Answer: The type of toxicology data required to clear the proposed use of a given substance will depend on the nature of the material and the cumulative estimated dietary intake (CEDI) for the substance. In this regard, there is a significant difference between the data requirements for Food Contact Notifications and traditional petitions.
For substances with CEDIs under 0.5 ppb, no toxicology data is required, although relevant data must be submitted if available. However, for exposures between 0.5 ppb and 50 ppb, two genotoxicity studies (a bacterial mutagenicity assay plus an in vitro cytogenetic damage or mouse lymphoma assay) are needed. These studies replace FDA's former requirement for petitions of an acute toxicity study (LD50). The rationale for this change is that for substances entering the diet at these minute levels, acute toxicity almost never is a concern (that is, virtually nothing will be acutely toxic at low parts-per-billion levels). On the other hand, it is possible, at least in theory, for carcinogenic effects to be elicited at low dietary levels; hence, the toxicity endpoint of greatest concern for low-exposure substances is carcinogenicity. The now-recommended genotoxicity screening assays are intended to provide an indication as to whether a given substance is likely to be a carcinogen.
Where the intake exceeds 50 ppb but is below 1 ppm, a third genotoxicity study (in addition to the two noted above) in the form of an in vivo chromosomal aberration study is recommended, as well as two subchronic (90-day) studies (one in a rodent and one in a non-rodent animal).
For food-contact substances that may be present in the diet at a level in excess of 1 ppm, a full range of toxicity studies is generally required, including chronic (2-year) toxicity/carcinogenicity studies in rats and mice, a 1-year feeding study in dogs, and multi-generation reproductive studies in rats. (Where cumulative dietary exposure exceeds this 1 ppm level, FDA recommends the filing of a Food Additive Petition instead of an FCN). The required data can be studies undertaken by the FCN submitter, or existing studies in the open literature where available and applicable to the intended use.
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