Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals

In the European Medicines Agency (EMA) “Guideline for Environmental Risk Assessment of Medicinal Products for Human Use,” a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screenin...

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Bibliographic Details
Published in:Regulatory toxicology and pharmacology 2024-08, Vol.151, p.105651, Article 105651
Main Authors: Constantine, Lisa A., Burden, Natalie, Davidson, Todd, Dolan, David G., Janer, Gemma, Häner, Andreas, Lee, Michael R., Maynard, Samuel K., Nfon, Erick, Nimrod Perkins, Alison, Ryan, James J., Tell, Joan
Format: Article
Language:English
Subjects:
Bioaccumulation
Bioconcentration
Bioconcentration factor (BCF)
Environment risk assessment (ERA)
Fish
Log D
Pharmaceuticals
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Summary:In the European Medicines Agency (EMA) “Guideline for Environmental Risk Assessment of Medicinal Products for Human Use,” a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation (‘B’) potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified. •Log Kow and BCF data are evaluated for 64 human pharmaceuticals.•The data support raising the trigger for BCF testing to log Kow ≥4.•No meaningful difference between BCF values determined in OECD 305 studies at high and low exposure concentrations.•Analysis of the data support 3 R s efforts to revise BCF testing criteria to reduce the use of fish.•The presence of halogens in an API is not a good predictor of bioaccumulation potential.
ISSN:0273-2300
1096-0295
1096-0295
DOI:10.1016/j.yrtph.2024.105651