Comparative analysis of the toxicity and hazards of phthalate plasticizers for human health and the environment

Introduction. In the international practice of chemical safety, the priority areas are the identification and prohibition (restriction) of highly hazardous chemicals (carcinogens, mutagens, reprotoxicants, endocrine disruptors, toxic, persistent and bioaccumulative compounds, substances toxic to the aquatic biota) in products in order to prevent their impact on human health and the environment. Phthalate plasticizers are among the substances of serious concern. They are widely used in various industries and can cause chronic negative effects when they migrate from materials and products.

The purpose of this study was to conduct a comparative analysis of the toxicity and hazard of six phthalate plasticizers for human health and the environment, and identify priority areas for their subsequent regulation.

Material and methods. The phthalate plasticizers most commonly used in the production of construction and finishing materials were selected as the objects of this study: 1-O-butyl-2-O-(phenylmethyl)benzene-1,2-dicarbonate (BBP), dibutylbenzene-1,2-dicarbonate (DBP), diisobutylbenzene-1,2-dicarbonate (DIBP), 1,4-dibutylbenzene-1,4-dicarbonate (DBTP), di(2-ethylhexyl)benzene-1,4-dicarbonate (DOTP), and di(2-ethylhexyl)benzene-1,2-dicarbonate (DEHP). The assessment of toxicity and hazard was based on data from official open national and international sources of information (databases, scientific articles, reports, monographs, and reference books).

Results. Terephthalic acid-based plasticizers (DBTP and DOTP) are the safest in terms of toxicity and health hazards compared to ortho-phthalic acid-based plasticizers (BBP, DIBP, DBP, and DEHP). The last ones have a significant hazardous effect on humans and the environment, including: hepatotoxic effects in animal experiments with prolonged exposure; negative effects on reproductive function and developing offspring, and are classified as hazard class 1B according to the GHS criteria; disruption of the morphology and functions of endocrine system organs (thyroid, adrenal glands, pituitary gland, male reproductive organs, etc.), and lipid metabolism; acute and chronic toxicity for aquatic biota (Class 1 according to toxicometry indicators); hazard class 2 (highly hazardous substances) according to GOST 12.1.007–76 based on the maximum permissible concentration in the air of the working area.

Limitations. The study is limited to the analysis of open literature sources, including databases such as Scopus, Web of Science, PubMed, ResearchGate, Cyberleninka, RSCI, and eLIBRARY.

Conclusion. The decision to replace a chemical substance with alternatives (analogues) is based not only on data on toxicity and hazard, but also on an assessment of the actual risk of exposure, which depends on the substance’s ability to migrate into boundary environments (air, water, and model environments).

To use DBTP as an alternative to hazardous plasticizers, it is necessary to study effects on the liver, reproductive function, and developing offspring, as well as on the endocrine system. Additionally, it is required to scientifically substantiate and approve the hygienic standards for DBTP in the air of the work area, in the atmospheric air of urban and rural settlements, and in water, since the legislation of the Russian Federation permits the activities of economic entities with chemicals only if there are hygienic standards.

It is advisable to study the migration of DBTP and DOTP from various materials in order to establish correlation between the content in products and the level of migration into the boundary environment.

Compliance with ethical standards. The study does not require a report from the Bioethics Commission.

Authors’ contribution:
Khamidulina Kh.Kh., Tarasova E.V. – concept and design of the study, editing, approval of the final version of the article, responsibility for the integrity of all parts of the article;
Nazarenko A.K., Tverskaya A.S., Zamkova I.V., Proskurina A.S., Rabikova D.N., Araslanov I.N., Zherenova A.A., Gorbunova D.I., Gonyukova E.S., Leontyeva A.N. – collecting and processing material, writing text, editing.

Conflict of interest. The authors declare that there are no obvious and potential conflicts of interest in connection with the publication of this article.

Funding. The study was conducted as part of the implementation of the research project “Development and Scientific Justification of Chemical Alternatives for Replacing Highly Hazardous Components in Various Types of Products” under the state program of the Russian Federation “Scientific and Technological Development of the Russian Federation in 2026–2028”.

Received: December 26, 2025 / Accepted: February 2, 2026 / Published: March 18, 2026

1. Proskurina A.S., Khamidulina Kh.Kh., Tarasova E.V. International approaches to reducing the risk of highly hazardous chemicals exposure on human health and to the selection criteria for substitution by safer analogues (literature review). Toksikologicheskii vestnik. 2022; 30(2): 68–78. https://doi.org/10.47470/0869-7922-2022-30-2-68-78 https://elibrary.ru/shxxpi (in Russian).

2. Khamidulina Kh.Kh., Tarasova Е.V., Nazarenko А.K., Rabikova D.N., Proskurina А.S., Zamkova I.V. Some proposals on regulation of highly hazardous chemicals in articles. Health Risk Analysis. 2023; (3): 17–28. https://doi.org/10.21668/health.risk/2023.3.02.eng

3. Khamidulina Kh.Kh., Proskurina A.S., Tarasova E.V. Development and implementation of a concept for substitution of the highly hazardous substances with safe chemical alternatives. Meditsina truda i promyshlennaya ekologiya. 2022; 62(11): 733–9. https://doi.org/10.31089/1026-9428-2022-62-11-733-739 https://elibrary.ru/dugaxx (in Russian)

4. Lappo L.G., Grynchak V.A., Sychik S.I. Assessment of in vitro blood compatibility of polymer and metal medical devices. Toksikologicheskii vestnik. 2025; 33(4): 280–7. https://doi.org/10.47470/0869-7922-2025-33-4-280-287 https://elibrary.ru/egigur (in Russian)

5. Lappo L.G., Grynchak V.A. Comparative assessment of the toxicity of diisononyl phthalate and diisodecyl phthalate in a subchronic experiment. In: Health and Environment. Proceedings of the International Scientific and Practical Conference Dedicated to the 95th Anniversary of the Republican Unitary Enterprise "Scientific and Practical Center of Hygiene" [Zdorov’e i okruzhayushchaya sreda: sbornik materialov mezhdunarodnoi nauchno-prakticheskoi konferentsii, posvyashchennoi 95-letiyu RUP "Nauchno-prakticheskii tsentr gigieny"]. Minsk; 2022: 457–61. (in Russian)

6. Radilov A.S., Solntseva S.A., Shkaeva I.E., Dulov S.A., Vivulanets E.V., Protasova G.A., et al. Experimental substantiation of the maximum allowable concentration of dioctyl terephthalate in the air of the working area. Toksikologicheskii vestnik. 2020; (1): 34–8. https://doi.org/10.36946/0869-7922-2020-1-34-38 https://elibrary.ru/twafum (in Russian)

7. Earl Gray L. Jr., Lambright C.S., Evans N., Ford J., Conley J.M. Using targeted fetal rat testis genomic and endocrine alterations to predict the effects of a phthalate mixture on the male reproductive tract. Curr. Res. Toxicol. 2024; 7: 100180. https://doi.org/10.1016/j.crtox.2024.100180

8. Sun G., Li Y. Molecular mechanisms of developmental toxicity induced by BBP in zebrafish embryos. Toxicology. 2022; 466: 153078. https://doi.org/10.1016/j.tox.2021.153078

9. Yu Y., Wang Y., Dong Y., Shu S., Zhang D., Xu J., et al. Butyl benzyl phthalate as a key component of phthalate ester in relation to cognitive impairment in NHANES elderly individuals and experimental mice. Environ. Sci. Pollut. Res. Int. 2023; 30(16): 47544–60. https://doi.org/10.1007/s11356-023-25729-8

10. Jiang Y., Wang D., Zhang C., Jiao Y., Pu Y., Cheng R., et al. Nicotinamide mononucleotide restores oxidative stress-related apoptosis of oocyte exposed to benzyl butyl phthalate in mice. Cell Prolif. 2023; 56(8): e13419. https://doi.org/10.1111/cpr.13419

11. Park M.S., Hwang S., Kang H.B., Ha M., Park J., Park S.Y., et al. Age-dependent effects of butyl benzyl phthalate exposure on lipid metabolism and hepatic fibrosis in mice. Cells. 2025; 14(2): 126. https://doi.org/10.3390/cells14020126

12. Jiang N., Song P., Li X., Zhu L., Wang J., Yin X., et al. Dibutyl phthalate induced oxidative stress and genotoxicity on adult zebrafish (Danio rerio) brain. J. Hazard. Mater. 2022; 424(Pt. D): 127749. https://doi.org/10.1016/j.jhazmat.2021.127749

13. Cui Y., Li B., Du J., Huo S., Song M., Shao B., et al. Dibutyl phthalate causes MC3T3-E1 cell damage by increasing ROS to promote the PINK1/Parkin-mediated mitophagy. Environ. Toxicol. 2022; 37(10): 2341–53. https://doi.org/10.1002/tox.23600

14. Yang R., Zheng J., Qin J., Liu S., Liu X., Gu Y., et al. Dibutyl phthalate affects insulin synthesis and secretion by regulating the mitochondrial apoptotic pathway and oxidative stress in rat insulinoma cells. Ecotoxicol. Environ. Saf. 2023; 249: 114396. https://doi.org/10.1016/j.ecoenv.2022.114396

15. Tao H.Y., Shi J., Zhang J., Ge H., Zhang M., Li X.Y. Developmental toxicity and mechanism of dibutyl phthalate and alternative diisobutyl phthalate in the early life stages of zebrafish (Danio rerio). Aquat. Toxicol. 2024; 272: 106962. https://doi.org/10.1016/j.aquatox.2024.106962

16. Quelhas A.R., Mariana M., Cairrao E. The Plasticizer Dibutyl Phthalate (DBP) impairs pregnancy vascular health: insights into calcium signaling and nitric oxide involvement. J. Xenobiot. 2025; 15(4): 127. https://doi.org/10.3390/jox15040127

17. Yan C., Wu M., Peng H., Wan J., Li R., Ye X., et al. Chronic DBP exposure may cause reduced fertility in female mice by interfering with the HPO axis. Environ. Pollut. 2025; 384: 127039. https://doi.org/10.1016/j.envpol.2025.127039

18. Kim S.M., Kim Y.H., Han G.U., Kim S.G., Bhang D.H., Kim B.G., et al. Diisobutyl phthalate (DiBP)-induced male germ cell toxicity and its alleviation approach. Food Chem. Toxicol. 2024; 184: 114387. https://doi.org/10.1016/j.fct.2023.114387

19. Pierozan P., Källsten L., Theodoropoulou E., Almamoun R., Karlsson O. Persistent immunosuppressive effects of dibutyl phthalate exposure in adult male mice. Sci. Total Environ. 2023; 878: 162741. https://doi.org/10.1016/j.scitotenv.2023.162741

20. Liu H., Sun W., Zhu H., Guo J., Liu M., Xu S. Eucalyptol relieves the toxicity of diisobutyl phthalate in Ctenopharyngodon idellus kidney cells through Keap1/Nrf2/HO-1 pathway: Apoptosis-autophagy crosstalk and immunoregulation. Fish Shellfish Immunol. 2022; 130: 490–500. https://doi.org/10.1016/j.fsi.2022.09.056

21. Li J., Chen R., Liu P., Zhang X., Zhou Y., Xing Y., et al. Association of Di(2-ethylhexyl) terephthalate and its metabolites with nonalcoholic fatty liver disease: an epidemiology and toxicology study. Environ. Sci. Technol. 2024; 58(19): 8182–93. https://doi.org/10.1021/acs.est.3c09503

22. Wang J., Deng Q., Qi L. Exploring the toxicological effects of DOTP exposure on periodontitis by combining molecular docking and molecular dynamics simulations. Sci. Rep. 2025; 15(1): 20915. https://doi.org/10.1038/s41598-025-05740-4

23. Potts C., Harbolic A., Murphy M., Jojy M., Hanna C., Nadeem M., et al. A common phthalate replacement disrupts ovarian function in young adult mice. Reprod. Toxicol. 2025; 131: 108748. https://doi.org/10.1016/j.reprotox.2024.108748

24. de Freitas T., Zapaterini J.R., Moreira C.M., de Aquino A.M., Alonso-Costa L.G., Bidinotto L.T., et al. Prenatal exposure to a mixture of different phthalates increases the risk of mammary carcinogenesis in F1 female offspring. Food Chem. Toxicol. 2021; 156: 112519. https://doi.org/10.1016/j.fct.2021.112519

25. Gonsioroski A.V., Aquino A.M., Alonso-Costa L.G., Barbisan L.F., Scarano W.R., Flaws J.A. Multigenerational effects of an environmentally relevant phthalate mixture on reproductive parameters and ovarian miRNA expression in female rats. Toxicol. Sci. 2022; 189(1): 91–106. https://doi.org/10.1093/toxsci/kfac066

26. Karabulut G., Barlas N. Endocrine adverse effects of mono(2-ethylhexyl) phthalate and monobutyl phthalate in male pubertal rats. Arh. Hig. Rada Toksikol. 2022; 73(4): 285–96. https://doi.org/10.2478/aiht-2022-73-3617

27. Liang X., Huang Q., Wu Y., Zhu D., Wei Z., Feng Q., et al. Probing the cardiovascular toxic effects of long-term exposure to dibutyl phthalate in Sprague-Dawley rats based on oxidative inflammation and metabolic pathways: implications for the heart and blood vessel. Toxics. 2025; 13(10): 815. https://doi.org/10.3390/toxics13100815

28. Almamoun R., Pierozan P., Karlsson O. Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations. Arch. Toxicol. 2024; 98(8): 2695–709. https://doi.org/10.1007/s00204-024-03767-6

29. Liu M., Du X., Chen H., Bai C., Lan L. Systemic investigation of di-isobutyl phthalate (DIBP) exposure in the risk of cardiovascular via influencing the gut microbiota arachidonic acid metabolism in obese mice model. Regen. Ther. 2024; 27: 290–300. https://doi.org/10.1016/j.reth.2024.03.024

30. Stanic B., Kokai D., Markovic Filipovic J., Tomanic T., Vukcevic J., Stojkov V., et al. Vascular endothelial effects of dibutyl phthalate: In vitro and in vivo evidence. Chem. Biol. Interact. 2024; 399: 111120. https://doi.org/10.1016/j.cbi.2024.111120

31. Alam M.S., Maowa Z., Hasan M.N. Phthalates toxicity in vivo to rats, mice, birds, and fish: A thematic scoping review. Heliyon. 2024; 11(1): e41277. https://doi.org/10.1016/j.heliyon.2024.e41277

32. Ge X., Weis K., Raetzman L. IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: Impact of developmental exposures to endocrine-disrupting chemicals on pituitary gland reproductive function. Reproduction. 2024; 168(6): e240072. https://doi.org/10.1530/REP-24-0072

33. Tiburcio D., Parsell M., Shapiro H., Adolphe S., Naranjo O., George S., et al. Endocrine disruption to metastasis: How phthalates promote breast carcinogenesis. Ecotoxicol. Environ. Saf. 2025; 303: 118874. https://doi.org/10.1016/j.ecoenv.2025.118874