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Review Article

Human relevance framework evaluation of a novel rat developmental toxicity mode of action induced by sulfoxaflor

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Pages 45-62 | Received 06 Oct 2013, Accepted 29 Mar 2014, Published online: 16 May 2014

Figures & data

Table 1. Summary of findings from developmental and reproductive toxicity studies on sulfoxalfor.

Figure 1. Key events for the postulated MoA of sulfoxaflor-induced muscle contracture abnormalities and associated death in neonatal rat offspring.

Figure 1. Key events for the postulated MoA of sulfoxaflor-induced muscle contracture abnormalities and associated death in neonatal rat offspring.

Figure 2. Dose–response for MoA Key Event #1: Competition radioligand binding with sulfoxaflor. The ability of sulfoxaflor to displace binding of [3H]-epibatidine was examined in rat fetal muscle tissue. Samples were incubated with [3H]-epibatidine (30 nM) in the presence of a range of concentrations of sulfoxaflor. Data are means + SEM of 3–4 independent experiments, each performed with triplicate samples. Levels of radioligand binding are normalized to the level of specific binding observed in the absence of sulfoxaflor. Concentrations are plotted as log molar concentrations.

Figure 2. Dose–response for MoA Key Event #1: Competition radioligand binding with sulfoxaflor. The ability of sulfoxaflor to displace binding of [3H]-epibatidine was examined in rat fetal muscle tissue. Samples were incubated with [3H]-epibatidine (30 nM) in the presence of a range of concentrations of sulfoxaflor. Data are means + SEM of 3–4 independent experiments, each performed with triplicate samples. Levels of radioligand binding are normalized to the level of specific binding observed in the absence of sulfoxaflor. Concentrations are plotted as log molar concentrations.

Table 2. Dose–response for MoA Key Event #2: Fetal-type muscle nAChR agonism.

Table 3. Dose–response and reversibility for MOA Key Event #3: Sustained agonism and sustained muscle contracture and associated death in neonatal offspring.

Table 4. Neonatal offspring limb and clavicle abnormalities resulting from sulfoxaflor-induced sustained muscle contracture.

Table 5. Neonatal offspring death resulting from sulfoxaflor-induced sustained muscle contracture.

Table 6. Sulfoxaflor: Summary of dose–response and reversibility for MOA Key events related to rat muscle contracture and associated death in neonatal offspring.

Table 7. Daily observations of pup death between PNDs 1 and 4. Data are expressed as a cumulative percent per study.

Table 8. Summary evaluation for other possible MoAs in the rat.

Table 9. Sulfoxaflor: Human dose–response data for MoA Key events one and two related to muscle contracture and associated death in neonatal offspring.

Table 10. Concordance of Key events for induction of skeletal muscle contracture and associated death in neonatal offspring in rats, rabbits, and humans.

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