Toxicokinetics and Metabolism ofN-[14C]N-Methyl-2-Pyrrolidone in Male Sprague-Dawley Rats: in Vivo and in Vitro Percutaneous Absorption

Payan, Jean-Paul; Boudry, Isabelle; Beydon, Dominique; Fabry, J.; Grandclaude, Marie-Christine; Ferrari, Elisabeth; André, Jean‐Claude

doi:10.1124/dmd.31.5.659

Cited by 32 publications

(26 citation statements)

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“…However, Payan et al (2003) suggested MSI and 2-HMSI as NMP metabolites in rats given a single dose of radioactively labelled NMP intravenously, by comparing HPLC retention times. These metabolites were confirmed using mass spectrometry in this study.…”

Section: Discussionmentioning

confidence: 99%

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Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Carnerup

Saillenfait

Jönsson

2005

Food and Chemical Toxicology

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The primary aims were to study the metabolism in rats and to determine the biological levels after one oral developmentally toxic dose of N-methyl-2-pyrrolidone (NMP), a widely used industrial chemical. Non-pregnant female Sprague-Dawley rats were given an oral single dose of either a non-toxic dose of 125 mg NMP/kg (group 1) by gavage or a developmentally toxic dose of 500 mg/kg (group 2). Blood plasma (7 rats per time point) and urine (10 rats per time point) were sampled up to 72h after administration and analyzed using mass spectrometry. In both plasma and urine NMP, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP), N-methylsuccinimide and 2-hydroxy-N-methylsuccinimide (2-HMSI) and 2-pyrrolidone (2-P) were identified. In urine 48% of the administered dose was recovered as 5-HNMP and 2-5% as 2-HMSI. The total recovery in urine was 53-59%. The peak concentrations for NMP in plasma were 1.2 and 6.9 mmol/l, 0.42 and 0.76 mmol/l for 5-HNMP, 0.07 and 0.31 mmol/l for MSI and for 2-HMSI the concentrations were 0.02 and 0.05 mmol/l for group 1 and 2, respectively. In summary, the same metabolites were found in rats as in humans and the biological levels were reported for NMP and its metabolites after oral exposure to a developmentally toxic dose and one non-toxic dose of NMP.

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Section: Discussionmentioning

confidence: 99%

“…In the rat, an extensive oral (Midgley et al, 1992) and percutaneous (Midgley et al, 1992;Payan et al, 2003) uptake has been shown. The metabolism is unclear but Wells et al (1992) showed that the major urinary metabolite was 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP).…”

Section: Introductionmentioning

confidence: 99%

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Carnerup

Saillenfait

Jönsson

2005

Food and Chemical Toxicology

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“…This conjecture is confi rmed by experiments intended to test NMP's ability to permeate the skin of humans and experimental animals [2,3]. NMP is also easily absorbed in the respiratory and alimentary tracts of experimental animals.…”

Section: Introductionmentioning

confidence: 77%

“…Neurobehavioral abnormalities and signifi cantly lower body weight were noted in the offspring of female rats exposed to NMP at 622 mg/m 3 from gestation day 7-20 [8]. In both the studies quoted above, NMP concentrations (680 mg/m 3 and 622 mg/m 3 ) were non-toxic to pregnant females, while they were detrimental to the offspring in spite of the relatively short period of exposure. NMP at the lower concentrations of 100 mg/m 3 and 360 mg/m 3 did not impair the prenatal development of the offspring of female rats exposed by inhalation during organogenesis.…”

Section: O R I G I N a L P A P E R S Ijomeh 2008;21(1)mentioning

confidence: 87%

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

Sitarek¹,

Stetkiewicz²

2008

International Journal of Occupational Medicine and Environmental Health

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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.

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“…This appears to be in contradiction with the physicochemical characteristics of nVP and the structurally similar compound, N-methyl-2-pyrrolidone (nMP), which would appear to predict significant dermal absorption. Indeed, in rats, the maximum absorption fluxes for nMP were 10 and 20 mg/cm 2 /h for an exposure to 20 and 40 µl/cm 2 /h, respectively (Payan et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Influence of water dilution on percutaneous absorption of N-vinyl-2-pyrrolidone in vivo and ex vivo in rats and ex vivo in humans

et al. 2014

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N-vinyl-2-pyrrolidone (NVP) is mainly used as a monomer in the production of polyvinylpyrrolidone or copolymers. Percutaneous absorption is an important source of exposure in the work environment. However, few studies have investigated this route of absorption. In this study, percutaneous absorption of neat or aqueous NVP solutions was measured in vivo and ex vivo in rats, and ex vivo in humans. Penetration and absorption fluxes were very similar following in vivo exposure to neat NVP (0.54 and 0.43 mg/cm(2)/h, respectively). Exposing rats to a 50% aqueous solution of NVP increased both fluxes threefold (to 1.48 and 1.55 mg/cm(2)/h, respectively). Ex vivo, the absorption flux increased with solutions from 10 to 25% of NVP, reached a plateau (between 25 and 50% in rat, 25 and 75% in human) and then decreased with neat NVP. In vivo and ex vivo absorption fluxes measured using rat skin were similar, supporting the hypothesis that the ex vivo measurements were a good representation of what was observed in vivo. Thus, for humans, the ex vivo measurements are likely the same as would be determined in vivo.

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Toxicokinetics and Metabolism ofN-[¹⁴C]N-Methyl-2-Pyrrolidone in Male Sprague-Dawley Rats: in Vivo and in Vitro Percutaneous Absorption

Abstract: This article is available online at http://dmd.aspetjournals.org

Cited by 32 publications

References 10 publications

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

Concentrations of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine following oral administration of NMP to rats

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

Influence of water dilution on percutaneous absorption of N-vinyl-2-pyrrolidone in vivo and ex vivo in rats and ex vivo in humans

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