Analysis for data-derived extrapolation factors for procymidone.

Regulatory Toxicology and Pharmacology : RTP
Bernard GadagbuiRhian B Cope

Abstract

The derivation of Chemical Specific Adjustment Factors (CSAFs) (IPCS, 2005; U.S. EPA, 2014) depends on the choice of appropriate dose metric. EPA and IPCS guidance was applied to derive a CSAF for developmental toxicity for procymidone (PCM). Although kinetic data were not available in humans at any dose, sufficient toxicokinetic data are available in a surrogate species, primates, and from chimeric mice with both rat and human liver cells to offer insights. Alternative approaches were explored in the derivation of the CSAG based on review of the available kinetic data. The most likely dosimetric adjustment is the Cmax based on the character of the critical effect - reduced anogenital distance and increased incidence of hypospadias in male rats, which likely occurs during a small window of time during development of the rat fetus. Cmax is also the default dosimeter from U.S. EPA (1991). However, in this case, the use of Cmax is also likely more conservative than the use of area under the curve (AUC), which otherwise is the default recommendation of the IPCS (2005). Despite human data, estimated tentative CSAF value is 0.48 (range, 0.22 to 0.74). The use of any of these values would be supported by the available data.

References

Jan 5, 2008·Environmental Health Perspectives·Ulla HassAndreas Kortenkamp
Oct 29, 2009·Journal of Agricultural and Food Chemistry·Hirokazu TaruiHideo Kaneko
Apr 26, 2011·The Journal of Steroid Biochemistry and Molecular Biology·Doug C Luccio-Camelo, Gail S Prins
Jun 27, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Justin M ConleyLeon Earl Gray

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