Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

MERCURY

Summary of PDE for Mercury

Mercury (Hg)

Oral

Parenteral

Inhalation

PDE (µg/day)

30

3.0

1.2

Introduction Mercury (Hg) is widely distributed in the global environment. Mercury exists in three forms: elemental mercury, inorganic mercury and organic mercury. The most likely form of residual mercury in drug products is the inorganic form. Therefore, this safety assessment is based on the relevant toxicological data of elemental or inorganic mercury. This safety assessment and derived PDEs do not apply to organic mercury. There is no data to indicate that inorganic mercury is carcinogenic in human. There is limited evidence in experimental animals for the carcinogenicity of mercuric chloride. The International Agency for Research on Cancer (IARC) concluded that inorganic mercury compounds are not classifiable as to their carcinogenicity to humans (Group 3; IARC, 1997). Inorganic mercury compounds show significantly lower oral bioavailability compared to organic mercury and induce different toxicological effects including neurological, corrosive, hematopoietic, and renal effects and cutaneous disease (acrodynia). The safety limiting toxicity for inorganic mercury and salts is renal toxicity. Direct absorption to the brain via the olfactory pathway has been reported (Shimada et al , 2005). There were well designed NTP studies in rats and mice of HgCl 2 of up to 2 years duration. The 6-month gavage study in rats was selected because it had more detailed clinical pathology assessment and a wider range of doses (0.312 to 5 mg HgCl 2 /kg/5d per week) than the 2-year study. Absolute and relative (to body weight) kidney weights were increased from 0.625 mg/kg. Some changes in clinical chemistry parameters (decreased creatinine, potassium, alanine aminotransferase and aspartate aminotransferase) were noted in all dosed males. The findings did not appear dose-dependent. An increase in the incidence and severity (minimal to mild) in nephropathy was noted from 0.625 mg HgCl 2 . In a Joint Expert Committee for Food Additives (JECFA) assessment (JECFA, 2011) a BMDL 10 of 0.06 mg Hg/kg/day (adjusted from 5 days/week dosing) was derived based on adverse renal effects (weight increase) from the 6-month rat study (NTP, 1993). Using the modifying factors (F1-F5 as discussed in Appendix 1) the oral PDE is calculated as: PDE – Oral Exposure Safety Limiting Toxicity

PDE = 0.06 mg/kg/d x 50 kg / 5 x 10 x 2 x 1 x 1 = 0.03 mg/d = 30 µg/day

F4 was set to 1 as the findings in the 6-month and 2-year studies were not considered significant at the lowest dose, and F5 was set to 1 as the BMDL 10 can be considered a NOAEL (Sargent et al , 2013).

PDE – Parenteral Exposure

Animal studies indicate that the oral bioavailability of inorganic mercury is in the 10- 30% range (ATSDR, 1999). Therefore, the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as described in Section 3.1).

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