Toxicological Evaluation of Benzethonium Chloride in Ketamine Formulations

Benzethonium chloride (BZT) is a quaternary ammonium compound widely used as an antimicrobial preservative in certain injectable ketamine formulations. Although intended to prevent microbial contamination, BZT is pharmacologically active at nanomolar to low micromolar concentrations. This toxicological evaluation integrates mechanistic in vitro data, in vivo animal studies, and modeled human exposure estimates to assess the potential risks of BZT during clinical ketamine administration. BZT inhibits neuronal nicotinic acetylcholine receptors (IC₅₀ = 49 nM), suppresses human cardiomyocyte contractility (IC₅₀ ≈ 0.13 μM), and induces eryptosis in erythrocytes (≥ 2.5 μM). It also engages diverse neuromodulatory receptor systems and potentiates ketamine-induced neurotoxicity in central nervous system cell models. Modeled plasma concentrations following labeled intravenous dosing (e.g., 2.88 mg/24 h) plausibly overlap these effect thresholds, especially during prolonged infusion or in patients with impaired renal clearance. Animal toxicokinetic studies demonstrate tissue accumulation and organ injury with repeated parenteral exposure. No human pharmacokinetic or safety data exist for BZT, and it is not recognized by the U.S. Food and Drug Administration as generally safe for parenteral use. Given the availability of preservative-free ketamine products and the absence of therapeutic benefit from BZT, these findings raise concern for unnecessary patient risk. The evidence supports reconsideration of BZT’s inclusion in parenteral ketamine and underscores the need for further research and regulatory review.