Identification and Quantitation Studies of Migrants from BPA Alternative

polymers

Article Identiﬁcation and Quantitation Studies of Migrants from BPA Alternative Food-Contact Metal Can Coatings

Nan Zhang *, Joseph B. Scarsella and Thomas G. Hartman *

Department of Food Science, Rutgers, The State University of New Jersey, 65 Dudley Road, New Brunswick, NJ 08901, USA; [email protected] * Correspondence: [email protected] (N.Z.); [email protected] (T.G.H.); Tel.: +1-848-932-5543 (N.J. & T.G.H.) Received: 28 October 2020; Accepted: 26 November 2020; Published: 29 November 2020

Abstract: Bisphenol A (BPA)-based epoxy resins have wide applications as food-contact materials such as metal can coatings. However, negative consumer perceptions toward BPA have driven the food packaging industry to develop other alternatives. In this study, four different metal cans and their lids manufactured with different BPA-replacement food-contact coatings are subjected to migration testing in order to identify migratory chemical species from the coatings. Migration tests are conducted using food simulants and conditions of use corresponding to the intended applications and regulatory guidance from the U.S. Food and Drug Administration. Extracts are analyzed by gas chromatography mass spectrometry (GC-MS) and high resolution GC-MS. The migratory compounds identified include short chain cyclic polyester migrants from polyester-based coatings and bisphenol-type migrants including tetramethyl bisphenol F (TMBPF), tetramethyl bisphenol F diglycidyl ether (TMBPF DGE), bisphenol F (BPF), bisphenol C (BPC), and other related monomers or oligomers. The concentration of the migrants is estimated using an internal standard, and validated trimethylsilyl (TMS) derivatization GC-MS methods are developed to specifically quantify TMBPF, BPF, BPC, and BPA in the coatings. The results will aid the safety evaluation of new food-contact material coating technology based on TMBPF chemistry and will provide an important reference for the industry in identifying and quantifying non-BPA coating-borne migrants.

Keywords: bisphenol A; bisphenol C; bisphenol F; tetramethyl bisphenol F; tetramethyl bisphenol F diglycidyl ether; cyclic polyester oligomer; GC-MS

1. Introduction Canned products constitute a major category of the foods and beverages consumed in the United States and abroad. Metal cans are often preferred over other packaging materials such as plastics and glass because metals can oﬀer superior properties. The rigidness and durability of metal cans provide protection for the food or beverage products during manufacturing, shipping, and storage. Metal cans are able to tolerate high temperature and pressure conditions, making them ideal for hot-ﬁll products or retort-sterilized shelf stable products. However, metals may interact with the food or beverage components, resulting in the corrosion of the can containers and deterioration of food quality and safety. Therefore, a polymeric coating is usually applied to the inner food-contact surface to prevent such interaction [1]. Bisphenol A (BPA)-based epoxy resins are one of the most widely used materials for metal can coating [2]. BPA is reacted with epichlorohydrin to form BPA epoxy resins composed of Bisphenol A diglycidyl ether (BADGE) and other epoxy oligomers [3]. These epoxy resins can further polymerize and crosslink, forming 4,40-methylenediphenol polymer chains that can

Polymers 2020, 12, 2846; doi:10.3390/polym12122846 www.mdpi.com/journal/polymers Polymers 2020, 12, 2846 2 of 13 pack in floccules and provide excellent coating barriers to protect the metals against corrosion [4]. Nevertheless, unreacted BPA, BADGE monomer, and other short-chain epoxy oligomers can remain in the coating products and potentially migrate into the food or beverage. There is extensive literature demonstrating the migration of chemical constituents, including BPA, BADGE, and related oligomers, from epoxy-coated food cans. Analytical methods used to identify and quantify these compounds include HPLC with UV and fluorescence detection [5], UPLC coupled to fluorescence detection and time-of-flight mass spectrometry [6], acylation and silylation derivatization of bisphenols coupled to thermal desorption-GC-MS [7], and HPLC-MS/MS [8,9]. The use of BPA-based coatings in food packaging materials has been greatly affected by negative consumer perceptions since toxicological studies have been published revealing potentially adverse effects of BPA [10,11]. These studies have shown that BPA can act as an endocrine disruptor and increase incidences of health problems such as polycystic ovary syndrome, infertility, precocious puberty, and hormone dependent tumors such as breast and prostate cancer [12,13]. BADGE, as well as BPA, has been demonstrated to be migratory in BPA-based can coating systems; in the 1990s, BADGE was found in several canned food products such as fish in oil and anchovy [14]. BADGE was initially a suspected carcinogen, due to its epoxide moieties which are often highly reactive, demonstrating alkylating properties. Later research, however, showed that BADGE is metabolized to the less toxic BADGE 2H O via enzyme hydrolysis and excreted in both free and conjugated • 2 forms [15,16]. Therefore, regulatory limits on BADGE migration are often higher compared to those for BPA. Currently, BPA is banned in many countries for infant feeding bottle applications and epoxy coatings for infant formula packaging, but it is approved for use in many other non-infant specific food contact materials [17–19]. In the United States, the Food and Drug Administration (FDA) regulates polymeric and resinous food contact coatings for metal substrates under 21 CFR Section 175.300, in which BPA and BPA-epichlorohydrin epoxy resins are listed as permitted substances [20]. In the European Union, metal can coatings are not specifically regulated, but (EU) 2018/213, which specifically regulates the use of BPA in varnishes and coatings intended to contact with food, lowered the migration limit for BPA from 0.6 to 0.05 mg/kg in food-contact plastics [21]. Based on years of extensive research and hundreds of publications regarding BPA safety, the U.S. FDA assures that the use of BPA in currently approved applications is safe [22]. Nevertheless, consumer concern with BPA in foods and food packaging, as influenced by BPA-free product advertisements, continues to grow. Chemical manufacturers have developed several novel coatings as replacements for BPA-based coatings. Early experimental formulations were based on other bisphenol compounds such as bisphenol F (BPF) and bisphenol S (BPS). These compounds react with epichlorohydrin analogously to BPA, forming epoxy resins and polymeric coating materials. Similarly to BPA, however, non-reacted monomers from these coatings are highly migratory and have questionable toxicological effects [23,24]. Tetramethyl bisphenol F (TMBPF) is a newly proposed bisphenol-type alternative that appears to be promising. TMBPF reacts in the same manner as other bisphenols, forming similar 4,4-methylenediphenol polymer chain functionality. Several toxicological studies have been published demonstrating very low toxicity of TMBPF [4,25,26].Tetramethyl bisphenol F diglycidyl ether (TMBPF DGE), the reaction product of TMBPF with epichlorohydrin, demonstrated low toxicity in previous in vitro assays as well [25]. Another BPA-free can coating currently being investigated is based on polyester chemistry [27]. Polyester polymer coatings are produced from polycondensation reactions between diol and dicarboxylic acid monomers. Polyesters are commonly used in food packaging materials, and many monomeric raw materials have previously been fully evaluated for toxicity and are compliant with food packaging regulations. Polyester can coatings generally have some resistance to corrosion and good adherence to metal surfaces, but they are more susceptible to hydrolysis than bisphenol epoxy can coatings. Additionally, many byproducts of polyester manufacturing are readily migratory. Low molecular weight compounds such as short chain cyclic polyester oligomers [28,29], polyester hydrolysis products, and manufacturing byproducts of polyester coatings can migrate into food or Polymers 2020, 12, 2846 3 of 13 beverage products, introducing non-intentionally added substances (NIAS). Several studies reporting the migration of polyester monomers and oligomers from polyester can coatings have been published. Analytical methods previously used include HPLC-MS/MS [30–32], HPLC with diode array (DAD) or charged aerosol (CAD) detection [30,32], and UPLC-HRAM-MS [31,33]. Apart from toxicity evaluations, suitable migration testing is required to identify and quantify all potential coating-borne migrants in order to assess the risks and safety of BPA replacement can coatings. Migration testing of novel coating materials presents three major challenges. First, non-targeted analyses are required because information regarding coating formulation is often proprietary to coating manufacturers and is unavailable to parties performing analytical testing. In addition, NIAS such as reaction byproducts and degradation products of the coatings may migrate into the food simulant, greatly increasing the complexity of the analyses [34]. Second, the new BPA replacement can coatings may contain novel chemical compounds for which reference standards are commercially available for related quantification analyses. Obtaining reference standards for NIAS is often even more challenging because many compounds can be formed as byproducts of coating manufacture and may not be available as pure standards [35]. Last, even when reference standards are available, establishing validated analytical methods with suitable limits of detection and quantification is considerably difficult and time consuming when extracts contain numerous compounds with a wide range of chemical properties. In this study, four representative metal can and lid sets manufactured with BPA replacement coatings are analyzed by GC-MS and high resolution accurate mass (HRAM) GC-MS using standardized migration test protocols according to U.S. FDA guidance. The goal of the study was to isolate and identify all potential migrants from the can coatings when they are used in their intended application conditions. Additionally, the study aims to develop validated quantification methods for migrants for which chemical standards are commercially available and compare these validated results with initial semi-quantitative evaluation results. This study presents, to the best of our knowledge, novel HRAM electron impact (EI) mass spectra of tetramethyl bisphenol F and its corresponding diglycidyl ether along with several cyclic polyester oligomers as well as the first reported data regarding the migration of tetramethyl bisphenol F from epoxy can coatings. The study will serve as a reference for analyses of BPA replacement coatings which are based on similar raw materials and chemistries.

2. Materials and Methods

2.1. Food Packaging Samples Four can and lid sample sets based on non-BPA formulations were provided by the project sponsors. The chemical composition of the coatings was not known prior to this study. Three of the can and lid sets were made of aluminum and were intended for aqueous non-alcoholic acidic or non-acidic beverage applications which would be hot filled or pasteurized at or below 66 ◦C (150 ◦F.) The fourth can and lid set was made of steel and was intended for acidic or nonacidic foods with or without surface fat or oil which would undergo high temperature sterilization at 121 ◦C (250 ◦F). All can samples were provided in the final product format before the closure sealing, while all lid samples were provided both in the final product format as well as in flat metal sheet stocks for the ease of sample extraction. The can samples and lids samples were packed separately. It was known that the food can and corresponding lid samples were coated with the same non-BPA-based coating chemistry.

2.2. Reagents, Reference Standards, and Materials Methylene chloride (Optima grade) and glacial acetic acid (ACS certified grade) were purchased from Thermo Fisher Scientific, Waltham, MA, USA. Anthracene-d , BPA ( 99%), bisphenol C (BPC) 10 ≥ (analytical standard grade), BPF (analytical standard grade) TMBPF (98%), and BSTFA (with 1% trimethylchlorosilane) derivatizing reagent (Sylon BFT) were purchased from Sigma-Aldrich Chemical Co, St. Louis, MO, USA. Ethanol was purchased from Pharmco Products, Brookfield, CT, USA and Polymers 2020, 12, 2846 4 of 13 was re-distilled prior to use. Distilled and de-ionized water used in the study was prepared by double distillation in a glass-lined still followed by activated carbon filtration and de-ionization treatment in a Waters Milli-Q Nanopure system.

2.3. Migration Testing of Can and Lidstock Samples Sections of beverage can wall material and all lid stock samples were cut and sealed into custom stainless steel migration cell assemblies designed according to FDA specifications for food contact material migration testing. The migration cells were comprised of 10 cm 15 cm stainless steel plates × (top and bottom) with a PTFE spacer gasket between the plates. The assembly was bolted firmly together with 12 stainless cap screws around the perimeter. The top plate contained 0.635 cm (0.25 inch) O.D. tube ports for filling and emptying, and the ports were sealed with 0.635 cm (0.25 inch) stainless steel Swagelok caps with PTFE ferrules. The PTFE spacer provided 51 cm2 (7.9 in2) food contact surface area and 125 mL cavity volume available for extraction with the food simulant solvent. Migration cells were manufactured in-house for this experiment. Samples were sealed into migration cells with the food-contact side facing into the cavity such that only the food-contact surface would have contact with the food simulant. Migration cells were filled with 80 mL of food simulant, giving a volume to surface area ratio of 1.57 mL/cm2 (10 mL/in2), in accordance with FDA guidelines [36]. For beverage cans, 10% ethanol (ETOH) and 3% acetic acid (AA) were used as food simulants, corresponding to aqueous non-acidic and aqueous acidic food types, respectively. Analytical method blanks consisting of migration cells without samples sealed inside were prepared alongside the samples. Compounds detected in the method blanks were disregarded in the data treatment of test samples. Migration cells were incubated at temperatures corresponding to the appropriate FDA guidance based on the intended filling goods and filling and storage conditions of the test samples. For beverage can and lid stock samples, incubation conditions were 2 h at 66 ◦C followed by 238 h at 40 ◦C, in accordance with the FDA condition of use “C” for food packages hot-filled at 66 ◦C, and stored at room temperature [37]. The non-BPA-coated food can had thick and rigid ribbing on the side walls that prevented sealing into migration cells. For this reason, the food can and lid were extracted simultaneously, and the extract was therefore a composite extract of the can wall and lid. The food can and lid samples were intended for high temperature heat treatment, so they were extracted using a simulated retort procedure in which the food simulant was sealed inside the can, and the sealed cans were incubated in accordance with appropriate FDA guidelines. Food simulants used for the food can samples were 3% AA, 10% ETOH, and 95% ETOH, corresponding to aqueous acidic, aqueous non-acidic, and fatty food types, respectively. The inside surface area and filling volume of the can were measured to be 280 cm2 and 350 mL, respectively, giving a volume to surface area ratio of 1.25 mL/cm2. Sealed and filled cans were heated in an autoclave to 121 ◦C and held for 2 h before being transferred to a 40 ◦C incubator for 238 h, in accordance with the FDA condition of use “A” for high-temperature, retort-processed goods. Migration cells and sealed cans were removed from incubation and cooled to room temperature. Extracts were drained into 125 mL borosilicate glass media bottles sealed with PTFE-lined closures and processed immediately.

2.4. Extract Workup Procedure For 10% ETOH and 3% AA extracts, 40 mL aliquots of extracts were transferred to 50 mL borosilicate glass test tubes with PTFE-lined closures. Extracts were matrix-spiked with 4.0 µg of anthracene-d10 internal standard (100 parts per billion weight/volume (ppb w/v)), and 5 mL of methylene chloride was added. The solutions were vigorously extracted and then centrifuged for 30 min at 2500 rpm in order to promote complete phase separation. The methylene chloride fraction was then transferred to a 5.0 mL borosilicate glass conical-bottom vial and evaporated to approximately 400 µL under a gentle stream of nitrogen. The concentrated extracts were analyzed directly by GC-MS. For 95% ETOH extracts, 10 mL aliquots of extracts were transferred to 50 mL borosilicate glass test tubes with PTFE-lined closures and were diluted with 35 mL of distilled, deionized water. Extracts were Polymers 2020, 12, 2846 5 of 13

matrix-spiked with 10 µg of anthracene-d10 internal standard (1000 ppb w/v), and 5 mL of methylene chloride was added. The solutions were vigorously extracted and then centrifuged for 30 min at 2500 rpm in order to promote complete phase separation. The methylene chloride fraction was then transferred to a 5.0 mL borosilicate glass conical-bottom vial and evaporated to approximately 100 µL under a gentle stream of nitrogen. The concentrated extracts were analyzed directly by GC-MS.

2.5. GC-MS Analysis Methodology GC-MS analyses of migration test extracts described above were conducted using a Varian 3400 gas chromatograph directly interfaced to a Thermo-Finnigan TSQ 7000 triple stage quadrupole mass spectrometer or a Thermo 1300 gas chromatograph directly interfaced to a Thermo Scientific GC-Exactive HRAM Orbitrap (Resolution 60,000). Both instruments were equipped with Thermo Xcalibur data system. The Varian GC was equipped with a 30 m 0.32 mm ZB-5MS capillary column × with 0.25 µm film thickness (Phenomenex, Torrance, CA, USA). The Thermo 1300 GC was equipped with a 30 m 0.32 mm Rxi-5MS capillary column with 0.25 µm film thickness (Restek, Bellefonte, × PA, USA). Carrier gas was helium with 10 psi head pressure. The column temperature programs for both GC were 50 ◦C (3 min) followed by a 10 ◦C/minute ramp to 320 ◦C with a total analysis time of 35 min. The injector was maintained at 300 ◦C, and the heated transfer line was maintained at 320 ◦C. The GC injector was operated in splitless mode with a 100:1 split ratio septum purge 30 s post-injection. Sample injections were 1.0 µL. The mass spectrometers were operated in positive ion EI ionization mode (70 eV), scanning a mass range of 35–750 once each second.

2.6. TMS-Derivatization The bisphenol compounds identiﬁed in the can coatings contain active hydroxyl groups, which cause excessive interaction with the GC column stationary phase, leading to broad, non-symmetrical peak shape and reduced sensitivity. TMS-derivatization was used to generate di-trimethylsilyl (di-TMS) derivatives of the bisphenols in order to prevent these unwanted interactions and improve sensitivity of the method for these compounds. The bisphenol standards and methylene chloride sample extracts were derivatized by adding 100 µL of Sylon BFT reagent and heating for one hour at 85 ◦C (or 95 ◦C for TMBPF standard and TMBPF containing sample extracts because the hindered phenol structure of TMBPF requires higher derivatization temperature) in an aluminum heating block with periodic vortexing. The derivatized extracts were cooled to room temperature and re-analyzed by GC-MS.

2.7. GC-MS Method Validation For GC-MS method validation, calibration curves were established for BPA, BPC, BPF, and TMBPF by analyzing TMS-derivatized standards at nine diﬀerent concentrations in triplicate. Concentrations ranged from 0.1 µg/mL to 100 µg/mL (0.1 ppm w/v to 100 ppm w/v), and all standards contained a constant 50 µg/mL anthracene-d10 internal standard. This concentration range was equivalent to 1 ng/mL to 1000 ng/mL (1 ppb w/v to 1000 ppb w/v) for the food simulant extracts of a typical metal can sample in the screening analysis as the extracts were concentrated about 100-fold. The peak area ratios of the target analyte TMS derivatives to internal standard versus target analyte concentration were used for calibration curve plotting and linearity evaluation. Analytical system precision was performed by analyzing 6 replicates of the standard solution at 50 µg/mL (50 ppm w/v). Spiking and recovery was performed by matrix-spiking 50 µg of target analyte and 50 µg of anthracene-d10 into 40 mL of 10% ETOH, 40 mL of 3% AA or 10 mL of 95% ETOH prior to the 5 mL methylene chloride back-extraction as described in food simulant work-up procedure. The methylene chloride fraction was then transferred into a 5.0 mL borosilicate glass conical-bottom vial and evaporated to near dryness under a gentle stream of nitrogen. Extracts were then reconstituted with 1 mL of methylene chloride, TMS-derivatized as above, and analyzed by GC-MS. Polymers 2020, 12, 2846 6 of 13

3. Results and Discussion

3.1. Identification and Semi-Quantitation of Coating-Borne Migrants Polymers 2020, 12, x FOR PEER REVIEW 6 of 14 The results of migration studies performed on four commercially manufactured metal cans and theirand corresponding evaporated to near lids dryness are reported.under a gentle The stream identification of nitrogen. Extracts and semi-quantitation were then reconstituted of coating-borne migrantswith 1 mL were of methylene based on chloride, a non-targeted TMS-derivatized screening as above analysis, and analyzed approach, by GC-MS. where all captured migrant species3. Results were and analyzed Discussion and then quantified via the total ion chromatogram peak area ratio relative to the anthracene-d10 matrix-spiked internal standard assuming a detector response factor of 1.0. Table3.1.1 Identificationsummarizes and the Semi total-Quantitation number of ofCoatin detectedg-Borne migrantMigrants peaks from each sample extract along with 2 the averageThe results total of estimated migration studies migratory performed concentration on four commercially in micrograms manufactured per square metal cans centimeter and (µg/dm ) fromtheir replicate corresponding analyses. lids areOverall, reported the. The beverage identification can samples and semi showed-quantitation fewer of coating and lower-borne level migrants comparedmigrants to were other based samples. on a non-targeted screening analysis approach, where all captured migrant species were analyzed and then quantified via the total ion chromatogram peak area ratio relative to the anthracene-d10 matrix-spiked internal standard assuming a detector response factor of 1.0. Table Table 1. Number of detected migrants and estimated concentration of total migrants from metal cans. 1 summarizes the total number of detected migrant peaks from each sample extract along with the 2 average total estimated migratory concentration in micrograms per squareEstimated centimeter Level (µg/dm of) Total from Migrants Number of Detected Migrants replicate analyses. Overall, the beverage can samples showed fewer and lower level(µg / migrantsdm2) comparedSamples to other samples. 3% AA 10% ETOH 95% ETOH 3% AA 10% ETOH 95% ETOH FoodTable can 1. setNumber of detected 38 migrants and42 estimated concentration 41 of total 34.13 migrants from 51.65 metal 140.03 cans. Food can lid alone 26 25 26 3.37 3.16 41.42 Estimated Level of Total Migrants Beverage can 1Nu 4mber of Detected 2 Migrants - 0.44 0.08 - Samples (μg/dm2) Beverage can 23% 7 AA 10% ETOH 2 95% ETOH - 3% AA 0.8010% ETOH 95% 0.08 ETOH - BeverageFood c canan set 3 638 42 641 -34.13 0.5851.65 0.23140.03 - Food can lid alone 26 25 26 3.37 3.16 41.42 Beverage can lid 1 26 12 - 42.73 50.02 - Beverage can 1 4 2 - 0.44 0.08 - BeverageBeverage can lidcan 22 157 2 10- -0.80 1.360.08 3.81- - BeverageBeverage can lidcan 33 156 6 8- -0.58 1.490.23 0.47- - Beverage can lid 1 26 12 - 42.73 50.02 - Beverage can lid 2 15 10 - 1.36 3.81 - TwelveBeverage coating-bornecan lid 3 15 migrants8 were identified- in this1.49 study.0.47 Their identification- and average estimated migration levels are listed in Table2. Seven of the migrants were bisphenols or bisphenol-epoxy-relatedTwelve coating-borne substances migrants were and identified four of in them this study were. cyclicTheir identification polyester oligomers.and average An additional migrant,estimated triphenyl migration phosphine levels are oxidelisted in (TPPO), Table 2 was. Seven found of the in migrantsthe food were can andbisphenols food can or lid samples. bisphenol-epoxy-related substances and four of them were cyclic polyester oligomers. An additional TPPOmigrant, is antriphenyl oxidation phosphine product oxide (TPPO) of triphenylphosphine,, was found in the food whichcan and isfood often can lid used samples as. a catalyst in epoxy-phenolTPPO is an oxidationpolymerization product reactions of triphenylphosphine, and as a coupling which is agent often used that as improves a catalyst coating in adhesion to metalepoxy-phenol surfaces polymerization [38–40]. TPPO reactions can and exist as a incoupling the final agent coating that improves product coating and adhesion then migrate to into the foodmetal system. surfaces [38–40]. TPPO can exist in the final coating product and then migrate into the food system. Table 2. Food-contact coating-borne migrants from metal cans (name, molecular formula, structure, Table 2. Food-contact coating-borne migrants from metal cans (name, molecular formula, structure, mass,mass, five five major major EI EI mass mass spectra spectra fragmen fragmentt ion peak ion percent peak percentabundance, abundance, estimated concentration estimated,concentration, and and source).source).

5 Major EI Estimated Molecular Formula and 5 Major EI Name1 1 Molecular Formula and Mass Fragments (% Level EstimatedSource Name Structure Mass Fragments (% 2 Source Structure Level2 (µg/dm ) AbundanceAbundance)) (μg/dm ) C17H20O2 241(100.00)241(100.00) C17H20O2 Food can 256(59.39256(59.39)) Food can set set TMBPFTMBPF 256256 226(24.63226(24.63)) 0.04–0.780.04–0.78 Food can lid Food can 255(18.67)255(18.67) alone Polymers 2020, 12, x FOR PEER REVIEW lid alone7 of 14 242(17.99)242(17.99)

TMBPF MGE CC2020HH2424OO33 312 312(100.00)239(45.30)312(100.00) 0.03–1.33 lidFood alone can 239(45.30) 254(41.26) Food can lid TMBPF MGE 312 254(41.26) 0.03–1.33 209(30.63) alone 135(27.34)209(30.63) 135(27.34)

C23H28O4 175(100.00) Food can 353(86.00) set TMBPF DGE 368 191(66.51) 0.04–5.10 Food can 335(63.68) lid alone 368(35.86)

C23H30O5 241(100.00) Food can 256(58.60) TMBPF set 386 135(28.19) 0.04–0.40 DGE•H2O Food can 75(19.47) lid alone 386(16.59) C18H15OP 277(100.00) Food can 278(58.99) set TPPO 278 77(27.03) 0.05–2.91 Food can 201(25.00) lid alone 199(15.50)

C15H16O2 213(100.00) 228(24.99) Beverage BPA 228 119(20.01) 0.04–0.06 can lid 1 214(17.26) and lid 3 91(10.02)

C17H20O2 241(100.00) 133(22.57) Beverage BPC 256 256(19.37) 0.01–0.03 can lid 1 242(18.21) and lid 3 77(8.76)

C13H12O2 200(100.00) 104(77.47) Beverage BPF 200 199(46.37) 0.04 can lid 1 183(21.16) 94(14.20)

C10H16O5 173(100.00) 55(78.00) Beverage Cyclic 216 99(35.86) 0.02–0.04 Can 1,2 DEG-AA 84(32.54) and 3 56(25.04)

C12H12O5 149(100.00) 193(98.57) Beverage Cyclic DEG-PA 236 104(33.37) 0.10 Can 2 76(24.76) 148(17.20)

173(100.00) 99(61.02) Cyclic Beverage C16H24O8 344 55(41.78) 0.05 EG-AA-EG-AA can lid 1 113(32.68) 111(24.45) Polymers 2020, 12, x FOR PEER REVIEW 7 of 14 Polymers 2020, 12, x FOR PEER REVIEW 7 of 14 PolymersPolymers2020 2020, 12, 12,,2846 x FOR PEER REVIEW 7 of 14 7 of 13 Polymers 2020, 12, x FOR PEER REVIEW 7 of 14 PolymersPolymersPolymers 20 2020202020,, , 1 11222,, , x xx FOR FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 239(45.30) lid alone777 ofof of 141414 239(45.30) lid alone 239(45.30)254(41.26) lid alone 254(41.26)239(45.30) lid alone 239(45.30)254(41.26)209239(45.30)239(45.30)(30.63) lidlidlid alone alonealone Table 2. Cont209254(41.26).(30.63) 254(41.26)209135(27.34)254(41.26)254(41.26)(30.63) 135(27.34)209(30.63) 209135(27.34)209209(30.63)(30.63)(30.63) 135(27.34)5 Major EI Molecular23 Formula28 4 and 135(27.34)135(27.34) Estimated Name 1 C H O Mass 175(100.00)135(27.34)Fragments (% Source 23 28 4 2 StructureC23H28O4 175(100.00) Level (µFoodg/dm can) C23H28O4 175(100.00)353(86.00)Abundance) C23H28O4 175(100.00) Foodset c an CC232323HH282828OO444 175(100.00)353(86.00) Food can TMBPF DGE C H O 368 175(100.00)175(100.00)175(100.00)191(66.51) 0.04–5.10 C H O 353(86.00)175(100.00) FoodFoodset c can canan TMBPF DGE 23 28 4 368 353(86.00)191(66.51)335353(86.00)(63.68) 0.04–5.10 Foodset c an TMBPF DGE 368 191(66.51)353(86.00)353(86.00) 0.04–5.10 Foodlid setaloneset can Food can set TMBPF DGE 368 191(66.51)335(63.68) 0.04–5.10.10 Foodset can TMBPFTMBPFTMBPF DGE DGEDGE 368368368 335368(35.86)191(66.51)191(66.51)(63.68)191(66.51) 0.00.044––55.10.100.04–5.10 Foodlid alone can Food can lid 368(35.86)335(63.68) FoodFoodlidFood alone can cancan 335335335(63.68)(63.68)(63.68) lid alone C23H30O5 241(100.00)368(35.86)335(63.68) lidlid alone alone alone 368(35.86) Foodlid alone can C23H30O5 241(100.00)368(35.86)368(35.86)368(35.86) C23H30O5 241(100.00)256(58.60) Food can TMBPF C23H30O5 241(100.00)256(58.60) Foodset can TMBPF CC232323HH303030OO555 386 241(100.00)241(100.00)241(100.00)135(28.19) 0.04–0.40 Foodset can DGE•HTMBPF2O 256(58.60)241(100.00) FoodFoodset can can TMBPF C23H30O5 386 256(58.60)135(28.19)256(58.60)75(19.47) 0.04–0.40 Foodset can DGE•HTMBPFTMBPF2O 386 135(28.19)256(58.60)256(58.60) 0.04–0.40 Foodlid setaloneset can Food can set TMBPFDGE•HTMBPF2O 386 135(28.19)75(19.47) 0.04–0.40 Foodset can DGE•H2O 386386386 135(28.19)386(16.59)135(28.19)135(28.19) 0.00.00.0444–––000.40.40.40 Food can DGE•H2O 386 75(19.47)135(28.19) 0.04–0.40Foodlid alone can Food can lid DGE•HDGE•H22OO 386(16.59)75(19.47) FoodlidFood alone cancan DGE H2O 18 15 75(19.47)75(19.47) • C H OP 386(16.59)75(19.47)75(19.47) lid alone alone 18 15 lidlidlid alone alonealone C18H15OP 277(100.00)386(16.59)386(16.59) C18H15OP 386(16.59)386(16.59) Food can C18H15OP 277(100.00) CC1818HH1515OPOP 277(100.00)278(58.99) Food can C18H15OP 277(100.00)278(58.99) set TPPO C18H15OP 278 277(100.00)277(100.00)278(58.99)77(27.03) 0.05–2.91 Food can 277(100.00)278(58.99)277(100.00) FoodFoodset can ca cann TPPO 278 278(58.99)201(25.00)278(58.99)77(27.03) 0.05–2.91 Foodset can TPPO 278 278(58.99)77(27.03)278(58.99) 0.05–2.91 Foodlid setaloneset ca n Food can set TPPOTPPO 278278 201(25.00)199(15.50)77(27.03)77(27.03) 0.00.055––22.91.91.91 Foodset ca n TPPOTPPO 278278 201(25.00)77(27.03)77(27.03) 0.05–2.910.05–2.91 FoodlidFood alone ca cann Food can lid 201(25.00)199(15.50)201(25.00) Foodlid alone can 199(15.50)201(25.00)201(25.00) lidlidlid alone alonealone alone 15 16 2 199(15.50) lid alone C H O 213(100.00)199(15.50)199(15.50)199(15.50) 15 16 2 199(15.50) C15H16O2 213(100.00) C15H16O2 213(100.00)228(24.99) Beverage C15H16O2 213(100.00) CC151515HH161616OO222 213(100.00)228(24.99)213(100.00) Beverage BPA C15H16O2 228 213(100.00)213(100.00)228(24.99)213(100.00)119(20.01) 0.04–0.06 Beveragecan lid 1 BPA 228 119(20.01)228(24.99)228(24.99) 0.04–0.06 Beveragecan lid 1 BPA 228 228(24.99)119(20.01)214(17.26)228(24.99)228(24.99) 0.04–0.06 BeveragecanandBeverage lidlid 13 Beverage can BPABPA 228228 214(17.26)119(20.01)119(20.01) 0.04–0.060.04–0.06 andcan lid 13 BPABPA 228228228 119(20.01)214(17.26)119(20.01)119(20.01)91(10.02) 0.00.00.0444–––000.06.06.06 andcancancan lid lidlid 1 311 lid 1 and lid 3 214(17.26)214(17.26)91(10.02)214(17.26) andand lid lid 3 3 C17H20O2 214(17.26)91(10.02) and lid 3 241(100.00)91(10.02)91(10.02) C17H20O2 241(100.00)91(10.02)91(10.02) C17H20O2 241(100.00)133(22.57) Beverage C17H20O2 241(100.00) C1717H2020O22 241(100.00)133(22.57)241(100.00) Beverage BPC CCC1717HHH20OO22 256 241(100.00)241(100.00)133(22.57)256(19.37) 0.01–0.03 Beveragecan lid 1 241(100.00)133(22.57)133(22.57) Beverage BPC 256 133(22.57)256(19.37)242(18.21)133(22.57) 0.01–0.03 BeverageandcanBeverage lidlid 13 Beverage can BPCBPC 256256 256(19.37)133(22.57)256(19.37) 0.01–0.03 0.01–0.03Beveragecan lid 1 BPCBPC 256256 256(19.37)242(18.21)256(19.37)77(8.76) 0.00.011––00.03.03.03 andcancan lid lidlid 1 31 lid 1 and lid 3 BPC 256 242(18.21)256(19.37)242(18.21) 0.01–0.03 andcan lid 31 242(18.21)242(18.21)77(8.76) andand lid lid 3 3 13 12 2 242(18.21)77(8.76) and lid 3 C H O 200(100.00)77(8.76)77(8.76) C13H12O2 200(100.00)77(8.76)77(8.76)77(8.76) C13H12O2 104(77.47) 13 12 2 200(100.00)200(100.00) C13H12O2 200(100.00)104(77.47) Beverage BPF CCC131313HHH1212OO22 2 200 200(100.00)200(100.00)104(77.47)199(46.37) 0.04 200(100.00)104(77.47)104(77.47) Beveragecan lid 1 BPF 200 104(77.47)199(46.37)183(21.16)104(77.47) 0.04 Beverage Beverage can BPFBPF 200200 199(46.37)104(77.47)199(46.37) 0.04 0.04BeveragecanBeverage lid 1 BPFBPF 200200 199(46.37)183(21.16)199(46.37)94(14.20) 0.040.04 Beveragecan lid 1 lid 1 BPF 200 183(21.16)199(46.37)183(21.16) 0.04 cancan lid lid 1 1 183(21.16)94(14.20) can lid 1 C10H16O5 183(21.16)94(14.20)183(21.16)94(14.20) 94(14.20) C10H16O5 173(100.00)94(14.20)94(14.20)94(14.20) C10H16O5 CC1010H16OO5 5 173(100.00) C10H16O5 55(78.00)173(100.00) Beverage Cyclic CC1010HH1616OO55 173(100.00) 216 173(100.00)173(100.00)55(78.00)99(35.86)55(78.00) 0.02–0.04 BeverageCan 1,2 DEGCyclic-AA 173(100.00)55(78.00) Beverage Beverage Can Cyclic DEG-AACyclic 216216 55(78.00)99(35.86)84(32.54)55(78.00)99(35.86) 0.02–0.04 0.02–0.04BeverageBeverageCanand 1,2 3 DEGCyclicCyclic-AA 216 99(35.86)55(78.00) 0.02–0.04 BeverageCan 1,2 1,2 and 3 DEGCyclic-AA 216216 99(35.86)84(32.54)56(25.04)99(35.86)84(32.54) 0.00.022––00.04.04.04 CanCanand 1,2 1,23 DEGDEG---AAAA 216 84(32.54)99(35.86) 0.02–0.04 Canand 1,23 DEG-AA 84(32.54)56(25.04)56(25.04) and 3 56(25.04)84(32.54)84(32.54) andand 33 56(25.04) C12H12O5 56(25.04) 56(25.04)56(25.04) CC12H12OO5 149(100.00) C1212H12O5 5 149(100.00) C12H12O5 149(100.00) C12H12O5 193(98.57) CC1212HH1212OO55 149(100.00)193(98.57) Beverage Cyclic DEG-PA 236 149(100.00)149(100.00)193(98.57)104(33.37) 0.10 Cyclic DEG-PA 236 149(100.00)193(98.57)104(33.37) 0.10BeverageCan 2 Beverage Can 2 Cyclic DEG-PA 236 193(98.57)104(3193(98.57)76(24.76)3.37) 0.10 Beverage Cyclic DEG-PA 236 104(3193(98.57)76(24.76)3.37) 0.10 BeverageBeverageCan 2 PolymersCyclic 20 20DEG, 12-,- PAx FOR PEER REVIEW 236 104(376(24.76)3.37) 0.10 BeverageCan 28 of 14 PolymersCyclicCyclic 20 20DEGDEG, 12-,- PAPAx FOR PEER REVIEW 236236 148(17.20)104(376(24.76)104(3148(17.20)3.37)3.37) 0.100.10 Can 28 of 14 148(17.20)76(24.76) CanCan 2 2 148(17.20)76(24.76)76(24.76)76(24.76) 173(100.00)148(17.20) C16H24O8 148(17.20)148(17.20)148(17.20) 173(100.00) 173(100.00)99(61.02)173(100.00) Cyclic 173(100.00)99(61.02) Beverage C16H24O8 344 173(100.00)173(100.00)99(61.02)55(41.78) 0.05 EG-AACyclic-EG -AA 173(100.00)99(61.02)99(61.02) Beveragecan lid 1 CyclicCyclic C16H24O8 344 99(61.02)55(41.78) 0.05 Beverage Beverage can EG-AACyclic-EG -AA C16H24O8 344344 113(32.68)55(41.78)99(61.02)99(61.02)55(41.78) 0.05 0.05Beveragecan lid 1 EG-AA-EG-AACyclicCyclic C16H24O8 344 55(41.78) 0.05 BeverageBeverage lid 1 EG-AA-EG-AA C16H24O8 344 113(32.68)55(41.78) 0.05 can lid 1 EG-AA-EG-AA CC1616HH2424OO88 344344 113(32.68)111(24.45)55(41.78)55(41.78)113(32.68) 0.050.05 can lid 1 EGEG---AAAA---EGEG---AAAA 111(24.45)113(32.68) cancancan lid lidlid 1 11 113(32.68)111(24.45)113(32.68)113(32.68)111(24.45) 111(24.45) 111(24.45)111(24.45)111(24.45) C22H28O8 C22H28O8 C22H28O8 237(100.00) 237(100.00)237(100.00) 149(81.43) Cyclic 149(81.43)149(81.43) Beverage CyclicCyclic 420 193(64.50) 5.05–9.77 Beverage Beverage can EG-SeA-EG-PA 420420 193(64.50)193(64.50) 5.05–9.775.05–9.77 can lid 1 EG-SeA-EG-PAEG-SeA-EG-PA 104(62.39) can lid 1 lid 1 104(62.39)104(62.39) 148(37.35)148(37.35) 148(37.35)

1 TMBPF,1 TMBPF, tetramethyl tetramethyl bisphenol bisphenol F; F; TMBPFTMBPF MGE, MGE, tetramethyltetramethyl bisphenol bisphenol F F monoglycidyl monoglycidyl ether; ether; TMBPF DGE, 1 TMBPF, tetramethyl bisphenol F; TMBPF MGE, tetramethyl bisphenol F monoglycidyl ether; tetramethylTMBPF DGE, bisphenol tetramethyl F diglycidyl bisphenol ether; F TMBPF diglycidyl DGE ether;H2O, TMBPF monohydrolysed DGE•H2O, tetramethylmonohydrolysed bisphenol F diglycidyl TMBPF DGE, tetramethyl bisphenol F diglycidyl ether;• TMBPF DGE•H2O, monohydrolysed ether,tetramethyl BPA, bisphenol bisphenol A; FBPC, diglycidyl bisphenol ether, C; BPF,BPA, bisphenol bisphenol F; A; TPPO, BPC, bisphenol triphenyl phosphineC; BPF, bisphenol oxide; EG, F; ethylene glycol; tetramethyl bisphenol F diglycidyl ether, BPA, bisphenol A; BPC, bisphenol C; BPF, bisphenol F; DEG,TPPO, diethylene triphenyl glycol; phosphine SeA, oxide; sebacic EG, acid; ethylene PA, phthalic glycol; acid;DEG, IPA. diethylene glycol; SeA, sebacic acid; TPPO, triphenyl phosphine oxide; EG, ethylene glycol; DEG, diethylene glycol; SeA, sebacic acid; PA, phthalic acid; IPA. PA, phthalic acid; IPA. TMBPF and TMBPF epoxy migrants were mainly found in the food can and food can lid TMBPF and TMBPF epoxy migrants were mainly found in the food can and food can lid samples. For the first time, high-resolution GC-MS EI mass spectra of TMBPF and TMBPF DGE samples. For the first time, high-resolution GC-MS EI mass spectra of TMBPF and TMBPF DGE migrants were reported (Figure 1). A mass accuracy ±5 ppm and an isotope confidence of <10% migrants were reported (Figure 1). A mass accuracy ±5 ppm and an isotope confidence of <10% difference from the theoretical isotope match (isotope distribution and ratio) were applied on the difference from the theoretical isotope match (isotope distribution and ratio) were applied on the molecular ions at 256.1460 [C17H20O2]+ and 368.1981 [C23H28O4]+ to assign the formula (Figure 2). The molecular ions at 256.1460 [C17H20O2]+ and 368.1981 [C23H28O4]+ to assign the formula (Figure 2). The characteristic electron ionization fragmentation ions at 241.1224 [C16H17O2]+, 226.0990 [C15H14O2]+, characteristic electron ionization fragmentation ions at 241.1224 [C16H17O2]+, 226.0990 [C15H14O2]+, 211.0754 [C14H11O2]+, 135.0805 [C9H11O]+, and 91.0543 [C7H7]+ were used for structure elucidation of 211.0754 [C14H11O2]+, 135.0805 [C9H11O]+, and 91.0543 [C7H7]+ were used for structure elucidation of TMBPF. The characteristic electron ionization fragmentation ions at 353.1746 [C22H25O4]+, TMBPF. The characteristic electron ionization fragmentation ions at 353.1746 [C22H25O4]+, 335.1640[C21H22O4]+, 293.1173 [C19H16O4]+, 191.1065 [C12H15O2]+, 175.0753 [C12H15O]+ and 91.0543 335.1640[C21H22O4]+, 293.1173 [C19H16O4]+, 191.1065 [C12H15O2]+, 175.0753 [C12H15O]+ and 91.0543 [C7H7]+ were used for structure elucidation of TMBPF DGE. The presence of the TMBPF-based [C7H7]+ were used for structure elucidation of TMBPF DGE. The presence of the TMBPF-based coating formulation was also confirmed with the sample supplier after data analysis. coating formulation was also confirmed with the sample supplier after data analysis.

95_Percent_ETOH_Food_Can_CouA2 #8346 RT: 22.57 AV:+ 1 SB: 147 22.38-22.53 , 22.60-22.78 NL: 1.56E7 [M-CH3] T:95_Percent_ETOH_Food_Can_CouA2FTMS + p EI Full ms [50.0000-700.0000] #8346 RT: 22.57 AV:+ 1 SB: 147 22.38-22.53 , 22.60-22.78 NL: 1.56E7 [M241.1224-CH3] T: FTMS100 + p EI Full ms [50.0000-700.0000] 241.1224 100 90 90 80 80 70 [M]+ 70 + 60 256.1460[M] 60 256.1460 50 TMBPF 50 TMBPF 40 + 40 [M-2CH3]

RelativeAbundance 30 + [M-226.09902CH3]

RelativeAbundance 30 20 135.0805 226.0990 20 91.0543 211.0754 10 135.0805 91.054397.0361 211.0754 10 269.1894 365.6985 470.5362 0 97.0361 95_Percent_ETOH_Food_Can_CouA2 #9469 RT: 25.18269.1894AV: 1 SB: 85 25.08-25.14365.6985 , 25.20-25.32 470.5362NL: 9.12E6 050 100 150 200 250 300 350 400 450 500 550 600 650 700 T:95_Percent_ETOH_Food_Can_CouA2FTMS + p EI Full ms [50.0000-700.0000] #9469 RT: 25.18 AV: 1 SB: 85 25.08-25.14 , 25.20-25.32 NL: 9.12E6 50 100 150175.0753200 250 300 350 m/z 400 450 500 550 600 650 700 T: FTMS100 + p EI Full ms [50.0000-700.0000] + 175.0753 [M-CHm/z3] 100 + 90 [M353.1746-CH3] 90 353.1746 80 + 191.1065 [M-2CH3] 80 + 70 191.1065 [M-2CH335.16403] 70 335.1640 60 60 50 325.1795 [M]+ 50 325.1795 + 40 368.1981[M] TMBPF DGE 40 368.1981 TMBPF DGE

RelativeAbundance 30 91.0543 149.0597

RelativeAbundance 30 293.1173 20 91.0543132.0388149.0597 293.1173 20 132.0388 255.1016 10 241.1223255.1016 10 403.2091 456.4372 646.1371 0 241.1223 403.2091 456.4372 646.1371 050 100 150 200 250 300 350 400 450 500 550 600 650 700 50 100 150 200 250 300 350 m/z 400 450 500 550 600 650 700 m/z Figure 1. High resolution GC-MS Spectra for tetramethyl bisphenol F (TMBPF) and tetramethyl Figure 1. High resolution GC-MS Spectra for tetramethyl bisphenol F (TMBPF) and tetramethyl bisphenol F diglycidyl ether (TMBPF DGE). bisphenol F diglycidyl ether (TMBPF DGE). Polymers 2020, 12, x FOR PEER REVIEW 8 of 14

C22H28O8 237(100.00) 149(81.43) Cyclic Beverage 420 193(64.50) 5.05–9.77 EG-SeA-EG-PA can lid 1 104(62.39) 148(37.35)

1 TMBPF, tetramethyl bisphenol F; TMBPF MGE, tetramethyl bisphenol F monoglycidyl ether; TMBPF DGE, tetramethyl bisphenol F diglycidyl ether; TMBPF DGE•H2O, monohydrolysed tetramethyl bisphenol F diglycidyl ether, BPA, bisphenol A; BPC, bisphenol C; BPF, bisphenol F; PolymersTPPO,2020 ,triphenyl12, 2846 phosphine oxide; EG, ethylene glycol; DEG, diethylene glycol; SeA, sebacic acid;8 of 13 PA, phthalic acid; IPA.

TMBPF and and TMBPF TMBPF epoxy epoxy migrants migrants were were mainly mainly found found in the in food the can food and can food and can food lid samples. can lid samplesFor the first. For time, the high-resolutionfirst time, high- GC-MSresolution EI mass GC-MS spectra EI mass of TMBPF spectra and of TMBPF TMBPF DGE and migrants TMBPF DGE were migrantsreported (Figurewere reported1). A mass (Figure accuracy 1). A mass5 ppm accuracy and an ±5 isotope ppm confidenceand an isotope of < 10% confidence difference of < from10% ± differencethe theoretical from isotope the the matchoretical (isotope isotope distribution match (isotope and distribution ratio) were appliedand ratio) on thewere molecular applied on ions the at + + molecular256.1460 [C ions17H 20atO 256.14602] and [C 368.198117H20O2 [C]+ and23H 28368.198O4] to1 assign[C23H28 theO4]+ formula to assign (Figure the formula2). The (Figure characteristic 2). The + + characteristicelectron ionization electron fragmentation ionization fragmentation ions at 241.1224 ions [C at16 241.122H17O2]4 ,[C 226.099016H17O2]+ [C, 226.0915H14O902 ][C,15 211.0754H14O2]+, + + + 211.075[C14H114O [C2]14,H 135.080511O2]+, 135.08 [C9H0511O] [C9,H and11O] 91.0543+, and 91.0543 [C7H7] [Cwere7H7]+used were for used structure for structure elucidation elucidation of TMBPF. of + + TMBPFThe characteristic. The characteristic electron ionization electron fragmentation ionization ions fragmentation at 353.1746 [C 22 ionsH25 O at4] , 353.174 335.16406 [C[C2122HH2225OO44]+,, + + + + 335.164293.11730[C [C2119HH2216OO4]4+,] 293.117, 191.10653 [C [C1912HH1615OO4]2+,] 191.106, 175.07535 [C [C1212HH1515OO]2]+, and 175.075 91.05433 [C [C12H7H15O]7] + wereand used 91.0543 for [Cstructure7H7]+ were elucidation used for of TMBPFstructure DGE. elucidation The presence of TMBPF of the TMBPF-based DGE. The presence coating of formulation the TMBPF was-based also coatingconfirmed formulation with the samplewas also supplier confirmed after with data the analysis. sample supplier after data analysis.

95_Percent_ETOH_Food_Can_CouA2 #8346 RT: 22.57 AV:+ 1 SB: 147 22.38-22.53 , 22.60-22.78 NL: 1.56E7 T: FTMS + p EI Full ms [50.0000-700.0000] [M-CH3] 241.1224 100

80 70 [M]+ 60 256.1460

50 TMBPF

40 + [M-2CH3]

RelativeAbundance 30 226.0990 20 135.0805 91.0543 211.0754 10 97.0361 269.1894 365.6985 470.5362 0 95_Percent_ETOH_Food_Can_CouA2 #9469 RT: 25.18 AV: 1 SB: 85 25.08-25.14 , 25.20-25.32 NL: 9.12E6 T: FTMS50 + p EI Full100 ms [50.0000-700.0000]150 200 250 300 350 400 450 500 550 600 650 700 175.0753 m/z 100 + [M-CH3] 90 353.1746

80 + 191.1065 [M-2CH3] 70 335.1640

60 50 325.1795 [M]+ 40 368.1981 TMBPF DGE

RelativeAbundance 30 91.0543 149.0597 293.1173 20 132.0388 255.1016 10 241.1223 403.2091 456.4372 646.1371 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 m/z Polymers 2020, 12, x FOR PEER REVIEW 9 of 14 Figure 1. HighHigh r resolutionesolution GC GC-MS-MS Spectra Spectra for for tetramethyl tetramethyl bisphenol bisphenol F F ((TMBPF)TMBPF) and tetramethyl bisphenol F diglycidyl ether ( (TMBPFTMBPF DGE DGE).).

256.1460 NL: 368.1981 NL: 100 8.73E6 100 3.54E6 95_percent_etoh_food_can_coua2 95_percent_etoh_food_can_coua2 80 #8347 RT: 22.57 AV: 1 SB: 223 80 #9469 RT: 25.18 AV: 1 SB: 64 22.36-22.52 , 22.62-22.97 T: 25.04-25.14 , 25.20-25.25 T: 60 FTMS + p EI Full ms 60 FTMS + p EI Full ms [50.0000-700.0000] [50.0000-700.0000] 40 40 369.2013

20 257.1492 20

RelativeAbundance RelativeAbundance 258.1523 370.2047 0 0 256.1458 NL: 368.1982 NL: 100 8.27E5 100 7.71E5 C H O : C H O : 80 17 20 2 80 23 28 4 C 17 H 20 O 2 C 23 H 28 O 4 pa Chrg 1 pa Chrg 1 60 60

40 40 369.2016 20 257.1491 20 258.1525 370.2049 0 0 256 257 258 259 368 369 370 371 m/z m/z

(a) (b)

Figure 2. Isotopic pattern comparisons of molecular ions (Top) and theoretical molecular ions (Bottom). Figure 2. Isotopic pattern comparisons of molecular ions (Top) and theoretical molecular ions (a) TMBPF; (b) TMBPF DGE. (Bottom). (a) TMBPF; (b) TMBPF DGE.

TMBPF can react with epichlorohydrin and form TMBPF DGE and TMBPF monodiglycidyl ether (TMBPF MGE). The epoxy groups of TMBPF DGE can further polymerize with phenols. It can also hydrolyze to form TMBPF DGE•H2O and TMBPF DGE•2H2O (Figure 3). TMBPF-based epoxy can coating was proposed to be a very promising alternative for BPA. In a previous study, the TMBPF migration level was found below a limit of detection (LOD) at 0.2 ppb (equivalent to 0.03 μg/dm2) using 3% AA and 50% ETOH as food simulants under FDA condition of use A, but TMBPF epoxy migrants were not mentioned [4]. While in our study, both TMBPF and TMBPF epoxy migrants were found; they can occur at 0.78 μg/dm2 and 5.10 μg/dm2, respectively, following extraction under the FDA condition of use A. The higher migration levels and more TMBPF epoxy migrant species can be caused by differences in can coating formulation and application conditions such as the baking temperature and curing time. Several studies also demonstrate that the extent of the bisphenol can coating migration phenomenon may depend on various factors including coating thickness and particle size, time and temperature of retort processing, interactions between the coating and food constituents, and denting or other physical damage to the can [6,41,42].

Figure 3. Epoxy TMBPF Formation, polymerization and hydrolysis. Polymers 2020, 12, x FOR PEER REVIEW 9 of 14

20 257.1492 20

RelativeAbundance RelativeAbundance 258.1523 370.2047 0 0 256.1458 NL: 368.1982 NL: 100 8.27E5 100 7.71E5 C H O : C H O : 80 17 20 2 80 23 28 4 C 17 H 20 O 2 C 23 H 28 O 4 pa Chrg 1 pa Chrg 1 60 60

40 40 369.2016 20 257.1491 20 258.1525 370.2049 0 0 256 257 258 259 368 369 370 371 m/z m/z

(a) (b)

PolymersFigure2020 , 12 2. ,Isotopic 2846 pattern comparisons of molecular ions (Top) and theoretical molecular ions9 of 13 (Bottom). (a) TMBPF; (b) TMBPF DGE.

TMBTMBPFPF can can react react with with epichlorohydrin epichlorohydrin and and form form TMBPF TMBPF DGE DGE and andTMBPF TMBPF monodiglycidyl monodiglycidyl ether ether(TMBPF (TMBPF MGE). MGE) The. epoxy The epoxy groups groups of TMBPF of TMBPF DGE DGE can further can further polymerize polymerize with with phenols. phenols It can. It alsocan hydrolyze to form TMBPF DGE H O and TMBPF DGE 2H O (Figure3). TMBPF-based epoxy can also hydrolyze to form TMBPF DGE•H• 2 2O and TMBPF DGE•2H• 2 2O (Figure 3). TMBPF-based epoxy cancoating coating was was proposed proposed to be to a very be a promising very promising alternative alternative for BPA. for In BPA a previous. In a previous study, the study, TMBPF the 2 TMBPFmigration migration level was level found was below found a below limit of a detectionlimit of detection (LOD) at (LOD) 0.2 ppb at (equivalent0.2 ppb (equivalent to 0.03 µ gto/dm 0.03) μg/dmusing 3%2) using AA and3% AA 50% and ETOH 50% as ETOH food as simulants food simulants underFDA under condition FDA condition of use A,of use but A TMBPF, but TMBPF epoxy epoxymigrants migrants were not were mentioned not mentioned [4]. While [4] in. ourWhile study, in both our study,TMBPF both and TMBPF TMBPF epoxy and TMBPF migrants epoxy were 2 2 migrantsfound; they were can found; occur at they 0.78 canµg/ dm occurand at 5.10 0.78µ g μg/dm/dm ,2 respectively, and 5.10 μg/dm following2, respectively, extraction under following the extractionFDA condition under of the use FDA A. The condition higher of migration use A. The levels higher and migration more TMBPF levels epoxy and more migrant TMBPF species epoxy can migrantbe caused species by di ﬀcanerences be caused in can by coating differences formulation in can coating and application formulation conditions and application such as theconditions baking suchtemperature as the baking and curing temperatur time.e Several and curing studies time also. Several demonstrate studies thatalso thedemonstrate extent of thethat bisphenol the extent can of thecoating bisphenol migration can phenomenoncoating migration may dependphenomenon on various may factors depend including on various coating factors thickness including and coating particle thicknesssize, time andand temperature particle size of, timeretort and processing, temperature interactions of retort between processing, the coating interactions and food betwe constituents,en the coatingand denting and food or other constituents, physical damageand denting to the or can other [6, 41physical,42]. damage to the can [6,41,42].

Figure 3. EpoxyEpoxy TMBPF TMBPF Formation, Formation, p polymerizationolymerization and h hydrolysis.ydrolysis.

Other bisphenol migrants including BPA, BPC, and BPF were only found in the beverage can lid samples. Their migration levels were lower compared to the TMBPF migration level in the food can and food can lid sample, likely because the extraction conditions were less extreme. It was notable that the beverage can coatings were not intentionally formulated with BPA. However, it is possible that the ﬁnal coating product still contains trace amounts of BPA from production line cross-contamination or polymer degradation. They were generally considered as BPA non-intent (BPANI) products. Short chain cyclic polyester oligomers including cyclic DEG-AA, cyclic DEG-PA, cyclic EG-AA-EG-AA, and cyclic EG-SeA-EG-PA were another group of coating-borne migrant identiﬁed in the beverage can and beverage can lid samples. These cyclic polyester oligomers are byproducts of the dicarboxylic acid-diol polycondensation reaction. They do not have free hydroxyl groups to form high molecular weight polymers, and they are low molecular weight, migratory compounds. The most common raw materials in polyester manufacturing include diol monomers, such as diethylene glycol (DEG) and ethylene glycol (EG), and dicarboxylic acid monomers, such as adipic acid (AA), sebacic acid (SeA) and phthalic acid (PA). Therefore, the short chain cyclic polyester oligomer migrants based on these diols and dicarboxylic acids are frequently observed in polyester-based coatings or lamination adhesive products [24]. Short chain cyclic polyesters are considered as NIAS, and chemical standards are usually not commercially available for related method validation and safety evaluation studies. Polymers 2020, 12, 2846 10 of 13

3.2. Quantitation of Bisphenol Monomer Migrants In this study, TMS derivatization GC-MS analytical methods were developed for BPA, BPC, BPF, and TMBPF quantitation. High-purity standards were available for these compounds. For BPA, BPC, and BPF, previous studies utilized both GC-MS and LC-MS for quantitation analysis. GC-MS analytical methods for TMBPF have not been reported previously. The developed method was validated for linearity, limit of detection (LOD), limit of quantitation (LOQ), recovery, and precision (Table3).

Table 3. Analytical performance of developed method for bisphenol monomer migrants.

Target Linearity LOD LOQ Precision Spiking and Recovery (Recovery%, n = 3) 2 Analyte (R ) (µg/mL) (µg/mL) (%) 10% ETOH 95% ETOH 3% AA BPA 0.9913 0.501 1.001 9.01 96.12 8.35 99.69 8.71 76.31 5.92 ± ± ± BPC 0.9957 0.499 0.998 10.24 81.45 7.42 96.64 6.16 94.21 7.99 ± ± ± BPF 0.9904 0.501 1.002 8.67 74.60 5.45 93.38 8.07 86.05 9.41 ± ± ± TMBPF 0.9915 0.100 0.500 9.63 122.78 9.38 103.99 9.02 77.41 4.42 ± ± ±

Calibration curves were obtained by plotting the peak area ratio of BPA-di-TMS/IS, BPC-di-TMS/IS, BPF-di-TMS, or TMBPF-di-TMS/IS versus the concentrations of standard solutions of BPA, BPC, BPF, or TMBPF, respectively. The dynamic range of calibration was 1.00–100.00 µg/mL (1.00–100.00 ppm w/v) and the coefficient of determination R2 equaled 0.9913, 0.9957, and 0.9904, respectively, for BPA, BPC, and BPF. The dynamic range of TMBPF calibration was 0.500–100.00 µg/mL (0.500–100.00 ppm w/v) and the coefficient of determination R2 equaled 0.9915. The LOD determined with a signal-to-noise (S/N) of 3 for BPA-di-TMS, BPC-di-TMS, and BPF-di-TMS were 0.501 µg/mL, 0.499 µg/mL, and 0.501 µg/mL, respectively, where the noise was selected from peaks adjacent to the peak of the target analytes. This concentration was equivalent to approximately 5 ng/mL (5 ppb w/v) for the food simulant extracts of a typical metal can sample in the screening analysis as the extracts were concentrated about 100-fold. The LOQ determined with a S/N of 10 for BPA-di-TMS, BPC-di-TMS and BPF-di-TMS were 1.001 µg/mL, 0. 998 µg/mL and 1.002 µg/mL, respectively. The LOD for TMBPF-di-TMS (S/N = 3) was 0.100 µg/mL, which is equivalent to approximately 1 ng/mL (1.0 ppb w/v) for the food simulant extracts of a typical metal can sample in the screening analysis. The LOQ for TMBPF-di-TMS (S/N = 10) was 0.500 µg/mL. Analytical system precision was accessed by running six replicate analyses of a solution containing target analytes at 50 µg/mL (50 ppm w/v). The precision of BPA, BPC, BPF, and TMBPF had an RSD of 9.01%, 10.24%, 8.67% and 9.63%, respectively. The mean back-fit to calibration for BPA, BPC, BPF, and TMBPF was 53.88 4.85 µg/mL, 50.47 5.17 µg/mL, 54.69 4.74 µg/mL, and 52.34 5.04 ± ± ± ± µg/mL, respectively. Spiking and recovery of BPA, BPC, BPF, and TMBPF was performed in triplicate in 10% ethanol and 3% acetic acid food simulants at a 1.25 µg/mL concentration level and in 95% ethanol food simulant at a 5.00 µg/mL concentration level. The recovery results of BPA spiked in 10% ethanol, 95% ethanol, and 3% acetic acid were 96.12% 8.35%, 99.69% 8.71%, and 76.31% 5.92%, respectively. The recovery results ± ± ± of BPC spiked in 10% ethanol, 95% ethanol, and 3% acetic acid were 81.45% 7.42%, 96.64% 6.16%, ± ± and 94.21% 7.99%, respectively. The recovery results of BPF spiked in 10% ethanol, 95% ethanol, and ± 3% acetic acid were 74.60% 5.45%, 93.38% 8.07%, and 86.05% 9.41%, respectively. The recovery ± ± ± results of TMBPF spiked in 10% ethanol, 95% ethanol, and 3% acetic acid were 122.78% 9.38%, ± 103.99% 9.02%, and 77.41% 4.42%, respectively. ± ± The validated method was applied to re-analyze the can and lid samples which showed bisphenol-type migrants. The resulting BPA, BPC, and BPF concentrations in the beverage can lid samples were all below the limit of detection at 5.0 ppb w/v (0.785 µg/dm2). The resulting TMBPF concentrations in the food can 10% ethanol, 3% acetic acid, and 95% ethanol extracts are all between LOD at 1.0 ppb w/v (0.125 µg/dm2) to LOQ at 5.0 ppb w/v (0.625 µg/dm2). The concentrations of TMBPF in the re-analyzed 10% ethanol and 3% acetic acid food can lid sample extracts were below Polymers 2020, 12, 2846 11 of 13

0.157 µg/dm2, while the TMBPF concentration in the re-analyzed 95% ethanol food can lid sample extract was between LOD at 1 ppb w/v (0.157 µg/dm2) to LOQ at 5.0 ppb w/v (0.785 µg/dm2).

4. Conclusions In this study, 12 coating-borne migrants based on bisphenol or polyester chemistry were found from non-BPA food-contact metal can coatings. Four of the migrants were based on TMBPF, a proposed low toxicity BPA replacement bisphenol monomer. They were identified and reported for the first time in food can packaging intended for high temperature application. Validated TMS derivatization GC-MS methods were developed to quantify the concentrations of bisphenol monomer migrants including BPA, BPC, BPF, and TMBPF from food-contact metal can coatings. The identification data of coating-borne migrants including the molecular structure, estimated migration levels, and high resolution EI mass spectra can be used as references for the food industry. The quantitation analysis of BPA, BPC, BPF, and TMBPF provided a validated GC-MS method able to determine the concentrations of bisphenol-type migrants from food packaging, and can assist manufacturers in performing systematic quality control of their BPA alternative can coating products.

Author Contributions: Conceptualization, methodology, resources, and project administration, N.Z. and T.G.H.; software, validation, formal analysis, investigation, data curation, and writing—original draft preparation, N.Z. and J.B.S.; writing—review and editing, N.Z., J.B.S., and T.G.H.; visualization, supervision, funding acquisition, T.G.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the International Life Sciences Institute (ILSI North America) Food Packaging Safety Committee. Acknowledgments: The authors thank the International Life Sciences Institute (ILSI) for the project funding and ILSI Food Packaging Safety Committee who provided the samples used in our analytical work. The authors also thank Intertek, Whitehouse Station, NJ for the high-resolution mass spec instrumentation support. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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