Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

PDE = 2.2 mg/kg/d x 50 kg / 5 x 10 x 1 x 1 x 10 = 0.22 mg/d = 220 µg/day

A factor of 10 was chosen for F5 because a LOAEL was used to set the PDE.

PDE – Parenteral Exposure

A human study using a stable nickel isotope estimated that 29-40% of the ingested label was absorbed (based on fecal excretion data) (Patriarca et al. 1997). In another study assessing the effect of food on nickel absorption, between 2-23% of an administered dose was absorbed (Nielsen et al , 1999). Therefore, on the basis of limited oral bioavailability of nickel and water-soluble nickel compounds, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as described in Section 3.1).

PDE = 220 µg/d / 10 = 22 µg/day

PDE – Inhalation Exposure

For calculation of the inhalation PDE, a relevant form of nickel was selected from the available data. In 2-year studies with nickel oxide, no tumors were observed in hamsters (Wehner et al. 1984) or mice (NTP, 2006). There was some evidence of carcinogenicity in rats (NTP, 2006) but no evidence of carcinogenicity with inhalation of metallic nickel (Oller et al , 2008). For nickel, the modifying factor approach was considered acceptable because the forms and levels likely to be in inhalation drug products have not shown evidence of carcinogenicity. Taking into account the modifying factors (F1-F5 as discussed in Appendix 1), the inhalation PDE is calculated based on the NOAEL in the rat study of 0.5 mg Ni/m 3 /day.

For continuous dosing = 0.5 mg/m 3 x 6 hr/d x 5 d/wk = 0.089 mg/m 3 = 0.000089 mg/L 24 hr/d x 7 d/wk 1000L/m 3

Daily dose = 0.000089 mg/L x 290 L/d =

0.060 mg/kg

0.425 kg bw

PDE = 0.060 mg/kg x 50 kg / 5 x 10 x 1 x 10 x 1 = 6.0 µg/day

A factor of 10 was chosen for F4 because of the potential of relatively insoluble forms of Ni to accumulate in the lungs and that inflammation was observed in the lungs upon histopathology after inhalation of all forms of Ni.

R EFERENCES

ATSDR. Toxicological profile for nickel. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2005. Benson J, Chang I-Y, Cheny YS, Hahn FF, Kennedy CH et al. Fundam Appl Toxicol 1995;28:232-244. EU EFSA. Opinion of the scientific panel on dietetic products, nutrition and allergies on a request from the Commission related to the tolerable upper intake level of nickel. European Food Safety Authority. EFSA Journal 2005;146:1-21.

Haney JY, McCant DD, Sielken RL, Valdez-Flores C, Grant RL. Development of a unit

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