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December 2, 2004 Meeting Agenda

November 22, 2004

OPP Docket Telephone: (703-305-5805)
Docket Number: OPP-2004-0343

Holiday Inn Rosslyn at Key Bridge
1900 North Fort Myer Drive,
Arlington, VA 22209
Telephone: (703-807-2000)


Use of Pharmacokinetic Data to Refine Carbaryl Risk Estimates from Oral and Dermal Exposure



Charge Question 1 - Design of Pharmacokinetic Studies:

A series of pharmacokinetic and metabolism studies were completed that serve as the basis for the proposed approach associated with childrens' exposure to carbaryl after lawn treatments.These studies included dosing rats via several routes (i.e., oral, dermal, and intravenous).In a subsequent study, carbaryl was administered to rats via the oral and dermal routes simultaneously at exposure levels similar to those calculated in the Agency's deterministic exposure assessment for toddlers playing on treated lawns.

(A) Please comment on the design of these experiments with respect to the usefulness of results to estimate peak tissue levels for risk assessment purposes.

(B) The design of the multi-route study was intended to mimic the concurrent oral and dermal exposures of toddlers playing on treated lawns.Please comment on this approach.



Charge Question 2 - Pharmacokinetic Approach:

Historically, risk assessments completed by the Agency have been based on comparison of endpoints associated with total administered dose levels from toxicology studies with daily human exposure.The proposed pharmacokinetic approach presented in this paper instead relies on the use of peak internal dose at the target tissue.Because of the rapid pharmacokinetics and pharmacodynamics of carbaryl, a more appropriate dose metric may be the use of peak target tissue levels for calculating exposure estimates instead of total daily absorbed dose values.

(A) Please comment on the appropriateness of using peak levels for estimating exposure.

(B) This pharmacokinetic approach assumes that toddlers put their hands in their mouths at a rate of 20 times an hour for 2 hours.A laboratory dosing regimen that exactly mimics this toddler behavior is impractical. As such, oral doses were administered in the multi-route rat study once per hour for 2 hours.The proposed approach uses an algorithm to adjust the results for 2 hourly bolus doses to that of a toddler which occurs 20 times per hour.Given the rapid metabolism of carbaryl, please comment on whether this algorithm can be reasonably used to predict the expected pharmacokinetic behavior of carbaryl.

(C) To convert the four 24-hour time periods in the biomonitoring study to a shorter time period and to account for plateau tissue concentrations, Bayer proposed extrapolating results from the rat mixed-dose study to the biomonitoring study in this manner.Because the argin-of-exposure calculated using estimated plateau brain concentrations was approximately 20-fold greater than the margin-of-exposure calculated using EPA's SOPs For Residential Exposure Assessment, Bayer proposed multiplying results from the biomonitoring study by an adjustment factor of 20.Please comment on whether this approach is appropriate for extrapolating from results in the rat pharmacokinetic study to the biomonitoring study.



Please be advised that agenda times are approximate.For further information, please contact the Designated Federal Official for the meeting, Joseph E. Bailey, via telephone: (202) 564-8450; fax (202) 564-8382; or email: bailey.joseph@epa.gov

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