Advanced SearchSearch Tips
Estrogenic and Androgenic Potential of Phthalates and Their Alternatives
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
 Title & Authors
Estrogenic and Androgenic Potential of Phthalates and Their Alternatives
Kwon, Bareum; Ji, Kyunghee;
  PDF(new window)
Objectives: Although information on the toxicity of phthalate diesters is readily available, little is known about phthalate alternatives. The present article provides a summary of available information on the toxicity of phthalate diesters and their alternatives, with a special focus on estrogenicity and androgenicity. Methods: We collected a battery of in vitro and in vivo assay data from the literature to assess the estrogenicity/anti-estrogenicity and androgenicity/anti-androgenicity of 15 phthalate diesters and 21 phthalate alternatives. Results: A number of in vitro studies show that certain phthalate diesters can bind to estrogen receptors and have a weak estrogenic potential. However, this potential was not seen in in vivo studies. Phthalate diesters produced anti-androgenic effects in animals by reducing testosterone production. Among them, di-(2-ethyl-hexyl) phthalate (DEHP) was the most potent. While almost all phthalate alternatives have a lower toxic potential than does DEHP, evidence of reproductive toxicity and estrogenic potential were found in several substances. Conclusion: Significant data gaps exist for phthalate alternatives regarding reproductive endocrine disruption, requiring further investigation.
Alternatives;anti-androgenicity;endocrine disruption;estrogenicity;phthalate;
 Cited by
US EPA. 2012. Phthalates Action Plan. Available: [accessed 30 March 2016].

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. crossref(new window)

CDC, 2009. Fourth National Report on Human Exposure to Environmental Chemicals. CDC, Atlanta, GA, USA.

Serrano SE, Braun J, Trasande L, Dills R, Sathyanarayana S. Phthalates and diet: a review of the food monitoring and epidemiology data. Environ Health. 2014; 13: 43. DOI: 10.1186/1476-069X-13-43. crossref(new window)

ECPI. 2006. DIBP Information Centre-CAS Number 84-69-5 [on line]. Available: [accessed 30 March 2016].

European Union. Risk Assessment Report for DEHP. Final report, European Commission, EUR 23384EN, European Union Risk Assessment Report, Volume 80, Luxembourg: Office for Official Publications of the European Communities, ISSN 1018-5593; 2008

European Union. Directive 2005/84/EC of the European Parliament and of the Council of 14 December 2005; 2005

European Union. Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food; 2011

Korea Ministry of Government Legislation (KMGL). 2012. enforcement decree of the quality management and safety control of industrial products act, MKE regulation 248, Available: [accessed 30 March 2016].

Korea Food and Drug Administration (KFDA). 2007. Regulation on safe containers, packaging, etc. KFDA 2007-64. Available: [accessed 30 March 2016].

Korea Ministry of Government Legislation (KMGL). 2010. Regulation on cosmetic ingredients, KFDA 2010-99. Available: [accessed 30 March 2016].

Korean Agency for Technology and Standards (KATS). 2011. Regulation on the quality management and safety control of industrial products. KATS 2011-0553. Available: [accessed 30 March 2016].

Korean Agency for Technology and Standards (KATS). 2012. Regulation on the quality management and safety control of industrial products. KATS 2012-0800. Available: [accessed 30 March 2016].

Korea Food and Drug Administration (KFDA). 2009. Regulation on safe containers, packaging, etc. KFDA 2009-29. Available: [accessed 30 March 2016].

Andersen A. Amended final report of the safety assessment of dibutyl adipate as used in cosmetics. Int J Toxicol. 2006; 25 Suppl 1: 129-134. crossref(new window)

Stuer-Lauridsen F, Mikkelsen S, Havelund S, Birkved M, Hansen LP. Environmental and Health Assessment of Alternatives to Phthalates and to Flexible PVC. Danish Environmental Protection Agency, COWI Consulting Engineers and Planners AS, Copenhagen, Denmark; 2001

Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR). Preliminary Report on the Safety of Medical Devices Containing DEHP-Plasticized PVC or Other Plasticizers on Neonates and Other Groups Possibly at Risk. Scientific Committee on Emerging and Newly-Identified Health Risks, Health and Consumer Protection Directorate-General, European Commission; 2007

Borch J, Ladefoged O, Hass U, Vinggaard AM. Steroidogenesis in fetal male rats is reduced by DEHP and DINP, but endocrine effects of DEHP are not modulated by DEHA in fetal, prepubertal and adult male rats. Reprod Toxicol. 2004; 18: 53-61. crossref(new window)

Bui TT, Giovanoulis G, Cousins AP, Magner J, Cousins IT, de Wit CA. Human exposure, hazard and risk of alternative plasticizers to phthalate esters. Sci Total Environ. 2016; 541: 451-467. crossref(new window)

Schutze A, Kolossa-Gehring M, Apel P, Bruning T, Koch HM. Entering markets and bodies: increasing levels of the novel plasticizer Hexamall(R) DINCH(R) in 24 h urine samples from the German Environ mental Specimen Bank. Int J Hyg Environ Health. 2014; 217: 421-426. crossref(new window)

Takeshita A, Igarashi-Migitaka J, Nishiyama K, Takahashi H, Takeuchi Y, Koibuchi N. Acetyl tributyl citrate, the most widely used phthalate substitute plasticizer, induces cytochrome P450 3A through steroid and xenobiotic receptor. Toxicol Sci. 2011; 123: 460-470. crossref(new window)

Liu X, Ji K, Choi K. Endocrine disruption potentials of organophosphate flame retardants and related mechanisms in H295R and MVLN cell lines and in zebrafish. Aquat Toxicol. 2012; 114-115: 173-181. crossref(new window)

Wirnitzer U, Rickenbacher U, Katerkamp A, Schachtrupp A. Systemic toxicity of di-2-ethylhexyl terephthalate (DEHT) in rodents following four weeks of intravenous exposure. Toxicol Lett. 2011; 205: 8-14. crossref(new window)

Klimisch HJ, Andreae M, Tillmann U. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol. 1997; 25: 1-5. crossref(new window)

Foster PM, Lake BG, Cook MW, Thomas LV, Gangolli SD. Structure-activity requirements for the induction of testicular atrophy by butyl phthalates in immature rats: effect on testicular zinc content. Adv Exp Med Biol. 1981; 136 Pt A: 445-452.

Heindel JJ, Gulati DK, Mounce RC, Russell SR, Lamb JC 4th. Reproductive toxicity of three phthalic acid esters in a continuous breeding protocol. Fundam Appl Toxicol. 1989; 12: 508-518. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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.

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. crossref(new window)

Ghisari M, Bonefeld-Jorgensen EC. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol Lett. 2009; 189: 67-77. crossref(new window)

Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors ${\alpha}$ and ${\beta}$, and androgen receptor. Toxicology. 2005; 210: 223-233. crossref(new window)

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. crossref(new window)

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.

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. crossref(new window)

Harris CA, Henttu P, Parker MG, Sumpter JP. The estrogenic activity of phthalate esters in vitro. Environ Health Perspect. 1997; 105: 802-811. crossref(new window)

Blom A, Ekman E, Johannisson A, Norrgren L, Pesonen M. ffects of xenoestrogenic environmental pollutants on the proliferation of a human breast cancer cell line (MCF-7). Arch Environ Contam Toxicol. 1998; 34: 306-310. crossref(new window)

Chen FP, Chien MH. Lower concentrations of phthalates induce proliferation in human breast cancer cells. Climacteric. 2014; 17: 377-384. crossref(new window)

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. crossref(new window)

Tanay Das M, Kumar Singh M, Thakur IS. Differential toxicological endpoints of di(2-ethylhexyl) phthalate (DEHP) exposure in MCF-7 and MDAMB-231 cell lines: possible estrogen receptor ${\alpha}$ (ER ${\alpha}$) independent modulations. Indian J Exp Biol. 2014; 52: 1052-1061.

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. crossref(new window)

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. crossref(new window)

Papaconstantinou AD, Fisher BR, Umbreit TH, Brown KM. Increases in mouse uterine heat shock protein levels are a sensitive and specific response to uterotrophic agents. Environ Health Perspect. 2002; 110: 1207-1212. crossref(new window)

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. crossref(new window)

Yamasaki K, Noda S, Imatanaka N, Yakabe Y. Comparative study of the uterotrophic potency of 14 chemicals in a uterotrophic assay and their receptor-binding affinity. Toxicol Lett. 2004a; 146: 111-120. crossref(new window)

Kumar N, Sharan S, Srivastava S, Roy P. Assessment of estrogenic potential of diethyl phthalate in female reproductive system involving both genomic and non-genomic actions. Reprod Toxicol. 2014; 49: 12-26. crossref(new window)

Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, et al. Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2014b; 195: 177-186.

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. crossref(new window)

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. crossref(new window)

Lee BM, Koo HJ. Hershberger assay for antiandrogenic effects of phthalates. J Toxicol Environ Health A. 2007; 70: 1365-1370. crossref(new window)

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. crossref(new window)

Stroheker T, Cabaton N, Nourdin G, Regnier JF, Lhuguenot JC, Chagnon MC. Evaluation of antiandrogenic activity of di-(2-ethylhexyl)phthalate. Toxicology. 2005; 208: 115-121. crossref(new window)

Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, et al. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci. 2000; 58: 339-349. crossref(new window)

Foster PM, Mylchreest E, Gaido KW, Sar M. Effects of phthalate esters on the developing reproductive tract of male rats. Hum Reprod Update. 2000; 7: 231-235.

European Chemicals Agency (ECHA). 2016. Information on Chemicals. Available: [accessed 30 March 2016].

OECD SIDS. Dibutyl Adipate. CAS No: 105-99-7. SIDS Initial Assessment Report; 1996

CSTEE. Opinion on the Toxicological Characteristics and Risks of Certain Citrates and Adipates Used as a Substitute for Phthalates as Plasticisers in Certain Soft PVC Products. Opinion adopted at the 11th CSTEE plenary meeting on the 28th of September 1999; 1999

Miyata K, Shiraishi K, Houshuyama S, Imatanaka N, Umano T, Minobe Y, et al. Subacute oral toxicity study of di(2-ethylhexyl)adipate based on the draft protocol for the "Enhanced OECD Test Guideline no. 407". Arch. Toxicol. 2006; 80: 181-186. crossref(new window)

Nielson BS, Andersen DN, Giovalle E, Bjergstrom M, Larsen PB. Alternatives to Classified Phthalates in Medical Devices. Danish Ministry of the Environment. Environmental Protection Agency. Environmental Project No. 1557, Copenhagen, Denmark; 2014

Dalgaard M, Hass U, Vinggaard AM, Jarfelt K, Lam HR, Sorensen IK, et al. Di(2-ethylhexyl) adipate (DEHA) induced developmental toxicity but not antiandrogenic effects in pre-and postnatally exposed Wistar rats. Reprod Toxicol. 2003; 17: 163-170. crossref(new window)

Lee HC, Yamanouchi K, Nishihara M. Effects of perinatal exposure to phthalate/adipate esters on hypothalamic gene expression and sexual behavior in rats. J Reprod Develop. 2006; 52: 343-352. crossref(new window)

Maag J, Lassen C, Brandt UK, Kjoholt J, Molander L, Mikkelsen SH. Identification and Assessment of Alternatives to Selected Phthalates. Danish Ministry of the Environment. Environmental Project No. 1341 2010; 2010

National Industrial Chemicals Notification and Assessment Scheme (NICNAS). Public Report. 1,2-Cyclohexanedicarboxylic Acid, 1,2,-Diisononyl Ester ('Hexamoll DINCH'). File No: EX/170 (STD/1259); 2012

Van Vliet EDS, Reitano EM, Chhabra JS, Bergen GP, Whyatt RM. A review of alternatives to di (2-ethylhexyl) phthalate-containing medical devices in the neonatal intensive care unit. J. Perinatol. 2011; 31: 551-560. crossref(new window)

ToxServices. 2012a. $GreenScreen^{TM}$ Assessment for Hexamoll(R) DINCH(R) (Diisononyl cyclohexanedicarboxylate).

Ohta M, Oshima S, Iwasa T, Ito N. Examination of sex-hormonal activity of some additives for PVDC film. Shokuhin Eiseigaku Zasshi. 2003; 44: 227-233. crossref(new window)

Kojima H, Takeuchi S, Itoh T, Iida M, Kobayashi S, Yoshida T. In vitro endocrine disruption potential of organophosphate flame retardants via human nuclear receptors. Toxicology. 2013; 314: 76-83. crossref(new window)

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. crossref(new window)

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. crossref(new window)

ter Veld MGR, Schouten B, Louisse J, van Es DS, van der Saag PT, Rietjens IMCM, et al. 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. 2006; 54: 4407-4416. crossref(new window)

Ohashi A, Kotera H, Hori H, Hibiya M, Watanabe K, Murakami K, et al. Evaluation of endocrine disrupting activity of plasticizers in polyvinyl chloride tubes by estrogen receptor alpha binding assay. J Artif Organs. 2005; 8: 252-256. crossref(new window)