Abstract
The Extended One-Generation Toxicity Study (EOGRTS) was adopted as OECD TG 443 in July 2011. A full protocol based on the draft guideline was performed at CiToxLAB Hungary and presented jointly with Syngenta at the SOT meeting 2011. Lead Acetate was provided in drinking water to the F0 adult Wistar rats at 0 (sodium acetate control), 100, 800 and 1700 ppm Pb, from 2 to 4 weeks pre-mating, gestation, and lactation, and to the F1 generation to adulthood. Adults were mated and evaluated for standard in-life parameters, reproductive function and histopathology. Resulting litters were assigned to 3 subgroups for clinical pathology/thyroid function/neurotoxicity; immunotoxicity; and reproductive toxicity assessments. Selected pups were evaluated for developmental milestones, growth, neurobehaviorial assessments (FOB, grip strength, landing foot splay, and motor activity with automated image analysis via a SMARTTM Video Tracking System), TDAR immunotoxicity (IgM response to sheep-RBC challenge), thyroid hormones, standard pathology and neurohistopathology (with perfusion-fixation in situ and serial brain sectioning). The work conducted demonstrated the feasibility of a CRO performing this study. Careful planning and good communication between the Study Director, technical staff and Sponsor was required, especially following data analysis to decide if an F2 generation phase should be performed. In the final guideline, changes were made, including reduction of the pre-mating period of the parental P generation to 2 weeks and reassignment of the pups to cohorts to reproductive/developmental toxicity testing (including cohort 1B possibly extended to include an F2 generation), developmental neurotoxicity testing and developmental immunotoxicity testing .
