Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PDE = 6000 µg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 1200 µg/day

PDE – Parenteral Exposure

Adverse liver findings (liver capsule inflammation, liver cell necrosis, and liver degeneration.) were the most sensitive endpoint in rats after repeated intraperitoneal administration. Thus, the parenteral PDE was determined on the basis of the lowest NOAEL, i.e., 3.0 mg APT/kg/day (equivalent to 1.1 mg Sb/kg/d). This value was obtained from a 90-day study in rats (based on adverse liver findings at 6 mg/kg in male rats exposed to APT via intraperitoneal injection) (NTP, 1992). No systemic effects were observed at this dose. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), and correcting for continuous dosing from 3 days per week (factor of 3/7), the parenteral PDE is calculated as below: Sub chronic and chronic inhalation rat studies have been conducted. The lung effects observed across these studies were consistent. Using the data from a 13-week inhalation rat study using antimony trioxide dust at exposure levels of 0.25, 1.08, 4.92 and 23.46 mg/m 3 , (Newton et al , 1994), a NOAEL of 1.08 mg/m 3 was used to determine the inhalation PDE (~83% Sb). At higher dose levels an increase in mean absolute and relative lung weights were observed, a finding not seen in the one year oncogenicity study using exposure levels of 0.06, 0.51 and 4.5 mg/m 3 . Carcinogenicity was not observed in this study. No adverse effects on hematology or clinical chemistry were seen in either study. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated as: For continuous dosing = 0.9 mg/m 3 x 6 h/d x 5 d/wk = 0.16 mg/m 3 = 0.00016 mg/L 24 h/d x 7 d/wk 1000 L/m 3 PDE = 1100 µg/kg/d x 3/7 x 50 kg / 5 x 10 x 5 x 1 x 1 = 94 µg/day PDE – Inhalation Exposure

Daily dose =

0.00016 mg/L x 290 L/d = 0.11 mg/kg/day 0.425 kg bw

PDE = 0.11 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 0.022 mg/d = 22 µg/day

R EFERENCES

ATSDR. Toxicological profile for antimony and compounds. Agency for Toxic Substances and Disease Registry, Public Health Service, US Department of Health and Human Services, Atlanta, GA. 1992. Lynch BS, Capen CC, Nestmann ER, Veenstra G, Deyo JA. Review of subchronic/chronic toxicity of antimony potassium tartrate. Reg Toxicol Pharmacol 1999;30(1):9-17. Newton PE, Bolte HF, Daly IW, Pillsbury BD, Terrill JB, Drew RT et al. Subchronic and chronic inhalation toxicity of antimony trioxide in the rat. Fundam Appl Toxicol 1994;22:561-76. NTP. Technical report on toxicity studies of antimony potassium tartrate in F344/N rats and B6C3F 1 mice (drinking water and intraperitoneal injection studies). National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC. 1992; NTP Toxicity Report Series No. 11.

28