N-nitrosophenacetin: its synthesis, characterization, mutagenicity, and teratogenicity

Reaction of phenacetin (CAS: 62-44-2; p-acetophenetidide) with nitrous fumes (N2O3) in glacial acetic acid at 0-5 degrees C yields N-nitrosophenacetin (NP), 2-nitrophenacetin, N-nitroso-2-nitrophenacetin (NNP), and other compounds. Both NP and NNP are fairly stable at low temperature (-30 degrees C) but extremely labile at ambient temperature. NP (median lethal dose to Sprague-Dawley rat: 21 mg/kg body wt) is 80 times more toxic than its parent compound phenacetin and is directly mutagenic to bacterial cells including Salmonella typhimurium and Sarcina lutea. The mutagenicity of NP is comparable to that of N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] and requires no microsomal metabolic activation. The teratogenic potential of NP was studied in White Leghorn chick embryos given a single dose of 5-15 micrograms/egg on day 6 of incubation. A low incidence of exencephaly and eyelid defect and a high incidence of feather and claw malformations were found in the treated group; no such malformed embryos were found in the control group. The teratogenicity of NP was found to be weaker than that of MNNG, but stronger than that of N-methyl-N-nitrosourea (CAS: 684-93-5), dimethylnitrosamine (CAS: 62-75-9; N-nitrosodimethylamine), and diethylnitrosamine (CAS: 15-18-5; N-nitrosodiethylamine).