A screening method for trace analysis of potentially genotoxic alkylating compounds has been developed using butyl 1-(pyridin-4-yl) piperidine 4-carboxylate (BPPC) as a new, selective pre-column derivatization reagent for their subsequent analysis by hydrophilic interaction liquid chromatography (HILIC) hyphenated with tandem mass spectrometry (LC-MS/MS). The new derivatization reagent is a modification of 4-dimethylaminopyridine (4-DMAP) previously used for the determination of potentially genotoxic compounds. By using the new reagent the screening potential was enhanced without compromising reactivity. Derivatization at a high pH value was carried out and the reaction time at 60°C was 24h to anticipate for alkyl chlorides showing to be less reactive. The new reagent was designed to obtain reagent related fragmentation of the whole reagent as well as a side group of the reagent. Collision energies for detection of alkylating components derivatized using the new reagent are shown to be significantly more universal than with 4-DMAP. Neutral loss scanning on the fragmentation related to the build in side group remedies shortcomings in the screening for alkyl halides observed when using 4-DMAP. The new approach allows for screening of alkyl halides and alkyl sulfonates at trace levels down to 1 mg kg(-1) and target analysis at about a factor of 10 lower without a significant effect of the active pharmaceutical ingredient (API) matrix. The synthesis of the reagent, investigation of reactivity, the specificity of the fragmentation of derivatives and screening conditions in MS/MS analysis are described.