DOI QR코드

DOI QR Code

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

어린이제품 내 프탈레이트류 및 대체제의 규제와 독성자료에 대한 연구

  • 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)
  • 이인혜 (용인대학교 자연과학연구소) ;
  • 나진성 (한국생산기술연구원) ;
  • 지경희 (용인대학교 산업환경보건학과)
  • Received : 2020.12.01
  • Accepted : 2021.01.15
  • Published : 2021.02.28

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

Acknowledgement

본 연구는 한국산업기술평가관리원 소비자제품안전기술기반조성사업(과제번호 20007183)의 지원을 받아 수행되었습니다.

References

  1. 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.
  2. United States Environmental Protection Agency. Child-Specific Exposure Factors Handbook. EPA/600/R-06/096F. 2008.
  3. 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. https://doi.org/10.1021/es2007462
  4. 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. https://doi.org/10.1016/j.scitotenv.2017.10.198
  5. 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. https://doi.org/10.1289/ehp.6115
  6. 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. https://doi.org/10.1080/15376516.2019.1650145
  7. 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. https://doi.org/10.1016/j.yrtph.2019.104574
  8. 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. https://doi.org/10.1016/j.envres.2011.01.013
  9. Lee JH. Study on Analytical Migration and Risk Assessment of Phthalates for Children's Product. Konkuk University; 2017. Doctoral Dissertation.
  10. 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. https://doi.org/10.3390/ijerph16245075
  11. 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. https://doi.org/10.4491/KSEE.2014.36.2.127
  12. 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. https://doi.org/10.1038/jes.2015.33
  13. 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. https://doi.org/10.5668/JEHS.2008.34.4.271
  14. Kwon B, Ji K. Estrogenic and androgenic potential of phthalates and their alternatives. J Environ Health Sci. 2016; 42(3): 169-188. https://doi.org/10.5668/jehs.2016.42.3.169
  15. 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. https://doi.org/10.1080/10934529.2013.762734
  16. 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. https://doi.org/10.1016/j.toxlet.2011.11.033
  17. 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].
  18. 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].
  19. 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].
  20. 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].
  21. 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].
  22. 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].
  23. 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].
  24. 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.
  25. 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.
  26. 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].
  27. European Chemicals Agency (ECHA). Information on Chemicals. Available: https://echa.europa.eu/ [accessed 17 September 2020].
  28. 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. https://doi.org/10.1006/rtph.1996.1076
  29. 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.
  30. 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. https://doi.org/10.1365/s10337-008-0672-9
  31. 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. https://doi.org/10.1007/s00244-013-9925-1
  32. 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. https://doi.org/10.1007/BF02987640
  33. Ministry of Trade, Industry and Energy. Monitoring of Chemical Substances in Consumer Products and Establishment of Computerized Risk Information. 2020.
  34. 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. https://doi.org/10.1080/15376516.2019.1650145
  35. 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. https://doi.org/10.1038/jes.2015.71
  36. 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. https://doi.org/10.1210/jc.2015-2478
  37. 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. https://doi.org/10.1289/ehp.0901091
  38. 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. https://doi.org/10.1289/ehp.97105734
  39. 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. https://doi.org/10.1177/0748233713491803
  40. 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. https://doi.org/10.1016/S0300-483X(01)00505-4
  41. 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. https://doi.org/10.1080/15287390500182354
  42. 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.
  43. 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. https://doi.org/10.1006/toxs.1998.2505
  44. 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. https://doi.org/10.1002/(SICI)1099-1263(200001/02)20:1<35::AID-JAT633>3.0.CO;2-8
  45. Lee BM, Koo HJ. Hershberger assay for antiandrogenic effects of phthalates. J Toxicol Environ Health A. 2007; 70: 1365-1370. https://doi.org/10.1080/15287390701432285
  46. 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. https://doi.org/10.1080/01926230490265894
  47. 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. https://doi.org/10.1016/j.reprotox.2003.10.006
  48. 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. https://doi.org/10.1016/S0890-6238(00)00105-2
  49. 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. https://doi.org/10.1093/toxsci/kfq147
  50. 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. https://doi.org/10.1006/taap.2000.8972
  51. 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. https://doi.org/10.1080/15287390600630054
  52. 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. https://doi.org/10.1016/j.reprotox.2004.11.005
  53. 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. https://doi.org/10.1007/s11356-015-5021-6
  54. 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. https://doi.org/10.3390/ijerph13030246
  55. 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. https://doi.org/10.1016/j.fct.2012.09.010
  56. 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. https://doi.org/10.1016/j.toxlet.2015.01.015
  57. 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. https://doi.org/10.1177/0748233717711868
  58. 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. https://doi.org/10.1016/j.toxlet.2009.04.023
  59. 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. https://doi.org/10.1002/jat.1436
  60. 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. https://doi.org/10.1093/toxsci/kfn077
  61. 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. https://doi.org/10.1093/toxsci/kfr146
  62. Saillenfait AM, Sabate JP, Gallissot F. Diisobutyl phthalate impairs the androgen-dependent reproductive development of the male rat. Reprod Toxicol. 2008; 26: 107-115. https://doi.org/10.1016/j.reprotox.2008.07.006
  63. 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. https://doi.org/10.1016/j.reprotox.2017.06.133
  64. 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.
  65. 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. https://doi.org/10.1016/j.chemosphere.2017.01.011
  66. 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. https://doi.org/10.1093/toxsci/kfr315
  67. 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. https://doi.org/10.1016/j.toxlet.2005.10.020
  68. 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. https://doi.org/10.1016/j.fct.2008.02.012
  69. 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. https://doi.org/10.1016/j.reprotox.2013.01.004
  70. 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. https://doi.org/10.1002/bdrb.20130
  71. 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. https://doi.org/10.1093/toxsci/58.2.350
  72. 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. https://doi.org/10.1289/ehp.99107s189
  73. 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. https://doi.org/10.1248/bpb.31.375
  74. 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. https://doi.org/10.1289/ehp.95103582
  75. 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. https://doi.org/10.1016/j.toxlet.2009.07.019
  76. Harris CA, Henttu P, Parker MG, Sumpter JP. The estrogenic activity of phthalate esters in vitro. Environ Health Perspect. 1997; 105: 802-811. https://doi.org/10.1289/ehp.97105802
  77. Ghisari M, Bonefeld-Jorgensen EC. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett. 2009; 189: 67-77. https://doi.org/10.1016/j.toxlet.2009.05.004
  78. 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. https://doi.org/10.1016/j.tox.2005.02.002
  79. Chen FP, Chein MH. Lower concentrations of phthalates induce proliferation in human breast cancer cells. Climacteric. 2014; 17: 377-384. https://doi.org/10.3109/13697137.2013.865720
  80. 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. https://doi.org/10.1007/s002449900322
  81. 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. https://doi.org/10.1371/journal.pone.0231171
  82. 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. https://doi.org/10.1248/bpb.26.1219
  83. 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. https://doi.org/10.11626/KJEB.2017.35.1.021