Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PDE = 0.014 mg/kg/d x 50 kg / 1 x 10 x 1 x 1 x 5 = 14 µg/day

A factor of 5 was chosen for F5 as the finding of argyria was considered a LOEL because accumulation of silver in the skin is not considered adverse.

PDE – Inhalation Exposure

Lung and throat irritation and stomach pains were the principal effects in humans after inhalation of high Ag levels. Using the Threshold Limit Value (TLV) of 0.01 mg/m 3 for silver metal and soluble compounds (US DoL, 2013), and taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated as:

For continuous dosing = 0.01 mg/m 3 8 hr/d x 5 d/wk = 0.0024 mg/m 3 =0.00000238 mg/L 24 hr/d x 7 d/wk 1000 L/m 3

Daily dose = 0.0000024 mg/L x 28800 L/d = 0.0014 mg/kg/day 50 kg

PDE = 0.0014 mg/kg x 50 kg / 1 x 10 x 1 x 1 x 1= 0.007 mg/d = 7.0 µg/day

R EFERENCES

ATSDR. Toxicological Profile for Silver. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 1990. Hymowitz N, Eckholt H. Effects of a 2.5-mg silver acetate lozenge on initial and long- term smoking cessation. Prev Med 1996;25:537-46. Rungby J, Danscher G. Hypoactivity in silver exposed mice. Acta Pharmacol Toxicol 1984;55:398-401. Rungby J, Danscher G. Localization of exogenous silver in brain and spinal cord of silver exposed rats. Acta Neuropathol 1983;60(1-2):92-8. US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of Labor. 2013.

US EPA. Silver (CASRN 7440-22-4). Integrated Risk Information System (IRIS). 2003.

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