Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

MOLYBDENUM

Summary of PDE for Molybdenum

Molybdenum (Mo)

Oral 3400

Parenteral

Inhalation

PDE (µg/day)

1700

11

Introduction

The main oxidation states for Mo are +4 and +6, the most common forms of which are oxyanions. The predominant form of Mo occurring in soils and natural waters is the molybdate ion, MoO 4 2- which forms soluble compounds with a variety of cations including K + , NH 4 + and Ca 2+ . Mo exists in soil in various forms at concentration of 0.1-10 mg/kg. MoO 2 and MoS 2 are insoluble in water. It is widely present in vegetables, dairy products and meats. Mo combinations (e.g., Bi-Mo, Fe-Mo, molybdenum oxide and Mo-complexes) are being used as catalysts in organic synthesis. Molybdenum is an essential element with an estimated upper level intake range of 100- 600 µg/day for infants to adults, respectively (EC Scientific Committee on Food, 2000). Molybdenum deficiency is characterized by night blindness, nausea, disorientation, coma, tachycardia and tachypnea and associated with various biochemical abnormalities including high plasma methionine. In addition an almost undetectable serum uric acid concentration has been reported in a patient receiving total parenteral nutrition (Abumrad et al , 1981). Molybdenum as the trioxide was not mutagenic (NTP, 1997) and a Ruksinstutuut Voor Volksgezondheid En Milieu (RIVM) assessment concluded that molybdenum is not genotoxic (RIVM, 2001). Carcinogenicity has not been evaluated by IARC or US EPA. Molybdenum by the oral route has low toxicity. There is some evidence of carcinogenicity in the mouse when molybdenum is administered by the inhalation route. The possible carcinogenic effects were considered the endpoint of greatest toxicological relevance for this route of exposure. A good laboratory practice compliant 90-day toxicology study that investigated the toxicity of sodium molybdate dehydrate administered in the diet of rats demonstrated effects at 60 mg Mo/kg/day, including effects on body weight, weight gain, food conversion efficiency, some organ weights (absolute and relative to body weight) and renal histopathology (slight diffuse hyperplasia in the proximal tubules in 2 females) (Murray et al , 2014). No adverse effects were noted after a 60-day recovery period, with the exception of reduced body weights in male rats. No adverse effects on reproductive organs, estrus cycles, or sperm parameters were noted. The authors conclude that the NOAEL for this study was 17 mg Mo/kg/day. No treatment-related toxicity was seen at this dose. Using modifying factors (F1-F5 as discussed in Appendix 1) the oral PDE is: Safety Limiting Toxicity PDE – Oral Exposure

PDE = 17 mg/kg x 50 kg / 5 x 10 x 5 x 1 x 1 = 3.4 mg/d = 3400 µg/day

PDE – Parenteral Exposure

In Vyskocil and Viau (1999), it was reported that oral bioavailability in humans ranged from 28-77%. Turnland et al. (2005) report that molybdenum absorption was about 90% in healthy men. Therefore, the parenteral PDE is divided by a modifying factor of 2 (as described in Section 3.1).

53