Di(2-ethylhexyl) Phthalate (DEHP): A Comprehensive Review of Chemical Properties, Exposure Pathways, Toxicity Mechanisms, and Mitigation Strategies

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous plasticizer used in a wide range of consumer products. While its presence improves the flexibility and durability of plastics, its inherent toxicity raises significant concerns. This report provides a comprehensive review of DEHP, encompassing its chemical properties, sources of exposure, diverse health risks (including reproductive effects and cancer, extending beyond previously documented cardiovascular impacts), mechanisms of toxicity at the molecular level, and regulatory landscape across different countries. Furthermore, we delve into potential alternative plasticizers and offer evidence-based guidance on minimizing individual exposure to DEHP. A critical assessment of the scientific literature reveals the complexity of DEHP toxicity and highlights the need for ongoing research to fully elucidate its long-term health effects and to facilitate the development and adoption of safer alternatives. The report aims to provide researchers, policymakers, and the public with a detailed and nuanced understanding of the risks associated with DEHP exposure and the strategies to mitigate them.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Phthalates are a family of synthetic chemicals primarily used as plasticizers to impart flexibility, transparency, durability, and longevity to polyvinyl chloride (PVC) and other plastics. Among these, di(2-ethylhexyl) phthalate (DEHP), also known as bis(2-ethylhexyl) phthalate, is one of the most widely produced and studied. Its extensive use in consumer products has led to widespread environmental contamination and human exposure. While phthalates do not chemically bind to the polymers they plasticize, they can leach out over time, leading to exposure through various routes, including ingestion, inhalation, and dermal absorption (ATSDR, 2002). This ease of migration is one of the critical drivers behind the concerns surrounding their safety.

DEHP’s widespread use is attributable to its effectiveness as a plasticizer and its relatively low cost. However, its toxicological profile has been a subject of intense scientific scrutiny for decades. Initial studies raised concerns about its potential reproductive and developmental toxicity, leading to regulatory restrictions in some regions. Subsequent research has expanded our understanding of its diverse adverse health effects, including potential carcinogenic effects and endocrine disruption (Koch et al., 2017).

This review aims to provide an in-depth examination of DEHP, moving beyond the well-established knowledge of its effects on the heart and focusing on a broader spectrum of health risks, with particular emphasis on reproductive and carcinogenic effects. We will explore the underlying mechanisms of its toxicity at the cellular and molecular levels, providing insights into how DEHP interacts with biological systems. The report also assesses the regulatory landscape surrounding DEHP in different countries and examines the availability and suitability of alternative plasticizers. Finally, we will offer practical guidance on how individuals can minimize their exposure to this ubiquitous chemical.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Chemical Properties and Production

DEHP is a colorless, odorless, viscous liquid with a high boiling point (384 °C) and a low water solubility (0.3 mg/L at 20°C). Its chemical formula is C24H38O4, and its molecular weight is 390.56 g/mol. The IUPAC name is bis(2-ethylhexyl) benzene-1,2-dicarboxylate. DEHP is synthesized through the esterification of phthalic anhydride with 2-ethylhexanol. The reaction is typically catalyzed by strong acids, such as sulfuric acid or p-toluenesulfonic acid.

Globally, DEHP production reached millions of tons annually in the past, although production has decreased in recent years due to growing health and environmental concerns and regulatory restrictions (European Chemicals Agency, 2024). The primary applications of DEHP are in the production of PVC, which is used in a vast array of products, including flooring, wall coverings, medical devices (e.g., blood bags, tubing), toys, and food packaging. Its versatility and relatively low cost compared to other plasticizers have made it a preferred choice for many manufacturers. Although its use is declining in some applications, legacy products continue to be sources of exposure for years, if not decades. Moreover, DEHP remains in use where local regulations permit or enforcement is weak, further complicating efforts to mitigate its overall impact.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Sources of Exposure

Human exposure to DEHP occurs through multiple pathways, including:

• Ingestion: DEHP can leach from food packaging materials into food, particularly fatty foods. Contamination of drinking water is another potential source, although typically at lower concentrations. Children are particularly vulnerable due to their tendency to mouth toys and other objects made of PVC (Frederiksen et al., 2007).
• Inhalation: DEHP can be released into the air from PVC products, especially during manufacturing or when products are heated. Indoor air can be a significant source of exposure, particularly in environments with a high concentration of PVC materials (e.g., homes, offices, vehicles).
• Dermal Absorption: DEHP can be absorbed through the skin from contact with PVC products, such as clothing, toys, and personal care products. The rate of dermal absorption can be influenced by factors such as temperature, humidity, and the presence of other chemicals.
• Medical Procedures: Historically, medical devices made of PVC, such as blood bags, intravenous tubing, and catheters, have been a significant source of DEHP exposure for patients, particularly neonates and those undergoing long-term medical treatments (Tickner et al., 2001). Although efforts have been made to replace DEHP in medical devices, some products still contain it.

Exposure levels vary widely depending on factors such as geographical location, lifestyle, and occupational setting. Individuals working in the plastics manufacturing industry are at the highest risk of exposure. Children, pregnant women, and individuals with pre-existing health conditions are considered to be particularly vulnerable to the adverse effects of DEHP.

Measuring human exposure often involves analyzing urine samples for DEHP metabolites. While this method provides a snapshot of recent exposure, it does not capture long-term or cumulative exposure. Moreover, different metabolites have varying half-lives and may not accurately reflect total DEHP exposure (Silva et al., 2006).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Health Risks

DEHP has been extensively studied for its adverse health effects, which include:

4.1. Reproductive Effects

DEHP is a well-established reproductive toxicant, with numerous studies demonstrating its adverse effects on male reproductive development and function. Exposure to DEHP can lead to decreased testosterone production, reduced sperm count and motility, and increased abnormal sperm morphology (Duty et al., 2003). In animal studies, DEHP exposure has been shown to cause testicular atrophy, Leydig cell damage, and altered Sertoli cell function. These effects are believed to be mediated through disruption of the hypothalamic-pituitary-gonadal (HPG) axis, as well as direct effects on testicular cells.

In females, DEHP exposure has been associated with altered ovarian function, disrupted estrous cycles, and decreased fertility. Animal studies have shown that DEHP can disrupt folliculogenesis, alter hormone levels, and increase the risk of pregnancy complications. Furthermore, DEHP can cross the placenta and expose the developing fetus to its toxic effects. Prenatal DEHP exposure has been linked to adverse reproductive outcomes in both male and female offspring, including altered sexual development and decreased fertility later in life (Barrett, 2015).

4.2. Carcinogenic Effects

DEHP has been classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer (IARC). Animal studies have shown that DEHP can cause liver tumors, particularly in rats and mice. The mechanism of DEHP-induced liver carcinogenesis is complex and likely involves multiple pathways, including peroxisome proliferator-activated receptor alpha (PPARα) activation, oxidative stress, and epigenetic modifications (IARC, 2013).

While epidemiological evidence linking DEHP exposure to cancer in humans is limited, some studies have suggested a possible association between DEHP exposure and increased risk of certain cancers, such as liver cancer and breast cancer. However, these studies are often limited by small sample sizes, potential confounding factors, and difficulties in accurately assessing long-term DEHP exposure. Further research is needed to fully elucidate the carcinogenic potential of DEHP in humans.

4.3. Endocrine Disruption

DEHP is an endocrine disruptor, meaning that it can interfere with the normal function of hormones in the body. DEHP can mimic or block the action of hormones, alter hormone production, or disrupt hormone signaling pathways. As previously stated, this disruption of the HPG axis is significant. DEHP’s endocrine-disrupting effects have been implicated in a variety of adverse health outcomes, including reproductive and developmental abnormalities, metabolic disorders, and immune dysfunction. Several in vitro and in vivo studies support the idea that DEHP acts as both an anti-androgen and an estrogen mimic, depending on the specific tissue and concentration (Gray et al., 2000).

4.4. Other Health Risks

Beyond reproductive effects and cancer, DEHP exposure has been associated with a range of other health risks, including:

• Developmental Toxicity: DEHP can adversely affect the development of the nervous system, immune system, and other organ systems in developing fetuses and children. Animal studies have shown that DEHP exposure during pregnancy can lead to neurodevelopmental deficits, immune dysfunction, and altered metabolic function in offspring (Thompson et al., 2011).
• Metabolic Disorders: DEHP exposure has been linked to an increased risk of obesity, insulin resistance, and type 2 diabetes. Animal studies have shown that DEHP can disrupt glucose metabolism, alter lipid profiles, and promote inflammation in adipose tissue (Stahlhut et al., 2007).
• Respiratory Effects: DEHP exposure can exacerbate asthma and other respiratory conditions. Some studies have suggested a link between DEHP exposure and increased risk of allergic sensitization and airway inflammation (Trasande et al., 2005).

It is important to note that many of these health risks are based on animal studies or observational studies in humans, and further research is needed to confirm these findings and to fully understand the mechanisms underlying these effects. The complex interactions between DEHP and biological systems make it challenging to fully assess its long-term health impacts.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Mechanisms of Toxicity

The toxicity of DEHP is mediated through multiple mechanisms, including:

5.1. Peroxisome Proliferator-Activated Receptor Alpha (PPARα) Activation

DEHP is a known activator of PPARα, a nuclear receptor that plays a crucial role in regulating lipid metabolism, inflammation, and cellular proliferation. Activation of PPARα by DEHP can lead to increased peroxisome proliferation in the liver, altered lipid profiles, and increased oxidative stress. These effects are believed to contribute to DEHP-induced liver carcinogenesis and metabolic disorders (Gonzalez & Shah, 2008).

However, the role of PPARα in DEHP toxicity is complex and context-dependent. While PPARα activation can mediate some of the adverse effects of DEHP, it can also have protective effects in certain situations. For example, PPARα activation has been shown to promote fatty acid oxidation and reduce inflammation in some tissues. The specific effects of PPARα activation depend on factors such as the tissue type, the dose of DEHP, and the presence of other chemicals.

5.2. Endocrine Disruption

As discussed previously, DEHP is an endocrine disruptor that can interfere with the normal function of hormones. DEHP can bind to estrogen receptors and androgen receptors, mimicking or blocking the action of these hormones. This disruption of hormone signaling can lead to a variety of adverse health outcomes, including reproductive and developmental abnormalities.

The mechanisms by which DEHP disrupts endocrine function are complex and not fully understood. DEHP can affect hormone synthesis, metabolism, and transport, as well as hormone receptor expression and signaling. Furthermore, DEHP can interact with other endocrine disruptors, leading to synergistic or additive effects.

5.3. Oxidative Stress

DEHP exposure can induce oxidative stress, an imbalance between the production of reactive oxygen species (ROS) and the ability of the body to detoxify them. ROS can damage DNA, proteins, and lipids, leading to cellular dysfunction and increased risk of chronic diseases. DEHP-induced oxidative stress has been implicated in a variety of adverse health outcomes, including liver damage, reproductive toxicity, and neurotoxicity (Hsin-Yi Lo et al., 2017).

DEHP can induce oxidative stress through multiple mechanisms, including increasing ROS production, decreasing antioxidant enzyme activity, and disrupting mitochondrial function. Furthermore, DEHP can interact with other chemicals that induce oxidative stress, leading to synergistic effects.

5.4. Epigenetic Modifications

Epigenetic modifications are changes in gene expression that do not involve alterations in the DNA sequence. DEHP exposure can induce epigenetic modifications, such as DNA methylation and histone modification, which can alter gene expression and contribute to its toxic effects. These modifications can even be passed on to future generations. Prenatal exposure to DEHP has been linked to epigenetic changes in offspring, which may increase their risk of developing chronic diseases later in life (Zhang et al., 2021).

The mechanisms by which DEHP induces epigenetic modifications are not fully understood. DEHP can affect the activity of enzymes that regulate DNA methylation and histone modification, as well as alter the availability of methyl donors and other cofactors required for these processes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Regulatory Status

The regulatory status of DEHP varies widely across different countries and regions. In the European Union (EU), DEHP is classified as a substance of very high concern (SVHC) under the REACH regulation (Registration, Evaluation, Authorisation and Restriction of Chemicals). Its use is restricted in certain applications, such as toys and childcare articles, and requires authorization for continued use in other applications (European Chemicals Agency, 2024).

In the United States, DEHP is regulated by the Consumer Product Safety Commission (CPSC) and the Environmental Protection Agency (EPA). The CPSC has banned DEHP from use in children’s toys and childcare articles at concentrations above 0.1%. The EPA regulates DEHP under the Toxic Substances Control Act (TSCA) and has implemented various measures to reduce its release into the environment.

Other countries, such as Canada, Australia, and Japan, have also implemented regulations to restrict or phase out the use of DEHP in certain products. However, the regulatory landscape surrounding DEHP is constantly evolving, and new regulations are being implemented in response to emerging scientific evidence.

The effectiveness of these regulations in reducing human exposure to DEHP is a subject of ongoing debate. While regulations have undoubtedly reduced DEHP exposure in some areas, they have not eliminated it entirely. Furthermore, the substitution of DEHP with other phthalates or alternative plasticizers raises concerns about the potential for regrettable substitutions, where the replacement chemicals may have similar or even worse toxicological properties.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Potential Alternatives

Given the health concerns associated with DEHP, there is a growing demand for safer alternative plasticizers. Some potential alternatives include:

• Diisononyl phthalate (DINP): DINP is another phthalate plasticizer that has been used as a replacement for DEHP in some applications. While DINP is generally considered to be less toxic than DEHP, it is still subject to regulatory scrutiny and has been linked to some adverse health effects (EFSA, 2006).
• Diisodecyl phthalate (DIDP): DIDP is another phthalate plasticizer with a higher molecular weight than DEHP. It is considered to be less volatile and less likely to leach from plastics. However, some studies have suggested that DIDP may have similar toxicological properties to DEHP.
• Citrate esters: Citrate esters are a class of bio-based plasticizers derived from citric acid. They are generally considered to be less toxic than phthalates and have been approved for use in food contact materials. However, citrate esters may not be as effective as phthalates in terms of plasticizing performance.
• Epoxidized soybean oil (ESBO): ESBO is a bio-based plasticizer derived from soybean oil. It is widely used in PVC applications and is generally considered to be safe. However, ESBO can be less stable than phthalates and may require the addition of stabilizers.
• Trioctyl trimellitate (TOTM): TOTM is a non-phthalate plasticizer that is used in high-temperature applications. It is considered to be less toxic than DEHP and has been approved for use in medical devices. However, TOTM can be more expensive than phthalates.

The suitability of these alternatives depends on the specific application and the desired properties of the plasticized material. Factors to consider include toxicity, cost, performance, and availability. A comprehensive risk assessment should be conducted before switching to an alternative plasticizer to ensure that it does not pose unacceptable risks to human health or the environment.

It is crucial to recognize that simply replacing DEHP with other phthalates may not be an adequate solution. A more sustainable approach involves developing and implementing truly safer alternatives that minimize or eliminate the potential for adverse health effects. This requires a multidisciplinary approach involving chemists, toxicologists, engineers, and policymakers.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Minimizing Exposure

Individuals can take several steps to minimize their exposure to DEHP:

• Choose PVC-free products: Opt for products made from alternative materials, such as polyethylene (PE), polypropylene (PP), or glass. Look for labels that indicate that a product is “phthalate-free” or “PVC-free.”
• Avoid plastic food containers: Use glass or stainless steel containers for storing food and beverages. Avoid heating food in plastic containers, as this can increase the leaching of DEHP.
• Wash hands frequently: Wash hands thoroughly with soap and water, especially before eating and after handling plastic products.
• Dust regularly: Dust your home regularly to remove DEHP-contaminated dust.
• Ventilate your home: Open windows and doors to ventilate your home and reduce the concentration of DEHP in indoor air.
• Choose personal care products carefully: Select personal care products that do not contain phthalates. Look for products labeled “phthalate-free.”
• Be cautious with medical devices: If you are undergoing a medical procedure, ask your healthcare provider about the materials used in medical devices and whether they contain DEHP. Advocate for the use of DEHP-free alternatives when available.

Pregnant women and children should take extra precautions to minimize their exposure to DEHP, as they are particularly vulnerable to its adverse effects.

These measures, while helpful, highlight the difficulty in completely avoiding DEHP exposure given its widespread presence. A more systemic approach involving regulatory action and industry innovation is necessary to significantly reduce population-level exposure.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

9. Conclusion

DEHP is a ubiquitous plasticizer with a complex toxicological profile. While its use has been declining in some regions due to regulatory restrictions and health concerns, it remains a significant environmental contaminant and a source of human exposure. Its diverse health effects, including reproductive toxicity, carcinogenic potential, endocrine disruption, and other adverse outcomes, warrant continued scientific scrutiny and regulatory action. The multiple mechanisms of DEHP toxicity, including PPARα activation, endocrine disruption, oxidative stress, and epigenetic modifications, highlight the complexity of its interactions with biological systems.

The development and implementation of safer alternative plasticizers are crucial to reducing human exposure to DEHP and mitigating its associated health risks. A comprehensive risk assessment should be conducted before switching to an alternative plasticizer to ensure that it does not pose unacceptable risks. Individuals can take steps to minimize their exposure to DEHP by choosing PVC-free products, avoiding plastic food containers, washing hands frequently, and ventilating their homes.

Further research is needed to fully elucidate the long-term health effects of DEHP exposure and to develop more effective strategies for preventing and treating DEHP-related diseases. This includes epidemiological studies to assess the association between DEHP exposure and various health outcomes in humans, as well as mechanistic studies to further elucidate the molecular pathways involved in DEHP toxicity. A more proactive and precautionary approach to the regulation of DEHP and other potentially harmful chemicals is essential to protect public health and the environment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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