Risk assessment of food contact materials.

Bisphenol A (BPA) is authorised for use as a chemical compound for the production of plastic food contact materials (FCMs) under Regulation (EU) No 10/2011. But according to requirements of the Regulation (EU) No 2018/213, BPA has been banned in the manufacture of polycarbonate drinking cups or feeding bottles intended for infants and young children. Food has been identified as the main source of human exposure to BPA, followed by dermal absorption, air and dust inhalation, revealing ubiquitous and continuous contact with BPA. Considering that BPA is able to enter the food chain through the migration from food packaging into foodstuffs, assessment of dietary exposure is necessary for accurate estimations and identification of potential exposure from food sources. In 2015, EFSA set a temporary tolerable daily intake (TDI) for BPA of 4 µg/kg body weight (bw) per day and concluded that no health concern from BPA exposure for any age group was to be expected. In 2023, EFSA has re-evaluated BPA safety and the new TDI was reduced by a factor of 20,000 resulting in a TDI of 0.2 ng/kg bw per day. In this case, the CEP Panel concluded that there is a health concern from dietary exposure to BPA. Amongst others, the BfR identified several points of criticism which, in the opinion of the BfR, call into question the risk assessment carried out by EFSA. The BfR derived a TDI of 200 ng/kg bw per day and suggests taking this into account for risk assessment. In the proposed EU-FORA programme, the fellow had the opportunity to gain experience in the exposure assessment and then integrate the data together with the BfR hazard assessment to perform a comprehensive risk assessment. As second objective of the work programme, the fellow was in charge of performing a toxicokinetic analysis in an attempt to correlate external exposure with urinary BPA levels.

Risk assessment of food contact materials.

In the EU, any material or article intended to come into contact with food, which is placed on the market, has to comply with the requirements of the Regulation (EC) No 1935/2004 - the so called 'framework regulation' for food contact materials (FCM). FCM covers a wide range of materials, including plastics, paper, metal and glass, which contain chemicals that might migrate into food. These chemicals must not migrate into the foodstuff in quantities that could endanger human health, bring about an unacceptable change in the composition of the food, or bring about a deterioration in the organoleptic characteristics thereof. Despite of this general regulation, the safety of new and specific materials that are not covered must be assessed case-by-case. In addition, national authorities can set their own regulations, and in this context, the BfR sets recommendations, which are not legal norms, but represent a standard for the production of materials not subjected to any specific legislation and are well accepted by other European Commission member states according to the mutual recognition principle. The BfR Unit 74 is responsible not only to deal with chemical risk assessment of FCM but also to evaluate application dossiers to include new substances in the positive list of FCM chemicals. In the proposed EU-FORA programme, the fellow had the opportunity to gain experience in the evaluation of toxicological data from applicant dossiers and in the methodologies of migration tests performed in the laboratories. Moreover, the fellow also made a bibliographic review on scientific literature on the migration studies from starch-based materials.

Migration of styrene oligomers from food contact materials: in silico prediction of possible genotoxicity.

Styrene oligomers (SO) are well-known side products formed during styrene polymerization. They consist mainly of dimers (SD) and trimers (ST) that have been shown to be still residual in polystyrene (PS) materials. In this study migration of SO from PS into sunflower oil at temperatures between 5 and 70 °C and contact times between 0.5 h and 10 days was investigated. In addition, the contents of SD and ST in the fatty foodstuffs créme fraiche and coffee cream, which are typically enwrapped in PS, were measured and the amounts detected (of up to 0.123 mg/kg food) were compared to literature data. From this comparison, it became evident, that the levels of SO migrating from PS packaging into real food call for a comprehensive risk assessment. As a first step towards this direction, possible genotoxicity has to be addressed. Due to technical and experimental limitations, however, the few existing in vitro tests available are unsuited to provide a clear picture. In order to reduce uncertainty of these in vitro tests, four different knowledge and statistics-based in silico tools were applied to such SO that are known to migrate into food. Except for SD4 all evaluated SD and ST showed no alert for genotoxicity. For SD4, either the predictions were inconclusive or the substance was assigned as being out of the chemical space (out of domain) of the respective in silico tool. Therefore, the absence of genotoxicity of SD4 requires additional experimental proof. Apart from SD4, in silico studies supported the limited in vitro data that indicated the absence of genotoxicity of SO. In conclusion, the overall migration of all SO together into food of up to 50 µg/kg does not raise any health concerns, given the currently available in silico and in vitro data.

Risk Assessment of Food Contact Materials II.

Food contact materials (FCMs) are materials and articles intended to be placed in direct or indirect contact with foodstuffs, or which can reasonably be expected to come into contact with food under normal or foreseeable conditions of use. Substances intentionally used to manufacture FCMs, as well as non-intentionally added substances resulting from impurities, by-products and/or degradation products, can migrate from FMCs into food and, consequently, are taken up by humans. To protect consumers' health, EU legislation requires that FCMs must be sufficiently inert to prevent substances from being transferred into the food in quantities that could endanger human health. At the German Federal Institute for Risk Assessment (BfR), Unit 74 'Safety of Food Contact Materials' deals with the risk assessment of FCMs and provides recommendations on the use of substances for the production of FCMs for which no specific European measures exist yet (e.g. silicone, rubber, paper and board). The BfR 'Recommendations on Food Contact Materials' are not legally binding; however, they represent the current state of the scientific and technical knowledge for the conditions under which these materials meet the requirements for consumer safety. As part of the EU-FORA programme, the fellow was involved in the risk assessment tasks and projects undertaken by Unit 74, which include: (i) the scientific evaluation of analytical and toxicological data from dossiers for adding new substances to the database 'BfR Recommendations on Food Contact Materials'; (ii) the hazard assessment of cyclic volatile methylsiloxanes (cVMS) migrating from silicone FCMs into foodstuff; and (iii) in vitro metabolic stability study of cyclic methylsiloxanes in the presence of S9 fraction, performed in the BfR laboratories. Moreover, the EU-FORA fellowship was a great opportunity for the fellow to build a strong network of food safety experts and to be part of an international community of risk assessment professionals.

Risk Assessment of Food Contact Materials.

Food contact materials (FCM) can contain chemicals that could migrate from the material itself to the foodstuff posing health concerns if ingested in non-safe quantities by the consumer. FCM include containers, packaging, machinery or kitchenware and can be made from different materials like plastics, paper and board, metal or glass. Printing inks are also an important part of FCM. FCM have an important role in preventing damage or spoilage of the foodstuff and are essential along the food chain. Therefore, their safety needs to be carefully assessed in order to reduce the exposure to potentially hazardous substances and protect the health of the consumer. At the EU level, the legislation on FCM establishes general safety requirements for FCM. In addition, for certain materials, specific measures concerning usage and release of substances have been set. For materials or articles not specifically regulated in this harmonised framework, safety must be proven on a case-by-case basis. National legislations and lists of substances evaluated by competent authorities are important data sources in this context. One of the most important databases are the 'BfR Recommendations on Food Contact Materials' and the soon to come German national regulation on printing inks. BfR Unit 74, besides dealing with chemical risk assessment of FCM, is responsible for the evaluation of application dossiers for including substances into the BfR recommendations on FCM or the substance list of the printing inks regulation. Through the proposed work programme the fellow has been involved in risk assessment of substances that migrate from FCM into foodstuff gaining experience in the methodologies used to perform the scientific data evaluation as well as to support the BfR Unit 74s work.

Energetic Profiles of the Yo-Yo Intermittent Recovery Tests 1 and 2.

PURPOSE: To analyze the energetic profiles of the Yo-Yo Intermittent Recovery Tests 1 and 2 (YYIR1 and YYIR2). METHODS: Intermittent running distance (IR1D and IR2D), time to exhaustion (IR1T and IR2T), and total recovery time between shuttles (IR1R and IR2R) were measured in 10 well-trained male athletes (age 24.4 [2.0] y, height 182 [1] cm, weight 75.8 [7.9] kg). Respiratory gases and blood lactate (BLC) were obtained preexercise, during exercise, and until 15 min postexercise. Metabolic energy, average metabolic power , and energy share (percentage of aerobic [WAER], anaerobic lactic [WBLC], and anaerobic alactic energy system [WPCr]) were calculated using the PCr-La-O2 method. RESULTS: Peak oxygen consumption was possibly higher in YYIR2 (60.3 [5.1] mL·kg-1·min-1) than in YYIR1 (P = .116, 57.7 [4.5] mL·kg-1·min-1, d = -0.58). IR1D, IR1T, and IR1R were very likely higher than IR2D, IR2T, and IR2R, respectively (P < .001, 1876 [391] vs 672 [132] m, d = -2.83; P < .001, 916 [175] vs 304 [57] s, d = -3.03; and P < .001, 460 [100] vs 150 [40] s, d = -2.83). Metabolic energy was most likely lower in YYIR2 than in YYIR1 (P < .001, 493.5 [118.1] vs 984.8 [171.7] kJ, d = 3.24). Average metabolic power was most likely higher in YYIR2 than in YYIR1 (P < .001, 21.5 [1.7] vs 14.5 [2.2] W·kg-1, d = 3.54). When considering aerobic phosphocreatine restoration during breaks between shuttles, WAER (P = .693, 49% [10%] vs 48% [5%], d = -0.16) was similar, WPCr (P = .165, 47% [11%] vs 42% [6%], d = -0.54) possibly higher, and WBLC (P < .001, 4% [1%] vs 10% [3%], d = 1.95) almost certainly lower in YYIR1 than in YYIR2. CONCLUSIONS: WAER and WPCr are predominant in YYIR1 and YYIR2 with almost identical WAER. Higher IR1D and IR1T in YYIR1 result in higher metabolic energy but lower average metabolic power and slightly lower peak oxygen consumption. Higher IR1R allows for higher reliance on WPCr in YYIR1, while YYIR2 requires a higher fraction of WBLC.

Quantification of PET cyclic and linear oligomers in teabags by a validated LC-MS method - In silico toxicity assessment and consumer's exposure.

Determination of polyethylene terephthalate (PET) dimer up to heptamer 1st series cyclic oligomers, applying an LC-qTOF-MS method, has been developed and validated. Recoveries ranged between 80 and 112% with RSDs lower than 15%. An innovative semi-quantitative approach has been applied for 2nd and 3rd series cyclic oligomers, using the closest structural-similar 1st series cyclic oligomer standard as analytical reference. Oligomers from the three series were quantified in PET teabags after migration experiments with water and food simulants C (20% v/v ethanol in water) and D1 (50% v/v ethanol in water). No legal migration limits exist currently for these substances. In silico genotoxicity assessment of all identified oligomers has been performed and showed no genotoxicity alert for linear or cyclic molecules. Exposure assessment was performed using EFSA's approach on the total sum of migrating oligomers and on toxicological threshold-of-concern. Amounts found in water were in some cases significantly higher than the respective limits, especially in the worst-case scenario of multiple consumption.

Aggregated aluminium exposure: risk assessment for the general population.

Aluminium is one of the most abundant elements in earth's crust and its manifold uses result in an exposure of the population from many sources. Developmental toxicity, effects on the urinary tract and neurotoxicity are known effects of aluminium and its compounds. Here, we assessed the health risks resulting from total consumer exposure towards aluminium and various aluminium compounds, including contributions from foodstuffs, food additives, food contact materials (FCM), and cosmetic products. For the estimation of aluminium contents in foodstuff, data from the German "Pilot-Total-Diet-Study" were used, which was conducted as part of the European TDS-Exposure project. These were combined with consumption data from the German National Consumption Survey II to yield aluminium exposure via food for adults. It was found that the average weekly aluminium exposure resulting from food intake amounts to approx. 50% of the tolerable weekly intake (TWI) of 1 mg/kg body weight (bw)/week, derived by the European Food Safety Authority (EFSA). For children, data from the French "Infant Total Diet Study" and the "Second French Total Diet Study" were used to estimate aluminium exposure via food. As a result, the TWI can be exhausted or slightly exceeded-particularly for infants who are not exclusively breastfed and young children relying on specially adapted diets (e.g. soy-based, lactose free, hypoallergenic). When taking into account the overall aluminium exposure from foods, cosmetic products (cosmetics), pharmaceuticals and FCM from uncoated aluminium, a significant exceedance of the EFSA-derived TWI and even the PTWI of 2 mg/kg bw/week, derived by the Joint FAO/WHO Expert Committee on Food Additives, may occur. Specifically, high exposure levels were found for adolescents aged 11-14 years. Although exposure data were collected with special regard to the German population, it is also representative for European and comparable to international consumers. From a toxicological point of view, regular exceedance of the lifetime tolerable aluminium intake (TWI/PTWI) is undesirable, since this results in an increased risk for health impairments. Consequently, recommendations on how to reduce overall aluminium exposure are given.

Four-coordinate trispyrazolylboratomanganese and -iron complexes with a pyrazolato co-ligand: syntheses and properties as oxidation catalysts.

A series of complexes of the type [(Tp(R1,R2))M(X)] (Tp = trispyrazolylborato) with R(1)/R(2) combinations Me/tBu, Ph/Me, iPr/iPr, Me/Me and for M = Mn or Fe coordinating [Pz(Me,tBu)](-) (Pz = pyrazolato) or Cl(-) as co-ligand X has been synthesised. Although the chloride complexes were very unreactive and stable in air, the pyrazolato series was far more reactive in contact with oxidants like O(2) and tBuOOH. The [(Tp(R1,R2))M(Pz(Me,tBu))] complexes proved to be active pre-catalysts for the oxidation of cyclohexene with tBuOOH, reaching turnover frequencies (TOFs) ranging between moderate and good in comparison to other manganese catalysts. Cyclohexene-3-one and cyclohexene-3-ol were always found to represent the main products, with cyclohexene oxide occasionally formed as a side product. The ratios of the different oxidation products varied with the reaction conditions: in the case of a peroxide/alkene ratio of 4:1, considerably more ketone than alcohol was obtained and cyclohexene oxide formation was almost negligible, whereas a ratio of 1:10 led to a significant increase of the alcohol proportion and to the formation of at least small amounts of the epoxide. Pre-treatment of the dissolved [(Tp(R1,R2))M(Pz(Me,tBu))] pre-catalysts with O(2) led to product distributions and TOFs that were very similar to those found in the absence of O(2), so that it may be argued that tBuOOH and O(2) both lead to the same active species. The results of EPR spectroscopy and ESI-MS suggest that the initial product of the reaction of [(Tp(Me,Me))Mn(Pz(Me,tBu))] with O(2) contains a Mn(III)(O)(2)Mn(IV) core. Prolonged exposure to O(2) leads to a different dinuclear complex containing three O-bridges and resulting in different TOFs/product distributions. Analogous findings were made for other complexes and formation of these overoxidised products may explain the deviation of the catalytic performances if the reactions are carried out in an O(2) atmosphere.

Unprecedented binding and activation of CS2 in a dinuclear copper(I) complex.

The first structural characterisation of a copper-carbondisulfide complex revealed a hitherto unknown binding mode for CS(2): it interacts with two metal centres (Cu(I)) simultaneously via both C=S π bonds. DFT calculations showed that complex formation occurs mainly due to a donation of electron density from the copper centres into the C=S π* orbitals.

A novel tripodal ligand containing three different N-heterocyclic donor functions and its application in catechol dioxygenase mimicking.

We describe a novel chiral ligand, L, in which three different N-donor functions are linked to a methoxymethine unit: a methylpyrazole derivative, a methylimidazole unit, and a pyridyl residue. Complexes with FeCl(2), FeBr(2), and FeCl(3) have been synthesized and fully characterized, including with respect to their molecular structures. While in combination with FeCl(3) L coordinates in a tripodal fashion, with FeX(2) (X = Cl, Br) it binds only through two functions and the pyridyl unit remains dangling. For potential modelling of intradiol and extradiol catechol dioxygenase reactivity, the complexes [LFeCl(2)], 1, and [LFeCl(3)], 3, have been treated with 3,5-di-tert-butylcatechol, triethylamine, and O(2). Both complexes yielded similar results in such investigations, since the LFe(II)-catecholate complex reacts with O(2) through one-electron oxidation in the first step. Employing 3 in acetonitrile solution, intradiol cleavage occurred, although the undesired quinone was formed as the main product. If reagents were added (NaBPh(4), H(+)) or reaction conditions were chosen (CH(2)Cl(2) instead of CH(3)CN as the solvent) that made the coordination sphere at the iron centre more accessible for a third substrate donor function, an alternative reaction route, presumably involving O(2) binding at the metal, became more important, which led to extradiol cleavage. In the extreme case (CH(2)Cl(2) as the solvent and with the addition of NaBPh(4)), mainly the extradiol cleavage products were formed; the intradiol products were only observed as side products then and quinone formation became negligible. Protonated base functions in the second coordination sphere increased the efficiency of extradiol cleavage only slightly. The obtained results are in line with current understanding of the function of intradiol/extradiol dioxygenases.