Phthalates and bisphenol chemicals have been widely used globally in packaging materials and consumer products for several decades. These highly functional chemicals have become a concern due to their toxicity (i.e., endocrine/hormone modulators) and ability to migrate from food contact materials (FCMs) into food matrices and the environment resulting in human and environmental health risks. FCMs, composed of postconsumer materials, are particularly high risk for containing these compounds. The evaluation of postconsumer recycled feedstocks in FCMs is compulsory and selection of an appropriate detection method to comply with applicable regulations is necessary to evaluate human and environmental safety. Numerous regulations have been proposed and passed globally for both compound classes that are recognized as priority pollutants by the United States Environmental Protection Agency and the European Union. Several brand owners and retailers have also released their own “restricted substance lists” due to the mounting consumer and regulatory concerns. This review article has two goals: (1) discuss the utilization, toxicology, human exposure routes, and occurrence levels of phthalates and bisphenols in FCMs and associated legislation in various countries and (2) discuss critical understanding and updates for detection/quantification techniques. Current techniques discussed include extraction and sample preparation methods (solid-phase microextraction [SPME], headspace SPME, Soxhlet procedure, ultrasound-assisted extraction), chromatographic techniques (gas, liquid, detectors), and environmental/blank considerations for quantification. This review complements a previous review of phthalates in foods from 2009 by discussing phthalate and bisphenol characteristics, analytical methods of determining concentrations in packaging materials, and their influence on the migration potential into food.

Abbreviations

BADGE: bisphenol A diglycidyl ether
BFDGE: bisphenol F diglycidyl ether
BPA: bisphenol A
BPF: bisphenol F
BPS: bisphenol S
BSTFA: bis(trimethylsilyl)trifluoroacetamide
BW: body weight
BZP: benzyl butyl phthalate
DCHP: dicyclohexyl phthalate
DEHA: Di-(2-ethylhexyl) adipate
DEHP: di(2-ethylhexyl) phthalate
DEHT: bis(2-ethylhexyl) terephthalate
DEP: diethyl phthalate
DIDP: diisodecyl phthalate
DINP: diisononyl phthalate
DTDP: ditridecyl phthalate
DOP: dioctyl phthalate
EFSA: European Food Safety Authority
EI: electron impact ionization
EMC: endocrine-modulating chemicals
FCM: food contact material
FUSLE: focused ultrasound solid–liquid extraction
HDPE: high-density polyethylene
HMW: high molecular weight
HS-SPME: headspace solid-phase microextraction
IOEL: identified occupational exposure limit
LOD: limit of detection
LOQ: limit of quantification
LMW: low molecular weight
MRM: multiple reaction monitoring
NCI: negative chemical ionization
NIAS: nonintentionally added substances
PCR: postconsumer recycled
PE: polyethylene
PET: polyethylene terephthalate
PFBOCl: pentafluorobenzoyl chloride
phr: parts per hundred resin
PS: polystyrene
PVC: polyvinyl chloride
REACH: Regulation, Evaluation, Authorization and Restriction of Chemicals
SML: specific migration limit
SPME: solid-phase microextraction
TDI: tolerable daily intake
TMS: trimethylsilyl
UAE: ultrasound-assisted extraction

1 INTRODUCTION

Packaging is a critical component of the food industry designed to maintain shelf life and protect food contents from biological and chemical changes after processing (Fan et al., 2019; García Ibarra et al., 2019). Snacks, takeaway foods, and ready-to-eat food type consumption rates are increasing with current societal trends, technological changes, and the implementation of engineering single-use plastic materials. The increasing use of packaging materials has elevated consumer and environmental exposure to these materials and their constituents. New packaging materials and technologies are rapidly emerging to accommodate the growth in these food consumption sectors (Fan et al., 2019).

Different polymers are used in packaging such as polyethylene (PE) in various forms (low-density polyethylene [LDPE], high-density polyethylene [HDPE], etc.), polypropylene (PP), polyethylene terephthalate (PET), polystyrene (PS) (Lorber et al., 2015), ethylene vinyl alcohol, polyvinylidene chloride, polyvinyl chloride (PVC), and so forth (García Ibarra et al., 2019; Stark et al., 2005). The selection of packaging material depends on several factors such as intended use (e.g., rapid reheat, frozen storage, cook-in-bag), heat stability, print capability, strength, barrier properties (e.g., water, oxygen, carbon dioxide), cost-effectiveness, recyclability, and legal requirements. Although packaging materials have significant benefits to extend shelf life and protect food, some packaging constituents have been implicated in several health hazards by transferring chemical compounds into food (Craver & Carraher, 2000).

Plasticizers account for one third of global plastic additives (Cision, 2022). The International Union of Pure and Applied Chemistry defines plasticizers as a substance that is incorporated into a material (usually plastic or elastomer) to add pliability, workability, or distensibility (Cadogan & Howick, 2000; Gilbert, 2017). Phthalates are used as additives (Cision, 2022) or plasticizers to make soft, flexible plastics products that bring pliability, workability, and printability. Low molecular weight (LMW) phthalates are soluble in water and polar in nature (EFSA, 2019).

Bisphenols are often used as components in food packaging as metal can coatings to protect the food from metal surfaces and vice versa (FDA, 2018a). Apart from being used in polycarbonates and epoxy resins production, bisphenol A (BPA) has applications as a developer in thermal paper (e.g., receipts, tickets), which is a significant source of BPA exposure through incorporating more recycled content in recycled paper (Frankowski et al., 2020). Bisphenol S (BPS) is a monomer in synthetic polymers production (polyethersulfone, polysulfone) including epoxy resins (Geueke, 2015). These are a class of compounds with two hydroxyphenyl groups (Farris, 2014) with differing joining chemistry. There is potential for a portion of these compounds to migrate from packaging to the contents if the polymerization does not reach 100% conversion (Stark et al., 2005). Incomplete polymerization and noncovalent interactions between the additive and the polymer enable migration from the polymer matrix to the food matrix (Kumar, 2021). Bisphenols are moderately water-soluble (120–300 mg/L) compounds and possess pK_a values of 9.9–11.3. BPA has two OH groups that make it water soluble in alkaline pH and does not deprotonate at lower pH levels (<pH 7) (Davies, 2011). The pK_a value and solution pH as ionization (pH closer to its pK_a) influence BPA leaching potential and solubility (Zeng et al., 2006).

Studies have suggested people are exposed to phthalates and bisphenols through their diet (Craver & Carraher, 2000; García Ibarra et al., 2018; Wilkes et al., 2005). Phthalates and bisphenols are well known to be toxic substances with serious human and environmental health risks depending on exposure conditions. Certain phthalates, bisphenols, and their analogs are banned or regulated with defined concentrations for food contact material (FCM) applications (Craver & Carraher, 2000). The toxicity and negative health implications of these compounds depend on exposure conditions and their concentrations in consumed food. The U.S. Food and Drug Administration (FDA) is establishing the national allowable specific migration limit (SML) for most of these compounds to increase consumer safety. On May 19, 2022, the FDA issued a request for information regarding the use and safety data of eight phthalates: diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), di(2-ethylhexyl) phthalate (DEHP), dicyclohexyl phthalate (DCHP), butyl phthalyl butyl glycolate, diethyl phthalate (DEP), ethyl phthalyl ethyl glycolate, and diisooctyl phthalate (FDA, 2022b). These phthalates are currently authorized for use as plasticizers in FCMs (Food Safety Magazine, 2022; PackagingLaw, 2022). The permitted level of DEHP in bottled water is 6.0 μg/L (FDA, 2018b). Based on the survey by Da Silva Costa et al. (2021), DEHP was detected in bottled water between 2017 and 2019 all over the world with the highest amount in samples from Thailand at 64.0 μg/L; when compared to U.S. thresholds, it is 10 times the allowable limit.

The conditions of exposure influence the nature of small molecule migration, such as the nature of the food (fat, oil, acidic, aqueous), storage condition (temperature and time), and processing condition (temperature of in packaging cooking/heating) (ASCE, 2021). Condensation-type polymers (e.g., PET, nylons) can degrade liberating monomers and other additives under highly acidic or alkaline conditions (Krauskopf, 1993); therefore, the intended use of the application is critical to understanding the migration and exposure risks.

Understanding the diffusion mechanism and phthalate/bisphenol desorption kinetics may mitigate chemical migration. Phthalate/bisphenol migration from packaging material happens in two phases: (i) diffusion from the polymer interior to the surface (ASCE, 2021) and (ii) desorption from surface to environment. Fick's second law of diffusion is often used to define the molecule diffusion process (Ekelund et al., 2008; Stark et al., 2005; Wang et al., 2015). The migration of these chemicals increases with temperature and time of exposure according to the Arrhenius equation. This is an important aspect for FCMs due to the convenience of hot retail and microwaveable packaging. As phthalate/bisphenol are small molecules, the available free energy becomes sufficient to enhance migration from the polymer. This free energy obtained by the small molecules (phthalate/bisphenol) increases with temperature and facilitates breaking down the polymer–small molecule interaction forces (Liu et al., 2020). A study by Ayamba et al. (2020) determined that DEHP (4 h contact time into aqueous food simulant) showed migration rising from 0.83 to 1.21 μg/kg as temperature increased from 5 to 80°C in black PE bags. The migration of dibutyl phthalate (DBP) was lower (0.5 μg/kg at 80°C) in concentration compared to the DEHP (1.21 μg/kg at 80°C) in food simulant. DEHP has similar core structure to DBP and other phthalates such as DIDP and DINP, but has longer and branched side chains compared to DBP. Branching in carbon chain decreases the diffusion coefficient in polymers. The study suggested that the long chain DEHP has poor interactions with the polymer and migrates easily upon heating (Ayamba et al., 2020).

Migration of bisphenols (e.g., BPA) follows similar trends. For example, migration of BPA in polycarbonate bottles was observed to increase with a temperature over 80°C (Ekelund et al., 2008; Wang et al., 2015; Xie et al., 2016). Acidic and alkaline conditions facilitate degradation in polycarbonate through hydrolysis, which accelerates BPA migration (Cadogan & Howick, 2000; Godwin, 2000; Krauskopf, 1993). Measuring trace levels of contaminants is complex for analysts as the required level of detection and/or quantification is often very low (μg/L or ng/L). Adapted strategies are necessary to solve these problems and focus on regulating hazardous contaminants in food packaging. Due to their intrinsic toxicity and migration potential, it is essential to detect the concentration level of phthalates and bisphenols in different FCMs. This review highlights the use of these substances in FCMs and analytical considerations for determining phthalate/bisphenol concentrations in FCMs. It was designed to complement the previous review by Cao (2010) discussing phthalates in food matrices.

2 PROPERTIES OF PHTHALATES

Phthalates are composed of one benzene ring with two aliphatic ester groups attached to the ring most commonly in the ortho configuration (Figure 1). Newer, lower toxicity phthalates are based on the para configuration, such as the DEHP analog bis(2-ethylhexyl) terephthalate (DEHT) (Xie et al., 2016). Some phthalates are colorless, lipophilic, and odorless liquids (Giuliani et al., 2020), while some are solid at room temperature. For example, DEHP is a clear, oily liquid with boiling point 384°C (CPSC, 2015) and DCHP is granular solid (EPA, 2019). Their boiling points are variable with a range of 190–530°C, for example, boiling point of benzyl butyl phthalate (BZBP), DCHP, DEP, DIBP, DIDP, DINP, and diisoheptyl phthalate (DIHP) are 370, 218, 302, 296, 250, 283, and 185°C respectively (Yang et al., 2015). The low water solubility of these compounds remains constant as carbon atom numbers decrease (Ekelund et al., 2008; Wang et al., 2015). These are synthetic organic chemicals that were first produced in the 1920s (Xie et al., 2016) from alkyl alcohols (C1 up to C17) and isophthalic acid (see Figure 1).

Details are in the caption following the image — **FIGURE 1**
Open in figure viewer PowerPoint

General chemical structure of phthalates.

In Europe, DEHP accounted for over 95% of plasticizer usage in 2008. Synthesis of DEHP (also known as dioctyl phthalate [DOP]) includes dimerization of butyraldehyde (Godwin, 2017). The current market of plasticizer demand for dialkyl phthalates homologues to DOP, for example, diisoheptyl (C7), diisooctyl (C8), diisononyl (C9), and diisodecyl (C10) phthalates or their combined usage, accounts for a major portion of the worldwide plasticizer market (Markets, 2017). Current regulations focus on specific phthalates that are listed as toxic at various concentrations of exposure. In this review, we focus on the phthalates with high application rates that have been detected in food from packaging migration studies in literature and are defined as toxic by numerous government entities. For example, according to EU No. 143/2011 EC (CMR category 1B) (European Union, 2011) and U.S. EPA “priority toxic pollutant list” (EPA, 2014), BZBP, DBP, and DEHP are listed as toxic chemicals. According to Registration, Evaluation, Authorization and Restriction of Chemicals (REACH), DEHP, BZBP, DBP, and DIBP can be used under regulation with specific maximum concentrations (Vinod & Harathi, 2022). The phthalates DINP and DIDP are sometimes used to replace DEHP and are not categorized as hazardous compounds, but DINP, DIDP, and DNOP combined should not exceed 0.1% by mass (Nagorka et al., 2022). Di-(2-ethylhexyl) adipate (DEHA) is also used as a plasticizer in food packaging (e.g., cling film) (Cao et al., 2014). DEHA is considered toxic under the Government of Canada's Chemicals Management Plan (Government of Canada, 2022). A study by the Cao et al. (2014) analyzed DEHA in meat, fish, and cheese cling films and found its presence in most of the food samples with levels ranging from 0.71 to 879 mg/g in cheese samples exceeding the European specific migration limit of 18 mg/kg in food matrix. Additional work by Cao et al. (2015) detected a phthalate or DEHA in 141 of the 159 different food composite samples analyzed; in particular, relatively high levels of DEHA were detected in individual food items that were likely packaged in poly(vinyl chloride) wrapping film.

2.1 Polymer plasticizer (phthalate esters) interaction

Plasticizers need to be adequately incorporated into the polymer matrix to be effective. Heat is generally applied to dissolve the resin into the plasticizer or vice versa (Stark et al., 2005). Unplasticized polymers are less flexible because they have strong interactions between adjacent polymer chains and Van der Waals forces (Howick, 1998; Kutz, 2011). Heating polymers reduces the polymer–polymer interaction acting as a lubricant due to a reduction in the intermolecular forces; incorporating plasticizers into polymers reduces interpolymer interactions leading to increased flexibility and low-temperature performance (Kutz, 2011). Incorporating plasticizers into a polymer can be divided into four steps: (i) plasticizer is mixed with a polymer; (ii) the plasticizer pierces and swells the polymer particles; (iii) polar groups in the polymer start to move freely; and (iv) polar groups of the plasticizer interact with the polar group in the polymer backbone (Cadogan & Howick, 2000; Godwin, 2011).

Because of the plasticization process, new dipole–dipole interactions in the amorphous region of the polymer exterior occurs, extending to the crystalline spaces, lowering the potential energy and stabilizing the system. When two molecules move closer by attraction, the energy gradually decreases to a minimum and becomes stable (Godwin, 2017; Langer et al., 2020). The alkyl side group of the plasticizer generates free volume within the polymer, which lowers the glass transition temperature (Hiemenz & Lodge, 2007). Howick's study regarding the polar and nonpolar groups interactions in plasticizers–polymer found minimum energy configurations. The plasticizer's polar regions interact with the CH₂ molecules in the polymeric structure initiating an alteration in the alkyl side group conformation in the plasticizers and generate additional free volume initiating the plasticization effect (Godwin, 2017). Generally, at high temperatures, the plasticizer solvates the amorphous region of the polymer. The crystalline regions (depending on the polymer) also start to interact with the plasticizer at higher temperatures (Kutz, 2011). According to thermodynamic or mechanistic theory, a dynamic equilibrium is present between the polymer chains and plasticizers. And according to gel theory, there is a weak secondary force between the plasticizer and the polymer (Godwin, 2000). A different class of plasticizers can force different polymer properties, dramatically changing physical properties and polymer chain dynamics. These considerations are important to understanding the migration potential of phthalates in FCMs during the intended use of packaging applications (i.e., room temperature store vs. microwave) and become critical in applications that enable high-heat consumer abuse where polymers can melt. Depending on molecular weight, LMW phthalates (DBP, BZBP, DEHP) with shorter alkyl chain are used as solvents and adhesives, while the high molecular weight (HMW) phthalates (DINP, DIDP) are used as plasticizers (Giuliani et al., 2020) because of their ability to induce high ductility, plasticity, and flexibility in polymers (Liu et al., 2022). The details of realized properties from these phthalates are discussed more in depth later in this article. If the plasticizer and the polymer do not attract each other, self-association occurs in the plasticizer forming micropools resulting in plasticizer exudation (Langer et al., 2020).

Balance between the polar and apolar functional groups of the plasticizers is crucial. Excessively polar molecules can work as a strong solvent generating poor performance; when the plasticizer is too apolar, compatibility issues can arise leading to pools of concentrated plasticizer (Stark et al., 2005; Xie et al., 2016). The applicability of plasticizer polar groups is polymer dependent and yields different compatibility depending on the polymer. For example, in PVC (analogous in other polymers), a polar carbon–chlorine bond exists in every repeat unit. The plasticizer solvates the amorphous regions of polymer, but the crystalline regions remain intact. As temperature increases up to 170°C (T_m, crystalline region melting point), the crystalline region also solvates (Summers, 2008). For example, in flexible PVC, the crystalline region melts around 150°C (Daniels & Cabrera, 2015). When the temperature rises above the glass transition temperature (T_g), additional free volume is generated in the polymer. The addition of plasticizers lowers the T_g and increases free volume (Stark et al., 2005). A shift in Fourier transform infrared spectra can be observed due to interactions of the carbonyl group in plasticizers and the carbon–chlorine bond in the polymer. Because of this interaction, polymer intramolecular bonding forces are reduced in the functional group (Xie et al., 2016). This electrostatic interaction is strong between the electronegative region (plasticizer) and the electropositive region (polymer). Additional free volume in the polymer is generated when thermal motion occurs in the plasticizer's alkyl side chain (Cadogan & Howick, 2000). These interactions are temperature dependent influencing phthalate permanence (described in Section 2.3) and diffusion characteristics in the polymer that influence migration potential and environmental/human exposure risks.

2.2 Plasticizer performance/plasticizing efficiency

Plasticizer efficiency is defined as the efficiency to make the polymer flexible (Kutz, 2011), which is influenced by the plasticizer concentration, plasticizer structure, and polymer structure. Matching polarity and hydrogen bonding characteristics between the polymer and the plasticizer requires less energy to solvate resulting in higher compatibility. A larger difference of attractive force may cause exudation (Stark et al., 2005). LMW phthalates generally have a higher polarity that reduces compatibility, while phthalates prepared from higher alcohols (C10 and higher carbon number) can result in exudation. More thermal energy is required for plasticization when larger plasticizer molecules are used. The fusion temperature or processing temperature increases by 7−8°C as carbon numbers increase (Godwin, 2011). The plasticizer diffusion coefficient trends are known to increase with temperature, decrease as alkyl chain length increases, and decrease as alkyl chain branching increases (Xie et al., 2016). Phthalates mostly used as PVC plasticizers are generally in C4–C13 (Cadogan & Howick, 2000; Craver & Carraher, 2000; García Ibarra et al., 2018; Godwin, 2017; Krauskopf, 1993). The diffusion coefficients in PVC for a series of n-alkyl phthalates and branched phthalates increased linearly with temperature and decreased with increasing plasticizer molecular size and degree of branching. For phthalates, a gradual decrease for fusion temperature is in the following order: BZBP (C19) > DHP (C20) > DIHP (C22) > DOP (C24) > DINP (C26) > DIDP (C28) (Craver & Carraher, 2000). It is important to understand the influence of plasticizer structure on the plasticization efficiency and diffusion characteristics as it relates to migration from food packaging under different conditions of use (frozen storage compared to microwave reheat) leading to potentially different human exposure risks.

To represent plasticizer efficiency for the different molecular structures, a term “substitution factor” (SF) (Asensio et al., 2020) has been employed (see Table 1). The SF determines how much plasticizer is necessary in parts per hundred resin (phr) for realizing the same desirable hardness as using DOP. As a result, the SF can be used to help understand the relative concentration of different phthalates in polymers used in food packaging. The polymer hardness is defined as the resistance of the polymer against local deformation (Briscoe & Sinha, 1999). The equation for comparing the plasticizer efficiency was described by Krauskopf (1993):

\begin{eqnarray}&&{\rm{SF}}\;\nonumber\\ &&= \frac{{\left( {{\rm{First\;phr\;plasticizer [}}56.2{\rm{\;for\;DINP]\;}}\;{\rm{at}}\;{\rm{Durometer}}\;80} \right)}}{{\left( {{\rm{Second\;phr\;plasticizer\;[}}52.9{\rm{\;for\;DOP]}}\;{\rm{at}}\;{\rm{Durometer}}\;80} \right)}}.\end{eqnarray}

(1)

TABLE 1. Plasticizer acronyms, chemical composition, and substitution factors (Asensio et al., 2020; Cadogan & Howick, 2000; Carlson & Patton, 2011; García Ibarra et al., 2018; Wilkes et al., 2005).

Acronyms	IUPAC name	Alcohol carbon no.	Formula	Cas no.	Molecular weight (g/mol)	Substitution factors
DBP	Di-n-butyl phthalate	4	C₁₆H₂₂O₄	84-74-2	278.34	0.86
BZBP	Butyl benzyl phthalate	4, 7	C₁₉H₂₀O₄	85-68-7	312.36	0.94
DIHP	Diisoheptyl phthalate	9	C₂₂H₃₄O₄	41451-28-9	362.50	0.97
DEHP, DOP	Di(2-ethylhexyl) phthalate	8	C₂₄H₃₈O₄	117-81-7	390.56	1.00
DIOP	Diisooctyl phthalate	8		27554-26-3	390.56	1.01
DINP	Diisononyl phthalate	9	C₂₆H₄₂O₄	28553-12-0	418.61	1.06
DIDP	Diisodecyl phthalate	10	C₂₈H₄₆O₄	26761-40-0	446.66	1.10
DTDP	Deoxythymidine diphosphate	13	C₃₄H₅₈O₄	27253-26-5	530.8	–

Note: Substitution factor = phr required for 80A Durometer hardness at room temperature versus required DOP level (52.9 phr).

In the above equation, the measurement equipment for hardness is often performed using a durometer per ASTM D2240-15 (ASTM, 2021). To realize the same hardness or softness of a polymer using DOP, an additional six parts per hundred of DINP (SF = 1.06; 6% less efficient) are required compared to DOP when all other constituents remain constant (Asensio et al., 2020; Krauskopf, 1993). Branching also has a significant impact because linear isomers are more effective compared to branched ones (Cadogan & Howick, 2000; Wilkes et al., 2005).

2.3 Plasticizer gelation and permanence properties

The gelation characteristics define plasticizer interactions with the polymer inducing softness and flexibility. The gelation characteristics depend on the plasticizer's polarity where acid type and length/structure of alcohol chain play a key role. Aromatic acid esters possess higher polarity with increased gelation properties than aliphatic acid-based esters (Cadogan & Howick, 2000). For the phthalates, gelation ability is reduced in the following order: BZBP > DBP > DIHP > DOP > DINP > DIDP > DTDP (ditridecyl phthalate) (Cadogan & Howick, 2000; Ekelund et al., 2008). On the other hand, their permanence also depends on several factors like storage time, food matrix in the package, package composition, storage condition, and so forth. For example, it was determined that phthalates leached more from HDPE water bottle compared to PET water bottle (Angnunavuri et al., 2022). This can be attributed to the generally higher diffusion coefficients in polyolefins compared to PET (Anonymous, 2006; Anouar et al., 2015; Dvorak et al., 2011). Plasticizer migration decreases when the interaction of plasticizer with polymer increases. For example, when the crystallinity in PE increases, the plasticizer migration decreases as diffusion mainly occurs in the amorphous phase (Senichev & Tereshatov, 2004).

Plasticizers are not covalently attached to polymer and have varying degrees of affinity for polymers, which influences diffusion rates (Stark et al., 2005). The permanence characteristic of a plasticizer is the ability to remain in the plasticized material during its service life. Permanence depends on the plasticizer molecular weight and chemical structure and both influence diffusion. Plasticizer performance is influenced by the alcohol carbon number (number of carbons in the alcohol group) and molecular structure of the corresponding alcohols. The alcohol carbon number for select phthalates are provided in Table 1. The lower alcohol carbon phthalates can more readily enter the polymer matrix than larger molecules and bring the desired interaction with the polymer due to higher diffusion coefficients and smaller occupied volume. Plasticizers with higher carbon number alcohols have increased exudation tendencies and are often described as poor plasticizers. For example, when DEHP is replaced with DINP during application in polymer, almost 50% volatile loss will be reduced (Godwin, 2011). However, the increased diffusion rates that enable rapid plasticization of the polymer also increase the potential for faster migration into packaged food corresponding to potential health risks.

Dialkyl phthalate plasticizers vary in molecular weight ranging from 278 g/mol (dibutyl) to about 530 g/mol (ditridecyl). Through the service lifetime, the chemical and physical properties of polymers change influencing phthalate migration potential. In addition, the plasticizer migration rate depends on volatility, diffusion, exudation under pressure, and exposure to environmental agents (Cadogan & Howick, 2000). Dibutyl (C4 alkane) is often considered undesirably volatile for most commercial purposes, while ditridecyl (C13 alkane) phthalate can be useful (Craver & Carraher, 2000; Xie et al., 2016) as phthalate volatility decreases with the increasing molecular weight. Lower volatility is observed in linear alkyl phthalates with higher oxidative resistance compared to their branched counterparts (Xie et al., 2016). Plasticizers with more polarity, for example, BZBP or DHP, also migrate less as they have more attraction for polymers, although it depends on the compatibility of plasticizer and polymer (Cadogan & Howick, 2000; Stark et al., 2005). This explains the trend that plasticizer migration decreases in PE compared to PVC as plasticizer polarity increased. High degree of crystallinity in the PE realized a decrease in the migration of plasticizers due to reduced amorphous content where phthalates can diffuse (Senichev & Tereshatov, 2004). To improve compatibility, polar plasticizers with polar polymers can be beneficial because plasticizer with higher polarity is necessary to overcome the distance between the polar groups in their chemical structure in the polymer (Immergut & Mark, 1965).

2.4 Phthalate stability and potential for generation for nonintentionally added substances

In phthalate-based plasticizers, thermal stability decreases in the order DTDP > DIDP > DINP > DOP > DIHP > DBP. Thermal degradation is more frequent at temperatures generally more than 200°C for o-phthalic acid (Moldoveanu, 2019) (e.g., phthalic acid decomposes into phthalic anhydride at 230°C [Wypych, 2015]). Still, phthalates from more branched alcohol isomers are more susceptible to such degradation because of the tertiary carbon stabilizing the intermediate. Tertiary carbon sites are the susceptible point to initiate radical formation by heat due to the increased stability of intermediates (Wypych, 2015) as hydrogen abstraction is stabilized by the tertiary carbon group (Carraher Jr., 2017). At the industry level, the inclusion of antioxidants can minimize the thermal degradation of both the polymer and plasticizers. The steps that take place during thermal degradation are shown in Figure 2.

Degradation of intentionally added phthalates during and after the material service life generates nonintentionally added substances (NIAS) in the host polymer that may not be approved for direct food contact applications. Phthalates are one of the typical recycling-related NIAS in postconsumer recycled (PCR) materials that could hinder their use as an FCM (Ong et al., 2022). In May 2022, the FDA limited the use of certain phthalates in FCMs by removing these substances from the authorized list of substances regulated in 21 CFR parts 175 through 178 (FDA, 2022a). The degradation products from these phthalate compounds as NIAS may not be acceptable for all packaging-intended conditions of use. The identification and concentration of phthalates and their degradation byproducts are critical to understanding a postconsumer material's potential for use as an FCM, depending on the intended use and corresponding specific migrating legal limit (Geueke, 2018). Thermal degradation in phthalates via ester bond hydrolysis produces either an isophthalic acid ester or isophthalic acid in addition to the corresponding alcohols. The degradation products migrating into the food matrix from packaging are only authorized under certain migration limits if defined. The alcohol side groups of plasticizers boil at different temperatures and possess different diffusion coefficients according to their branching characteristics and molecular weights. The various molecular structures and diffusion coefficients realize different magnitudes of human and environmental health risks depending on the time and temperature of exposure/disposal. Plasticizer evaporation occurs during polymer degradation events, but plasticizer evaporation can be increased due to environmental conditions, which may facilitate the heating of plasticized polymer. Polymeric materials that are kept outdoors and exposed to the sun or temperatures more than 110°C can result in plasticizer evaporation/loss and material performance deterioration. The loss rate increases with increasing temperature for small plasticizers compared to higher molecular weights; the plasticizer loss can be calculated from below theoretical models according to Wypych (2004):

\begin{equation}\;\frac{{{M_\tau }}}{{{M_0}}} = K{\tau ^d},\end{equation}

(2)

where M_τ is the loss of plasticizer during time τ, M₀ is the initial plasticizer content, k is the plasticizer initial content, τ is the time, and d is a constant (under experimental conditions d = 0.5) (Wypych, 2004).

3 PROPERTIES OF BISPHENOLS

BPA is a commercial chemical with one of the largest volumes of production and demand (9618.7 kilotons by 2020) in the world (Lorber et al., 2015). The chemical formula of BPA is C₁₅H₁₆O₂ with a molecular weight of 228.29 g/mol, which is a colorless solid substance with a mild phenolic or medicine odor from the diphenylmethane groups with two hydroxyphenyl groups. The chemical composition of common bisphenols is described in Table 2. The hydroxyl groups in BPA are highly reactive. BPA and its analogs—bisphenol F (BPF), bisphenol A diglycidyl ether (BADGE), and bisphenol F diglycidyl ether (BFDGE)—are used as monomers for the production of polycarbonate, epoxy resins, an antioxidant in plasticizers, and an additive (color developer) in thermal paper (Gallo et al., 2017). BPF epoxy resins have several applications, including adhesives, plastics, and food packaging manufacturing. Application of bisphenols includes cross-linking agents in PE and polypropylene formulations (Wilkes et al., 2005) that are found in a wide range of food packaging containers. Epoxy resins synthesized from BPA or the analog BADGE can be used for water storage tank liners and the internal coating in food cans restricting the contact between the metal wall and the food matrix preventing degradation. Because of incomplete polymerization, monomeric BPA remains within the coating, increasing the potential for migration into food (García Ibarra et al., 2018). BPF is an aromatic organic compound with lower molecular weight than BPA composed of a mixture of three isomers (2,2′-, 2,4′-, and 4,4′-dihydroxydiphenyl methane). BPF is commonly used in the synthesis of epoxy resins. BPS (4,4ʹ-sulphonyl diphenol) is used as a BPA substitute as the increasing trend for “BPA-free” food packaging and thermal printing papers (Liao et al., 2012). BPS shares a very close chemical structure to BPA and is also used for fast curing epoxy adhesives and coatings. Pal et al. (2017) demonstrated the health risks related to BPS in an animal study showing estrogenic activity.

TABLE 2. Bisphenol acronyms and chemical composition (Gallart-Ayala et al., 2013; Lestido Cardama et al., 2019).

Acronyms	IUPAC name	Formula	Cas no.	Molecular weight (g/mol)
BPF	4,4′-Dihydroxydiphenylmethane	C₁₃H₁₂O₂	620-92-8	200.23
BPE	1,1-Bis(4-hydroxyphenyl)ethane	C₁₄H₁₄O₂	2081-08-5	214.26
BPA	2,2-Bis(4-hydroxyphenyl)propane	C₁₅H₁₆O₂	80-05-7	228.29
BPB	2,2-Bis(4-hydroxyphenyl)butane	C₁₆H₁₈O₂	11-40-7	242.31
BPS	4,4′-Sulfonyldiphenol	C₁₂H₁₀O₄S	80-09-1	250.27
BPC	2,2-Bis(4-hydroxy-3-methylphenyl)propane	C₁₇H₂₀O₂	79-57-0	256.34
BADGE	2,2-Bis(4-hydroxyphenyl)propane bis(2,3-epoxypropyl) ether	C₂₁H₂₄O₂	1675-54-3	340.41

Due to its widespread use, almost 90% of people have trace levels of BPA in their urine (Wells, 2019). It was found that the use of alkaline detergent during dishwashing on the surface of the polymer can facilitate BPA release (Testai et al., 2016). Exceptions are observed in legislations for some BPA analogs such as bisphenol M, bisphenol P, and BPS (Sanchis et al., 2017). BPA and its analogs have similar characteristics of phenols leading to reactions forming ethers, esters, and salts. From study reports, bisphenols can be considered severe toxic compounds as they bioaccumulate in the human body from consuming animal-derived foodstuffs (e.g., eggs, milk, and meat) from animals that eat contaminated feed (Russo et al., 2019). BPA and its analogues have evidence of migration into food exceeding known migration limits. For example, BPA was determined to exceed the European Commission SML of 0.5 μg/g BPA in food-grade oil packaged in plastic, glass, and metal containers from China and Iran (Liu et al., 2013; Nemati et al., 2018). These substances can alter the endocrine system from human ingestion above the tolerable daily intake (TDI) limit (4 μg/kg) indicating the importance of regular testing to ensure consumer safety (Ong et al., 2022). One study in Spain detected BPA concentrations in canned products of 88.66 μg/kg, which exceeded the established migration limit of 50 μg/kg (González et al., 2020).

Overall, a majority of research demonstrated BPA migration did not exceed the TDI of 4 μg/kg body weight (BW) per day but other exposure including dermal absorption or air inhalation may influence the daily overall exposure (Huang et al., 2017). When other substitutes are used to avoid BPA exposure, it is important that regrettable substitutes are not used since their toxicity may not be known and may not have a TDI threshold. The presence of other endocrine-modulating chemical (EMC) substances may increase the chance of cumulative EMC exposure (Michałowicz, 2014). More research is necessary to properly understand the impact of these substances at a molecular level. For example, DEHP increases mitochondrial damage and slows respiration more quickly than DINP (Poitou et al., 2022). These substances can act together to increase the individual phthalate impact on health from continued human exposure to these complex mixtures (Ghisari & Bonefeld-Jorgensen, 2009).

BPA and the other analogs were our focus of review as they are used intentionally in food packaging (Ong et al., 2022) (e.g., can coatings) and can be introduced into the packaging structure through incidental contamination during the manufacturing process or via utilization of recycled materials. As there are certain regulations on the use of BPA, manufacturers often use alternatives, for example, BPS, BPF, BADGE, and so forth (Zhao et al., 2022) as they still provide performance and may not be specifically targeted for regulatory limitations. These alternatives are also discussed with their potential toxicity and migration tendency in this article.

4 TOXICOLOGICAL ASPECTS OF EMCs AND HUMAN HEALTH IMPACTS

Endocrine disrupting chemicals are also known as EMCs (Britannica, 2022). These chemicals can alter normal hormone activity in the human body. Phthalates/bisphenols are considered EMCs because of their toxic nature and their potential bioaccumulation that has been reported for over 20 years by the chronic hazard advisory panel (Panel, 1985). Phthalates can migrate from the polymer and enter the human body by dermal absorption (Dutta et al., 2020) in addition to ingestion. The European Union risk assessment and the FDA declared phthalates as EMCs (Moret et al., 2012; Ventrice et al., 2013). The source of human exposure to phthalates is generally from two sources: (i) desorption from consumer products migrating to the skin and (ii) migration from food-packaging materials into the food matrix (Yang et al., 2015). Phthalates are abundant in the environment as their release is accessible into the water, air, and soil (Gómez-Hens & Aguilar-Caballos, 2003).

LMW phthalates are defined as having C4–C8 carbon in the alkyl side chains and HMW phthalates have C9–C13 in the alkyl side chains (Chang et al., 2015; Otero et al., 2015; Pivnenko et al., 2016). Lin et al. (2011) stated that LMW phthalates, such as DEP, DBP, DMP, DNOP, and DEHP, are embryo envelope structure damaging and can cause physiological homeostasis to the embryo. Further research is required for HMW phthalates to confirm their ecotoxicity and cytotoxicity. Several works (Gallo et al., 2017; Jurek & Leitner, 2017; Lopez-Espinosa et al., 2007) reported that DBP can delay female sexual maturation, inhibiting follicle growth and harming sperm quality. DBP was found to be an estrogen antagonist (stops the action of another substance) (Zhang et al., 2011). Benson (2014) found that LMW phthalates can irritate eyes, nose, and throat. Experiments on animals (Noda et al., 2007) presented that phthalates were linked to lung, liver, and kidney damage, causing asthma and allergies (Haji Harunarashid et al., 2017; Ventrice et al., 2013; Yang et al., 2015). Experiments have already traced these phthalates in blood serum, amniotic fluids, breast milk, and so forth, showing a negative correlation between phthalates exposure and child brain health reported by several epidemiological studies (Benson, 2014; Ventrice et al., 2013). The environmental impact of phthalates is also powerful. The high hydrophobicity of phthalates (the calculated log now is 8.6) results in high persistence and bioaccumulation (Russo et al., 2019).

Bisphenols are also considered endocrine modulators (Gallart-Ayala et al., 2013). Several studies have demonstrated that BPA at very low doses (ng/L or mg/L) disrupts hormone action and modifies testosterone synthesis (Gao et al., 2013). Míguez et al. (2012) reported that BADGE and BFDGE are tumorigenic and mutagenic. BPA shows antiandrogenic activity, and as a result, the molecule can interact with the pregnane X, thyroid, and glucocorticoid receptors (Dreolin et al., 2019; Jurek & Leitner, 2015). Other bisphenols of the same family, such as BPS, BPF, BPAP, and BPAF, which have been used as BPA substitutes, are also marked as toxic (Chen et al., 2016). As these compounds have a similar structure as BPA and they also show resistance to biodegradability, increased obesity and type 2 diabetes risks are noted (Vilarinho et al., 2019).

5 REGULATIONS AND REPORTED CONCENTRATIONS IN FOOD PACKAGING: PHTHALATE AND BISPHENOL

5.1 Phthalates

Materials and articles used as FCMs are regulated by governmental regulation worldwide. European framework regulation 1935/2004/EC (directives 80/590/EEC and 89/109/EEC) provides human health protection concerning FCMs (Sanchis et al., 2017). The phthalates DMP, DEP, DBP, and DEHP were reported as priority toxic pollutants by the EPA (Yang et al., 2015). Commercially, the use of phthalates in plastic materials, PVC, PET, PVA, and PE, ranges from 10% to 60% by weight (Giuliani et al., 2020), presenting a significant reservoir increasing potential for environmental and human exposure.

Certain phthalates (BZBP, DEHP, bis-(2-methoxyethyl) phthalate, DBP, DIBP) are classified as category 1B (carcinogen, clear evidence for endocrine modulation) by the EU Regulation (EC) 1272/2008 and mandated to control their use in FCMs (European Union, 2008). This regulation banned the use of BZBP, DBP, and DEHP in 2015 (Russo et al., 2019). The use of six phthalates (DBP, BZBP, DEHP, DNOP, DINP, DIDP) in toddler toys has been restricted in Europe by the European Union (2005/84/EC) since 2007 (Chan & Shuang, 2012), and in the United States since 2018 (“82 FR 49938 - Prohibition of children's toys and child care articles aontaining specified phthalates”). The Consumer Product Safety Improvement Act in 2018 has permanently prohibited toys and child articles that contain higher than 0.1% of DEHP, DBP, and BZBP (CPSC, 2019). Assigned by the European Union, most of these substances have SMLs of 0.3 mg/kg for DBP, 30 mg/kg for BZBP, 1.5 mg/kg for DEHP, 18 mg/kg for DEHA, and 60 mg/kg for DEHT (Ong et al., 2022), and substances that do not have an SML should be within overall 0.01 mg/kg SML. Regulation from the FDA for DEHP in packaging liquid foods, for example, bottled water, is 0.006 mg/L (FDA, 2018b). Despite ongoing regulations (EU Regulation 10/2011, 2011), phthalates accounted for over 70% of the plasticizer market in 2014, and 65% in 2019 (Nagorka et al., 2022).

Phthalate annual global production approached 8 million tons in 2015 and DEHP accounted for 50% of the world production of phthalates. Two other commercially important phthalates are DIDP and DINP (Angnunavuri et al., 2022; Domínguez-Romero et al., 2022). The TDI for DEP (0.2 mg/kg), BZBP (0.5 mg/kg), DBP (0.01 mg/kg), and DEHP (0.05 mg/kg) BW per day is mandated by the European Food Safety Authority (EFSA) (Fan et al., 2014; Yang et al., 2015). The normal use of plasticizers in commercial products ranges from 25 to 100 phr of phthalates in PS, 30 phr in LDPE plastics, and 1 to 5 wt% (DMP, DEP, DBP, DNOP, BZBP, DEHP) in PET bottles (Grignard et al., 2012). Technical reports by the national toxicology program (NTP, 1982), USA, classify phthalates under substances of very high concern and cannot be authorized to use more than 0.1% by weight (REACH Annex XIV).

Recycling has been encouraged worldwide. The European Union recently proposed amendments regarding packaging waste (EC, 2015), which require 75% recycling of packaging waste by 2030. Recycling has the potential to contaminate direct food contact polymers with phthalates by including polymers from unapproved feedstocks (Pivnenko et al., 2016). According to the U.S. Federal Food, Drug, and Cosmetic Act (FFDCA), new substances such as FCMs must be screened first and get approval from the FDA as a food additive and dietary exposure should be within ≤1.5 μg per person per day. When used as a direct food additive under current Code of Federal Regulation (CFR) lists, dietary exposure should be within 1% of total daily intake (Ong et al., 2022). In virgin and recycled PET bottle analysis, recycled PET (20%−30% [w/w]) contained higher phthalate concentrations than virgin polymer (Fankhauser-Noti & Grob, 2007). PCR plastics are a potentially significant source of phthalate contamination especially when recycled feedstock material was manufactured prior to current regulations or from a different intended application. Recycled materials receive exemption status from REACH if 80% of the main constituent is the same as virgin materials and the remaining 20% (impurities) can be recycled without registration. This regulation may enable phthalates and bisphenols to re-enter polymer and paper manufacturing. It was estimated from material flow analysis in Europe 2012 that 5706 tons of DEHP contaminated plastic waste went for recycling, which accounts for 2% of total DEHP production in Europe. Similarly, 406 tons of DBP (5% of total production) and 120 tons of BZBP (1% of total production) remained in plastic while recycling, and re-entered into the polymer cycle through material recycling (Lee et al., 2014). There are only a few examples of research demonstrating the potential impact of recycling on phthalate content (Alabi et al., 2019), leaving the relationship between recycling and phthalate contamination unclear.

5.2 Bisphenol

The European Union allows BPA use in FCM only under SML of 0.05 mg/kg (BFR, 2022). Due to recent animal studies and evaluation of the toxic effect on human cells conducted by the (EFSA (2021), the enforced TDI has been reduced to 0.004 mg/kg BW (EFSA, 2021) (Hessel et al., 2016; Jurek & Leitner, 2015). Still, in the case of BADGE (including its hydrolyzed derivatives), the SMLs regulation is 9 mg/kg (Sanchis et al., 2017). According to commission directive No. 2002/72/EC, the BPA acceptance quantity is 0.1 mg/kg. As per calculation, 1 kg of food has a contact surface of 6 dm² of packaging material, and BPA concentrations are calculated based on the grammage (mass per m²) in the case of paper (Jurek & Leitner, 2015).

Different countries have variations in regulations toward bisphenols in FCMs. Denmark outright banned BPA in food contact plastic materials for infants (0–3 years) (Siddique et al., 2021). As there is little information regarding the effect of BPA exposure on child brain health at a low dose, commission directive 2011/8/EU prohibits using BPA in polycarbonate infant feeding bottles (Christensen et al., 2014). The Canadian Government (2009) banned the importation and marketing of children's products that contain BPA, while the United States (2011, effective from 2013) imposed a ban on marketing BPA-containing bottles or cups that have a detection level of more than 0.1 μg/kg and intended for children (Siddique et al., 2021). Identified occupational exposure limits (IOELs) is 10 mg/m⁻³ in the European Union, although some of the member states have lower IOELs, for example, in Germany, the limit is 5 mg/m⁻³ (Christensen et al., 2014).

The World Health Organization (WHO) suggests imposing the “as low as reasonably achievable” principle to limit the use of BPA and decrease the human exposure from food packaging and specifically in the case of prepackaged infants’ formula (FAO-WHO, 2009). There is an increasing number of prohibitions on the use of BPA. However, the annual production increased by 5.1% from 2014 to 2019 (Businessware, 2015; Vilarinho et al., 2019; Wang et al., 2021). In 2018, the EFSA (EFSA Panel on food contact materials & Aids), initiated a scientific approach to evaluate BPA hazards for future occurrences (Dreolin et al., 2019; European Commission, 2013). A noticeable source of bisphenol exposure comes from paper, cardboard, ink products, and thermal papers (as a color developer) (Cunha et al., 2011; Lopez-Cervantes & Paseiro-Losada, 2003). Cunha et al. (2011) revealed that canned beverages and powdered infant formula contain BPA and BPB when analyzing products from the Portuguese market.

(2014), On average, 30% of all thermal papers are included in the recycling stream (Schreder 2010). Using recycled paper and cardboard products as FCMs can pose more risks by migrating toxic components from the packaging into packed goods (Jurek & Leitner, 2015). Higher BPA concentrations were found in recycled fiber products compared to virgin paper products (Vinggaard et al., 2000). Bisphenol-contaminated paper can be observed in food packaging to kitchen towels. Printing inks are another probable source of contamination (Gao et al., 2013; Sanchis et al., 2017). The scenario can be understood from analysis where the detected concentration of BPA in virgin PET polymer was remarkably lower (25–432 ng/g) than in recycled material (394–10,120 ng/g) (Dreolin et al., 2019).

6 PHTHALATES AND BISPHENOLS DETECTION TECHNIQUES IN FCMs

6.1 Blank measurements for phthalate and bisphenol in analysis

Process blank measurements are derived from analyzing the matrix, reagent, or any residual contamination in the analytical device or process affecting the measurements while performing the analytical procedure. Phthalates are ubiquitous in the laboratory environment, potentially generating false positive results at low concentration thresholds. For example, DEHP and DBP have been detected at low concentrations in process blanks, which could contribute to compliance failures, but DINP, DIDP, and BZBP cause fewer problems as they have higher regulatory limits. Blank concentrations can measure relatively high because of phthalate contamination during analysis, sample preparation, or extraction. DBP and DEHP have been detected at 3 and 2.4 μg/m level, respectively, in laboratory air and 100 μg/L DBP in commercially available hexane by Frankhauser-Noti and Grob (2007) using TRACE GC–MS integrated with programmed temperature vaporizing injector and a mass spectrometer. In this analysis, phthalates were enriched in the stationary phase by vacuuming the mass spectrometer to collect the atmosphere and cooled to ambient temperature. The quantification of phthalates in the laboratory air was determined by dividing the result from MS by the volume of air sampled into the column (Fankhauser-Noti & Grob, 2007).

Cross-contamination is also crucial for BPA analyses to ensure accurate measurements with low limits of detection (LODs). Examples to avoid cross-contamination include soaking all glassware in acetone (30 min) or an appropriate solvent, washing with acetone or dichloromethane, rinsing with solvent, and drying at 120–200°C for a fixed period or overnight (Ayamba et al., 2020; Fierens et al., 2012; Pivnenko et al., 2016; Shen, 2005). Another technique is to clean glassware with blank tested solvents, bake glassware at 400°C for approximately 2 h, and add aluminum oxide with the wash solvent into the vials on an autosampler plate (Yang et al., 2015). This ensures that the glassware, the syringe needle, and reagents are free of phthalate and bisphenol contamination, making analysis quick and simple. The decontamination procedure for both phthalate and bisphenol analysis is the same. To clean the syringe properly, it is important to ensure the needles are sufficiently submerged in the wash solvent (hexane, xylene containing activated aluminum oxide, or silica gel). Contamination problems can be frequent when the syringe sampler is connected to an autosampler. Other options can be fast injection of sample into a cool chamber (40°C), which reduces desorption and evaporates the split outlet to discard the analyte, setting precolumn in back-flush mode. In glassware, 90% reduction in DBP and DEHP is possible by solvent rinsing followed by heating at 400°C for 1–2 h (Fankhauser-Noti & Grob, 2007) or keeping overnight in an oven. Placing glassware in a desiccator containing aluminum oxide will help avoid phthalate adsorption from the air. Apparatuses that cannot be processed by heating (volumetric glass wares) should be rinsed in a blank tested solvent containing aluminum oxide (Haji Harunarashid et al., 2017; Moret et al., 2012).

6.2 Sample preparation/extraction for phthalate and bisphenol analysis

To analyze contaminants in polymer and paper specimens, it is necessary to extract them first to separate the analyte from the matrix (Gawlik-Jędrysiak, 2013). In most cases, the samples (packaging materials) are cut into small pieces ranging from 1 cm² (Fierens et al., 2012; Park et al., 2016) to 3 cm² (Ayamba et al., 2018), and 1−2 g of sample is collected for solvent extraction (Al-Natsheh et al., 2015; Bonini et al., 2008; Fierens et al., 2012). There are several approaches for extractions of FCM contaminants, including Soxhlet extraction (Bonini et al., 2008; Gawlik-Jędrysiak, 2013), solid–liquid extraction (Ronderos-Lara et al., 2018), ultrasound-assisted extraction (UAE) (Fierens et al., 2012; Gawlik-Jędrysiak, 2013; Otero et al., 2015), focused ultrasound solid–liquid extraction (FUSLE), solid-phase microextraction (SPME) (Cao, 2008), quenchers, and microwave-assisted extraction. Overall, the extraction procedure of the sample for both phthalate and bisphenol analysis is similar in most scenarios.

The SPME technique is popular for extracting volatile and semivolatile compounds where mostly GC is conjugated in headspace mode (HS-SPME). This method uses fused silica or metallic fiber (coated with an extractive phase for analytes) without direct contact with the sample (Sanchis et al., 2017). The traditional method, Soxhlet extraction, has moderate use in phthalates/bisphenols investigation, while the UAE technique is becoming popular. In the Soxhlet procedure, cyclohexane, hexane, dichloromethane, or ethyl acetate is used as the solvent with extraction time ranging from a minimum of 4 h up to 24 h at room temperature. However, increasing the extraction temperature can reduce the extraction time due to increased diffusion rates similar to the migration risks mentioned above. The major disadvantages in Soxhlet extraction are the long extraction times, and consumption of large amounts of solvents (100−500 mL) that can increase costs and environmental disposal issues. On the other hand, it minimizes any type of agitator to contact the matrix and solvent, which can introduce incidental contamination (Salazar-Beltrán et al., 2018). The microwave-assisted extraction method was used by Pivnenko et al. (2016) at 120°C for 20 min to extract phthalates in waste plastics from households and industry (Pivnenko et al., 2016). Nonetheless, there is always improvement in the extraction methods with higher recovery percentages. The UAE is a quick extraction method (10–60 min) with an acceptable recovery range. This technique also requires a small solvent amount (4–50 mL), making it feasible for researchers and for high-throughput analyses and reduced costs. This method generates a high-frequency pulse (e.g., 20 kHz) at high shear stress, resulting in localized high temperatures and pressure to make good contact between the solvent and the solid matrix. Shen (2005) used sample soaking in a solvent followed by sonication.

Different solvents like hexane, acetone, and water were compared, in which acetone provided good recoveries up to 90%−124% (Relative Standard Deviation (RSD): 12.5) and hexane with the recovery of 90.5% (RSD 8.5), with a detection level of phthalates at 10.0 μg/kg. Recoveries of more than 100% can raise the question about contamination (Russo et al., 2015) or less certainty in the measurement; although recovery 100% + 15% is acceptable in some cases because of ion enhancement/suppression. UAE has been successfully employed to extract from PET (Li et al., 2004; Otero et al., 2015) and PS (Fasano et al., 2012; Guart et al., 2011; Shen, 2005). Fierens et al. (2012) employed an ultrasonic bath to extract DMP, DEP, DBP, BZBP, and DEHP from a plastic sample (polymer type not mentioned) with recovery percentages up to 99% and as low as 82% (Salazar-Beltrán et al., 2018; Shen, 2005). Shen et al. (2004) performed a sonication-assisted extraction method to determine eight phthalates in plastic products with a recovery of 82%–106% (Shen, 2005).

Simple agitation methods (e.g., stirring, vortexing, and sonication) are efficient in extracting bisphenols (BPA, BPF, BADGE, and BFDGE) readily using moderately polar solvents (e.g., ethanol, methanol, and acetonitrile) (Björnsdotter et al., 2017). Van Holderbeke et al. (2014) employed modifications from the Fierens et al. (2012) method (ultrasonic method with n-hexane) with additional steps to exchange the sample extracts with dichloromethane after purification with gel permeation chromatography. Qiao et al. (2014) used a more advanced phthalate determination technique with magnetic dummy molecularly imprinted dispersive SPE as template mimic (Qiao et al., 2014). Sonication/ultrasonication coupled to SPE/SMPE followed by GC–MS analysis was also used in the analysis. In Shen's (2005) work, phthalate in plastic products was analyzed by soaking the sample in solvent for 30 min, followed by 10-min sonication, which facilitates the contact between solvent and sample. Bisphenols were extracted with the ultrasonic method at the amplitude of 100% for 5 s. A 100-time increased extraction rate can be gained by FUSLE, which is a simple, safe, and inexpensive method. This extraction method has been used for bisphenol extraction in recycled paper used as food packaging (Pérez-Palacios et al., 2012; Sanchis et al., 2017).

Medium-polarity solvents, for example, acetone acetonitrile, are preferable when extracting polar to apolar compounds. The extraction efficiency is calculated by adding or fortifying the sample with target compounds and calculating the recovery of the compound. Vavrouš et al. (2016) yielded comparable amounts of spiked analytes when using acetone, but lower recoveries were determined when using acetonitrile. Extraction for 1 h using a moderately polar solvent (e.g., acetonitrile, ethanol, and methanol) extracted BPA with a recovery of 96%–98% (Björnsdotter et al., 2017). An advanced process is ambient MS that can directly analyze samples with little to no sample pretreatment required. This technique is growing rapidly because of its rapid, high-throughput criteria to analyze hazardous molecules (Chen et al., 2017).

6.3 Derivatization for bisphenol sample preparation

Analytically, BPA can be detected at as low as nanograms per kilogram levels by both HPLC and GC methods. However, GC-MS or GC-MS/MS is the most commonly cited technique. In the case of LC analysis, LC–MS, fluorescence detection (Santillana et al., 2011), and diode array detection are favored (Rezaee et al., 2009), but in complex sample analysis (e.g., paperboard) with LC–MS or LC–MS/MS, sometimes ion suppression occurs reducing the response. Derivatization is often required for bisphenol analysis to increase the volatility and selectivity in GC methods. GC–MS and GC–MS/MS use several ionization modes, among which negative chemical ionization (NCI) (Li et al., 2010) or electron impact ionization (EI) (Albero et al., 2012; Lu et al., 2013) are prominent. The analysis with low limits of quantification (LOQs) needs GC–MS in selected ion monitoring mode (Paci & La Mantia, 1999) or GC–MS/MS in multiple reaction monitoring (MRM) as they increase response more compared to scanning modes.

Derivatization is a beneficial step that replaces the active (polar) hydrogen atoms in the analyte, lowering the boiling point. The active hydrogens increase the capability of the compound to form hydrogen bonds and compound polarity, as many compounds with active (polar) hydrogens have low volatility, which hinders GC analysis. If these hydrogens are replaced with a derivatizing agent, the compounds become more volatile, which facilitates analysis by GC–MS. Silylation is often employed for the derivatization of metabolites by chemical reaction. In silylation derivatization, silyl groups replace hydrogen atoms in OH, COOH, SH, NH, CONH, POH, or SOH; the most popular silylation agents are based on trimethylsilyl (TMS) molecules with a good leaving group (Moldoveanu & David, 2018). Jurek and Leitner (2015) applied the derivatization process to increase the volatility and thermal stability of the polar compounds containing phenolic groups (bisphenol). According to literature, silylation reagents are the most common derivatization reagents, for example, bis(trimethylsilyl)trifluoroacetamide (BSTFA), with or without trimethylchlorsilane used as catalyst (Albero et al., 2012; Fenlon et al., 2010), N-methyl-N-(trimethylsilyl) trifluoroacetamide, and N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide, to analyze the presence of bisphenols in FCM samples by GC–MS/MS (Kosjek et al., 2007). In another study, Jurek and Leitner (2015) performed four different GC analyses comparing BPA concentrations in paper food packaging samples where two derivatization reactions were applied prior to injection. One was BSTFA and the second was halide alkylation with pentafluorobenzoyl chloride (PFBOCl). For PFBOCl derivatives, GC–MS using EI and GC–MS with NCI were used, whereas for BSTFA derivatives, GC–MS and GC–MS/MS were used. Only the EI is used for the silylated derivatives (up to 96% recovery for the GC–MS) as they show low electrophilicity toward NCI.

Tandem mass spectrometry methods such as MRM are more selective and sensitive compared to MS in single-ion monitoring mode. The GC–MS/MS method was determined to be 10 times more sensitive than the GC–MS method due to the increased selectivity and sensitivity. For the analysis of PFBOCl, NCI–GC–MS was 100 times more sensitive than EI–GC–MS. Recovery for each method was 74%–88% with residual standard deviation scores <4%. (Jurek & Leitner, 2015). European Union (2018) and Ronderos-Lara et al. (2018) developed a reproducible method for GC–MS (71.8% and 111.0% recovery) where a silylation step was carried out after solid-phase extraction (SPE). The analysis successfully determined BPA (174.6 ng/mL) in a sample where the instrumental LODs ranged between 24.7 and 37.0 ng/mL (Ronderos-Lara et al., 2018). The bisphenol compounds have an active hydroxyl group in their chemical structure that is responsible for imprudent interaction with the GC column stationary phase during analysis and as a result, broad, nonsymmetrical peaks were observed resulting in low sensitivity. Derivatization using TMS to detect BPA, BPC, BPF, and TMBPF from metal food container was analyzed by Zhang et al. (2020) using GC–MS analytical methods. Here, TMS derivatization is important as it generates di-trimethylsilyl derivatives of bisphenols analyte to minimize the interactions with GC column stationary phase.

6.4 Analytical method for phthalates

Several methods have been developed and employed in different studies to measure analytes in different matrices, mainly based on GC methods coupled to MS or other detectors (diode array detector, flame ionization detector, and UV detector). A detailed list of the utilized methodologies and techniques by researchers for detecting phthalates in food packaging are tabulated in the Supporting Information. Phthalates are low in molecular weight and polarity, thermally stable, and adequately volatile for GC analysis. LC (Prakash et al., 2020) has also been reported in the analysis of various phthalates in beverages, polymers, and paper packaging (Chang et al., 2015; Li et al., 2004) coupled to different detectors (Salazar-Beltrán et al., 2018). For LC analysis, hydrophobic stationary phase columns such as C18, or C8, and a combination of polar solvents, for example, methanol, acetonitrile, or water, have common applications in phthalate quantification. LODs reported as a minimum 0.12 μg/L to a maximum 0.50 μg/L using C8 column and a minimum 2.0 μg/L to a maximum 2.2 μg/L using C18 column. However, the lowest was 0.013 μg/L using an XDB-C8 column (Fan et al., 2014; Salazar-Beltrán et al., 2018). During analysis, analytes’ polarity plays a crucial role in selecting an analytical column.

Many studies have reported that GC methods performed better at lowering LODs than LC methods as LC co-elution can occur during separation and consumes large volumes of solvent (Moret et al., 2012; Salazar-Beltrán et al., 2018). Short analysis times, good resolution, reproducibility, and sensitivity have made GC–MS analysis a popular choice for researchers (Al-Natsheh et al., 2015; Otero et al., 2015; Yang et al., 2015) in targeted and nontargeted analyte analysis in packaging materials. In the nontarget approach, a spectral library compares the derived mass spectra with the stored reference mass spectra. As we already know that phthalates have relatively low polarity and, for this reason, apolar column with description 5% phenyl–95% dimethylpolysiloxane and a mid-polar column with description 50% phenyl–50% dimethylpolysiloxane have applicability with EI as the ionization technique (Alabi et al., 2014; Dreolin et al., 2019).

When a screening approach is selected, GC–MS can quantify an analyte in several matrices (García Ibarra et al., 2018). GC–MS is suggested for detection of DEHP, BZBP, DBP, DEP, DEHP, DCHP, and DINP (Chang et al., 2015; Otero et al., 2015; Park et al., 2016). Phthalates were determined in many food packaging materials, such as in paper cups (Park et al., 2016), polythene film (Bonini et al., 2008; Yang et al., 2015), plastic beverage packaging (Chang et al., 2015), plastic-based food packages, PE bags (Ayamba et al., 2018), and cardboards (Fierens et al., 2012). GC–MS analysis measures the mass-to-charge (m/z) ratio of ionsproduced by analytes in the sample after induced ionization (Salazar-Beltrán et al., 2018). The most abundant ion of orthophthalates in the EI ionization mass spectrum at 70 eV is 149 m/z and is usually selected for many phthalates (Chang et al., 2015). In GC–MS analysis, DB-5 MS column (5% phenyl, 95% dimethylpolysiloxane) is mostly used in single-ion monitoring (Paci & La Mantia, 1999) mode for phthalate detection (Fankhauser-Noti & Grob, 2007; Haji Harunarashid et al., 2017; Yang et al., 2015). GC is used combined with a tandem mass spectrometer (Yang et al., 2015), quadrupole mass spectrometry, triple quadrupole (Ayamba et al., 2020; Fan et al., 2014), or high-resolution GC with flame ionization detector (Bonini et al., 2008), which are the most used techniques.

6.5 Analytical method for bisphenols

Similar GC methods commonly used for phthalates (e.g., MS, diode array detector, flame ionization detector, and UV detector) are also used for the analysis of bisphenols. Chromatographic separation of bisphenols has been achieved with an Agilent DB-5 MS column (30 m × 0.25 mm × 0.25 μm) with an initial oven temperature averaged at 50°C and rising to a final temperature above 280°C (Chang et al., 2015; Fan et al., 2019; Shen, 2005). The injector temperatures ranged from 250 to 300°C in the literature (Ayamba et al., 2020; Bonini et al., 2008; Chang et al., 2015; Fierens et al., 2012; Park et al., 2016; Pivnenko et al., 2016; Yang et al., 2015). From literature, BPA quantification was mostly conducted on paper packaging samples. Sanchis et al. (2017) performed chromatographic analysis using the column 5% polysilarylene–95% polydimethylsiloxane with EI ionization source having LOD and LOQ between 0.05 and 0.064 mg/L when MS quadrupole was used. BPA is ubiquitous making it necessary to understand the background contamination by using a process blank test to confirm reliability of the results as described above.

BPA, DBP, and DEHP in the paper matrix were analyzed by both HPLC and GC–MS (Lopez-Espinosa et al., 2007) with 40 sample counts. The analysis found DBP in most samples, while BPA was present in 50% of samples with less frequency. The author found BPA levels in takeaway paper packaging in a range of 0.00005−1.81 μg/g, which was lower than the concentrations (0.55–24.1 μg/g) detected by Vinggaard et al. (2000) in recycled kitchen rolls but the concentration was higher than virgin rolls (0.03–0.1 μg/g). BPA levels found by Ozaki et al. (2004) showed recycled material contained 10 times more BPA than virgin components (Ozaki et al., 2004). When used for kitchen rolls, the recycled paper showed BPA contamination, while virgin paper did not. In the case of phthalates, both virgin and recycled paper showed the contamination (Vinggaard et al., 2000).

A method was developed by Notardonato et al. (2019) to determine phthalates and BPA simultaneously in beverages by GC ion trap mass spectrometry using a TRB-Meta X5 (30 m × 0.25 mm × 0.25 μm) fused-silica capillary column (SE-54, 5% phenyl–95% dimethylpolysiloxane). Four types of solvents (i.e., n-hexane, n-heptane, iso-octane, and benzene) and volumes ranging from 150 to 250 μL were compared for optimal efficiency. Solvent choice is normally selected based on density (lower than that of water), which facilitates direct recovery of the solution. The best recoveries were obtained with n-hexane. During the extraction procedure, stirring the sample for 5 min and providing an ultrasonic bath for 6 min showed sufficient phthalates/bisphenols recovery (Notardonato et al., 2019).

7 CONCLUSION

Current data suggest that EMCs (phthalates, bisphenols) can migrate from polymers into food matrices. High-risk products are FCMs produced from postconsumer materials such as recycled paper fiber and plastic due to the potential for consumer abuse and cross-contamination from nonfood-grade materials. Although there has been limited research and scientific data to demonstrate the relation between recycling rates and the abundance of phthalates and bisphenols in FCMs, previous research has demonstrated that EMCs can be reintroduced into the plastic supply chain through the recycling stream in Europe. The evaluation of PCR polymer before use as raw material in FCMs is compulsory with appropriate detection methods and to comply with the applicable standards set by the specific country. The European Commission has developed a regulation to ensure that FCMs must meet the specific SML (DBP 0.3 mg/kg, DEHP 1.5 mg/kg, DEHT 60 mg/kg). According to the FDA, a substance is considered unsafe if not listed in Title 21 of the Code of Federal Regulations, and the daily exposure should not exceed 1.5 mg per person per day. A new FCM substance requires premarket approval from the FDA and a screening process according to the FFDCA. Manufacturers should closely monitor the source of plastics and their chemical composition before utilizing as FCMs to increase human and environmental safety and comply with local and global regulations.

Recent analytical techniques to determine the hazardous chemicals bisphenols and phthalates in FCMs and their related regulations were reviewed to provide guidance for researchers, manufacturers, brand owners, and governmental and nongovernmental agencies. Such information is critically important as bisphenols and phthalates regulations are stringent in some countries with very low allowable levels and research has detected migration exceeding these limits. Alternatively, some countries have little oversight in the absence of threshold levels or very high allowable levels. The existing permitted values are often evaluated and reconsidered depending on the outcome of animal model studies to evaluate the risk of human exposure. The increasing demand for BPA and phthalate-free (or nonintentional) products has resulted in new legislation across the globe and increased the introduction of suitable replacements in the market, of which some are not yet regulated. Screening and nontargeted procedures coupled with appropriate techniques can generate successful detection of emerging EMC analogs that potentially could possess similar toxicity traits and contribute to increased human and environmental safety.

SPME, sonication/ultrasonication coupled to SPE/SMPE, HS-SPME, and FUSLE are popular sample preparation techniques that have shown good recovery and potential for automation with less organic solvent consumption. Repeated solvent extractions can be used to confirm complete extraction from the matrix but also add extra steps and additional solvent use. Future research is needed to determine alternative strategies to allow simple, complete extractions whenever possible with appropriate LODs and quantification. In the current literature, one can find the application of several extraction methods, though a suitable, rapid, and definite extraction technique has yet to be developed. More research is needed to develop simultaneous screening methods that are both economical and robust to enable proper screen of FCMs materials, particularly those composed of recycled materials due to the higher potential for unapproved intentionally added substances and NIAS. GC–MS techniques are more popular for analyzing phthalates, bisphenols, and other analogues, and are useful tools for screening nontargeted contaminants. This review provides an updated resource for addressing regulatory concerns and potential impact to human and environmental health by determining appropriate methods and limitations for detecting EMCs in FCMs.

AUTHOR CONTRIBUTIONS

Khairun Tumu: Conceptualization; visualization; writing—original draft; investigation. Keith Vorst: Funding acquisition; project administration; writing—review and editing; supervision. Greg Curtzwiler: Conceptualization; investigation; funding acquisition; writing—original draft; writing—review and editing; project administration; resources; supervision; visualization.

ACKNOWLEDGEMENT

Open access funding provided by the Iowa State.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Supporting Information

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Citing Literature

Volume22, Issue2

March 2023

Pages 1337-1359

Endocrine modulating chemicals in food packaging: A review of phthalates and bisphenols