Comparative developmental toxicities of the three major metabolites of N-methyl-2-pyrrolidone after oral administration in rats.
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.
Saillenfait
A M
AM
Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27, 54501 Vandoeuvre, France. anne-marie.saillenfait@inrs.fr
Sabaté
J P
JP
Gallissot
F
F
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D018376:Cardiovascular Abnormalities / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D006548:Hernia, Diaphragmatic / Q000139:chemically induced; D011247:Pregnancy; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D013388:Succinimides / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
C107901:2-hydroxy-N-methylsuccinimide; C107902:5-hydroxy-N-methylpyrrolidone; C110990:N-methylsuccinimide; D011760:Pyrrolidinones; D012997:Solvents; D013388:Succinimides; C038678:N-methylpyrrolidone