Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

COPPER

Summary of PDE for Copper

Copper (Cu)

Oral 3400

Parenteral

Inhalation

PDE (µg/day)

340

34

Introduction

Copper (Cu) is a Group 11 element of the first transition series and has two main oxidation states, Cu(1+) and Cu(2+). It is an essential trace element in both animals and humans. Copper plays a vital role in a number of critical enzyme systems and is closely linked with normal hematopoiesis and cellular metabolism. Copper compounds (e.g., copper chromite) are being used as catalysts in hydrogenolysis and decarboxylation reactions.

Safety Limiting Toxicity

A general review of relevant safety data for animals and humans indicates that copper can produce adverse effects to the gastrointestinal tract, liver, and kidney upon ingestion of toxic doses (Araya et al , 2003).

PDE – Oral Exposure

Studies on cupric sulfate and copper 8-quinolinolate have been conducted in mice, rats and dogs (IPCS, 1998). Rats were determined to be the most sensitive of these species to effects on liver and kidney. In a 13-week study in which rats were fed 500 to 8000 ppm cupric sulfate pentahydrate, the NOEL for hyperplasia and hyperkeratosis of the forestomach mucosa was 1000 ppm. Hepatic and renal toxicity was observed from doses equal to and greater than 2000 ppm. The NOEL was 1000 ppm, equivalent to 64 mg CuSO 4 /kg/day (17 mg Cu/kg/day). (Hébert et al , 1993; IPCS, 1998). Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as:

PDE = 17 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 3400 µg/day

PDE – Parenteral Exposure

The safety review for copper was unable to identify any significant assessments upon which to calculate a PDE for parenteral routes of exposure. The human gastrointestinal system can absorb 30-40% of ingested copper from the typical diets consumed in industrialised countries (Wapnir, 1998). On the basis of limited oral bioavailability of 30- 40% for copper and inorganic copper salts, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as described in Section 3.1). The recommended PDE for copper for parenteral exposure is:

PDE = 3400 µg/d / 10 = 340 µg/day

PDE – Inhalation Exposure

The available data on the toxicity of inhaled copper were considered inadequate for derivation of acute-, intermediate-, or chronic-duration inhalation MRLs (ATSDR, 2004). The inhalation PDE was calculated by dividing the oral PDE by a modifying factor of 100 (as described in Section 3.1).

PDE = 3400 µg/day / 100 = 34 µg/day

R EFERENCES

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