Constantine, LA, Davidson, T, Häner, A, Janer Gual, Gemma, Maynard, SK, Lee, M, Perkins, AN, Ryan, JJ, Tell, J, Van Ginneken, I, Burden, N and Dolan, D (2024) EVALUATION OF THE EMA TRIGGER FOR FISH BCF TESTING AND SECONDARY POISONING ASSESSMENT: EVALUATION OF LOG D AND FISH BCF DATA FOR SEVERAL PHARMACEUTICALS. Regulatory toxicology and pharmacology, 151 (105651). pp. 1-11. ISSN 1096-0295; 0273-2300

Abstract

As per the European Medicines Agency (EMA) Guideline for Environmental Risk Assessment of Medicinal Products for Human Use (EMA 2006), a fish bioconcentration study is triggered in Phase I for pharmaceuticals having a log Kow >4.5 to support screening for Persistence, Bioaccumulation and Toxicity (PBT) and in Phase II for pharmaceuticals having a log Kow >3 to assess bioaccumulation potential. The recommended protocol for bioaccumulation is OECD Test Guideline 305: Bioaccumulation in Fish, Aqueous and Dietary Exposure (OECD 2012). Based on the standard OECD 305 sampling schedule, approximately 200 fish per study may be required to determine steady-state (BCFSS) and kinetic (BCFK) bioconcentration factors following fish exposures to a low- and high-test concentration and a negative control. As per the draft revision of the EMA guideline, released for consultation in 2018, when log Kow is ≥3 the potential for secondary poisoning should be evaluated by first determining the experimental fish BCF, and when the resulting BCF is >100 L kg-1, a secondary poisoning assessment is required. Considering the potential for fish to metabolize and excrete xenobiotics and the number of animals required for a standard BCF test, the BCF values for several pharmaceuticals were evaluated to understand whether existing data support the current log Kow trigger of 3 for BCF testing. In the interest of animal welfare, BCF data were also evaluated to determine if study design could be limited to a single test concentration and still provide a good estimate of the BCF while reducing the number of fish required. Based on the data presented, increasing the log Kow trigger for BCF testing from 3 to 4 is proposed, and use of a single test concentration to evaluate bioaccumulation potential is recommended. Future plans include an evaluation of the proposed EMA BCF trigger for a secondary poisoning assessment.

Item Type:	Article
Date Deposited:	02 Jul 2024 00:46
Last Modified:	02 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/49196