In vivo percutaneous absorption of acetochlor in the rhesus monkey: dose-response and exposure risk assessment.
Percutaneous absorption of three topical dose levels of [14C]acetochlor in the rhesus monkey were determined for exposure risk assessment. The topical doses were 30.7, 0.43 and 0.03 mg acetochlor in 40 microliters commercial formulation and aqueous dilutions thereof, spread over 10 cm3 skin surface area (lower abdominal). The dosing area was not covered. The skin application time was 24 hr. The dosed skin surface area was washed with 50% soap (Ivory Liquid) and water at the end of the 24-hr dosing period. An intravenous dose of 0.43 mg was also administered to determine the excretory kinetics of acetochlor in the rhesus monkey. The same four monkeys were used for all dose administrations. Bioavailability was determined by radioactivity disposition in blood, urine and faeces. Percutaneous absorption was 23.1 +/- 8.7, 17.3 +/- 5.9 and 4.9 +/- 1.4% for 0.03, 0.43 and 30.7 mg doses, respectively. Assuming a constant state of absorption, the hourly exposure flux (microgram/cm2/hr) was 0.03 +/- 0.01 for the 0.03 mg dose (3 micrograms/cm2). Increasing the dose approximately 15-fold to 0.43 mg (43 micrograms/cm2) resulted in a 10-fold increase in flux to 0.3 microgram/cm2/hr. Increasing the dose a further 70-fold to 30.7 mg (3070 micrograms/cm2) resulted in only another 21-fold increase in flux (6.3 +/- 1.8 micrograms/cm2/hr). Thus, the efficiency of absorption (%) decreased with increased topical dose, but the amount (mass/flux) of acetochlor absorbed always increased with increased dose. Plasma levels of topical acetochlor at the high dose were detectable at 1 hr and continued at a relatively steady level through the 24-hr dosing period. After the skin surface wash (24 hr) plasma levels decreased but were still detectable at the last 168-hr sampling period. Acetochlor, recently EPA approved as an herbicide for corn crops, is carcinogenic; however, farmers will use half as much acetochlor/acre as other herbicides. The percutaneous absorption of acetochlor is equal to that of alachlor. Therefore, human exposure based on one-half usage suggests that human risk assessment should be one-half all other factors being equal.
Wester
R C
RC
Department of Dermatology, University of California, San Francisco 94143, USA.
Melendres
J L
JL
Maibach
H I
HI
D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D005260:Female; D006540:Herbicides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D007275:Injections, Intravenous; D007553:Isotope Labeling; D008253:Macaca mulatta; D018570:Risk Assessment; D012869:Skin Absorption / Q000187:drug effects*; D014052:Toluidines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine
D006540:Herbicides; D014052:Toluidines; C043377:acetochlor