Analysis for data-derived extrapolation factors for procymidone.

Area of Science:

• Toxicology
• Risk Assessment
• Pharmacokinetics

Background:

• Deriving Chemical Specific Adjustment Factors (CSAFs) requires selecting appropriate dose metrics.
• Guidance from the U.S. EPA and the International Programme on Chemical Safety (IPCS) was followed.
• Procymidone (PCM) developmental toxicity was assessed.

Purpose of the Study:

• To derive a CSAF for developmental toxicity of procymidone (PCM).
• To explore alternative approaches for CSAF derivation using available kinetic data.
• To determine the most appropriate dose metric for dosimetric adjustment.

Main Methods:

• Applied U.S. EPA and IPCS guidance for CSAF derivation.
• Utilized toxicokinetic data from primates and chimeric mice (rat/human liver cells).
• Evaluated Cmax and Area Under the Curve (AUC) as potential dose metrics.

Main Results:

• Cmax was identified as the most likely dosimetric adjustment, considering the critical developmental effects (reduced anogenital distance, hypospadias).
• Cmax is consistent with U.S. EPA default guidance and is more conservative than AUC for this endpoint.
• A tentative CSAF value of 0.48 (range, 0.22–0.74) was estimated, despite the lack of direct human kinetic data.

Conclusions:

• The Cmax metric is appropriate for deriving a CSAF for procymidone developmental toxicity.
• The estimated CSAF range provides a scientifically supported basis for risk assessment.
• Further refinement may be possible with additional human kinetic data.