While a “functional barrier” may effectively prevent migration of uncleared substances into food from the outside surface of packaging,

what are the FDA considerations when there is potential transfer into food via set-off to the food contact side in the reel or stack of printed material? Is there a certain "migration limit" for substances not cleared under FDA CFR 21 and for which no toxicological data is available?

The migration limit requirements for FDA cleared materials are specified in each corresponding 21 CFR listing and in the individual FCNs. However, the "functional barrier" exemption applies only to the design of the food package, with the reasonable expectation that the barrier prevents migration of substances from the outside of the barrier into food.
However, packaging materials often are rolled up or stacked one inside the other, so that there can be offset between a printed/coated side of the packaging material and the other, food contact side. If the migrating substance is cleared under an existing FDA regulation, then the specified migration limit must be respected. This can be confirmed by appropriate testing (see below).
If the front-to-back migrating substance is not cleared under an existing FDA regulation, and if it is not a carcinogen or reproductive toxin or other problematic substance, then it still can be used in food packaging if it can be shown by test data or calculations that it would be present "in the diet" at a concentration of 0.5 ppb or less. Below this de minimis concentration the substance is not considered to be a food additive under the "threshold of regulation" principle. Calculations to determine the concentration in the diet can be found in section IIE of FDA Guidance for Industry: Preparation of Premarket Submissions for Food Contact Substances: Chemistry Recommendations at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodIngredientsandPackaging/ucm081818.htm. In general, if the concentration of the migrating uncleared substance in food is below 50 ppb, then the eventual concentration in the diet normally will be less than 0.5 ppb.
Highly cross-linked coatings over printed surfaces can act to minimize such front-to-back migration. If a coating is not practical, then non-FDA inks should be UV/EB cured or heat set to "lock in" any potentially migrating substances.
In any case, if a printer is concerned about possible front-to-back migration, then appropriate testing of the food contact surface should be conducted to identify and quantify potential migrating substances. Test methods must be validated to assure that they are capable of detecting the target substance at the required low level of migration.

Source: Ron Golden, rgolden@focalconsulting.com