TABLE 6-2 Three-Month Dose-Range Finding Toxicity Study in Cynomolgus Monkeys

Dose Groups

  • Two of each sex in each group at 0 (control), low, middle, upper middle, and high dose

  • Ammonium perchlorate administered daily in drinking water for 3 months

Observations

  • General observations for morbidity and mortality, body weight, food consumption

Thyroid Function Assessment

  • Serum T3, T4, and TSH should be measured before dosing, on day 1, at weeks 1, 2, 4, 6, 8, 10, 12

  • Thyroid 123I uptake should be measured at appropriate times.

Clinical Test Measures

  • Comprehensive hematology and clinical chemistry before dosing, periodically during study

Pharmacokinetic Measures

  • Appropriate pharmacokinetic measures

Necropsy and Histopathology

  • Full necropsy, macroscopic examination, histopathologic examination of many tissues, including the thyroid and pituitary glands

ment, refinement, and validation be considered. As discussed in Appendix E, if additional studies are conducted in rats to elucidate the mode of action of perchlorate or dose-response relationships in potentially sensitive life stages (pregnant dams, fetuses, or neonates), a number of issues identified as potential data gaps with existing PBPK models could be addressed by studies that

  • Develop a more biologically based description of placental transfer of perchlorate and iodide in rats.

  • Determine whether perchlorate is transported by thyroid NIS if analytic methods of sufficient sensitivity can be developed or radiolabeled perchlorate with high radiochemical purity can be synthesized.

  • Modify the adult human model to include the physiology of pregnancy and lactation to incorporate data from the recommended human clinical studies (if they are conducted).



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