Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

doses may lead to adverse responses e.g., for the kidney especially in newborns and preterm infants. The safety review for chromium 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 10% for chromium and inorganic chromium compounds (ATSDR, 2012), the parenteral PDE was calculated by dividing the oral PDE by a modifying factor of 10 (as described in Section 3.1). The recommended PDE for chromium for parenteral exposure is:

PDE = 10700 µg/d / 10 = 1070 µg/day

PDE – Inhalation Exposure

The study by Derelenko et al. (1999) used inhalation of Cr(3+) sulfate particles during 13 weeks (6h/day and 5 days per week), and the predominant observed effects were chronic inflammation of the airways (mononuclear infiltrate, particular material) and local thickening of alveolar walls. The effect was observed at all doses. The LOAEL is 17 mg/m 3 (3 mg Cr(3+)/m 3 ). A lack of systemic toxicity was noted in a 13-week inhalation study in rats administered soluble or insoluble Cr(3+). Based on these data, the inhalation MRL of 0.1µg/m 3 was used to set the PDE (ATSDR, 2012).

PDE =0.0001 mg/m 3 / 1000 m 3 /L x 28800 L/day = 2.9 µg/day

No modifying factors were applied because they are incorporated into the derivation of the MRL.

R EFERENCES

Anderson RA. Recent advances in the clinical and biochemical effects of chromium deficiency. Prog Clin Biol Res 1993;380:221-34.

Anderson RA. Chromium and parenteral nutrition. Nutr 1995;11(1 suppl.):83-6.

ATSDR. Toxicological profile of chromium. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. 2012. Derelanko MJ, Rinehart WE, Hilaski RJ, Thompson RB, Löser E. Thirteen week subchronic rat inhalation toxicity study with a recovery phase of trivalent chromium compounds, chromic oxide, and basic chromium sulfate. Toxicol Sci 1999;52:278-88. Glaser U, Hochrainer D, Klöppel H, Oldiges H. Carcinogenicity of sodium dichromate and chromium (VI/III) oxide aerosols inhaled by male Wistar rats. Toxicology. 1986;42(2- 3):219-32. Moukarzel A. Chromium in parenteral nutrition: too little or too much. Gastroenterology 2009;137:S18-S28. NTP. Technical report on the toxicology and carcinogenesis studies of chromium picolinate monohydrate (CAS NO. 27882-76-4) in F344/N rats and B6C3F1 mice (feed studies). National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services. 2010;NTP TR 556. US DoL (OHSA). 29 CRF 1910.1000 Table Z-1. Limits for air contaminants. U.S. Department of Labor. 2013. US EPA. Chromium (III), insoluble salts. Integrated Risk Information System (IRIS). 1998.

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