Submitters of new Food Contact Notifications for substances intended for use in infant formula packaging should carefully consider the toxicity profiles of potential migrants to food to determine whether additional safety data may be warranted for these applications, Dr. April P. Neal-Kluever, a toxicologist at the U.S. Food and Administration's (FDA) Division of Food Contact Notifications (DFCN) told attendees at Keller and Heckman's 15th Annual Food Packaging Seminar. She added that the Agency recommends that potential submitters request a pre-notification consultation (PNC) with FDA when additional testing may be necessary.
DFCN formed a working group in March 2010 to consider potential exposure and safety issues related to chemical migration from packaging into infant food, namely, infant formula and human breast milk. The formation of the group was motivated by recent progress in the fields of infant biology and developmental toxicology, and in juvenile toxicity testing paradigms, in addition to enhanced public awareness regarding the possible exposure to infants of chemicals used in food packaging (e.g., bisphenol A), Neal-Kluever explained.
The group's publication, "Infant toxicology: State of the science and considerations in evaluation of safety," Food and Chemical Toxicology, 70 (2014): 68-83, discusses key biological and exposure elements that impact safety evaluations for substances used in infant formula packaging and in articles that may be used in contact with human breast milk. One of the key issues, regardless of the susceptibility of the population, is the difference in exposure pattern for this population as compared to historical approaches that have been used for food contact materials. Moreover, because a single type of infant formula and/or breast milk can be the sole source of nutrition for the first six months after birth and infants consume almost three times as much food per kilogram of bodyweight per day as compared to adults, there exists a potential for elevated exposure to food packaging migrants for infants during this time period.
Also, infant pharmacokinetics (or toxicokinetics) during the first six months of life is highly variable, Neal-Kluever said. She added that developing organ systems and the different physiological make-up of infants as compared to adults may alter (enhance or decrease) an infant's susceptibility to toxicants. She then discussed the potential impact of chemical exposure on the reproductive, endocrine, skeletal, nervous, and immune systems during this period of rapid development. Details regarding these systems and their differences with regard to infants and adults as well as the ability of existing guideline studies to investigate relevant toxicity are discussed in the group's publication.
FDA's Guidance for Industry: Preparation of Food Contact Notifications for Food Contact Substances: Toxicology Recommendations, 2002, recommends different tiers of toxicological testing, depending on the cumulative estimated daily intake (CEDI) for the substance, which is currently listed in micrograms per person per day (µg/p/d). Due to the varying body weights and food intake levels between the adult and infant populations, however, FDA more recently has been recommending a CEDI reported in micrograms per kilograms body weight per day (µg/kg bw/d), which would standardize the toxicity testing tiers across all populations. (Of note, this position, indicating exposure per kg bw, was also highlighted in EFSA's recent review of the TTC approach and reflects a more general shift in approaches to describing exposures adequately across exposed sub-populations.)
Neal-Kluever suggested that notifiers consider the following in identifying a potential safety concern or need for additional safety data:
- Do the available toxicity data or chemical structure suggest a concern for developmental toxicity?
- What, if any, positive endpoints identified in a juvenile or adult animal toxicity study might be expected to result in a different effect or change in magnitude or sensitivity of effect in a neonate?
- What other data may be useful to inform age- or species-dependent differences?
- Do the available data/testing address the concern identified?
- Can the available information address the variability or differences between infants and adults?
With respect to carcinogens, Neal-Kluever suggested that, due to the shortened exposure duration (6 months) and potential for enhanced susceptibility to carcinogens, an age-dependent adjustment factor (ADAF) can be applied in lifetime cancer risk assessment. (The ADAF approach with exposure duration adjustment is elaborated upon in the 2005 U.S. EPA Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens.)
See the link below to view slides from the presentation.