Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

NICKEL

Summary of PDE for Nickel

Nickel (Ni)

Oral

Parenteral

Inhalation

PDE (µg/day)

220

22

6.0

Introduction

Nickel (Ni) is a Group 10 element of the first transition series. Although nickel may exist in the 0, +1, +2 and +3 oxidation states, its main oxidation state is +2. Nickel is a naturally occurring metal existing in various mineral forms. In general, nickel compounds are grouped based on solubility in water, and the more soluble nickel compounds, including nickel chloride, nickel sulfate, and nickel nitrate, tend to be more toxic than less soluble forms, such as nickel oxide and nickel subsulfide (ATSDR, 2005). Nickel is nutritionally not essential for humans, but nickel deficiency may cause adverse effects in animals. Nickel as Ni-Al alloys is being used as catalyst in hydrogenation reactions. Stainless steel, which may be used in metered-dose inhaler components, is an iron-based alloy containing chromium and may also contain <1-38% nickel as an oxide (Stockmann-Juvala et al , 2013; NTP, 2006). Daily intake of nickel ranges from 100-300 µg/day (US EPA, 1996). Nickel is genotoxic, but not mutagenic (IARC 2012). There is no indication of carcinogenicity of Ni salts after oral administration (Heim et al , 2007). Depending on the type of salt there was an increase in tumors in some rodent inhalation studies (ATSDR, 2005; EU EFSA, 2005). The US EPA has concluded that there is sufficient evidence of carcinogenicity of nickel refinery dust (US EPA, 2012). In contrast to nickel refinery dust, no significant increase in cancer risk was found in workers in nickel alloy or stainless steel production (ATSDR, 2005). Combining all forms of nickel, IARC (2012) classified nickel as a human carcinogen (Group 1). In humans and animals, ingestion of large amounts of nickel may cause stomach pain, depression of body weight and adverse effects on blood and kidneys. Humans generally become sensitized to nickel after prolonged contact with the skin. Human data show that an oral challenge to a single dose of nickel administered in drinking water can induce dermatitis in nickel-sensitized individuals (Nielsen et al , 1999). In the derivation of the oral reference dose (US EPA, 1996) for soluble salts of nickel, individuals with nickel hypersensitivity were not taken into account. Chronic inhalation may produce adverse changes such as inflammation in lung and nasal cavity in both humans and animals; bronchitis, emphysema, fibrosis and impaired lung function have been reported in nickel welders and foundry workers (ATSDR, 2005). The inflammatory lung lesions which developed in rats administered the soluble NiSO 4 were qualitatively similar, but less severe than those occurring in rats administered the insoluble NiO (Benson, 1995). The toxicity of nickel appears greater for soluble forms, which are more rapidly absorbed from the lung (Schaumlöffel, 2012). In a 2-year carcinogenicity study in rats administered nickel sulfate hexahydrate at 10, 30 or 50 mg/kg/day, no treatment-related tumors were observed. There was a significant exposure-response in mortality in females during weeks 0-105 at all dose levels, and a dose-dependent decrease in body weights in both sexes at week 103 that reach significance in the 30 and 50 mg/kg/day groups (Heim et al , 2007). Using the LOAEL of 10 mg/kg/day (2.2 mg Ni/kg/d), and taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the oral PDE is: Safety Limiting Toxicity PDE – Oral Exposure

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