Browse > Article
http://dx.doi.org/10.5668/JEHS.2021.47.1.1

Regulation of Phthalates and Their Alternatives in Children's Products and Their Toxicity Data  

Lee, Inhyae (Institute of Natural Science, Yongin University)
Ra, Jinsung (Regulatory Chemical Analysis & Risk Assessment Center, Korea Institute of Industrial Technology)
Ji, Kyunghee (Department of Occupational and Environmental Health, Yongin University)
Publication Information
Journal of Environmental Health Sciences / v.47, no.1, 2021 , pp. 1-19 More about this Journal
Abstract
Objectives: Phthalates, which are widely used as plasticizers, have been recognized as endocrine disruptors. In the present study, we provided information on the regulation of these chemicals and summarized the information available on their detection and toxicity in children's products and those of their alternatives. Methods: The regulatory frameworks related to phthalates in children's products in Korea, the United States (US), and the European Union (EU) were compared. Data on the detection concentration of 16 phthalates and seven phthalate alternatives that could be used in polyvinyl chloride (PVC) plastic products for children as well as on their toxicity classification and endocrine disruption toxicity were collected from the literature. Results: Korea adopted US and EU chemical standards for six phthalates (DEHP, BBP, DBP, DINP, DIDP, and DNOP), but not others (e.g., DIBP, DPP, DHP, and DCHP). Among the ten phthalates and seven substitutes for which regulatory standards were not determined, DIBP, DHP, DEHA, DIBA, DINA, and DEHT were detected in children's products made from PVC plastic. DIBP and DHP, which have a reproductive toxicity classification of 1B, were frequently detected in PVC toys. The reproductive toxicity, estrogenicity, and anti-androgenic activity of the unregulated phthalates and their alternatives have been reported in diverse in vitro and in vivo assays. Conclusion: The use of unregulated phthalates and their substitutes in children's products is increasing. Further monitoring and toxicological information on phthalate alternatives is required to develop proper management plans.
Keywords
Adipates; children's products; endocrine disruption; phthalates; terephthalates;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Tranfo G, Caporossi L, Paci E, Aragona C, Romanzi D, Carolis CD, et al. Urinary phthalate monoesters concentration in couples with infertility problems. Toxicol. Lett. 2012; 213: 15-20.   DOI
2 Ministry of Trade, Industry and Energy. Ministry of Trade, Industry and Energy Notice No. 2019-201. Notification of Revision of Common Safety Standards for Children's Products. Available: https://www.motie.go.kr/motie/in/ay/policynotify/notify/bbs/bbsView.do?bbs_seq_n=63555&bbs_cd_n=5. [accessed 17 September 2020].
3 Ministry of Environment. Regulations on restrictions on the use of environmentally harmful factors for children's products. Available: http://www.law.go.kr/admRulInfoP.do?admRulSeq=2100000061809#J1835732. [accessed 17 September 2020].
4 Ministry of Food and Drug Safety. Ministry of Food and Drug Safety Notice No. 2020-43. Food Utensils, Containers, and Packaging Regulations. Available: https://www.mfds.go.kr/brd/m_207/view.do?seq=14529 [accessed 21 December 2020].
5 Satoh K, Nonaka R, Ohyama K, Nagai F, Ogata A, Iida M. Endocrine disruptive effects of chemicals eluted from nitrile-butadiene rubber gloves using reporter gene assay systems. Biol Pharm Bull. 2008; 31: 375-379.   DOI
6 Jobling S, Reynolds T, White R, Parker MG, Sumpter JP. A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. Environ Health Perspect. 1995; 103: 582-587.   DOI
7 Shen O, Du G, Sun H, Wu W, Jiang Y, Song L, et al. Comparison of in vitro hormone activities of selected phthalates using reporter gene assays. Toxicol Lett. 2009; 191: 9-14.   DOI
8 Harris CA, Henttu P, Parker MG, Sumpter JP. The estrogenic activity of phthalate esters in vitro. Environ Health Perspect. 1997; 105: 802-811.   DOI
9 Ghisari M, Bonefeld-Jorgensen EC. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett. 2009; 189: 67-77.   DOI
10 Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors α and β, and androgen receptor. Toxicology. 2005; 210: 223-233.   DOI
11 Chen FP, Chein MH. Lower concentrations of phthalates induce proliferation in human breast cancer cells. Climacteric. 2014; 17: 377-384.   DOI
12 Blom A, Ekman E, Johannisson A, Norrgren L, Pesonen M. Effects of xenoestrogenic environmental pollutants on the proliferation of a human breast cancer cell line (MCF-7). Arch Environ Contam Toxicol. 1998; 34: 306-310.   DOI
13 Kirchnawy C, Hager F, Piniella VO, Jeschko M, Washuttl M, Merti J, et al. Potential endocrine disrupting properties of toys for babies and infants. PLoS One. 2020; 15(4): e0231171.   DOI
14 European Union. Toys Safety Directive 88/368/ EEC. Available: http://www.loc.gov/law/foreign-news/article/european-union-new-toy-safety-rules-enter-into-force/ [accessed 18 December 2020].
15 The Consumer Product Safety Improvement Act of 2008. Available: https://www.cpsc.gov/Business--Manufacturing/Business-Education/Business-Guidance/Phthalates-Information. [accessed 17 September 2020].
16 US Consumer Product Safety Commission. Toy Safety Standard ASTM F963-17. Available: https://www.cpsc.gov/Business-Manufacturing/BusinessEducation/Toy-Safety/ASTM-F-963-Chart. [accessed 17 September 2020].
17 European Commission. Directive 2005/84/EC. Available: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:344:0040:0043:en:PDF [accessed 18 December 2020].
18 Ksenia G, Ema S. S48, CCPDBLISTA, Database of Chemicals Likely (List A) associated with Plastic Packaging (CPPdb). Available: https://zenodo.org/record/265814#.X8C-uKZ7ky8. [accessed 27 November 2020].
19 European Union. Commission Regulation (EU) No 552/2009 of 22 June 2009 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annex XVII. 2009.
20 European Union. Commission Regulation (EU) 2018/2005 of 17 December 2018 amending Annex XVII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and diisobutyl phthalate (DIBP). 2018.
21 European Chemicals Agency (ECHA). Information on Chemicals. Available: https://echa.europa.eu/ [accessed 17 September 2020].
22 Klimisch HJ, Andreae M, Tillmann U. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol. 1997; 25(1), 1-5.   DOI
23 Akkbik M, Turksoy VA, Kocoglu S. Simultaneous quantitative detection of 10 phthalates in PVC children's toys by HPLC-PDA. Toxicol Mech Methods. 2019; 30(1): 33-38.   DOI
24 Maag J, Lassen C, Brandt UK, Kjoholt J, Molander L, Mikelsen SH. Identification and Assessment of Alternatives to Selected Phthalates. Danish Ministry of the Environment. Environmental Project No. 1341 2010; 2010.
25 Biedermann-Brem S, Biedermann M, Pfenninger S, Bauer M, Altkofer W, Rieger K, et al. Plasticizers in PVC toys and childcare products: what succeeds the phthalates? market survey 2007. Chromatographia. 2008; 68: 227-234.   DOI
26 Okubo T, Suzuki T, Yokoyama Y, Kano K, Kano I. Estimation of estrogenic and anti-estrogenic activities of some phthalate diesters and monoesters by MCF-7 cell proliferation assay in vitro. Biol Pharm Bull. 2003; 26: 1219-1224.   DOI
27 Kim W, Gye MC. Maleficent effects of phthalates and current states of their alternatives: a review. Korean J Environ Biol. 2017; 35(1): 21-36.   DOI
28 Korfali SI, Sabra R, Jurdi M, Taleb RI. Assessment of toxic metals and phthalates in children's toys and clays. Arch. Environ Contam Toxicol. 2013; 65: 368-381.   DOI
29 Stringer R, Labunska I, Santillo D, Johnston P, Siddorn J, Stephenson A. Concentrations of phthalate esters and identification of other additives in PVC children's toys. Environ Sci Pollut Res. 2000; 7: 1-7.   DOI
30 Ministry of Trade, Industry and Energy. Monitoring of Chemical Substances in Consumer Products and Establishment of Computerized Risk Information. 2020.
31 Xie M, Wu Y, Little JC, Marr LC. Phthalates and alternative plasticizers and potential for contact exposure from children's backpacks and toys. J Expo Sci Environ Epidemiol. 2016; 26(1): 119-124.   DOI
32 Kim SH, Cho SH, Ihm HJ, Oh YS, Heo SH, Chun S, et al. Possible role of phthalate in the pathogenesis of endometriosis: in vitro, animal, and human data. J Clin Endocrinol Metab. 2015; 100: E1502-E1511.   DOI
33 Lopez-Carrillo L, Hernandez-Ramirez RU, Calafat AM, Torres-Sanchez L, Galvan-Portillo M, Needham LL, et al. Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect. 2010; 118: 539-544.   DOI
34 Zacharewski TR, Meek Md, Clemons JH, Wu ZF, Fielden MR, Matthews JB. Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters. Toxicol Sci. 1998; 46: 282-293.   DOI
35 Coldham NG, Dave M, Sivapathasundaram S, McDonnell DP, Connor C, Sauer MJ. Evaluation of a recombinant yeast cell estrogen screening assay. Environ Health Perspect. 1997; 105: 734-742.   DOI
36 Ahmad R, Verma Y, Gautam AK, Kumar S. Assessment of estrogenic potential of di-n-butyl phthalate and butyl benzyl phthalate in vivo. Toxicol Ind Health. 2015; 31: 1296-1303.   DOI
37 Yamasaki K, Takeyoshi M, Yakabe Y, Sawaki M, Imatanaka N, Takatsuki M. Comparison of reporter gene assay and immature rat uterotrophic assay of twenty-three chemicals. Toxicology. 2002; 170: 21-30.   DOI
38 Kim HS, Kang TS, Kang IH, Kim TS, Moon HJ, Kim IY, et al. Validation study of OECD rodent Uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats. J Toxicol Environ Health Part A. 2005; 68: 2249-2262.   DOI
39 Kim YJ, Ryu JC. Evaluation of estrogenic effects of phthalate analogues using in vitro and in vivo screening assays. Mol Cell Toxicol. 2006; 2: 106-113.
40 Ashby J, Lefevre PA. The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators. J Appl Toxicol. 2000; 20: 35-47.   DOI
41 Lee BM, Koo HJ. Hershberger assay for antiandrogenic effects of phthalates. J Toxicol Environ Health A. 2007; 70: 1365-1370.   DOI
42 Barlow NJ, Mcintyre BS, Foster PMD. Male reproductive tract lesions at 6, 12, and 18 months of age following in utero exposure to di(n-butyl) phthalate. Toxicol Pathol. 2004; 32: 79-90.   DOI
43 Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H, Ladefoged O. Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. Reprod Toxicol. 2005; 19: 505-515.   DOI
44 Tyl RW, Myers CB, Marr MC, Fail PA, Seely JC, Brine DR, et al. Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. Reprod Toxicol. 2004; 18: 241-264.   DOI
45 Nagao T, Ohta R, Marumo H, Shindo T, Yoshimura S, Ono H. Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study. Reprod Toxicol. 2000; 14: 513-532.   DOI
46 Blystone CR, Kissling GE, Bishop JB, Chapin RE, Wolfe GW, Foster PMD. Determination of the di-(2-ethylhexyl) phthalate NOAEL for reproductive development in the rat: importance of the retention of extra animals to adulthood. Toxicol Sci. 2010; 116(2): 640-646.   DOI
47 Li LH, Jester Jr WF, Laslett AL, Orth JM. A single dose of di-(2-ethylhexyl) phthalate in neonatal rats alters gonocytes, reduces sertoli cell proliferation, and decreases cyclin D2 expression. Toxicol Appl Pharmacol. 2000; 166(3): 222-229.   DOI
48 Tomonari Y, Kurata Y, David RM, Gans G, Kawasuso T, Katoh M. Effect of di(2-ethylhexyl) phthalate (DEHP) on genital organs from juvenile common marmosets: I. morphological and biochemical investigation in 65-week toxicity study. J Toxicol Environ Health. 2006; 69: 1651-1672.   DOI
49 Sedha S, Gautam AK, Verma Y, Ahmad R, Kumar S. Determination of in vivo estrogenic potential of di-isobutyl phthalate (DIBP) and di-isononyl phthalate (DINP) in rats. Environ Sci Pollut Res. 2015; 22: 18197-18202.   DOI
50 Li X, Chen X, Hu G, Li L, Su H, Wang Y, et al., Effects of in utero exposure to dicyclohexyl phthalate on rat fetal Leydig cells. Int J Environ Res Public Health. 2016; 13: 246.   DOI
51 Yamasaki K, Okuda H, Takeuchi T, Minobe Y. Effects of in utero through lactational exposure to dicyclohexyl phthalate and p,p'-DDE in Sprague-Dawley rats. Toxicol Lett. 2009; 189: 14-20.   DOI
52 Ahbab MA, Barlas, N. Developmental effects of prenatal di-n-hexyl phthalate and dicyclohexyl phthalate exposure on reproductive tract of male rats: postnatal outcomes. Food Chem Toxicol. 2013; 51: 123-136.   DOI
53 Ahbab MA, Barlas N. Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. Toxicol Lett. 2015; 233(2): 125-137.   DOI
54 Ahbab MA, Guven C, Kockaya EA, Barlas N. Comparative developmental toxicity evaluation of di-n-hexyl phthalate and dicyclohexyl phthalate in rats. Toxicol Ind Health. 2017; 33(9): 696-716.   DOI
55 Saillenfait AM, Gallissot F, Sabate JP. Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats. J Appl Toxicol. 2009; 29: 510-521.   DOI
56 Howdeshell KL, Wilson VS, Furr J, Lambright CR, Rider CV, Blystone CR. A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rat in a cumulative, dose-additive manner. Toxicol Sci. 2008; 105(1): 153-165.   DOI
57 Hannas BR, Lambright CS, Furr J, Howdeshell KL, Wilson VS, Gray Jr. LE. Dose-response assessment of fetal testosterone production and gene expression levels in rat testis following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and diisononyl phthalate. Toxicol Sci. 2011; 123(1): 206-216.   DOI
58 Saillenfait AM, Sabate JP, Gallissot F. Diisobutyl phthalate impairs the androgen-dependent reproductive development of the male rat. Reprod Toxicol. 2008; 26: 107-115.   DOI
59 Saillenfait AM, Sabate JP, Denis F, Antoine G, Robert A, Roudot AC, et al. Evaluation of the effects of α-cypermethrin on fetal rat testicular steroidogenesis. Reprod Toxicol. 2017; 72: 106-114.   DOI
60 Landrigan P, Goldman L. Children's vulnerability to toxic chemicals: a challenge and opportunity to strengthen health and environmental policy. Health Aff. 2011; 30: 5842-5850.
61 Koniecki D, Wang R, Moody RP, Zhu J. Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. Environ Res. 2011; 111: 329-335.   DOI
62 United States Environmental Protection Agency. Child-Specific Exposure Factors Handbook. EPA/600/R-06/096F. 2008.
63 Han SY, Kim HS, Han SK, Lee RD, Park KL, Yang KW. Study on the estrogenic activity of di-(2-ethylhexyl) adipate in E-screen assay and uterotrophic assay. Korean J Food Sci Technol. 2000; 32(4): 964-969.
64 Wang X, Sheng N, Cui R, Zhang H, Wang J, Dai J. Gestational and lactational exposure to di-isobutyl phthalate via diet in maternal mice decreases testosterone levels in male offspring. Chemosphere. 2017; 172: 260-267.   DOI
65 Negev M, Berman T, Reicher S, Balan S, Soehl A, Goulden S, et al. Regulation of chemicals in children's products: How U.S. and EU regulation impacts small markets. Sci Total Environ. 2018; 616-617: 462-471.   DOI
66 Landrigan PJ, Kimmel CA, Correa A, Eskenazi B. Children's health and the environment: public health issues and challenges for risk assessment. Environ Health Perspect. 2004; 112(2): 257-265.   DOI
67 Akkbik M, Turksoy VA, Kocoglu S. Simultaneous quantitative detection of 10 phthalates in PVC children's toys by HPLC-PDA. Toxicol Mech Methods. 2020; 30(1): 33-38.   DOI
68 Babich MA, Bevington C, Dreyfus MA. Plasticizer migration from children's toys, child care articles, art materials, and school supplies. Reg Toxicol Pharmacol. 2020; 111: 104574.   DOI
69 Borch J, Axelstad M, Vinggaard AM, Dalgaard M. Diisobutyl phthalate has comparable anti-androgenic effects to di-n-butyl phthalate in fetal rat testis. Toxicol Lett. 2006; 163: 183-190.   DOI
70 Hannas BR, Lambright CS, Furr J, Evans N, Foster PMD, Gray EL, et al. Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: a targeted RT-PCR array approach for defining relative potency. Toxicol Sci. 2012; 125(2): 544-557.   DOI
71 Saillenfait AM, Gallissot F, Sabate JP. Evaluation of the developmental toxicity of diallyl phthalate administered orally to rats. Food Chem Toxicol. 2008; 46: 2150-2156.   DOI
72 Saillenfait AM, Gallissot F, Sabate JP, Remy A. Prenatal developmental toxicity studies on diundecyl and ditridecyl phthalates in Sprague-Dawley rats. Reprod Toxicol. 2013; 37: 49-55.   DOI
73 Faber WD, Deyo JA, Stump DG, Navarro L, Ruble K, Knapp J. Developmental toxicity and uterotrophic studies with di-2-ethylhexyl terephthalate. Birth Defects Res B Dev Reprod Toxicol. 2007; 80: 396-405.   DOI
74 Gray LE Jr, Ostby J, Furr J, Price M, Veeramachaneni DNR, Parks L. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci. 2000; 58: 350-365.   DOI
75 Andersen HR, Andersson AM, Arnold SF, Autrup H, Barfoed M, Beresford NA, et al. Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals. Environ Health Perspect. 1999; 107: 89-108.   DOI
76 Stapleton HM, Klosterhaus S, Keller A, Ferguson PL, van Bergen S, Cooper E, et al. Identification of flame retardants in polyurethane foam collected from baby products. Environ Sci Technol. 2011; 45: 5323-5331.   DOI
77 Lee JH. Study on Analytical Migration and Risk Assessment of Phthalates for Children's Product. Konkuk University; 2017. Doctoral Dissertation.
78 Sardar SW, Choi Y, Park N, Jeon J. Occurrence and concentration of chemical additives in consumer products in Korea. Int J Environ Res Public Health. 2019; 16: 5075.   DOI
79 Choi IS, Choi SC. Contents and migration of heavy metals and phthalates in children's products and phthalates in children's products. J Kor Soc Environ Eng. 2014; 36(2): 127-138.   DOI
80 Lioy PJ, Hauser R, Gennings C, Koch HM, Mirkes PE, Schwetz BA, et al. Assessment of phthalates/phthalate alternatives in children's toys and childcare articles: review of the report including conclusions and recommendation of the chronic hazard advisory panel of the consumer product safety commission. J. Expo. Sci. Environ. Epidemiol. 2015; 25(4): 343-353.   DOI
81 Kho YL, Jeong JY, Choi KH, Kim PG. Determination of phthalate metabolites in Korean children's urine by high performance liquid chromatography with triple quadrupole tandem mass spectrometry. J Environ Health Sci. 2008; 34(4): 271-278.   DOI
82 Kwon B, Ji K. Estrogenic and androgenic potential of phthalates and their alternatives. J Environ Health Sci. 2016; 42(3): 169-188.   DOI
83 Yum T, Lee S, Kim Y. Association between precocious puberty and some endocrine disruptors in human plasma. J. Environ. Sci. Health A. 2013; 48: 912-917.   DOI