Evaluation of exposure biomarkers from percutaneous absorption of N-methyl-2-pyrrolidone

Åkesson, Bengt; Carnerup, Martin A.; Jönsson, Bo

doi:10.5271/sjweh.799

Cited by 24 publications

(22 citation statements)

References 20 publications

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“…In humans, NMP is easily absorbed in the airways (Åkesson and Paulsson, 1997), from the gastrointestinal tract (Åkesson and Jönsson, 1997) and through the skin (Ursin et al, 1995;Akrill et al, 2002;Åkesson et al, 2004). Furthermore, a human metabolic pathway have been described (figure 1), where NMP is hydroxylated to 5-HNMP, further oxidized to N-methylsuccinimide (MSI) which is then hydroxylated to 2-hydroxy-Nmethylsuccinimide (2-HMSI).…”

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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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: 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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“…Previous studies have showed that the human body readily absorbs NMP, both in the respiratory system (Åkesson and Paulsson, 1997), the gastrointestinal tract and through the skin (Akrill et al, 2002;Åkesson et al, 2004). NMP is hydroxylated to 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) , partly by the enzyme cytochrome P450 isoform 1E (CYP1E) (Ligocka et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Levels of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine from volunteers after experimental exposure to NMP in dry and humid air

2006

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“…In addition, its peak level was only four times higher in rats than in women; i.e. 20 and 5.4 μmol l −1 , respectively (Akesson et al, 2004;Carnerup et al, 2005). However, the lack of 2-HMSI developmental toxicity in the current study indicated that it was not a critical metabolite in NMP-induced teratogenesis.…”

Section: -Hmsimentioning

confidence: 42%

“…Taken together, the toxicological and kinetics findings suggest that the developmental toxic effects of NMP are likely due to the parent compound itself. It has been suggested that unidentified metabolites of NMP exist (Akesson et al, 2004;Carnerup et al, 2005). It is not possible to exclude that they might also play a role.…”

Section: -Hmsimentioning

confidence: 99%

Comparative developmental toxicities of the three major metabolites of N‐methyl‐2‐pyrrolidone after oral administration in rats

Saillenfait

Sabaté

Gallissot

2007

J of Applied Toxicology

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The developmental toxicity of the three main metabolites of N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats. Pregnant rats were given 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP; 0, 250, 500, 750 or 1000 mg kg(-1) day(-1)), N-methylsuccinimide (MSI; 0, 500, 750, 1000 or 1250 mg kg(-1) day(-1)), or 2-hydroxyN-methylsuccinimide (2-HMSI; 0, 250, 500, 1000 or 1500 mg kg(-1) day(-1)), by gavage, on gestational days (GD) 6-20. No evidence of maternal toxicity was observed in dams given 5-HNMP. Administration of 2-HMSI resulted in overt maternal toxicity at 500 mg kg(-1) day(-1) and higher doses, as indicated by a significant reduction in weight gain and food consumption at the beginning of treatment. There was no evidence of embryo/fetal toxicity in any of the groups treated with 5-HNMP or 2-HMSI. MSI produced marked developmental toxicity in the presence of maternal effects. Maternal body weight gain and food consumption were affected at 750 mg kg(-1) day(-1) MSI, and above. A significant increase in post-implantation loss occurred at 1250 mg kg(-1) day(-1) MSI, and the incidence of fetuses with external or with visceral malformations was significantly increased at 1000 and 1250 mg kg(-1) day(-1) MSI. Malformations mainly consisted of anasarca, cardiovascular defects and diaphragmatic hernia. Fetal weight was significantly reduced at 1000 and 1250 mg kg(-1) day(-1). The incidence of skeletal variations (predominantly cervical ribs, and delayed ossification of skull bones and sternebrae) was significantly elevated at 750 mg kg(-1) day(-1) and higher doses. However, MSI was much less potent than the parent compound. These results indicate that the embryotoxic and teratogenic effects of NMP are not attributable to these metabolites.

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Evaluation of exposure biomarkers from percutaneous absorption of N-methyl-2-pyrrolidone

Cited by 24 publications

References 20 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

Levels of N-methyl-2-pyrrolidone (NMP) and its metabolites in plasma and urine from volunteers after experimental exposure to NMP in dry and humid air

Comparative developmental toxicities of the three major metabolites of N‐methyl‐2‐pyrrolidone after oral administration in rats

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