Determination of offspring NOAEL for zeta-cypermethrin using internal exposure data from rat developmental neurotoxicity studies

Abstract

Developmental neurotoxicity (DNT) studies via dietary method of administration have been conducted for zeta-cypermethrin, a pyrethroid insecticide. The objectives of the current study were to determine the toxicokinetics (TK) of zeta-cypermethrin in postnatal day (PND) 11, 21 and 90 rats after gavage doses and use the internal exposure data from the DNT and TK studies to calculate an offspring NOAEL in mg/kg/day during lactation. The DNT studies showed that zeta-cypermethrin is not a developmental neurotoxicant. The NOAEL for maternal and offspring was determined to be 125 ppm (9.0 and 21.4 mg/kg/day for dams during gestation and lactation, respectively), based on systemic toxicity of reductions in maternal body weight, body weight gains and food consumption and offspring body weight at 300 ppm (LOAEL). The TK data from the gavage study showed that dose normalized Cmax and AUC is approximately 3-fold and 2-fold higher in PND 11 and 21 than those in PND 90 rats. By using the mean maternal/offspring plasma concentrations (535/245 ng/mL) during lactation day LD/PND 5–21 from the range-finding DNT studies, a conservative 3.1X relative TK factor (exposure ratio from the gavage study) and equation 3.1 × 535/21.4 = 245/x, the offspring NOAEL of 125 ppm was calculated to be 3.2 mg/kg/day during lactation. The offspring NOAEL based on internal exposure data from DNT studies and TK data after gavage doses is considered conservative for risk assessment for all human populations including infants and children for zeta-cypermethrin.