Safety assessment for Tris(2,4-di-tert-butylphenyl) phosphite (Irgafos 168) used as an antioxidant and stabilizer in food contact applications.

During and after fabrication of polymeric food contact articles (FCA), polymers undergo oxidation by thermal decomposition processes initiated by oxygen, heat, light, shear, and catalyst residues. To reduce degradation of the polymer, a commonly used secondary antioxidant (AO), Irgafos 168 (I-168), may be included. Use of I-168 in polymeric FCAs presents a potential concern for neurotoxicity due to its phosphate-containing degradation species, I-168ate. As a result, we evaluated dietary exposure and oral toxicity data for I-168 and its degradants when used as an AO in FCAs. Our exposure assessment included extensive review of the U.S. food-contact regulatory history of I-168 resulting in a combined cumulative estimated daily intake (CEDI) of 0.09 mg/kg bw/day for I-168 and I-168ate when used as an AO in FCAs. Our comprehensive literature review of toxicological data and supporting structure activity relationship (SAR) analysis of I-168 reactivity against acetylcholinesterase diminished concern for potential neurotoxic effects of I-168 and its degradants. An acceptable daily intake (ADI) value of 1 mg/kg bw/day for I-168 was derived from a two-year rodent combined chronic toxicity/carcinogenicity study, which is higher than the CEDI and supports the safety of current authorized food contact use levels of I-168.

Exploring the use of current immunological assays for the developmental immunotoxicity assessment of food contact materials.

The mammalian immune system is a highly complex, interactive network of cells that facilitates innate and adaptive immune responses. The neonatal immune system may be more susceptible to chemical perturbations than that of the adult. The effects of immunotoxicants during development may not be fully detected in toxicity studies performed on adult animals. Studies characterizing the ontogeny of the immune system in developing animals have shown that there are different critical windows of susceptibility to immunotoxicants. Developmental differences are evident among species compared to humans. Functional immune assays, such as the T-cell antibody dependent response assay, in rat models have been validated for use in the assessment of immunotoxicity with other assays. Recently, published studies have explored the feasibility of using additional techniques, such as in vitro studies using human whole blood cells or cell lines, mostly lacking either sensitivity or proper validation for regulatory purposes. However, some techniques may be developed further to enable translation of animal toxicity findings to human risk assessment of potential immunotoxicants. This paper summarizes the information on the developing immune system in humans versus rats and how the currently available assays might be used to contribute to the safety assessment of food contact substances.

A review of dietary exposure and toxicological information on epoxidised soybean oil (ESBO) in food-contact applications.

Plasticisers have a long history of use in the industrial manufacture and processing of polymers for the purpose of increasing the flexibility and strength of the material. Approximately, 80-90% of the plasticiser market is devoted to the production of PVC, a highly versatile thermoplastic used to produce both rigid and flexible articles. Many types of plasticisers, including ortho-phthalate esters (OPE), can be added to PVC to impart flexibility. Recently, alternatives to OPEs, such as epoxy esters and aliphatic adipates, are becoming more prevalent for use in PVC-based food-contact articles. Epoxidised soybean oil (ESBO) is used as a plasticiser in flexible PVC for many food-contact articles, including food packaging and food processing equipment, from which it can potentially migrate into food and become a component of an individual's daily diet. The purpose of this review is to provide an update on the US dietary exposure and toxicological information on ESBO used in PVC-based food-contact articles. The cumulative dietary concentration (CDC) and cumulative estimated daily intake (CEDI) for ESBO from its use as a plasticiser in PVC-based food-contact articles (i.e. gaskets for glass jar lids and film wraps) was calculated to be 2.6 mg/kg (i.e. ppm) and 0.13 mg/kg bw/d, respectively, for the general population. Some regulatory agencies have reported safety levels for ESBO, and the most conservative no observed adverse effect level (NOAEL) was identified to be 100 mg/kg bw/d (i.e. 2000 ppm) based on a two-year feeding study in rats. The current CEDI is well below these levels, supporting the safe use of ESBO in food-contact applications.

Infant toxicology: state of the science and considerations in evaluation of safety.

Differences in the physiology and biological susceptibilities of adults and infants have led to growing interest in safety evaluation methods for exposures from infant formula packaging. In addition to potential physiological differences, infants aged 0-6 months may consume a sole source of food, infant formula or breast milk, and consume higher amounts of food relative to body weight compared to adults. While the duration of the exposure is short compared to the expected lifespan of the individual, it occurs during a period of important developmental processes. The purpose of this document is to (1) review key biological and exposure elements that may impact the evaluation of safety for food contact products intended for use by infants, (2) summarize the current reproductive and developmental toxicity testing protocols available, and (3) identify potential data gaps concerning this period of development.

Regulatory use of computational toxicology tools and databases at the United States Food and Drug Administration's Office of Food Additive Safety.

Over 10 years ago, the Office of Food Additive Safety (OFAS) in the FDA's Center for Food Safety and Applied Nutrition implemented the formal use of structure-activity relationship analysis and quantitative structure-activity relationship (QSAR) analysis in the premarket review of food-contact substances. More recently, OFAS has implemented the use of multiple QSAR software packages and has begun investigating the use of metabolism data and metabolism predictive models in our QSAR evaluations of food-contact substances. In this article, we provide an overview of the programs used in OFAS as well as a perspective on how to apply multiple QSAR tools in the review process of a new food-contact substance.