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FDA describes assay standards and test conditions for nitrosamine evaluation
Summary
FDA recommended testing up to 5,000 micrograms per plate in enhanced AMES when toxicity allows, using appropriate solvents, positive controls, metabolic activation conditions, and transgenic rodent assays when needed to support AI limits above 1,500 ng/day.
The presenter explained technical assay expectations that FDA reviewers use to judge mutagenicity data. Key recommendations included testing at sufficiently high doses (guideline: up to 5,000 micrograms per plate for plate-based assays when toxicity permits), avoiding solvents or solvent concentrations that interfere with metabolic activation, and including proper nitrosamine positive controls and sufficient metabolic activation conditions.
"The standard guideline recommend to test up to 5000 microgram per plate if the test article did not cause, severe toxicity," the speaker said, adding that when AI limits exceed 1,500 ng/day, FDA recommends an additional negative in vivo transgenic rodent gene mutation assay. The presenter also cautioned that general toxicology data alone are not acceptable to characterize mutagenicity or carcinogenicity of nitrosamines.
Applicants were advised to design assays mindful of metabolic activation needs, ensure appropriate controls and solvent selection, and to use the recommended battery of tests to support proposed AI limits.
