Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

Appendix 3: Individual Safety Assessments

ANTIMONY

Summary of PDE for Antimony

Antimony (Sb)

Oral 1200

Parenteral

Inhalation

PDE (µg/day)

94

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Introduction

Antimony (Sb) is a silvery white naturally occurring metalloid element that is used in various manufacturing processes. Small amounts of antimony are found in the earth's crust. It exists in of the +3 and +5 oxidation states. Metallic antimony and a few trivalent antimony compounds are the most significant regarding exposure potential and toxicity. Some antimonials, such as Antimony Potassium Tartrate (APT), have been used medicinally as parasiticides. Antimony trioxide is being used as a catalyst (e.g., in the manufacturing of Polyethylene Terephthalate [PET] used for container closure system components). Antimony is nutritionally not essential and no metabolic function is known (ATSDR, 1992). Antimony and antimony trioxide have low solubility in water whereas ATP is water soluble (WHO, 2003). APT was negative for mutagenicity in Salmonella in the presence or absence of S9 (NTP, 1992). In a review of genotoxicity data, conflicting results are obtained, although it appears that Sb(3+) may be positive for clastogenicity (WHO, 2003). Available studies are considered inadequate to assess the risk of carcinogenicity by the oral route (Lynch et al , 1999). In humans and animals, the gastrointestinal tract appears to be the primary target organ after oral exposure and can result in irritation, diarrhea and vomiting. Antimony is poorly absorbed after oral administration (NTP, 1992). In subchronic studies in rats lower mean body weights and adverse liver findings were the most sensitive endpoints. Inhalation of high levels of antimony over a long period can cause adverse respiratory effects in both humans and animals, including carcinogenicity. In an inhalation carcinogenicity study conducted by Newton et al. (1994), rats were exposed to antimony trioxide for 12 months, followed by a 12-month observation period. Neoplasms were observed with comparable incidence among all groups. The authors conclude that Sb 2 O 3 was not carcinogenic and propose that in previous studies, positive for carcinogenicity, the tumors may be the result of overload with insoluble particulates (Newton et al , 1994; WHO, 2003). Limited oral data on antimony exposure is available in mice and rats (Schroeder et al. , 1968; Schroeder et al , 1970; Poon et al , 1998). The National Toxicology Program (NTP) conducted a 14-day study in rats and mice where APT was administered in the drinking water. In this study APT was found to be relatively nontoxic by this route (NTP, 1992). Reevaluating the data of Poon et al. (1998), Lynch et al. concluded that a NOAEL from a 90 day drinking water study in rats using 0.5 to 500 ppm APT was 50 ppm based on lower mean body weight and reduced food consumption at the highest dose (Lynch et al , 1999). This finding is consistent with the earlier reports from Schroeder et al. (1970). Thus, the PDE for oral exposure was determined on the basis of the lowest NOAEL, i.e., 50 ppm (equivalent to 6.0 mg Sb/kg/day). Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is calculated as below: Safety Limiting Toxicity PDE – Oral Exposure

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