Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

VANADIUM Summary of PDE for Vanadium

Vanadium (V)

Oral 120

Parenteral

Inhalation

PDE (µg/day)

12

1.2

Introduction Vanadium (V) is present as a trace element in the earth’s crust and can exist in a variety of oxidation states (-1, 0, +2, +3, +4 and +5). V is also present in trace quantities in most biological organisms with the principal ions being vanadate, VO 3 - and vanadyl, VO 2 + . Absorption of vanadium from the gastrointestinal tract is poor. Estimates of total dietary intake of vanadium in humans range from 10 to 60 µg/day. Intake from drinking water depends on the water source and estimates are up to 140 µg/day. Human populations have variable serum concentrations of vanadium, with 2 µg/L being the high end of the normal range. Despite its being ubiquitous in the body, an essential biological role for vanadium in humans has not been established. Safety Limiting Toxicity Vanadium is genotoxic, but not mutagenic (ATSDR, 2012). Vanadium pentoxide is classified as a possible human carcinogen (Group 2B; IARC, 2012). PDE – Oral Exposure Following oral administration to animals and humans the gastrointestinal tract, cardiovascular, and hematological system are the primary targets of toxicity. The most appropriate study to assess vanadium toxicity through oral administration was conducted in humans exposed to vanadium for 12 weeks. In this study, no significant alterations in hematological parameters, liver function (as measured by serum enzymes), cholesterol and triglyceride levels, kidney function (as measured by blood urea nitrogen), body weight, or blood pressure were observed in subjects administered via capsule 0.12 or 0.19 mg vanadium as ammonium vanadyl tartrate or vanadyl sulfate for 6–12 weeks (ATSDR, 2012). The oral NOAEL of 0.12 mg vanadium/kg/day for hematological and blood pressure effects was used to calculate the oral PDE. Taking into account the modifying factors (F1- F5 as discussed in Appendix 1), the oral PDE is calculated as below. PDE = 0.12 mg/kg/d x 50 kg / 1 x 10 x 5 x 1 x 1 = 0.12 mg/d = 120 µg/day PDE – Parenteral Exposure The safety review for vanadium was unable to identify any significant assessments upon which to calculate a PDE for parenteral routes of exposure. On the basis of an approximate oral bioavailability of <1–10% for vanadium and inorganic vanadium compounds (ATSDR, 2012), the parenteral PDE was calculated by dividing the oral PDE by a modifying factor

of 10 (as described in Section 3.1). PDE = 120 µg/day / 10 = 12 µg/day PDE – Inhalation Exposure

A two year chronic inhalation exposure study in rats was considered for use for the inhalation PDE for vanadium. In this study, carcinogenic effects were observed to the lowest dose tested, 0.5 mg/m 3 vanadium pentoxide (Ress et al. 2003). Vanadium pentoxide is a caustic agent and is not considered to be present in drug products. Therefore, the

74