Impact of Partitioning in Short-Term Food Contact Applications Focused on Polymers in Support of Migration Modelling and Exposure Risk Assessment.

Food contact materials (FCMs) can transfer chemicals arising from their manufacture to food before consumption. Regulatory frameworks ensure consumer safety by prescribing methods for the assessment of FCMs that rely on migration testing either into real-life foods or food simulants. Standard migration testing conditions for single-use FCMs are justifiably conservative, employing recognized worst-case contact times and temperatures. For repeated-use FCMs, the third of three consecutive tests using worst-case conditions is taken as a surrogate of the much shorter contact period that often occurs over the service life of these items. Food contact regulations allow for the use of migration modelling for the chemicals in the FCM and for the partitioning that occurs between the FCM and food/simulant during prolonged contact, under which steady-state conditions are favored. This study demonstrates that the steady-state is rarely reached under repeated-use conditions and that partitioning plays a minor role that results in migration essentially being diffusion controlled. Domains of use have been identified within which partitioning does not play a significant role, allowing modelling based upon diffusion parameters to be used. These findings have the potential to advance the modelling of migration from repeated-use articles for the benefit of regulatory guidance and compliance practices.

Repeated use food contact materials: A categorisation approach in support of risk assessment.

The current migration assessment requirements regarding safety of plastic food contact materials in Europe (e.g. kitchen utensils, kitchen appliances, packaging, etc.) widely rely on migration testing. According to Annexe V of Regulation (EU) No 10/2011 migration testing requirements consider the specificities of repeated use applications only to a limited extent. Repeated use food contact materials should be tested for three consecutive times at the worst-case contact time and temperature. If diffusion controlled, the migration decreases with increasing number of repeated uses. Compared to single use applications, repeated use food contact materials typically exhibit much shorter contact times, much lower ratios of surface in contact with a given amount of food, and in some cases higher temperatures. Compared to real use, in many cases highly overestimated migration testing result are observed. Overestimation by testing at the beginning of use may be coupled with underestimation at later times. National legislation of the Netherlands on food contact materials has established a classification for repeated use rubber materials based on the R-value indicating whether migration testing is required or not. The R-value considers in more detail specificities of repeated use applications. This publication investigates to which extent it is possible to apply the approach to plastics food contact materials in Europe. It is practically impossible to perform migration tests for various materials by putting them many times in contact with food over a long period of time, typically several years, at several temperatures and areas to food amount ratios migration. Modelling has therefore been used to predict migration from various food contact materials under different repeated use scenarios. Realistic diffusion properties of materials and migrant partitioning behaviour have been assumed to minimise the risk of underestimation.

Probabilistic migration modelling focused on functional barrier efficiency and low migration concepts in support of risk assessment.

Migration modelling provides reliable migration estimates from food-contact materials (FCM) to food or food simulants based on mass-transfer parameters like diffusion and partition coefficients related to individual materials. In most cases, mass-transfer parameters are not readily available from the literature and for this reason are estimated with a given uncertainty. Historically, uncertainty was accounted for by introducing upper limit concepts first, turning out to be of limited applicability due to highly overestimated migration results. Probabilistic migration modelling gives the possibility to consider uncertainty of the mass-transfer parameters as well as other model inputs. With respect to a functional barrier, the most important parameters among others are the diffusion properties of the functional barrier and its thickness. A software tool that accepts distribution as inputs and is capable of applying Monte Carlo methods, i.e., random sampling from the input distributions of the relevant parameters (i.e., diffusion coefficient and layer thickness), predicts migration results with related uncertainty and confidence intervals. The capabilities of probabilistic migration modelling are presented in the view of three case studies (1) sensitivity analysis, (2) functional barrier efficiency and (3) validation by experimental testing. Based on the predicted migration by probabilistic migration modelling and related exposure estimates, safety evaluation of new materials in the context of existing or new packaging concepts is possible. Identifying associated migration risk and potential safety concerns in the early stage of packaging development is possible. Furthermore, dedicated material selection exhibiting required functional barrier efficiency under application conditions becomes feasible. Validation of the migration risk assessment by probabilistic migration modelling through a minimum of dedicated experimental testing is strongly recommended.

Feasibility study on the use of probabilistic migration modeling in support of exposure assessment from food contact materials.

The use of probabilistic approaches in exposure assessments of contaminants migrating from food packages is of increasing interest but the lack of concentration or migration data is often referred as a limitation. Data accounting for the variability and uncertainty that can be expected in migration, for example, due to heterogeneity in the packaging system, variation of the temperature along the distribution chain, and different time of consumption of each individual package, are required for probabilistic analysis. The objective of this work was to characterize quantitatively the uncertainty and variability in estimates of migration. A Monte Carlo simulation was applied to a typical solution of the Fick's law with given variability in the input parameters. The analysis was performed based on experimental data of a model system (migration of Irgafos 168 from polyethylene into isooctane) and illustrates how important sources of variability and uncertainty can be identified in order to refine analyses. For long migration times and controlled conditions of temperature the affinity of the migrant to the food can be the major factor determining the variability in the migration values (more than 70% of variance). In situations where both the time of consumption and temperature can vary, these factors can be responsible, respectively, for more than 60% and 20% of the variance in the migration estimates. The approach presented can be used with databases from consumption surveys to yield a true probabilistic estimate of exposure.

Investigation into the sorption of nitroglycerin and diazepam into PVC tubes and alternative tube materials during application.

Plastic bags and tubes are increasingly used for the storage and application of pharmaceutical formulations. The most common polymer material for drug application sets is plasticized poly(vinylchloride) (PVC). During application of pharmaceutical drug solution through PVC tubes, the polymer and the contact media interact which leads to leaching out of polymer additives or sorption of ingredients of the drug solution. Whereas the discussion of leaching of plasticizers is focussed on the toxicological properties of a drug packaging system, the sorption of drug formulation compounds has an influence on the dosage of the active pharmaceutical ingredient resulting in a reduced drug delivery to the patient. Therefore sorption has an influence on the effectiveness and success of the therapy. Within the study, the concentration profiles of nitroglycerin and diazepam solutions were determined after pumping the solutions through infusion administration sets. The study includes plasticized PVC tubes with different plasticizers (DEHP, DEHA, DEHT, TEHTM, DINCH, poly adipate), PVC (DEHP) tubes with different shore hardness as well as alternative polymer materials like EVA, TPE, PUR, silicone, LDPE and PP. From the experimental concentration curves it could be shown, that in the first minutes of the application of the drug solution the sorption of the active compound is at its maximum, resulting in the lowest concentration in the applied pharmaceutical solution. For a PVC tube with DEHP as plasticizer and a shore hardness of 80 only about 57% of the initial nitroglycerin concentration in the solution is applied to the patient in the first minutes of the application. For PVC tube (DEHP, shore 80) the experimental data were simulated using mathematical diffusion models. The concentration profiles during application could be well simulated using the partition coefficient K=50 (nitroglycerin) and K=300 (diazepam), respectively. However, the experimental results indicate, that the sorption of nitroglycerin into the PVC tube alters the diffusion behaviour of the polymer over flow time, which results in an increase of the diffusion coefficient during application. On the other hand, the other investigated alternative tube materials like PE or PP show a significantly lower sorption compared to PVC plasticizer systems. Due to the fact that the amount of sorption is varying over time, the concentration of the active pharmaceutical compound in the solution after passing the infusion administration set is not constant which makes the application of a constant concentration of a certain active ingredient to the patient very difficult. The simulated partition and diffusion coefficients for given PVC(DEHP) tubes were therefore used to simulate the initial concentrations profile of the feeding drug solution to assure a constant concentration flow profile after passing the administration set. The proposed methodology of this study represents a straight forward approach for the assessment of the drug sorption in dynamic flow systems based on experimental data as well as mathematical diffusion modelling. From the results a non-constant initial concentration profile for the active ingredient in a pharmaceutical drug solution can be established in order to compensate the loss of the pharmaceutical compound by sorption during infusion.