Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

CHROMIUM

Summary of PDE for Chromium

Chromium (Cr)

Oral

Parenteral

Inhalation

PDE (µg/day)

10700

1070

2.9

Introduction

Chromium (Cr) is found in a variety of oxidation states, the most important being Cr(0) (in stainless steel) Cr(2+), Cr(3+) and Cr(6+). Cr (2+) is readily oxidized and is used as a reducing agent in chemical synthesis. Cr(6+) is a powerful oxidant, chromate, CrO 4 2- , and dichromate, Cr 2 O 7 2- , being the best known oxyanions. Cr(3+), the most abundant environmental form, is an essential element that plays a role in glucose metabolism. Chromium deficiency causes changes in the metabolism of glucose and lipids and may be associated with maturity-onset diabetes, cardiovascular diseases, and nervous system disorders (Anderson, 1993, 1995). Sources of chromium in pharmaceuticals may include colorants, leaching from equipment or container closure systems, and catalysts. Except when it is used as a catalyst, intake of chromium from pharmaceuticals will be in the form of metallic chromium (Cr(0)) or Cr(3+) rather than the more toxic Cr(6+); therefore, for drug products, this safety assessment is based on the known toxicity of Cr(3+) and Cr(6+) is excluded from this assessment. If Cr(6+) is used as a catalyst, then the assessment should incorporate this form. Chromium present as a colorant (e.g., chromium oxide green, chromium hydroxide green) is intentionally added and thus beyond the scope of this guidance. Rats fed diets containing up to 5% Cr 2 O 3 (equivalent to 1468 mg Cr/kg/day) for a lifetime showed no adverse effects. In a more recent dietary rat study (Anderson et al , 1997), no adverse effects were detected at 15 mg Cr(3+)/kg/day. No specific target organ toxicities have been identified for the oral intake of chromium. Generally oral intake of 1.5 mg/kg/day Cr(3+) (US EPA, 1998) is not expected to be associated with adverse health. The data was reviewed to identify the safety limiting toxicities based on routes of administration. The 2-year NTP studies (2010) on the carcinogenicity of Cr(3+) picolinate administered in feed to rats and mice at 2000, 10000 and 50000 ppm provided the most relevant safety information for chromium as present in drug products. The NOAEL was the low dose of 90 mg/kg Cr(3+) picolinate (11.9 weight %; 10.7 mg/kg/day Cr(3+)) in rats based on increase in the incidence of preputial gland adenoma in male rats at 460 mg/kg. This finding was not dose-dependent and was considered an equivocal finding by the study authors. This finding was not observed male mice or in the female counterpart in either species (clitoral gland). Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as: Safety Limiting Toxicity PDE – Oral Exposure

PDE = 10.7 mg/kg/d x 50 kg / 5 x 10 x 1 x 1 x 1 = 10.7 mg/day

PDE – Parenteral Exposure

Recommendation for the nutritional intravenous administration of Cr(3+) vary per age group between 0.05 µg/kg/day in preterm infants and 15 µg/kg in adults (Moukazel, 2009). There is insufficient information to assess if exceeding these recommended daily

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