Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides

Publication date: April 2018 Source:Regulatory Toxicology and Pharmacology, Volume 94 Author(s): J.P. Bercu, S.M. Galloway, P. Parris, A. Teasdale, M. Masuda-Herrera, K. Dobo, P. Heard, M. Kenyon, J. Nicolette, E. Vock, W. Ku, J. Harvey, A. White, S. Glowienke, E.A. Martin, L. Custer, R.A. Jolly, V. Thybaud This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for ...
Source: Regulatory Toxicology and Pharmacology - Category: Toxicology Source Type: research