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

Abstract

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.

• Authors: A M Saillenfait, J P Sabaté, F Gallissot
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) 2007 Nov-Dec Vol. 27 Issue 6 Pg. 571-81 ISSN: 0260-437X [Print] England
• PMID: 17370238 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 2-hydroxy-N-methylsuccinimide
• 5-hydroxy-N-methylpyrrolidone
• N-methylsuccinimide
• Pyrrolidinones
• Solvents
• Succinimides
• N-methylpyrrolidone

Topics

• Abnormalities, Drug-Induced
• Administration, Oral
• Animals
• Biotransformation
• Body Weight (drug effects)
• Bone and Bones (abnormalities, drug effects)
• Cardiovascular Abnormalities (chemically induced)
• Dose-Response Relationship, Drug
• Eating (drug effects)
• Embryonic Development (drug effects)
• Female
• Fetal Death (chemically induced)
• Fetal Weight (drug effects)
• Fetus (drug effects)
• Gestational Age
• Hernia, Diaphragmatic (chemically induced)
• Pregnancy
• Pyrrolidinones (administration & dosage, metabolism, toxicity)
• Rats
• Rats, Sprague-Dawley
• Solvents (administration & dosage, metabolism, toxicity)
• Succinimides (administration & dosage, metabolism, toxicity)