toxics Review Comprehensive Insight from Phthalates Occurrence: From Health Outcomes to Emerging Analytical Approaches Catarina Luís 1,2 , Manuel Algarra 3 , José S. Câmara 1,4 and Rosa Perestrelo 1,* 1 CQM-Centro de Química da Madeira, Campus da Penteada, Universidade da Madeira, 9020-105 Funchal, Portugal; [email protected] (C.L.); [email protected] (J.S.C.) 2 Faculdade de Ciências da Vida, Unidade de Ciências Médicas, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal 3 Department of Inorganic Chemistry, Faculty of Science, Campus de Teatinos s/n, University of Málaga, 29071 Malaga, Spain; [email protected] 4 Departamento de Química, Faculdade de Ciências e Engenharia, Campus da Penteada, Universidade da Madeira, 9020-105 Funchal, Portugal * Correspondence: [email protected]; Tel.: +351-291-705-224 Abstract: Phthalates are a group of chemicals used in a multitude of important industrial products (e.g., medical devices, children’s toys, and food packages), mainly as plasticizers to improve me- chanical properties such as flexibility, transparency, durability, and longevity of polyvinyl chloride (PVC). The wide occurrence of phthalates in many consumer products, including foods (e.g., bottled water, soft drinks, wine, milk, and meat) brings that most people are exposed to phthalates every day, which raises some concerns. Adverse health outcomes from phthalates exposure have been associated with endocrine disruption, deformities in the human reproductive system, increased risk of preterm birth, carcinogen exposure, among others. Apprehension related to the health risks and Citation: Luís, C.; Algarra, M.; ubiquitous incidence of phthalates in foods inspires the development of reliable analytical approaches Câmara, J.S.; Perestrelo, R. that allow their detection and quantification at trace levels. The purpose of the current review is to Comprehensive Insight from provide information related to the presence of phthalates in the food chain, highlighting the health Phthalates Occurrence: From Health risks associated with their exposure. Moreover, an overview of emerging extraction procedures and Outcomes to Emerging Analytical high-resolution analytical approaches for a comprehensive quantification of phthalates is presented. Approaches. Toxics 2021, 9, 157. https://doi.org/10.3390/toxics9070157 Keywords: phthalates; health risk; extraction techniques; analytical approaches Academic Editors: Lidia Caporossi and Maria Marino Received: 18 May 2021 1. Introduction Accepted: 28 June 2021 Phthalates, generally known as phthalate esters (PAEs, Supplementary Material), are Published: 1 July 2021 a family of chemicals used industrially in a wide variety of consumer products, primarily as plasticizers (e.g., substances added to plastics to increase their flexibility, longevity, Publisher’s Note: MDPI stays neutral durability, and transparency), is durable, flexible polyvinyl chloride (PVC) applications with regard to jurisdictional claims in and polyvinyl acetate, largely for the construction, automotive, wire and cable sectors, in published maps and institutional affil- addition to non-PVC applications such as rubber products, sealants, adhesives, and coat- iations. ings. Generally, they are organized into two main distinct groups: higher-molecular weight (HMW) phthalates (chemical backbone with 7–13 carbon atoms), and lower-molecular weight (LMW) phthalates (chemical backbone with 3–6 carbon atoms), with differentiated applications, legal requirements, and toxicological properties. While the LMW phthalates, Copyright: © 2021 by the authors. such as butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP), and diethyl phthalate Licensee MDPI, Basel, Switzerland. (DEP), are mainly used as solvents in different consumer and personal care products, HMW This article is an open access article phthalates including di-isononyl phthalate (DiNP), and di-2-ethylhexyl phthalate (DEHP), distributed under the terms and are primarily used as plasticizers to soften PVC products. The structures, common uses, conditions of the Creative Commons and health effects of phthalates commonly monitored in foods and packaging materials are Attribution (CC BY) license (https:// summarized in Table1. creativecommons.org/licenses/by/ 4.0/). Toxics 2021, 9, 157. https://doi.org/10.3390/toxics9070157 https://www.mdpi.com/journal/toxics Toxics 2021, 9, x FOR PEER REVIEW 2 of 28 Toxics 2021, 9, x FOR PEER REVIEW 2 of 28 Toxics 2021, 9, x FOR PEER REVIEW 2 of 28 Toxics 2021Toxics, 9, 1572021, 9, x FOR PEER REVIEW The structures, common uses, and health effects of phthalates commonly monitored2 of 262 of in28 Toxics 2021, 9, x FOR PEER REVIEW The structures, common uses, and health effects of phthalates commonly monitored2 of in28 foods and packaging materials are summarized in Table 1. foodsThe structures, and packaging common materials uses, areand summarized health effects in ofTable phthalates 1. commonly monitored in foods and packaging materials are summarized in Table 1. Toxics 2021, 9, x FOR PEER REVIEW Table 1. The most widely used PAEs and their metabolites [1–6]. 2 of 28 TableThe 1.TableThe structures, most1. The widely most common widely used PAEs used uses, and PAEs and their and health metabolites their metaboliteseffects [1– 6of]. phthalates [1–6]. commonly monitored in TheTable structures, 1. The most common widely used uses, PAEs and and health their metaboliteseffects of phthalates [1–6]. commonly monitored in Chemical foods and packaging materials are summarized in Table 1. Phthalate Chemical foodsCF and a/MWa packaging bb Common materials Uses are summarizedEffects in Table 1. Metabolitesc c PhthalatePhthalate ChemicalStructure CFCF a/MW/MW b CommonCommon Uses UsesEffects Effects MetabolitesMetabolites c Structure a b c Phthalate Structure TheTableCF structures, 1. /MWThe most common Commonwidely used uses, Uses PAEs and and health theirEffects metaboliteseffects of phthalates [1–6]. commonlyMetabolites monitored in Structure C7H7 O C7H7 Table 1. The most widely used PAEs and their metabolitesLong-term [1–6]. O foods and packagingAs a materialsplasticizerAs a plasticizer are for summarized vinyl for Long-term in Table occupational 1. Chemical C7H7 As a plasticizer for vinyl Long-termoccupational occupational O a b c ButylPhthalate benzyl Chemical CCF19 H/MW20O4/ Asfoams,Common a plasticizer oftenvinyl Uses foams,used for as oftenvinyl EffectsLong-termexposure to occupational BBP increase the MetabolitesMono benzyl Butyl benzyl O C19Ha 20O4/ b foams, often used as exposureexposure to to BBP BBP increase the Mono benzylc Phthalate Structure O TableCFC 191. /MWHThe20O most4 / Commonwidely usedused Uses PAEs as floor and tiles. theirEffects metabolites [1–6]. Mono benzylMetabolites ButylButylphthalate benzyl benzyl Structure C312.419H20 g/molO4/ foams,floor tiles. often Traffic used conesas , exposureriskincrease of multiple to the BBP risk myeloma, increase of the Monophthalate benzyl phthalate OC7H7 312.4312.4 g/mol g/mol floor tiles.Traffic Traffic cones, cones food, risk of multiple myeloma,phthalate phthalate phthalatephthalate(BBP) (BBP) ChemicalO OC7H7 312.4(LMW) g/mold d floorfood conveyortiles. Traffic belts cones, and, riskteratogenicity,multiple of multiple myeloma, and myeloma, phthalate(MBzP) (BBP)Phthalate O O (LMW)CF(LMW) a/MWd b foodAsCommon a plasticizerconveyorconveyor Uses belts for belts, vinyl, and teratogenicity,Long-termEffects occupational and (MBzP) (MBzP)Metabolites c d As a plasticizer for vinyl Long-termteratogenicity, occupational and Butyl(BBP) benzyl StructureO C(LMW)19H20O4/ foams,foodartificial conveyor oftenand leather. artificial used belts as, and exposureteratogenicity,reproductive to BBP effects. and increase the Mono(MBzP) benzyl O OC H artificial leather. reproductivereproductive effects. Butyl benzyl C4H9 C19H20O4/ foams, often used as exposure to BBP increase the Mono benzyl O CO47H97 artificialleather. leather. reproductive effects. phthalate O 312.4 g/mol floor tiles. Traffic cones, riskeffects. of multiple myeloma, phthalate phthalate OC4H9 312.4 g/mol Asfloor a plasticizertiles. Traffic for cones vinyl, Long-termrisk of multiple occupational myeloma, Mono-n-butylphthalate (BBP) O (LMW)d food conveyor belts, and teratogenicity, and Mono-n-butyl(MBzP) (BBP) (LMW)d food conveyor belts, and teratogenicity, and (MBzP) Butyl benzyl O C19H20O4/ foams, oftenAs a plasticizer. used as exposureSuspected to BBP increaseMono-n-butyl the Mono-n-butylphthalateMono benzyl Di-n-butyl O CC16HH22OO4/ / Asartificial a plasticizer. leather. Most reproductive effects. phthalate Di-n-butylphthalate O C H C312.41616H22 g/mol22O4/ 4 Asfloorartificial a plasticizer. tiles. leather. Traffic Most cones , Suspectedriskreproductive of multiple teratogenic effects. myeloma, and phthalate(MBP); Mono- Di-n-butyl O4 9 Most common teratogenic and phthalate (MBP); Di-n-butylphthalate C4H9 C278.3278.316H22 g/molO g/mol4/ Ascommon a plasticizer. phthalate Most Suspected teratogenic and (MBP); Mono- phthalatephthalate(BBP) (DBP) 278.3(LMW) g/mold commonfood conveyorphthalate phthalate belts added , and to Suspectedendocrineteratogenicity,endocrine disruptorteratogenic and Mono-isobutyland (MBP);isobutyl(MBzP) Mono- (LMW) Mono-n-butyl phthalate(DBP) 278.3(LMW) g/mol commonadded tonail phthalatenail polish. polish. endocrinedisruptor disruptor phthalate (MiBP)isobutylMono-n-butyl (DBP) O (LMW) addedartificial to leather.nail polish. endocrinereproductive disruptor effects. isobutylphthalate (DBP) (LMW) added to