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BOX 13-1
Principles for Evaluating Data to Determine Unreasonable Risk

  • Information that is generally referred to as “safe historical use” should not be used as prima facie evidence that the ingredient does not cause harm.

It is important to carefully consider the actual existence of information about historical use and the relevance of this information, taking into consideration whether the preparations are similarly processed, similar in route of exposure and duration of use, the potential for differences in concurrent use with substances, and whether or not the historical use would have revealed any possible adverse event. Appropriate historical use can then be weighed against the strength of other types of evidence suggesting possible harm (human, animal, and in vitro data or information about related substances).

  • Even in the absence of information on adverse events in humans, evidence of harm from animal studies is often indicative of potential harm to humans.

This indication assumes greatest importance when the route of exposure is oral, the formulation tested is identical or highly similar to that consumed as an ingredient, and more than one species shows the same or similar toxicity.

  • Validateda in vitro studies can stand alone as independent indicators of risk to human health if a comparative exposure is attained in humans.

  • It is scientifically appropriate and acceptable to use information about safety concerns of related substances to inform a decision about the risk associated with a dietary supplement ingredient, by considering whether:

    • the ingredient’s constituents are compounds with established toxicity, or closely related to compounds with established toxicity, or

    • the plant sources of the botanical dietary supplement are taxonomically related to known toxic plants.


In this report, in vitro assays are considered validated when their results have been proven to predict a specific effect in animals and/or humans with reasonable certainty.


Through the process of developing the Framework to evaluate the safety of dietary supplement ingredients, a number of legal and regulatory barriers were identified that hamper FDA’s ability to protect the public’s health. The following findings are designed to enhance the utility of the Framework and enhance the ability of FDA to protect consumers from unreasonable risk of illness or injury.

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