Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

THALLIUM

Summary of PDE for Thallium

Thallium (Tl)

Oral

Parenteral

Inhalation

PDE (µg/day)

8.0

8.0

8.0

Introduction

Pure thallium (Tl) is a bluish-white metal. It exists primarily in two oxidation states: +1 and +3. Monovalent thallium is similar to potassium (K+) in ionic radius and electrical charge, which contributes to its toxic nature. Many of the thallium salts are soluble in water with the exception of the insoluble Tl(3+) oxide. Thallium sulfate has been used in medicine, primarily as a depilatory agent, but also to treat infections, such as venereal diseases, ringworm of the scalp, typhus, tuberculosis, and malaria. Tl(3+) salts are being used in organic synthesis. Thallium is nutritionally not essential and no metabolic function is known (ATSDR, 1992).

Safety Limiting Toxicity

In humans and animals, the skin, especially the hair follicles, appears to be the most sensitive target of toxicity from repeated oral exposure to thallium (US EPA, 1992; US EPA, 2009). Water soluble salts (sulphate, acetate, or carbonate) have higher toxicity than other forms (Moore et al , 1993).

PDE – Oral Exposure

The primary target organ for oral exposure to thallium in humans and animals appears to be the skin, especially the hair follicles, as shown in a 90-day toxicity rat study with thallium sulfate. The NOAEL was defined at 0.04 mg Tl/kg on the basis of an increased incidence of alopecia at the higher doses (OEHHA, 1999; US EPA, 2009). Thus, the oral PDE was determined on the basis of the NOAEL of 0.04 mg Tl/kg in rat. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as below.

PDE = 0.04 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 0.008 mg/day = 8.0 µg/day

PDE – Parenteral Exposure

No relevant data on parenteral exposure to thallium compounds were found. The bioavailability of soluble thallium salts is high (> 80%) (US EPA, 2009). Therefore, the parenteral PDE is the same as the oral PDE.

PDE = 8.0 µg/day

PDE – Inhalation Exposure

No relevant data on inhalation exposure to thallium compounds were found. The US EPA concluded that information on the inhalation toxicity of thallium is insufficient to derive an inhalation reference concentration. Occupational epidemiology studies involving possible inhalation exposures to thallium were limited and inconclusive (US EPA, 2009). The major toxicity identified in humans and animals is alopecia, and absorption and toxicity is considered high by the inhalation route (IPCS, 1996). Similar findings may be expected by Tl exposure via oral and respiratory routes. For this reason, the inhalation PDE is set at the parenteral PDE.

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