Abstract
Percutaneous absorption of pesticides is a major determinant for risk assessment. Furthermore, cutaneous metabolism plays a role in penetration of certain chemicals. Therefore, the aim of these studies was to determine the transdermal metabolism of three related compounds [the herbicide, fluroxypyr methylheptyl ester (FPMH), fluroxypyr methyl ester (FPM), and fluroxypyr (FP)] during penetration through human and rat skin in vitro. The data presented in this article show that both FPM and FPMH were completely metabolized during their passage through human and rat skin in vitro. The only metabolite produced was that of the hydrolysis product, FP, with no parent ester penetrating through the skin. The extent of FP formation within the skin was directly correlated to the degree of stratum corneum reservoir formation. The larger the stratum corneum reservoir, the lower the levels of FP recovered from within the skin. This suggests that as the ester partitioned out of the SC it was immediately hydrolyzed to FP, which could then pass freely through the remainder of the epidermis and dermis. Similar metabolic profiles were observed for the transdermal metabolism of FPM and FPMH in previously frozen rat skin, indicating the robust nature of the esterase enzymes involved. In conclusion, systemic exposure after skin contact with FPM or FPMH is likely to be to the acid metabolite, FP, only and not to the parent ester. In addition, the rate and extent of percutaneous absorption will be a major determinant of cutaneous metabolism.
Footnotes
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Send reprint requests to: Dr. Philip Hewitt, Institute of Toxicology, Merck KGaA, Frankfurter Strasse 250, Darmstadt, 64271, Germany. E-mail: philip.hewitt{at}merck.de
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↵1 Current address: Section of Molecular Toxicology, Imperial College School of Medicine, South Kensington, London SW7 2AZ, UK.
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↵2 Current address: Dow AgroSciences Europe.
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This work was funded by Dow AgroSciences Europe.
- Abbreviations used are::
- FPMH
- fluroxypyr methylheptyl ester
- FP
- fluroxypyr
- FPM
- fluroxypyr methyl ester
- EC
- emulsifiable concentrate
- HHBSS
- HEPES-buffered Hank's balanced salt solution
- LSS
- liquid scintillation spectrometry
- SC
- stratum corneum
- Received November 8, 1999.
- Accepted April 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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