replace high energetics that are susceptible to accidental detonation from heat, shock, and impact. Although studies have shown NTO to be nontoxic at acute exposures, recent subacute and subchronic tests have demonstrated effects on testes and subsequent sperm production in rats. This study assessed endocrine disruption as a potential mechanism for these reproductive effects via the Hershberger and uterotrophic bioassays. These assays are 2 of the US Environmental Protection Agency's tier 1 in vivo screens for the Endocrine Disruptor Screening Program that measure differences in androgen- and estrogen-sensitive tissue weights in castrated and ovariectomized rats. The gonadectomized rats were orally exposed to NTO in a corn oil vehicle at doses of 250, 500, or 1000 mg/kg body weight (bw)/d for 10 and 3 days for the Hershberger and uterotrophic assays, respectively, according to standard protocols. Male rats also received testosterone (0.2 mg/kg/d, subcutaneous) and antiandrogenic flutamide (3mg/kg/d, oral) as negative and positive controls, and females received 17 α-ethynyl estradiol (0.3 µg/d, subcutaneous) as positive controls. 3-Nitro-1,2,4-triazol-5-one caused neither a decrease in androgen-sensitive male reproductive selected tissue (seminal vesicles with fluid/without fluid, glans penis, Cowper gland, ventral prostrate, and levator ani-bulbocavernosus) weights nor a change in uterine weights. The results of this study provide no evidence to suggest that NTO acts like an estrogenic or antiandrogenic endocrine disruptor in rats at these doses.
Substances used as explosives in munitions by the military often result in environmental releases through manufacturing, testing, training, and combat activities. The toxicity of 3-nitro-1,2,4-triazol-5-one (nitrotriazolone or NTO) was evaluated following oral exposure in Japanese quail (Coturnix japonica) to determine if environmental releases result in unacceptable risks to avian populations. In an acute test at the limit dose (2000 mg/kg), one female was ataxic, exhibited tremors, and showed signs of neurological toxicity approximately 24 h after dosing. In a subsequent one-generation study, parental generation (F0) birds were exposed orally to 1000, 500, 100, or 20mg/kg-day NTO suspended in corn oil. After 5 consecutive days of dosing, 2-week-old birds receiving 1000 mg/kg-day displayed ataxia, convulsions, backward arching of the neck (opisthotonos), and alternated between prostrate inactivity and ataxic wing activity. Birds in the 500 mg/kg-day group exhibited neuromuscular anomalies after 17 days exposure. Ultimately, all of the 1000 mg/kg-day birds and all but one of the 500 mg/kg-day birds met euthanasia criteria and were humanely euthanized prior to behavioral and reproductive evaluation. As such, first-generation (F1) birds were exposed to 100 or 20 mg/kg-day NTO. Mild neuromuscular anomalies occurred in 10% of F1 birds from the 100 mg/kg-day group, but not in birds from 20 mg/kg-day or controls in either generation. Vacuolization of cerebellum and/or the brainstem was observed on histopathologic examination in a dose-dependent manner. Therefore, brain vacuoles and neuromuscular anomalies were identified as critical endpoints in this study. A mean Benchmark Dose (BMD) for brain vacuoles of 62 mg/kg-day was derived for male and female F0-generation quail, which corresponded to a Benchmark Dose Low (BMDL) of 35 mg/kg-day.
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