Abstract: Objective To evaluate the mutagenic risks of 17 nitrosamine compounds using toxicology software and bacterial reverse mutation test, and explore the relationship between the substituent structure of nitrosamine compounds and their mutagenicity risk. Methods Derek Nexus and Sarah Nexus were used to predict the mutagenic risks of 17 nitrosamine compounds, and 6-well plate-based bacterial reverse mutation test of Salmonella typhimurium TA97, TA98, TA100, TA102, TA1535 and TA1537 in the absence and presence of rat S9 metabolic activation conditions was performed respectively, to evaluate their mutagenicity risks. Results Based on the nitroso structure, Derek Nexus predicted that 16 nitrosamines (excluding NDPh) had mutagenic risks. Sarah Nexus suggested all the 17 nitrosamines were mutagenic, whereas the mutagenic risks of NMEA, NEIPA and NDIPA were relatively lower. Under non-S9 metabolic activation conditions, except for NMPEA, the bacterial reverse mutation test results of all nitrosamine compounds were negative. NMPEA could only induce an increase in the number of revertants of TA1537 strain. Under rat S9 metabolic activation, NDEA, NMOR, NDPA, NPIP and NPYR showed positive results in all the TA97, TA100 and 1535 strains, and NDMA、NMEA、NEIPA、NDBA、NMPA、NNK、NDELA、NDPh and NMPEA were also positive in at least one of TA97, TA100 and TA1535 strains. Conclusion Mutagenicities of nitrosamine compounds are related to the factors of number of α-hydrogens and substitution of α-hydrogens, the presence of branched or larger/nonmetabolizable groups, and the stability of the formed diazonium ions in alkyl nitrosamine compounds, etc. This study provides the latest in vitro mutagenicity and DNA damage test data of nitrosamine compounds, validates the effect of substituent structure on the mutagenic potency of nitrosamine compounds, and can provide data support for their regulation.

Key words: nitrosamine, mutagenicity, structure-activity analysis, in silico toxicology, bacterial reverse mutation test