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Up‐and‐down procedure (UDP) determinations of acute oral toxicity of nitroso degradation products of hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX)
Author(s) -
Meyer Sharon A.,
Marchand Adam J.,
Hight Jennifer L.,
Roberts George H.,
Escalon Lynn B.,
Inouye Laura S.,
MacMillan Denise K.
Publication year - 2005
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1090
Subject(s) - metabolite , toxicity , chemistry , toxicology , median lethal dose , acute toxicity , pharmacology , urine , medicine , physiology , chromatography , biology , biochemistry , organic chemistry
Hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX), a widely used military explosive and soil and ground water contaminant of munitions manufacturing and artillery training sites, undergoes microbial nitroreductase metabolism to 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). Human occupational and accidental exposures to RDX, as well as acute oral exposures in rats, result in seizures, but little is known about the toxicity of the RDX degradation products. The main objective of the present study was to determine the oral LD 50 of the most potent RDX N ‐nitroso product in female Sprague‐Dawley rats using the recently validated up‐and‐down procedure (UDP). With only 26 rats, MNX was identified as the most potent metabolite and a maximum likelihood estimate of 187 mg kg −1 (95% confidence interval 118–491 mg kg −1 ) for its LD 50 was established and found equivalent to that of RDX determined with the same protocol. CNS toxicity, manifested as forelimb clonic seizures progressing to generalized clonic‐tonic seizures, was the critical adverse effect. Further, confirmation of the UDP LD 50 for MNX with a fixed‐dose design enabled identification of 94 mg kg −1 as the highest nonlethal dose. An ED 50 of 57 mg kg −1 was determined for neurotoxicity, while splenic hemosiderosis and decreased blood hematocrit and hemoglobin concentration occurred with a threshold at 94 mg kg −1 in 14‐day survivors. These studies, while providing new toxicity data necessary for the management of RDX‐contaminated sites, illustrate the efficiency of the UDP for comparative acute toxicity determinations and its value in guiding further characterization of dose dependency of identified adverse effects. Copyright © 2005 John Wiley & Sons, Ltd.