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Frequently Asked Questions on Food Contact Notifications: Toxicology Requirements

March 1, 2001

Are there any additional data requirements for biocides?

The testing requirements for biocides are the same, but biocides are held to lower thresholds. For a biocide with an EDI under 0.5 ppb, no toxicology data is required. For exposures between 0.5 ppb and 10 ppb, only in vitro genotoxicity testing is required. Where the EDI is between 10 ppb and 200 ppb, both in vitro and in vivo genotoxicity tests, plus two 90-day studies are required. In the event that the EDI for a biocide is greater than 200 ppb, a Food Additive Petition is usually required, and the full complement of toxicology tests is required.

Are there specific qualifications or credentials a lab should have?

Compliance with good laboratory practices (GLPs) is required for each non-clinical lab study, if the study is essential to the safety evaluation of the food-contact substance. Part 58 of the GLP regulations specifies that this requirement only applies to in vitro and in vivo toxicity tests. GLP certification must be submitted with the report as part of the FCN.

Note that there is a new requirement: studies conducted after 1978 that are not in compliance with Part 58 of the GLP regulations must be validated by an independent third party prior to the results being submitted to the FDA.

How is the estimated dietary intake calculated?

The estimated dietary intake (EDI) is calculated by multiplying the substance?s dietary concentration (usually obtained from migration studies) by the average daily intake of food, which is assumed by FDA to be 3,000 grams (including all liquids ingested). These calculations invariably represent a conservative estimate of the dietary intake of the additive because they are based on the assumption that the additive will always migrate at the maximum levels found in the extraction studies, and that all food-contact materials of a given type will be made using the subject substance.

One notable difference between petitions and FCNs is the new burden on submitters to calculate the cumulative estimated dietary intake (CEDI) from existing clearances of the substance, rather than just the EDI from the use that is the subject of the notification. FDA is already compiling its own estimates of CEDIs, beginning with the most widely used substances, and intends to make this information publicly available, probably through the FDA Web site. In the meantime, the required CEDI data can be obtained from FDA on a case-by-case basis.

How is the safe intake of an additive determined by FDA?

The level of safe intake of an additive is determined by the lowest ?no-observed effect level? (NOEL) established in the feeding studies. If two subchronic (but not two-year) studies have been conducted, FDA typically divides the lowest NOEL by a factor of 1,000 to yield the ?acceptable daily intake? (ADI), the highest intake level that may be cleared based on the available data. When chronic feeding studies have been conducted, the NOEL is divided by 100 to determine the ADI.

FDA does not determine an ADI based on feeding studies having a duration of less than approximately 90 days, or from genetic toxicity test results; generally, the agency merely determines that intake below 50 ppb is negligible and, thus, that extensive toxicity data are not required to establish safety.

We have done a lot of testing. Do we need to include all of our results?

FDA's toxicity guidelines set forth the minimum toxicity requirements, and are available at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodIngredientsandPackaging/ucm081825.htm. All relevant toxicity studies must be submitted, including genotoxicity testing and oral toxicity testing. Inhalation and dermal testing is generally not required to be submitted, since it is usually not relevant to oral exposure. However, if systemic effects (not associated with the site of the exposure) are found in such studies, then that data should be included as well.

What substances must be tested for an FCN?

Generally, the test substance should be identical to the substance expected to migrate to food. The toxicity testing requirements apply to the food-contact substance and to any constituents (e.g., raw materials, byproducts, or decomposition products) expected to migrate to food.

For a polymer, toxicity testing should be conducted on the low-molecular weight (oligomer) fraction, where feasible. However, if the monomers are not genotoxic, oligomer testing may not be needed. Also, for most polymer adjuvants, testing is conducted on the food-contact substance itself. However, if the food-contact substance decomposes in food-contact articles or food (hydrolysis products, or oxidation products for antioxidants, for example), the decomposition products should be tested.

What types of toxicity data must be submitted?

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.