Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PLATINUM

Summary of PDE for Platinum

Platinum (Pt)

Oral

Parenteral

Inhalation

PDE (µg/day)

108

10.8

1.4

Introduction

Platinum (Pt) is a Group 8 element of the third transition series. It is the most important of the six heaviest of the Group 8 elements, collectively called the “platinum group metals” or “platinoids”, including palladium, osmium, rhodium, ruthenium and iridium. Metallic platinum has been shown to catalyze many oxidation-reduction and decomposition reactions and the major industrial use of platinum is as a catalyst. Platinum complexes exhibiting a range of oxidation states are known, although the principal oxidation states are +2 and +4. Pt(2+) forms a tetra-coordinate aqua ion [Pt (H 2 O) 4 ] 2+ . The most common Pt IV catalysts are chloroplatinate salts such as tetra and hexachloroplatinate ions. No experimental data are available on the carcinogenicity of platinum and platinum compounds forms likely to be present in pharmaceuticals as impurities, and toxicology data are limited (US EPA, 2009). Chlorinated salts of platinum are responsible for platinum related hypersensitivity and are a major occupational health concern (US EPA, 2009). The hypersensitivity appears to be the most sensitive endpoint of chloroplatinate exposure, at least by the inhalation route. Signs include urticaria, contact dermatitis of the skin, and respiratory disorders ranging from sneezing, shortness of breath, and cyanosis to severe asthma (IPCS, 1991). Exposure reduction was effective in resolving symptoms (Merget et al , 2001). Neutral complexes and complexes without halogenated ligands do not appear allergenic (US EPA, 2009; EU SCOEL, 2011). The risk of hypersensitivity appears to be related to sensitizing dose and dose and length of exposure (IPCS, 1991; US EPA, 2009; Arts et al , 2006) and cigarette smoking (US EPA, 2009; Merget et al , 2000; Caverley et al , 1995). The data was reviewed to identify the safety limiting toxicities based on routes of administration In a study in male rats administered PtCl 2 (relatively insoluble) and PtCl 4 (soluble) in the diet for 4 weeks, no effects were observed on hematological and clinical chemistry parameters for PtCl 2 . Plasma creatinine was increased and a reduction in hematocrit and erythrocyte parameters was observed in animals dosed with 50 mg Pt/kg diet for four weeks in the form of PtCl 4 , the highest dose tested. Platinum concentrations increased in tissues in animals dosed with either compound, particularly the kidney (Reichlmayr-Lais et al , 1992). This study was used in the determination of the PDE because toxicity is observed in the kidney with platinum compounds and was a main site of accumulation in this study. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated based on the NOAEL of 10 mg Pt/kg diet (4.1 mg Pt taken over 28 days; 0.146 mg/d). The body weight of the rats was 35 g at the beginning of the study and the average weight gain over the course of the study was 235 g. A mean body weight of 135 g was used in the calculation. PDE – Oral Exposure Safety Limiting Toxicity

0.146 mg/d / 0.135 kg = 1.08 mg/kg/day

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