Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PDE = 1.08 mg/kg/d x 50 kg / 5 x 10 x 10 x 1 x 1 = 108 µg/day

PDE – Parenteral Exposure

The safety review for platinum identified limited assessments of platinum salt toxicity for parenteral routes of administration. The oral absorption of platinum salts is very low in rats (<1% when administered by gavage) and higher in humans (42-60% of dietary Pt; US EPA, 2009). Therefore, the oral PDE is divided by a factor of 10 (as described in Section 3.1) to obtain the parenteral PDE.

PDE = 108 µg/d / 10 = 10.8 µg/day

PDE – Inhalation Exposure

Due to the use of the chloroplatinates in catalytic converters, numerous animal (Biagini et al , 1983) and human (Pepys et al , 1972; Pickering 1972; Merget et al , 2000; Cristaudo et al. , 2007) studies have been conducted. The US EPA (1977; 2009) and the European Scientific Committee on Occupational Exposure Limits (EU SCOEL, 2011) have also examined the safety of chloroplatinates based on sensitization. The European Scientific Committee on Occupational Exposure Limits (EU SCOEL) concluded that the database does not allow for setting an occupational limit for soluble platinum salts. The US DoL (2013) has established an occupational limit for soluble platinum salts at 2 µg/m 3 . Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated as:

For continuous dosing = 2 µg/m 3 x 8 hr/d x 5 d/wk = 0.48 µg/m 3 = 0.00048 µg/L 24 hr/d x 7 d/wk 1000 m 3 /L

Daily dose = 0.00048 µg/L x 28800 L/d = 0.27 µg/kg/day 50 kg

PDE = 0.27 µg/kg/d x 50 kg / 1 x 10 x 1 x 1 x 1 = 1.4 µg/d

R EFERENCES

Arts JHE, Mommers C, de Heer C. Dose-response relationships and threshold levels in skin and respiratory allergy. Crit Rev Toxicol 2006;36:219-51. Biagini RE, Moorman WJ, Smith RJ, Lewis TR, Bernstein IL. Pulmonary hyperreactivity in cynomolgus monkeys (Macaca fasicularis) from nose-only inhalation exposure to disodium hexachloroplatinate, Na 2 PtCl 6 . Toxicol Appl Pharmacol 1983;69:377-84. Caverley AE, Rees D, Dowdeswell RJ, Linnett PJ, Kielkowski D. Platinum salt sensitivity in refinery workers: incidence and effects of smoking and exposure. Int J Occup Environ Med 1995;52:661-66. Cristaudo A, Picardo M, Petrucci F, Forte G, Violante N, Senofonte O et al. Clinical and allergological biomonitoring of occupational hypersensitivity to platinum group elements. Anal Lett 2007;40:3343-59. EU SCOEL. Recommendation from the scientific committee on occupational exposure limits for platinum and platinum compounds. European Union Scientific Committee on Occupational Exposure Limits. 2011;SCOEL/SUM/150.

IPCS. Platinum. Environmental Health Criteria 125. International Programme on

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