Oral Intake of Methylene Blue: Benchmark Dose Modelling, Dietary Exposure Assessment, and Margins of Exposure for Borderline Products Sold to Final Consumers

Methylene blue is the active substance of an authorised medicinal product and is increasingly taken as a self-administered oral preparation. It is offered to final consumers in dosed form, mostly declared as a laboratory chemical, reagent, or dye rather than as a food supplement. No health-based guidance value (HBGV) for oral intake has been established in any jurisdiction. Points of departure were derived from 2-year gavage bioassays: a no-observed-adverse-effect level (NOAEL) of 1.8 mg/kg bw/day for oxidative erythrocyte injury, and benchmark dose lower confidence limits (BMDL) of 2.6 and 10.3 mg/kg bw/day for pancreatic islet and small intestinal neoplasms. A survey of 63 products offered to final consumers in eight European Union (EU) member states found that only five stated an intake amount. Intakes estimated from these statements, co-marketed consumer literature, user reports, and documented oral therapeutic regimens spanned about 6 to 200 mg/day. Margins of exposure fell from 20.9 to 0.6 against the NOAEL and from 30.2 to 0.9 against the BMDL, so that neither the required margin of 100 nor that of 10,000 was attained in any scenario. A provisional HBGV of 0.018 mg/kg bw/day or 1.26 mg/day is suggested, based on NOAEL with uncertainty factor of 100.