Niclosamide is a restricted-use pesticide that has been successfully used for more than 40 years to control sea lampreys (Petromyzon marinus) in streams tributary to the Great Lakes. As the chemical is generally applied directly to waterways inhabited by fish, there is a potential for niclosamide residue to accumulate in fish muscle tissue. Niclosamide is also used to kill golden apple snail (Pomacea canaliculata) which is a major pest of rice. Despite its general use, niclosamide is found to be toxic to several aquatic organisms. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that niclosamide and its metabolites differ in their LUMO-HOMO energy differences and hence kinetic lability. TCFNA has the smallest LUMO-HOMO energy difference and hence the greatest reactivity. It has also a lower solubility in water and possibly a lower thermodynamic stability. These properties may make TCFNA to be a toxic and mutagenic metabolite.