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Food Chem Toxicol. 2018 Mar;113:171-178. doi: 10.1016/j.fct.2018.01.021. Epub 2018 Jan 31.

Updated procedure for the safety evaluation of natural flavor complexes used as ingredients in food.

Author information

Dept. of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE, 68198-3135, USA.
Food Chemistry & Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.
Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa, 257-0015, Japan.
Dept. of Surgery and Cancer, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, United Kingdom.
Dept. of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, 37232-0146, USA.
Masonic Cancer Center and Dept. of Laboratory Medicine and Pathology, University of Minnesota, Cancer and Cardiovascular Research Building, 2231 6th St. SE, Minneapolis, MN, 55455, USA.
Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
Flavor and Extract Manufacturers Association, 1101 17th Street, NW Suite 700, Washington, DC, 20036, USA.
Scientific Secretary to the FEMA Expert Panel, 1101 17th Street, NW Suite 700, Washington, DC, 20036, USA. Electronic address:


An effective and thorough approach for the safety evaluation of natural flavor complexes (NFCs) was published in 2005 by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). An updated procedure is provided here, which maintains the essential concepts of the use of the congeneric group approach and the reliance on the threshold of toxicological concern (TTC) concept. The updated procedure emphasizes more rigorous considerations of unidentified constituents and the genotoxic potential of constituents. The update of the previously established procedure is the first step in a multi-year project to conduct safety re-evaluations for more than 250 NFCs that have uses that are currently considered Generally Recognized as Safe (GRAS) by the FEMA Expert Panel. In addition, this procedure can be more generally employed in the safety evaluation of NFCs.


Botanicals; Complex mixtures; Flavoring; Food; GRAS; Threshold of toxicological concern; Toxicology

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