Assessment of Reproductive Toxicity and Gonadotoxic Potential of N-Methyl-2-Pyrrolidone in Male Rats

Abstract

Objectives: N-methyl-2-pyrrolidone (NMP) is a solvent used in petrochemical, electric and electronic industries, and in the production of paint removers, pesticides and veterinary drugs. The substance exhibits slight acute toxicity, and moderate irritant, embryotoxic and teratogenic effects. The aim of the study was to assess NMP reproductive toxicity and gonadotoxicity in male rats. Material and Methods: The animals were exposed per os to NMP at daily doses of 0, 100, 300 and 1000 mg/kg. After 10 weeks of exposure, each male was mated with nonexposed female, then all the males were autopsied, and epididymis and testis were fi xed for pathomorphological examination. Viability and development of offspring was observed to 28 days postbirth. Results: NMP at 1000 mg/kg was found to produce male infertility and extensive damage to the seminiferous epithelium in the seminal tubules of the testis. When administered at 100 mg/kg or 300 mg/kg, it did not signifi cantly affect fertility or spermatogenesis. NMP exposure at 100 mg/kg did not infl uence either the viability or the development of their offspring in the fi rst month of life, while exposure at 300 mg/kg resulted in a signifi cantly lower viability of the offspring in the fi rst four days of life. Conclusion: This study has demonstrated that sub-chronic exposure of male rats to NMP at 1000 mg/kg/day produces gonadotoxic effect and brings about infertility. Administration at lower doses of 100 and 300 mg/kg did not impair male fertility, but only the lowest dose of 100 mg/kg was found to have no infl uence on the prenatal development of the progeny.

Solvent‐based paint and varnish removers: a focused toxicologic review of existing and alternative constituents

“…A single case report links NMP with intrauterine growth retardation and lateterm fetal loss in a laboratory worker who had a substantial acute dermal exposure in the early second trimester (Solomon, Morse, Garbo, & Milton, 1996). With regard to potential male reproductive effects, in a 10-week feeding study of rats, the two highest dose groups showed either decreased viability of offspring (300 mg/kg) or depressed spermatogenesis with total infertility (1000 mg/kg) (Sitarek & Stetkiewicz, 2008 Acetone is readily absorbed by ingestion, inhalation and skin contact. It is also produced endogenously in diabetic keto-acidosis, or as breakdown product of lipids produced by so-called "ketogenic" diets.…”

A rational design of cosolvent exfoliation of layered materials by directly probing liquid–solid interaction

“…However, these pyrrolidone-based solvents are generally toxic and have a high-boiling point. Classified as a reproductive toxin, industrial scale use of such solvent may pose a significant environmental risk 22,23 .…”

Review of Pharmaceutical Applications of N-Methyl-2-Pyrrolidone

“…In a recent study by Saillenfait and coworkers, it has been shown that two metabolites of NMP (5-hydroxy-Nmethyl-2-pyrrolidone and 2-hydroxy-Nmethylsuccinimide) have no significant effects on embryos, whereas another metabolite (Nmethylsuccinimide) has lower toxicity in comparison with NMP (61). In a more recent work by Sitarek and Stetkiewicz, it has been shown that daily exposure to 1000 mg/kg of NMP causes infertility in male rats (62).…”