Evaluation of 2-methoxy-4-nitroaniline (MNA) in hypersensitivity, 14-day subacute, reproductive, and genotoxicity studies. (August 2020)

• Record Type: Journal Article
• Authors: Frawley, Rachel P.; Witt, Kristine L.; Cunny, Helen; Germolec, Dori R.; Jackson-Humbles, Daven; Malarkey, David; Shockley, Keith R.; Stout, Matthew; Travlos, Greg; Buccellato, Matthew; Fallacara, Dawn; Harris, Shawn; Kissling, Grace E.; Manheng, Wimolnut; Surh, Irene Inok; White, Kimber; Auerbach, Scott S.
• Is Part Of: Toxicology. Volume 441(2020)
• Publication Date: 2020-08
• Subjects: 2MPDA 2-methoxy-p-phenylenediamine -- ADME absorption, disposition, metabolism and elimination -- AhR arylhydrocarbon receptor -- ANOVA analysis of variance -- AT adenine-thymine -- BW body weight -- CAS Chemical Abstracts Service -- CEBS Chemical Effects in Biological Systems -- CNCNNA 2, 6-dicyano-4-nitroaniline -- CNNA 2-cyano-4-nitroaniline -- cTNI endogenous cardiac troponin I -- cTNT cardiac troponin T -- CYP1A cytochrome P450-1A -- CYP1A2 cytochrome P450-1A2 -- DAAS 2, 4-diaminoanisole sulfate -- DMF dimethylformamide -- DNFB dinitroflourobenzene -- E. coli Escherichia coli -- F344 Fischer 344 -- FABP3 fatty acid binding protein 3 -- Fe iron -- g gram -- GC guanine-cytosine -- GD gestation day -- GPMT guinea pig maximization test -- Hb hemoglobin -- HCA hexyl cinnamic aldehyde -- HSD Harlan Sprague Dawley -- ICCVAM Interagency Coordinating Committee on the Validation of Alternative Methods -- ILS Integrated Laboratory Systems, Inc -- IRR irritancy assay -- Kb base dissociation constant -- LLNA local lymph node assay -- μg microgram -- MEST mouse ear swelling test -- MN micronucleus -- MNA 2-Methoxy-4-nitroaniline -- MSD Meso-Scale Discovery -- Myl13 myosin light chain 3 -- NIOSH National Institute for Occupational Safety and Health -- IARC International Agency for Research on Cancer -- PBS phosphate buffered saline -- PCCO positive control challenge only -- PND postnatal day -- ppm parts per million -- QSAR Quantitative structure–activity relationship -- SAS Statistical Analysis System -- SE Standard error of the mean -- SI Sensitization Index -- sTnI skeletal troponin I -- VCU Virginia Commonwealth University -- VHIC vehicle irritancy control; 2-Methoxy-4-nitroaniline -- Contact hypersensitivity -- Reproductive toxicity -- Mutagenicity -- Hematopoietic toxicity -- Aromatic amine; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2020.152474
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: 2-Methoxy-4-nitroaniline (MNA), an intermediate in the synthesis of azo dyes used in textiles and paints, is structurally similar to carcinogenic anilines. Human exposure occurs primarily in the occupational setting through handling of dye dust, and through use and disposal of MNA-containing products. MNA has been reported to induce contact hypersensitivity in a human, myocardial necrosis in rats, and bacterial mutagenicity. This study assessed the subacute toxicity, genotoxicity, contact hypersensitivity, and reproductive toxicity of MNA in rodents in an effort to more fully characterize its toxicological profile. B6C3F1/N mice were exposed to 0, 650, 1250, 2500, 5000, or 10, 000 ppm MNA by dosed feed for 14-days to evaluate subacute toxicity and histopathological endpoints. In female mice, decreased body weight (13.5 %) and absolute kidney weight (14.8 %), compared to control, were observed at 10, 000 ppm MNA; increased relative liver weight (10–12 %), compared to control, occurred at 5, 000–10, 000 ppm MNA. In male mice, absolute (15 %) and relative liver weights (9–13 %) were increased at 2, 500−5, 000 ppm and 1250–10, 000 ppm MNA, compared to control, respectively. In both sexes of mice, minimal elevations of hemosiderin pigmentation (a breakdown product of erythrocytes), relative to control, were observed in the liver (10, 000 ppm); minimal to moderate elevations of hemosiderin pigmentation (5, 000–10, 000 ppm) and minimal increases in hematopoietic cell proliferation occurred in the spleen (≥ 1250 ppm). In a reproductive toxicity study, timed-mated female Harlan Sprague Dawley rats were exposed to 0–10, 000 ppm MNA by dosed feed from gestation day 6 through postnatal day (PND) 21. Decreases in mean litter weights were observed at 5000 ppm MNA, compared to control, beginning at PND1. To evaluate potential contact hypersensitivity, MNA (2.5–50 %, in dimethylformamide) was applied to the dorsa of both ears of female Balb/c mice once daily for three days. The increase observed in lymph node cell proliferation (10–50 % increase in thymidine uptake compared to control) did not reproducibly achieve the Sensitization Index (SI) 3 level, and there was no ear swelling evident following sensitization with 10–50 % MNA and challenge with 25 % MNA in the mouse ear swelling test. In bacterial mutagenicity assays, MNA (250−1000 μg/plate) induced significant increases, compared to control, in mutant colonies with and without metabolic activation enzymes in Salmonella typhimurium strains TA100 and TA98. These data indicate that MNA is genotoxic, and may induce erythrocyte damage and reactive phagocytosis by macrophages in the liver and spleen.