Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

TIN

Summary of PDE for Tin

Tin (Sn)

Oral 6400

Parenteral

Inhalation

PDE (µg/day)

640

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Introduction

Tin (Sn) is a silvery-white metal that exists in +2 and +4 oxidation states. The most important inorganic compounds of tin are its oxides, chlorides, fluorides and halogenated sodium stannates and stannites. Tin is present in some multi-vitamin and mineral food supplements (at levels up to 10 µg Sn/tablet). Tin is possibly nutritionally essential for some animals, but it has not been shown to be essential for humans. Tin(2+) chloride is being used as a reducing agent, and as a stabilizer of polyvinylchloride (PVC). This safety assessment focuses on inorganic tin considering that the more frequent occurrence of inorganic tin is more relevant with respect to metal impurities in drug products than organic tin compounds.

Safety Limiting Toxicity

There is no indication of in vivo genotoxicity or carcinogenicity for tin and tin salts. In several studies in rats, a decrease in hemoglobin as an early sign for anemia was the most sensitive endpoint. In general, in in vitro assays tin and tin salts were negative for mutagenicity but some forms were positive for chromosomal damage (CICAD, 2005). Stannous chloride was not carcinogenic in the two year assay in mice or rats (NTP, 1982).

PDE – Oral Exposure

Anemia was the most sensitive endpoint in rats after repeated oral administration. Thus, the PDE for oral exposure was determined on the basis of the lowest NOAEL, i.e., 150 ppm (equivalent to 32 mg Sn/kg/day; ATSDR, 2005). This value was obtained from a 90-day study in rats based on signs of anemia starting at 500 ppm in rats exposed to stannous chloride via diet (de Groot et al , 1973). This study was considered more relevant than the NTP study (NTP, 1982) in determining the oral PDE because in the 13- week NTP dose range finding study, the toxicological evaluation was more limited (e.g., no clinical chemistry, including effects on hemoglobin) than in the study by de Groot et al. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as below.

PDE = 32 mg/kg/d x 50 kg / 5 x 10 x 5 x 1 x 1 = 6.4 mg/d = 6400 µg/day

PDE – Parenteral Exposure

The safety review for tin was unable to identify any significant assessments upon which to calculate a PDE for parenteral routes of exposure. On the basis of an oral bioavailability of about 5% for tin and inorganic tin compounds (ATSDR, 2005), the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as described in Section 3.1).

PDE = 6400 µg/d / 10 = 640 µg/day

PDE – Inhalation Exposure

The safety review for tin was unable to identify any significant assessments on inorganic

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