Absorption, metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog

Abstract

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is ~1.3 mg kg^-1 and in dog is 0.2 mgkg^-1. In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (¹⁴C)-MCPA at 5 or 100 mg kg^-1 and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values based on total radioactivity: 5 mgkg^-1 rat: t_½dist 3.5 h, t_½elim 17.2-36.2 h, AUC_(0-∞) 230 µg equiv h g^-1; 5 mgkg^-1 dog: t_½47 h, AUC_(0-∞) 2500 µg equiv h g^-1; 100mg kg^-1 rat: t_½dist 10 h, t_½elim 10.27-25.4 h, AUC_(0-∞) 5400 µg equiv h g^-1; 100 mg kg^-1 dog: t_½41 h, AUC_(0-∞) 20 500µg equiv h g^-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.