Toxic and hygienic evaluation of the pyridine derivative — 2-ethyl-4-nitropyridine N-oxide

Introduction. The toxic and hygienic assessment of both the final product and intermediate synthesis products remains the key preventive measure to avoid intoxication of workers’ body by industrial xenobiotics in the chemical and pharmaceutical industry and in the context of a constant increase in the range of used compounds. In recent years, nitrogen-containing heterocyclic compounds of the pyridine group have been widely used in various industries. One of these substances is the anti-tuberculosis drug ethionamide, the intermediate product in the synthesis of which is 2-ethyl-4-nitropyridine N-oxide.

Materials and methods. In experiments, the toxic properties of 2-ethyl-4-nitropyridine N-oxide were studied. The investigations were carried out on outbred rats and mice, rabbits and guinea pigs. The effect of the substance on experimental animals was assessed using standard physiological, biochemical, hematological and morphological indices. Intermediate toxicity was studied with different methods of substance administration (oral, percutaneous and inhalation) both in single and repeated experiments. The obtained results were processed using the Statistic 10.0 software package.

Results. Mean lethal doses of 2-ethyl-4-nitropyridine N-oxide for female rats and male mice were 1250 mg/kg (976.6÷1600.0 mg/kg) and 430 mg/kg (355.4÷520.3mg/kg), respectively; for female mice — 675 mg/kg. The ability of the substance to accumulate was average: the cumulation coefficient was 4.0. There were no significant differences in the effect of the substance on animals of different species and gender. The substance didn’t show a local irritating effect on the skin, skin-resorptive and allergic effects, but a pronounced irritating effect on the mucous membranes of the eyes was revealed. In the subacute experiment, 2-ethyl-4-nitropyridine N-oxide showed a toxic effect mainly on the blood system. A specific damaging effect was revealed, which was expressed in an imbalance of the content of oxyhemoglobin and methemoglobin with a significant increase in the latter. The threshold index of acute inhalation effect was 76.7 mg/m³. The tentative safe exposure level in the air of the working area for the substance was calculated at the level of 0.5 mg/m³.

Limitations. The investigation is limited to the study of the toxicological characteristics of 2-ethyl-4-nitropyridine N-oxide. In accordance with the directive documents on the protection of experimental animals, the limited number of in vivo experiments is connected with the dangers for animals and with public ethical views on in vivo experiments.

Conclusion. The proposed tentative safe level of exposure to 2-ethyl-4-nitropyridine N-oxide in the air of the working area at the level of 0.5 mg/m³ makes it possible to attribute the xenobiotic to hazard class II. Under the conditions of compliance with the specified standard, the dose absorbed by the worker under the production conditions will be no more than 5–10 mg per work shift, which guarantees safety for health and minimizes the risk to the health of workers. Information on the toxicity of 2-ethyl-4-nitropyridine N-oxide can be useful for solving a wide range of tasks fixed in the control and supervisory activities of the Federal Service for Supervision in Protection of the Rights of Consumer and Man Wellbeing, hygienic rationing and monitoring, and will contribute to the prevention and reduction of incidence rate associated with the exposure to harmful factors of the production environment.

Compliance with ethical standards. The Local Ethics Committee of the Research Institute for Complex Problems of Hygiene and Occupational Diseases approved this study carried out under the European Convention for the Protection of Vertebrate Animals Used for Experiments or Other Scientific Purposes (ETS N 123), Directive of the European Parliament and Council of the European Union 2010/63/EU of 22.09.2010 on the protection of animals used for scientific purposes.

Contribution:
Gorokhova L.G. — the concept and design of the study, collection and processing of material, statistical processing, writing a text;
Mikhailova N.N. — editing, writing a text;
Zhukova A.G. — collection of material and data processing, writing a text;
Kazitskaya A.S. — collection and processing of material, statistical processing.
All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Conflict of interest. The authors declare no conflict of interest.

Acknowledgement. The study had no sponsorship.

Received: March 17, 2022 / Accepted: June 08, 2022 / Published: July 31, 2022