Introduction

Toluidine is an organic chemical raw material widely used in pesticides, dyes, medicines, spices, and other industries. Toluidine is an organic compound with three isomers: o-toluidine, m-toluidine, and p-toluidine. The difference between these three isomers is the spot where the methyl group (–CH3) is attached to the ring concerning the amino function. Toluidine becomes a weak base due to the combination of an amino group and an aromatic ring. Furthermore, it is poorly soluble in pure water but dissolves well in acidic water due to the formation of ammonium salts, which is common for organic amines. O-toluidine and m-toluidine are thick liquids, but p-toluidine is a pale solution.

Uses

Para-toluidine (p-toluidine) is a high-production volume chemical, and about 5,000 tons/year of it are imported into Korea as of the 2018 registration. This substance is mainly used as an intermediate in the manufacture of paints, azo dyes, and pigments. It was used for the preparation of water-soluble poly(p-toluidine). Recently, polymer amines have been recognized as excellent corrosion inhibitors for iron in acid solutions[1].

Toxicity

p-Toluidine, a chemical used as an intermediate in manufacturing dyes, pesticides and pharmaceutical intermediates, was carcinogenic in mice but not in rats after an 18-month diet exposure study.

Mechanisms for DMPT and p-toluidine liver toxicity may involve oxidative damage and metabolic activation. Both chemicals are known to oxidize hemoglobin to methemoglobin. The DMPT-induced methemoglobinemia in animals and humans putatively correlates with the formation and redox cycling of p-methyl-phenylhydroxylamine. Phenylhydroxylamine, a similar metabolite of aniline, is a potent inducer of methe-moglobinemia in rats. The formation of p-methylphenylhydroxylamine in DMPT-treated rats is inferred by the presence of N-methyl-p-toluidine and p-(N-acetylhydroxyamino) hippuric acid in the urine. N-hydroxylated arylamines are also capable of covalently binding to hemoglobin and/or DNA. DNA adduct formation may result in mutations, leading to a carcinogenic response. Further, the formation of a reactive imine methide via N-hydroxylation has been postulated. Imine methides may react with glutathione, other proteins or nucleic acids. The genotoxic potential of DMPT and p-toluidine appears to be low; both compounds were negative in bacteria mutagenicity tests[2].

In the liver of p-toluidine-treated rats, there were increased incidences of individual cell death in the 60 and 120 mg/ kg dose groups. Individual cell death was similar to that observed in animals exposed to DMPT. One animal in the 60 mg/kg dose group and one in the 120 mg/kg dose group had a minimal increase in mitotic figures in the liver. Mitotic figures were fairly common in the control animals due to their young age. However, the two animals that had minimal increased mitotic figures recorded contained more mitotic figures per 20× field (typically 3–5 or more compared to 1–3 in control animals). All lesions observed were considered to be of minimal to mild severity.

References

[1] Inhye Lee. “Ecological risk assessment of p-toluidine in freshwater, sediment, and soil media.” Ecotoxicology (2024).

[2] June K. Dunnick. “Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats.” Archives of Toxicology 91 4 (2016): 1685–1696.