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Categorical Read-Across Assessment of Cancer and Noncancer Endpoints for Amino-Dinitrotoluenes
Citation:
Petersen, Daniel. Categorical Read-Across Assessment of Cancer and Noncancer Endpoints for Amino-Dinitrotoluenes. Society of Toxicology, Annaheim, California, March 15 - 19, 2020.
Impact/Purpose:
This poster describes the use of a categorical read-across process to evaluate the chemical hazards of Amino-dinitrotoluenes. Reference doses are derived, as is a qualitative cancer analysis.
Description:
4-Amino-2,6-Dinitrotoluene (CASRN 19406-51-0 [4-ADNT]), and 2-Amino-4,6-Dinitrotoluene (CASRN 35572-78-2 [2-ADNT]), collectively ADNTs, are members of a category of compounds known as nitroaromatics or nitroarenes. Nitroaromatics are used as explosive materials, pesticides, solvents, and intermediates in chemical synthesis. Both ADNTs are primary biotransformation products of 2,4,6 trinitrotoluene (TNT) formed during biological degradation and reduction processes and are the main human urinary metabolites of TNT. There are no repeat-dose toxicity studies for the ADNTs, however, both are active in most genotoxicity tests, as is the urine from workers exposed to TNT. The parent compound, TNT, produces both cancer and noncancer effects in animals, and has a chronic reference dose (RfD) and oral slope factor (OSF) in IRIS. Screening subchronic and chronic provisional p-RfDs (3 x 10-4 and 1 x 10-4 mg/kg-d respectively) for the ADNTs were derived by analogue read-across, using the TNT point of departure (POD) from IRIS as the analogue. Three similarity contexts (structural, metabolic, and toxicity like) were utilized to facilitate the final noncancer analogue chemical selection. Six structural analogues with published toxicity values were identified (TNT, 2-Methyl-5-Nitroaniline, Isopropalin, Pendimethalin and Trifuralin). TNT was the most appropriate structural analogue (ChemIDplus % similarity score), and was also the most appropriate metabolic analogue, based on common metabolites. Whereas other analogues do not share common metabolites, all analogues share metabolic features such as reduction of nitro-groups to amino-groups during metabolism. Toxicity profiles of the analogues in animal studies show that all produce methemoglobinemia and related blood effects. Only isopropalin failed to produce hepatic effects. This suite of toxic effects, beginning with reactive oxidant species (ROS) produced in red blood cells resulting in oxidation of hemoglobin (methemoglobin), red blood cell destruction (anemia), splenic effects from damaged RBC processing and Kupffer cell and other liver effects subsequent to ROS, and other effects from damaged RBCs are common features of organic and inorganic nitrate exposure. TNT proved to be the most appropriate analogue, in terms of structural, metabolism and toxicity and its POD was adopted as the best choice for a noncancer analogue. The lack of direct cancer data makes a quantitative assessment not possible with current methods, but a qualitative assessment is described. Herein, analogues are identified through structural clustering with known carcinogens (ChemACE). ADME, genotoxicity, and carcinogenic data were evaluated and SAR/QSAR was performed on the target and potential analogues for structural alerts known to be associated with carcinogenicity. Based on similarities across these data streams, it was determined that ADNTs could reasonably be expected to promote carcinogenicity.