An oral developmental toxicity study of generic pesticide pinoxaden in rabbits

Abstract

The safety assessment of pinoxaden by the Joint Meeting on Pesticide Residues (JMPR) established a NOAEL of 30 mg/kg bw/day for maternal and embryo/fetal toxicity from a rabbit developmental toxicity study. However, the Pesticide Peer Review Expert meeting (EFSA) lowered the NOAEL to 10 mg/kg bw/day due to observed diaphragm malformations in one developmental toxicity study in rabbits, proposing a classification for developmental effects as Category 2 R63 or H361d. Both JMPR and EFSA set the Acceptable Daily Intake (ADI) at 0.1 mg/kg bw/day, derived from a 2-year rat study NOAEL with a safety factor of 100, but EFSA also supported ADI by teratology study in rabbits. The current prenatal developmental toxicity study on pinoxaden aimed to elucidate and clarify the potential teratogenic effects and could provide supplementary data for determining the ADI for pinoxaden. The study design exceeded the OECD TG 414 by including an assessment of internal organs. The test item was orally administered by gavage daily from day 6 to day 28 of gestation to three groups of animals, each composed of 21 females, in dose levels of 0, 10 and 30 mg/kg/bw/day. One female from the 30 mg/kg/bw/day dose group was euthanized in extremis on Day 27 post-coitum due to premature delivery, likely induced by poor general condition and was therefore considered to be an indirect effect of the test item. One female at 30 mg/kg/bw/day had entirely dead litters except for one live male pup (9 non-live implants vs 1 live fetus). Since the incidence of post-implantation loss or mean number of the dead pups within the remaining dams at 30 mg/kg/ bw/day that survived to necropsy was not significantly increased, we assume that the toxic effect was on the dam, rather than on the conceptus. No pinoxaden-related skeletal or visceral variations or malformations were observed. No evidence of developmental toxicity was observed. Under the conditions of the study, the pinoxaden produced maternal toxicity at a high dose tested; thus, NOAEL for maternal toxicity was determined to be 10 mg/kg bw/day. NOAEL for developmental toxicity was established at 30 mg/kg bw/day. The obtained results may supplement the overall safety and toxicity profile of pinoxaden. Nevertheless, the NOAEL determined in this study does not affect the previously established ADI.