Metabolism of 3H/14C-labeled 4''-deoxy-4''-epimethylaminoavermectin B1a benzoate in chickens. Identification of novel fatty acid conjugates of '4'-deoxy-4''-epimethylaminoavermectin B1a.

The metabolism of 3H/14C-labeled 4"-deoxy-4"-epimethylaminoavermectin B1a (MAB1a) benzoate, the major homologue (>/=90%) of the avermectin insecticide emamectin benzoate, was studied in laying chickens. Ten Leghorn hens (Gallus domesticus) were orally dosed once daily for 7 days (1 mg/kg of body weight/day). Eggs and excreta were collected daily, and eggs were subsequently separated into whites and yolks. Chickens were euthanized within 20 hr after the last dose, and liver, kidney, heart, muscle, fat, ovaries, gizzard, gastrointestinal tract and contents, and carcass were collected. Approximately 70 and 6% of the total administered dose were recovered in the excreta plus gastrointestinal tract and contents and in the tissues plus eggs, respectively. Two novel metabolites, i.e. the 24-hydroxymethyl derivative of the parent compound (24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B1a) and the N-demethylated derivative of 24-hydroxymethyl-4"-deoxy-4"-epimethylaminoavermectin B1a (24-hydroxymethyl-4"-deoxy-4"-epiaminoavermectin B1a), were identified. In addition, eight fatty acid conjugates of each of these two metabolites, comprising 8-75% of total radioactive residues in tissues and eggs, were isolated and identified. Although this represents some of the most extensive in vivo fatty acid conjugation to a xenobiotic reported to date, potential human exposure to MAB1a residues from consumption of chicken would be extremely low, because the dosage level in this study was approximately 1000-fold greater than the MAB1a residue levels seen in crops and because the majority of the applied dose was recovered in the excreta. Based on these findings, the avian biotransformation of MAB1a differs substantially from the mammalian biotransformation.

Dermal penetration of 4"-(epi-methylamino)-4"-deoxyavermectin B1a benzoate in the rhesus monkey.

The dermal absorption of the experimental avermectin insecticide emamectin benzoate was studied in the Rhesus monkey. Dermal absorption was calculated by comparing radioactivity levels in excreta following dermal application of the compound with those following administration of an equivalent intravenous dose. After i.v. administration of 300 micrograms [3H]MAB1a (prepared as a 1:1 solution of propylene glycol:saline) to three monkeys, plasma levels decreased biphasically with a rapid decline in radioactivity during the first 15 min followed by a slower decline to background. By 7 days post-dose, approximately 90% and 5% of the administered radioactivity was recovered in the faeces and urine, respectively. After a washout period, 300 micrograms [3H]MAB1a (dissolved in emulsifiable concentrate) was applied topically to the shaved forearm of the same monkeys. Following a 10-hr exposure period, approximately 90% of the radioactivity was recovered in a soap and water wash of the exposed forearms. Although plasma radioactivity levels generally remained below background levels, approximately 1.5% of the applied dose was recovered in the excreta. Dermal absorption of [3H]emamectin benzoate was calculated as 1.6%. The low dermal penetration of emamectin benzoate indicates that minimal actual exposure of agricultural workers to this compound will occur.