Formaldehyde generators: relationship between stability, lipophilicity and carcinogenic potency.

The rate of hydrolysis to formaldehyde of methylenedimorpholine (MDM), hexamethylenetetramine (HMT) and dinitrosopentamethylenetetramine (DNPT) have been compared with the enzyme-mediated formation of formaldehyde from hexamethylphosphoramide (HMPA). The bio-distribution of [14C]HMPA following nasal instillation in rats has also been studied and compared with that of [14C]methyl methanesulphonate (MMS). These data are used to relate the several carcinogenic/genotoxic properties of the chemicals named above. It is concluded from these data and related considerations that three classes of formaldehyde-generators should be recognized (a) labile agents such as MDM (and formaldehyde) which are likely to be locally active as carcinogens, (b) lipophilic and relatively stable agents such as HMPA which may be both locally active (if bio-accumulated) and systemically active as carcinogens, and (c) agents such as HMT and DNPT, of intermediate stability, which are unlikely to be systemically active and to be of low or zero activity locally.