Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Platinum-Group Elements

Summary of PDE for Platinum-Group Elements

Iridium (Ir), Osmium (Os), Rhodium (Rh), Ruthenium (Ru) Oral Parenteral Inhalation

PDE (µg/day)

100

10

1.0

Introduction

There is limited toxicological data for the Platinum-Group Elements (PGE) other than platinum, and, to a lesser extent, palladium. Occupational exposure to the PGE may cause hypersensitivity with respiratory symptoms and contact dermatitis (Goossens et al , 2011). Acute LD 50 s are available for some of the platinum-group elements but this information was not sufficient for setting a PDE; longer term toxicology studies are not available. RuO 4 appears to be a stronger oxidizing agent than OsO 4 , at least when used in fixing tissues (Gaylarde and Sarkany, 1968; Swartzendruber et al , 1995). It appears that the soluble salts of the PGE are more toxic than the metal (Wiseman and Zereini, 2009). Based on the lack of information on toxicity of the PGE, the PDEs for all routes of administration are based on the palladium PDEs rather than platinum as the more conservative approach. The limited safety information for the PGE is described below. There are very few published data on the safety of Iridium, Osmium, Rhodium and Ruthenium. Iridium o Iridium induced DNA single strand breaks in rat fibroblasts as measured in a Comet assay when fibroblasts were incubated with Ir(3+) chloride hydrate for 24 hours No strand breaks were seen after a 2 hour incubation (Iavicoli et al , 2012). o Groups of Wistar rats were administered Ir(3+) chloride hydrate in drinking water (0, 0.019, 0.19, 1.9, 9.5 and 19 µg Ir/d) for 90 days to assess nephrotoxicity Iavicoli et al , 2011). While there may have been some indication of renal toxicity from 0.19 µg/d, this study was not adequate to set an oral PDE. Osmium o Osmium tetroxide is not very soluble in water (Luttrell and Giles, 2007). Metallic osmium is not toxic (McLaughlin et al , 1946). o Osmium tetroxide has been used as a treatment for arthritis. As a vapor, OsO 4 can cause severe eye damage and irritation to the eye, nose, throat and bronchial tubes, lung, skin, liver and kidney damage (USDoL, 1978; Luttrell and Giles, 2007). o The Permitted Exposure Limit (PEL) TWA for osmium tetroxide (as osmium) is 0.002 mg/m 3 (UsD0L, 2013). Rhodium o Rh salts (K 2 RhCl 5 , (NH 4 ) 3 RhCl 6 ) were genotoxic in Salmonella typhimurium (Bünger et al , 1996). In this assay, rhodium was similar to palladium in terms of cytotoxicity and genotoxicity and much less toxic than platinum. Rhodium induced DNA single strand breaks in rat fibroblasts as measured in a Comet    Safety Evaluation

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