Methiocarb is a carbamate pesticide (an acetylcholinesterase inhibitor) which is used as an insecticide, bird repellent, acaricide and molluscicide since the 1960s. Methiocarb has contact and stomach action on mites and neurotoxic effects on molluscs. Seeds treated with methiocarb also affect birds. Other names for methiocarb are mesurol and mercaptodimethur. Due to its toxicity, methiocarb approval as a plant protection product has been withdrawn by the EU effective 2020.
Structure and reactivity The carbamate functional group in methiocarb can be cleaved by cholinesterase to result in the carbamate, which binds to the cholinesterase, and the phenol.
Synthesis
Methiocarb (3) is synthesised by Bayer from 4-methylthio-3,5-xylenol (1) and methyl isocyanate (2). The xylenol (1) will act as the nucleophile in this reaction attacking the partially positively charged carbon in the isocyanate (2).
Mechanism of action Methiocarb acts by acetylcholinesterase inhibition. The product of the cleavage of the carbamate group of methiocarb is methylcarbamic acid which is bound to cholinesterase after the reaction. The normal function of cholinesterase is to cleave the acetyl-choline bond which results in the binding of acetic acid to cholinesterase which is a fast reversible reaction. The carbamic acid also reversibly binds but the hydrolysis of the bond is slower and therefore the acid inhibits the function of cholinesterase which results in elevated acetylcholine levels. In comparison: organophosphates inhibit irreversibly and will therefore inhibit the acetylcholinesterase even more. In addition to its cholinergic effects, methiocarb has been found to be an endocrine disruptor, acting as an estrogen, antiandrogen, and aromatase inhibitor.
Metabolism Methiocarb is biotransformed in the liver mainly by sulfoxidation. This can happen to methiocarb itself but also to the phenol group which is cleaved from methiocarb by choline-esterase. In some cases this same sulfur can be oxidised once more to give the sulfone. A minor pathway that occurs is the hydroxylation of the N-methyl.
Absorption Methiocarb can be taken up through different routes. The most common for humans is up take through the skin or as an aerosol, because of its use as a pesticide in agriculture. For insects and birds this would be by the oral route. The NOAEL's of these routes have been determined as follows: For the oral route, the NOAEL is set to 3.3 mg/kg per day for rats, based on a 2-year study. For absorption through the skin the NOAEL is set to 150 mg/kg per day for rabbits, based on the reduction of food consumption. When methiocarb is fed to rats at a dose of 50 ppm, it gives a reduction of brain cholinesterase by 14% and 5% in males and females respectively. When methiocarb is administered as an aerosol to rats, the highest concentration (96 mg/m3 in solvent) showed signs of involuntary muscle contraction (tremors). These signs weren't observed in the other groups. The brain acetylcholine esterase is reduced in comparison to the solvent controls, to 61% and 74% for males and females respectively. There were no changes in organ weight. The NOAEL was determined to be 6 mg/m3 based on the reduction of brain acetylcholine esterase activity.
Distribution To determine the distribution of methiocarb through the body carbon-14 ([14C]) labeled methiocarb studies have been performed on rats. About 8 hours after IP injection of [14C]methiocarb more than 20 is present in the kidneys, 14 in the lungs, 14 in the heart, 6 in the body fat and 26 in the red blood cells. All the numbers are a measure of the radioactivity in dpm x 103/g of dried tissue. 30 Minutes after treatment gave, for all tissues except bodyfat, much higher values indicating that elimination takes place shortly after injection. Also, an increase in all tissues except the red blood cells has been observed between 2 and 4 hours after injection. This indicates that after two hours redistribution takes place shortly followed by elimination. This radioactivity study only measured the [14C] so the compound could already be metabolized to different compounds with different toxicities, which is not indicated in this study.
Toxicity
Short term toxicity In rats the cholinesterase activity fell down to 50 percent of the control values in 27 days where the dose applied in their diet was 2 mg/ kg bw in the first three days and 4 mg/kg bw for the next 24 days. No abnormal clinical signs were observed. In rabbits methiocarb was applied to the skin to a group of ten at doses of 0, 60, 150 or 375 mg/kg bw per day for 6 h/day. Two out of ten rabbits with the low dose did not survive and with the high dose had a reduced food consumption. Cholinesterase activity was reduced in males with a high dose at 14 and 21 days of treatment. There were no intergroup differences observed in cholinesterase activity among females. The erythrocyte acetylcholinesterase activity is apparently not inhibited in a dose-related fashion. The duration of the study was 24 days.
Long term toxicity In mice, a one-year study of 50 males and 50 females was performed. The mice received diets containing methiocarb at doses of 0, 15, 43 and 130 mg/kg bw per day in males and 0, 20, 57, and 170 mg/kg bw per day in females. Food consumption, behaviour and mortality rate were not affected at any dose. At one month the decrease in plasma acetylcholinesterase activity was the highest and the smallest reductions were observed at 24 months. Brain acetylcholinesterase activity was also lowered, more in males than in females. In rats a two-year study of 60 rats was performed. The rats received diets containing 0, 3.3, 9.3 and 29 mg/kg bw per day for males and 0, 5, 14, and 42 mg/kg bw per day for females. Food consumption, behaviour and mortality rate were not affected at any dose. The total protein concentrations were raised at higher doses of methiocarb. The plasma acetylcholinesterase activity was lowered at the high dose at day one and from eight weeks onwards in males and at day one and 1, 2, 4 and 13 weeks in females. No brain acetylcholinesterase activity was observed.
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