Distribution of 2-methyl-4-chlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid in male rats: evidence for the involvement of the central nervous system in their toxicity

The effects of different 2-methyl-4-chlorophenoxyacetic acid (MCPA) or 2,4-dichlorophenoxyacetic acid (2,4-D) pretreatments on the distribution of labeled [¹⁴C]MCPA or [¹⁴C]2,4-D given iv were studied in male rats. Single subcutaneous MCPA or 2,4-D pretreatment increased ¹⁴C activity in the brain, cerebrospinal fluid (CSF), liver, muscle, heart, or testis and decreased that in the plasma or kidney, while in the lung ¹⁴C activity remained approximately unchanged. Changes in the distribution of ¹⁴C activity as well as toxic signs such as myotonia and lethargy appeared within 0.5–1.5 hr after subcutaneous MCPA administration and disappeared in a few days. ¹⁴C activities in the brain and CSF of both saline-treated adult and 10- or 21-day-old animals were very low as compared to the other tissues, but in the treated animals these and also absolute MCPA concentration increased to about the level in the muscle or testis. Chronic MCPA exposure had only a slight effect on the distribution of ¹⁴C activity. The decreased binding of [¹⁴C]MCPA to plasma proteins caused by MCPA pretreatments may explain the increase of ¹⁴C activity in many tissues but not the high increase in the brain and CSF during intoxication. The results indicate that at large doses either the influx of MCPA and 2,4-D into the brain is highly increased or their efflux out of the brain is decreased. A potent increase in cerebral ¹⁴C activity coincided with the appearance of MCPA intoxication, which suggests that the central nervous system (CNS) is involved in the toxicity of chlorophenoxyacetic acids.