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Maleficent Effects of Phthalates and Current States of Their Alternatives: A Review

프탈레이트의 유해성과 대체재 현황: 소고

  • Kim, Woong (Department of Life Science and Insutitute of Natural Sciences, Hanyang University) ;
  • Gye, Myung Chan (Department of Life Science and Insutitute of Natural Sciences, Hanyang University)
  • 김웅 (한양대학교 생명과학과) ;
  • 계명찬 (한양대학교 생명과학과)
  • Received : 2017.03.12
  • Accepted : 2017.03.17
  • Published : 2017.03.31

Abstract

Phthalates, known as typical endocrine disruptors, are plasticizers used to soften plastics such as polyvinyl chloride (PVC). Because of their material properties, phthalates are used extensively in the production of toys, flooring, wood processing, detergents, and even cosmetics as lubricants and perfume solvents. Due to their endocrine disrupting effect and other adverse health effects published, recently, phthalates have been regulated in many countries. Besides, in an effort to replace phthalates, several chemical plasticizers such as trioctyltrimellitate (TOTM) and dioctylterephthalate (DIOP) have been used instead of the existing harmful phthalates, and novel alternatives are continuously being developed. Nonetheless, phthalates are still being detected in several plastic products, and the safety of alternatives that are considered safe is being questioned. In this review, we describe the adverse health effects of phthalates, their regulation and the current status of their alternatives.

대표적인 내분비계 교란물질인 프탈레이트의 이용실태, 위해성, 규제현황 및 이를 대체하여 사용되는 대체가소제 및 대체플라스틱소재들의 특성을 정리하였다. 프탈레이트는 대표적인 내분비계 장애물질 중 하나로 경구 또는 호흡과 피부를 통해 체내에 침투해 여성호르몬 및 남성호르몬과 갑상선호르몬이 작용을 교란하는 것으로 알려졌다. 특히, 태아의 발달 저하, 성체의 생식능력 저하, 암 유발 이외에도 신경발달 저하 및 정신질환까지도 프탈레이트 노출과 연관이 있음이 보고되었다. 각종 플라스틱 제품, 안료, 화장품 등 일상생활 곳곳에 광범위하게 사용되던 프탈레이트는 규제가 이뤄짐에 따라 여러 종류의 대체가소제들이 사용되고 있으며 가소제를 사용하지 않는 플라스틱 대체소재들이 개발되고 있다. 이들 대체가소제 및 대체소재들의 내분비 교란 및 위해성이 새로이 제기되고 있으며, 프탈레이트 만큼 구체적으로 안전성 평가가 이뤄지지 않았으므로 결코 안전하다고 할 수 없다. 또한 대체가소제 및 대체소재들의 물성적 한계와 낮은 가격경쟁력은 재고되어야 한다. 본 소고에서는 in vitro, in vivo 및 in silico 시험을 통해 알려진 프탈레이트 대체가소제 및 대체소재들의 안전성 자료들을 정리하여 안전성에 대한 의문을 제기함과 동시에 바람직한 대체재 발굴을 위한 가이드라인를 제시하고자 하였다.

Keywords

References

  1. Adibi JJ, FP Perera, W Jedrychowski, DE Camann, D Barr, R Jacek and RM Whyatt. 2003. Prenatal exposures to phthalates among women in New York City and Krakow, Poland. Environ. Health Perspect. 111:1719-1722. https://doi.org/10.1289/ehp.6235
  2. Alvarez-Chavez CR. 2009. Sustainability of bio-polymers: Comparative analysis of corn and potato based bio-polymers Doctoral Dissertation, University of Massachusetts. USA.
  3. Andrade AJM, SW Grande, CE Talsness, K Grote, A Golombiewski, A Sterner-Kock and I Chahoud. 2006. A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl)phthalate (DEHP): effects on androgenic status, developmental landmarks and testicular histology in male offspring rats. Toxicology 225:64-74. https://doi.org/10.1016/j.tox.2006.05.007
  4. Api AM. 2001. Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients. Food. Chem. Toxicol. 39:97-108. https://doi.org/10.1016/S0278-6915(00)00124-1
  5. ASTDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological profile for di-(2-ethylhexyl)phthalate. U.S. department of human health. Atlanta.
  6. Averous L and E Pollet. 2012. Environmental silicate nano-biocomposites. Springer-Verlag. London. UK.
  7. Barlow NJ and PMD Foster. 2003. Pathogenesis of male reproductive tract lesions from gestation through adulthood following in utero exposure to di(n-butyl)phthalate. Toxicol. Pathol. 31:397-410.
  8. Barlow NJ, SL Phillips, DG Wallace, M Sar, KW Gaido and PMD Foster. 2003. Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate. Toxicol. Sci. 73:431-441. https://doi.org/10.1093/toxsci/kfg087
  9. Bittner G and S Yaniger. 2012. Comment on "Lack of androgenicity and estrogenicity of the three monomers used in Eastman's TritanTM copolyesters" by Osimitz et al. (2012). Food Chem. Toxicol. 50:4236-4237. https://doi.org/10.1016/j.fct.2012.06.038
  10. Bornehag CG, J Sundell, CJ Weschler, T Sigsgaard, B Lundgren, M Hasselgren and L Hagerhed-Engman. 2004. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study. Environ. Health Perspect. 112:1393-1397. https://doi.org/10.1289/ehp.7187
  11. Chakraborty TR, E Alicea and S Chakraborty. 2012. Relationships between urinary biomarkers of phytoestrogens, phthalates, phenols, and pubertal stages in girls. Adolesc. Health Med. Ther. 3:17-26.
  12. Chase K and C Willoughby. 2002. Citroflex$^{(R)}$ A-4 toxicity study by dietary administration to HanWistar rats for 13 weeks with an in uteru exposure phase followed by a 4-week recovery period. Huntington Life Sciences Ltd. project No. I MOX 002/013180 for Morflex, Inc. Hungtington. England.
  13. Chiellini F, M Ferri, A Morelli, L Dipaola and G Latini. 2013. Perspectives on alternatives to phthalate plasticized poly (vinyl chloride) in medical devices applications. Prog. Polym. Sci. 38:1067-1088. https://doi.org/10.1016/j.progpolymsci.2013.03.001
  14. Cho SC, SY Bhang, YC Hong, MS Shin, BN Kim, JW Kim, HJ Yoo, IH Cho and HW Kim. 2010. Relationship between environmental phthalate exposure and the intelligence of school-age children. Environ. Health Perspect. 118:1027- 1032. https://doi.org/10.1289/ehp.0901376
  15. Choi W, JW Chung and SY Kwak. 2014. Unentangled Star- Shape Poly($\varepsilon$-caprolactone)s as Phthalate-Free PVC Plasticizers Designed for Non-Toxicity and Improved Migration Resistancen. ACS Appl. Mater. Interfaces. 6:11118-11128. https://doi.org/10.1021/am500740v
  16. Chou YY, PC Huang, CC Lee, MH Wu and SJ Lin. 2009. Phthalate exposure in girls during early puberty. J. Pediatr. Endocrinol. Metab. 22:69-78.
  17. Corton JC and PJ Lapinskas. 2005. Peroxisome proliferatoractivated receptors: mediators of phthalate ester-induced effects in the male reproductive tract?. Toxicol. Sci. 83:4- 17. https://doi.org/10.1093/toxsci/kfi011
  18. CPSC. 2010. Review of Exposure and Toxicity Data for Phthalate Substitutes. U.S. Consumer Product Safety Commission. Bethesda, Maryland. Available at https://www.cpsc.gov/th/content/review-of-exposure-and-toxicity-data-for-phthalate-substitutes.
  19. Desvergne B, JN Feige and C Casals-Casas. 2009. PPAR-mediated activity of phthalates: a link to the obesity epidemic? Mol. Cell. Endocrinol. 304:43-48. https://doi.org/10.1016/j.mce.2009.02.017
  20. Dickson-Spillmann M, M Siegrist, C Keller and M Wormuth. 2009. Phthalate exposure through food and consumers' risk perception of chemicals in food. Risk. Anal. 29:1170-1181. https://doi.org/10.1111/j.1539-6924.2009.01233.x
  21. Fasano E, F Bono-Blay, T Cirillo, P Montuori and S Lacorte. 2012. Migration of phthalates, alkylphenols, bisphenol A and di(2-ethylhexyl)adipate from food packaging. Food Control 27:132-138. https://doi.org/10.1016/j.foodcont.2012.03.005
  22. Fierens T, K Servaes, MV Holderbeke, L Geerts, SD Henauw, I Sioen and G Vanermen. 2012. Analysis of phthalates in food products and packaging materials sold on the Belgian market. Food. Chem. Toxicol. 50:2575-2583. https://doi.org/10.1016/j.fct.2012.04.029
  23. Finklestein M and H Gold. 1959. Toxicology of the citric acid esters: Tributyl citrate, acetyl tributyl citrate, triethyl citrate, and acetyltriethyl citrate. Toxicol. Appl. Pharmacol. 1:283- 298. https://doi.org/10.1016/0041-008X(59)90113-9
  24. Ghisari M and EC Bonefeld-Jorgensen. 2009. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol. Lett. 189:67-77. https://doi.org/10.1016/j.toxlet.2009.05.004
  25. Gironi F and V Piemonte. 2011. Bioplastics and petroleumbased plastics: strengths and weaknesses. Energ. Source. Part A. 33:1949-1959. https://doi.org/10.1080/15567030903436830
  26. Gobas FAPC, CE Mackintosh, G Webster, M Ikonomou, TF Parkerton and K Robillard. 2003. Bioaccumulation of phthalate esters in aquatic food-webs. In Series Anthropogenic Compounds: Springer Berlin Heidelberg. pp. 201- 225.
  27. Gold H, W Modell and M Finklestein. 1998. Report to Charles Pfizer and Company on the pharmacology of triethyl, acetyl triethyl, tributyl, and acetyl tributyl citrate by oral administration in rats and cats-no date given. Unpublished data submitted by CTFA (31 pages) 2. Wasington, D.C. U.S.
  28. Gray LE, J Laskey and J Ostby. 2006. Chronic di-n-butyl phthalate exposure in rats reduces fertility and alters ovarian function during pregnancy in female Long Evans hooded rats. Toxicol. Sci. 93:189-195. https://doi.org/10.1093/toxsci/kfl035
  29. Gray LE, J Ostby, C Wolf, C Lambright and W Kelce. 1998. The value of mechanistic studies in laboratory animals for the prediction of reproductive effects in wildlife: Endocrine effects on mammalian sexual differentiation. Environ. Toxicol. Chem. 17:109-118. https://doi.org/10.1002/etc.5620170113
  30. Gray LE, J Ostby, J Furr, M Price, DN Veeramachaneni and L Parks. 2000. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol. Sci. 58:350-365. https://doi.org/10.1093/toxsci/58.2.350
  31. Ha JY, SH Kim, HY Choi and YM Ahn. 2015. Early Puberty is associated with Psychological Health Problems in Korean Adolescents. Adv. Sci. Lett. 103:227-231.
  32. Harris CA, P Henttu, MG Parker and JP Sumpter. 1997. The estrogenic activity of phthalate esters in vitro. Environ. Health Perspect. 105:802-811. https://doi.org/10.1289/ehp.97105802
  33. Hauser R, P Williams, L Altshul and AM Calafat. 2005. Evidence of interaction between polychlorinated biphenyls and phthalates in relation to human sperm motility. Environ. Health. Perspect. 113:425-430. https://doi.org/10.1289/ehp.7305
  34. Henderson BE, RK Ross and MC Pike. 1993. Hormonal chemoprevention of cancer in women. Science 259:633-638. https://doi.org/10.1126/science.8381558
  35. Heudorf U, V Mersch-Sundermann and J Angerer. 2007. Phthalates: toxicology and exposure. Int. J. Hyg. Environ. Health. 210:623-634. https://doi.org/10.1016/j.ijheh.2007.07.011
  36. Hirata-Koizumi M, M Takahashi, M Matsumoto, T Kawamura, A Ono and A Hirose. 2012. Toxicity effects of phthalate substitute plasticizers used in toys. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 130:31-42.
  37. Horn O, S Nalli, D Cooper and J Nicell. 2004. Plasticizer metabolites in the environment.Environ. Health Perspect. 38:3693-3698.
  38. Huang XF, Y Li, YH Gu, M Liu, Y Xu, Y Yuan, F Sun, HQ Zhang and HJ Shi. 2012. The effects of Di-(2-ethylhexyl)- phthalate exposure on fertilization and embryonic development in vitro and testicular genomic mutation in vivo. PloS One 7:e50465. https://doi.org/10.1371/journal.pone.0050465
  39. IARC. 2015. Monographs on the Evaluation of Carcinogenic Risks to Humans: Complete List of Agents Evaluated and their Classification. Lyon, France. Available at http://monographs.iarc.fr/ENG/Classification/index.php
  40. Ibhazehiebo K and N Koibuchi. 2014. Thyroid hormone receptor- mediated transcription is suppressed by low dose Phthalate. Niger. J. Physiol. Sci. 26:143-149.
  41. Iwase H, S Oiso, H Kariyazono and K Nakamura. 2014. Biological Effects of the plasticizer tris (2-ethylhexyl) trimellitate. Clinic. Pharmacol. Biopharmaceut. S2:004. doi: 10.4172/2167-065X.S2-004
  42. Jang S and K Ji. 2015. Effect of chronic exposure to two components of Tritan copolyester on Daphnia magna, Moina macrocopa, and Oryzias latipes, and potential mechanisms of endocrine disruption using H295R cells. Ecotoxicology 24:1906-1914. https://doi.org/10.1007/s10646-015-1526-5
  43. Johnson W Jr. 2002. Final report on the safety assessment of acetyl triethyl citrate, acetyl tributyl citrate, acetyl trihexyl citrate, and acetyl trioctyl citrate. Int. J. Toxicol. 21(Suppl. 2):1-17.
  44. Kang J, Y Ding, B Li, H Liu, X Yang and M Chen. 2017. TRPA1 mediated aggravation of allergic contact dermatitis induced by DINP and regulated by NF-${\kappa}B$ activation. Sci. Rep. 7:43586. https://doi.org/10.1038/srep43586
  45. Karaolis-Danckert N, AE Buyken, A Sonntag and A Kroke. 2009. Birth and early life influences on the timing of puberty onset: results from the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study. Am. J. Clin. Nutr. 90:1559-1565. https://doi.org/10.3945/ajcn.2009.28259
  46. Kim HK, DW Jung, MY Lee, and DH Ko. 2014. Method for preparing ester composition and resin composition, U.S. Patent Application 761:14-314.
  47. Kim SH, SH Cho, HJ Ihm, YS Oh, SH Heo, S Chun, H Im, HD Chae, CH Kim and BM Kang. 2015. Possible role of phthalate in the pathogenesis of endometriosis: in vitro, animal, and human data. J. Clin. Endocrinol. Metab. 100: E1502-E1511. https://doi.org/10.1210/jc.2015-2478
  48. Koibuchi N and WW Chin. 2000. Thyroid hormone action and brain development. Trends. Endocrinol. Metab. 11:123-128. https://doi.org/10.1016/S1043-2760(00)00238-1
  49. Koniecki D, R Wang, RP Moody and J Zhu. 2011. Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. Environ. Res. 111:329-336. https://doi.org/10.1016/j.envres.2011.01.013
  50. Koo HJ and BM Lee. 2004. Estimated exposure to phthalates in cosmetics and risk assessment. J Toxicol. Environ. Health A. 67:1901-1914. https://doi.org/10.1080/15287390490513300
  51. Kumar N, S Sharan, S Srivastava and P Roy. 2014. Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actions. Reprod. Toxicol. 49:12-26. https://doi.org/10.1016/j.reprotox.2014.06.008
  52. Larionov AG and TE Cherkasova. 1998. Safety evaluation of acetyl tributyl citrate-no date given. Unpublished data submitted by CTFA (5 pages) 2. Wasington, D.C. U.S.
  53. Latini G, CD Felice, G Presta, AD Vecchio, I Paris, F Ruggieri and P Mazzeo. 2003. In utero exposure to di-(2-ethylhexyl) phthalate and duration of human pregnancy. Environ. Health Perspect. 111:1783-1785. https://doi.org/10.1289/ehp.6202
  54. Latini G, CD Felice and A Verrotti. 2004. Plasticizers, infant nutrition and reproductive health. Reprod. Toxicol. 19:27- 33. https://doi.org/10.1016/j.reprotox.2004.05.011
  55. Lee HC, K Yamanouchi and M Nishihara. 2006. Effects of perinatal exposure to phthalate/adipate esters on hypothalamic gene expression and sexual behavior in rats. J. Reprod. Dev. 52:343-352. https://doi.org/10.1262/jrd.17096
  56. LGchem. 2014. Non phthalate plasticizer LGflex GL500. LG Polymer J. 2014:10-17.
  57. Li Y. 2013. Life Cycle Assessment to Di-2-Ethylhexyl Phthalate (DEHP), Applications and Potential Alternatives, University of Pittsburgh. Pennsylvania. U.S.
  58. Lithner D, A Larsson and G Dave. 2011. Environmental and health hazard ranking and assessment of plastic polymers based on chemical composition. Sci. Total. Environ. 409: 3309-3324. https://doi.org/10.1016/j.scitotenv.2011.04.038
  59. Lopez-Carrillo L, RU Hernandez-Ramirez, AM Calafat, L Torres-Sanchez, M Galvan-Portillo, LL Needham, R Ruiz- Ramos and ME Cebrian. 2010. Exposure to phthalates and breast cancer risk in northern Mexico. Environ. Health Perspect. 118:539-544.
  60. Lovekamp-Swan T and BJ Davis. 2003. Mechanisms of phthalate ester toxicity in the female reproductive system. Environ. Health Perspect. 111:139-145.
  61. Lowell center. 2011. Phthalates and Their Alternatives: Health and Environmental Concerns. Lowell Center for sustainalble Production. University of Massachusetts. Wisconsin. U.S.
  62. Main KM, GK Mortensen, MM Kaleva, KA Boisen, IN Damgaard, M Chellakooty, IM Schmidt, AM Suomi, HE Virtanen, JH Petersen, AM Andersson, J Toppari and NE Skakkebaek. 2006. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ. Health Perspect. 114:270-276. https://doi.org/10.1289/ehp.8075
  63. Mankidy R, S Wiseman, H Ma and JP Giesy. 2013. Biological impact of phthalates. Toxicol. Lett. 217:50-58. https://doi.org/10.1016/j.toxlet.2012.11.025
  64. Martinez-Arguelles DB, E Campioli, M Culty, BR Zirkin and V Papadopoulos. 2013. Fetal origin of endocrine dysfunction in the adult: the phthalate model. J Steroid. Biochem. Mol. Biol. 137:5-17. https://doi.org/10.1016/j.jsbmb.2013.01.007
  65. Martino-Andrade AJ and I Chahoud. 2010. Reproductive toxicity of phthalate esters. Mol. Nutr. Food. Res. 54:148-157. https://doi.org/10.1002/mnfr.200800312
  66. McKee RH, AW Lington and KA Traul. 1986. An evaluation of the genotoxic potential of di-isononyl adipate. Environ. Mutagen. 8:817-827. https://doi.org/10.1002/em.2860080605
  67. Meek ME and PKL Chan. 1994. Bis(2-ethylhexyl)phthalate: Evaluation of risks to health from environmental exposure in Canada. J. Environ. Sci. Health C. 12:179-194. https://doi.org/10.1080/10590509409373439
  68. Meyers DB, J Autian and WL Guess. 1964. Toxicity of plastics used in medical practice II. Toxicity of citric acid esters used as plasticizers. J. Pharm. Sci. 53:774-777. https://doi.org/10.1002/jps.2600530716
  69. Mylchreest E, RC Cattley and PMD Foster. 1998. Male reproductive tract malformations in rats following gestational and lactational exposure to di(n-butyl)phthalate: an antiandrogenic mechanism?. Toxicol. Sci. 43:47-60. https://doi.org/10.1093/toxsci/43.1.47
  70. Nara K, K Nishiyama, H Natsugari, A Takeshita and H Takahashi. 2009. Leaching of the plasticizer, acetyl tributyl citrate: (ATBC) from plastic kitchen wrap. J. Health. Sci. 55:281-284. https://doi.org/10.1248/jhs.55.281
  71. Ng HW, M Shu, H Luo, H Ye, W Ge, R Perkins, W Tong and H Hong. 2015. Estrogenic activity data extraction and in silico prediction show the endocrine disruption potential of bisphenol a replacement compounds. Chem. Res. Toxicol. 28:1784-1795. https://doi.org/10.1021/acs.chemrestox.5b00243
  72. NTP-CERHR. 2003. NTP-CERHR monograph on the potential human reproductive and developmental effects of di-isodecyl phthalate (DIDP). National Toxicology Program Center for the Evaluation of Risks to Human Reproduction. NIH Publ No. 03-4485. Maryland. U.S.
  73. Osimitz TG, ML Eldridge, E Sloter, W Welsh, N Ai, G Sayler, FM Menn and C Toole. 2012. Lack of androgenicity and estrogenicity of the three monomers used in Eastman's TritanTM copolyesters. Food Chem. Toxicol. 50:2196-2205. https://doi.org/10.1016/j.fct.2012.02.010
  74. Park S, JM Lee, JW Kim, JH Cheong, HJ Yun, YC Hong, Y Kim, DH Han, HJ Yoo, MS Shin, SC Cho and BN Kim. 2015. Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder. Psychol. Med. 45:1601-1612. https://doi.org/10.1017/S0033291714002694
  75. Picard K, JC Lhuguenot, MC Lavier-Canivenc and MC Chagnon. 2001. Estrogenic activity and metabolism of n-butyl benzyl phthalate in vitro: identification of the active molecule( s). Toxicol. Appl. Pharmacol. 172:108-118. https://doi.org/10.1006/taap.2001.9141
  76. Poon R, P Lecavalier, R Mueller, VlE Valli, BG Procter and I Chu. 1997. Subchronic oral toxicity of di-n-octyl phthalate and di(2-ethylhexyl)phthalate in the rat. Food. Chem. Toxicol. 35:225-239. https://doi.org/10.1016/S0278-6915(96)00064-6
  77. Posnack NG. 2014. The adverse cardiac effects of di(2-ethylhexyl) phthalate and bisphenol A. Cardiovasc. Toxicol. 14: 339-357. https://doi.org/10.1007/s12012-014-9258-y
  78. Rasmussen LM, N Sen, X Liu and ZR Craig. 2016. Effects of oral exposure to the phthalate substitute acetyl tributyl citrate on female reproduction in mice. J. Appl. Toxicol. doi: 10.1002.
  79. Rhodes JE, WJ Adams, GR Biddinger, KA Robillard and JW Gorsuch. 1995. Chronic toxicity of 14 phthalate esters to Daphnia magna and rainbow trout (Oncorhynchus mykiss). Environ. Toxicol. Chem. 14:1967-1976. https://doi.org/10.1002/etc.5620141119
  80. Rivera M, MB Nicotra, GE Byron, R Patterson, DH Yawn, M Franco, CR Zeiss and SD Greenberg. 1981. Trimellitic anhydride Toxicity. A cause of acute multisystem failure. Arch. Intern. Med. 141:1071-1074. https://doi.org/10.1001/archinte.1981.00340080107022
  81. Robbins M. 1994. A two-generation reproduction study with acetyl tributyl citrate in rats. BIBRA Toxicol. Int. NO. 1298/1/2/94. Surrey. UK.
  82. Rochman CM, MA Browne, BS Halpern, BT Hentschel, E Hoh, H Karapanagioti, LM Rios-Mendoza, H Takada, S Teh and RC Thompson. 2013. Policy: Classify plastic waste as hazardous. Nature 494:169-171. https://doi.org/10.1038/494169a
  83. Roy JR, S Chakraborty and TR Chakraborty. 2009. Estrogenlike endocrine disrupting chemicals affecting puberty in humans-a review. Med. Sci. Monit. 15:RA137-RA145.
  84. Rozati R, PP Reddy, P Reddanna and R Mujtaba. 2002. Role of environmental estrogens in the deterioration of male factor fertility. Fertil. Steril. 78:1187-1194. https://doi.org/10.1016/S0015-0282(02)04389-3
  85. Rudel RA, DE Camann, JD Spengler, LR Korn and JG Brody. 2003. Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers, and other endocrine-disrupting compounds in indoor air and dust. Environ. Sci. Technol. 37:4543- 4553. https://doi.org/10.1021/es0264596
  86. Rudel RA and LJ Perovich. 2009. Endocrine disrupting chemicals in indoor and outdoor air. Atmos. Environ. 43:170- 181. https://doi.org/10.1016/j.atmosenv.2008.09.025
  87. Rusyn I, JM Peters and ML Cunningham. 2006. Effects of DEHP in the liver: modes of action and species-specific differences. Crit. Rev. Toxicol. 36:459-479. https://doi.org/10.1080/10408440600779065
  88. SDIS, OECD. 1996. a Dibutyl adipate. UNEP publications, Nairobi. Available at www.inchem.org/documents/sids/ sids/105997.pdf
  89. SDIS, OECD. 2002. Trimellitic Anhydride and Trimellitic Acid. UNEP publications, Nairobi. Available at http://www. inchem.org/documents/sids/sids/TLANA.pdf
  90. SDIS, OECD. 2005. $\varepsilon$-Caprolactone. UNEP publications, Nairobi. Available at http://webnet.oecd.org/hpv/UI/handler.axd?id=2ccdc186-93a9-47cd-b91d-26789738233d
  91. Shea KM. 2003. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics 111:1467-1474. https://doi.org/10.1542/peds.111.6.1467
  92. Shehata AS, ZAE Mohamed, MRA El-Haleem and MA Samak. 2013. Effects of Exposure to Plasticizers Di-(2-Ethylhexyl) Phthalate and Trioctyltrimellitate on the Histological Structure of Adult Male Albino Rats' Liver. J. Clin. Toxicol. 3:169. doi:10.4172/2161-0495.1000169
  93. Sheikh IA, M Yasir, M Abu-Elmagd, TA Dar, AM Abuzenadah, GA Damanhouri, M Al-Qahtani and MA Beg. 2016. Human sex hormone-binding globulin as a potential target of alternate plasticizers: an in silico study. BMC Struct. Biol. 16:15. doi:10.1186/s12900-016-0067-3
  94. Silva MJ, AR Slakman, JA Reidy, JL Preau, AR Herbert, E Samandar, LL Needham and AM Calafat. 2004. Analysis of human urine for fifteen phthalate metabolites using automated solid-phase extraction. J. Chromatogr. B. Analyt. Technol. Biomed. Life. Sci. 805:161-167. https://doi.org/10.1016/j.jchromb.2004.02.038
  95. Silva MJ, JA Reidy, E Samandar, AR Herbert, LL Needham and AM Calafat. 2005. Detection of phthalate metabolites in human saliva. Arch. Toxicol. 79:647-652. https://doi.org/10.1007/s00204-005-0674-4
  96. Simmchen J, R Ventura and J Segura. 2012. Progress in the removal of di-[2-ethylhexyl]-phthalate as plasticizer in blood bags. Transfus. Med. Rev. 26:27-37. https://doi.org/10.1016/j.tmrv.2011.06.001
  97. Stahlhut RW, E van Wijngaarden, TD Dye, S Cook and SH Swan. 2007. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult US males. Environ. Health Perspect. 115:876-882. https://doi.org/10.1289/ehp.9882
  98. Staples CA, DR Peterson, TF Parkerton and WJ Adams. 1997. The environmental fate of phthalate esters: a literature review. Chemosphere 35:667-749. https://doi.org/10.1016/S0045-6535(97)00195-1
  99. Stuer-Lauridsen F, S Mikkelsen, S Havelund, M Birkved and LP Hansen. 2001. Environmental and health assessment of alternatives to phthalates and to flexible PVC. Danish Environmental Protection Agency, COWI Consulting Engineers and Planners AS. Lyngby, Denmark. Available at http://www2.mst.dk/udgiv/publications/2001/87-7944-407-5/pdf/87-7944-408-3.pdf
  100. Suzuki Y, J Yoshinaga, Y Mizumoto, S Serizawa and H Shiraishi. 2012. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int. J. Androl. 35:236-244. https://doi.org/10.1111/j.1365-2605.2011.01190.x
  101. Swan SH. 2008. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ. Res. 108:177-184. https://doi.org/10.1016/j.envres.2008.08.007
  102. Takeuchi S, M Iida, S Kobayashi, K Jin, T Matsuda and H Kojima. 2005. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors ${\alpha}$ and ${\beta}$, and androgen receptor. Toxicology 210:223-233. https://doi.org/10.1016/j.tox.2005.02.002
  103. ter Veld MG, B Schouten, J Louisse, DS van Es, PT van der Saag, IM Rietjens and AJ Murk. 2006. Estrogenic potency of food-packaging-associated plasticizers and antioxidants as detected in ER${\alpha}$ and ER${\beta}$ reporter gene cell lines. J. Agric. Food. Chem. 54:4407-4416. https://doi.org/10.1021/jf052864f
  104. Testai E, P Hartemann, SC Rastogi, U Bernauer, A Piersma, W Jong, H Gulliksson, R Sharpe, D Schubert and E Rodriguez- Farre. 2016. The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update). Regul. Toxicol. Pharmacol. 76:209-210. https://doi.org/10.1016/j.yrtph.2016.01.013
  105. Tranfo G, L Caporossi, E Paci, C Aragona, D Romanzi, CD Carolis, MD Rosa, S Capanna, B Papaleo and A Pera. 2012. Urinary phthalate monoesters concentration in couples with infertility problems. Toxicol. Lett. 213:15-20. https://doi.org/10.1016/j.toxlet.2011.11.033
  106. Tyl RW, CB Myers, MC Marr, PA Fail, JC Seely, DR Brine, RA Barter and JH Butala. 2004. Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. Reprod. Toxicol. 18:241-264. https://doi.org/10.1016/j.reprotox.2003.10.006
  107. Wang C, L Yang, S Wang, Z Zhang, Y Yu, M Wang, M Cromie, W Gao and SL Wang. 2016. The classic EDCs, phthalate esters and organochlorines, in relation to abnormal sperm quality: a systematic review with meta-analysis. Sci. Rep. 6:19982. https://doi.org/10.1038/srep19982
  108. Wang IJ, CC Lin, YJ Lin, WS Hsieh and PC Chen. 2014. Early life phthalate exposure and atopic disorders in children: a prospective birth cohort study. Environ. Int. 62:48-54. https://doi.org/10.1016/j.envint.2013.09.002
  109. Wang X, W Tao, Y Xu, J Feng and F Wang. 2014. Indoor phthalate concentration and exposure in residential and office buildings in Xi'an, China. Atmos. Environ. 87:146-152. https://doi.org/10.1016/j.atmosenv.2014.01.018
  110. WHO. 2003. Diethyl phthalate. Concise international chemical assessment document 52. World Health Organization, Geneva, Switzerland. Available at http://www.inchem.org/documents/cicads/cicads/cicad52.htm.
  111. Whyatt RM, JJ Adibi, AM Calafat, DE Camann, Vi Rauh, HK Bhat, FP Perera, H Andrews, AC Just, L Hoepner, D Tang and R Hauser. 2009. Prenatal di(2-ethylhexyl)phthalate exposure and length of gestation among an inner-city cohort. Pediatrics 124:e1213-e1220. https://doi.org/10.1542/peds.2009-0325
  112. Whyatt RM, X Liu, VA Rauh, AM Calafat, AC Just, L Hoepner, D Diaz, J Quinn, J Adibi, FP Perera and P Factor-Litvak. 2012. Maternal prenatal urinary phthalate metabolite concentrations and child mental, psychomotor, and behavioral development at 3 years of age. Environ. Health Perspect. 120:290-295.
  113. Wofford HW, CD Wilsey, GS Neff, CS Giam and JM Neff. 1981. Bioaccumulation and metabolism of phthalate esters by oysters, brown shrimp, and sheepshead minnows. Ecotoxicol. Environ. Saf. 5:202-210. https://doi.org/10.1016/0147-6513(81)90035-X
  114. Wormuth M, M Scheringer, M Vollenweider and K Hungerbuhler. 2006. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans?. Risk Anal. 26:803-824. https://doi.org/10.1111/j.1539-6924.2006.00770.x
  115. Xie Z, R Ebinghaus, C Temme, R Lohmann, A Caba and W Ruck. 2007. Occurrence and air-sea exchange of phthalates in the Arctic. Environ. Sci. Technol. 41:4555-4560. https://doi.org/10.1021/es0630240
  116. Yum T, S Lee and Y Kim. 2013. Association between precocious puberty and some endocrine disruptors in human plasma. J. Environ. Sci. Health A. 48:912-917. https://doi.org/10.1080/10934529.2013.762734
  117. Zhang Q, XM Lu, XL Zhang, YG Sun, DM Zhu, BL Wang, RZ Zhao and ZD Zhang. 2013. Levels of phthalate esters in settled house dust from urban dwellings with young children in Nanjing, China. Atmos. Environ. 69:258-264. https://doi.org/10.1016/j.atmosenv.2012.12.029
  118. Zhou J and H Ritter. 2011. Copolyesters as non-toxic plasticizers. Polym. Int. 60:1158-1161. https://doi.org/10.1002/pi.3122