What are phthalates

Phthalates are diesters of phthalic acids or phthalate esters, is a family of man-made industrial chemicals extensively used since the early 20th century as softeners of plastics, solvents in perfumes, and additives to hairsprays and lubricants and as insect repellents ¹. Phthalates are a class of manufactured chemicals commonly used to increase the flexibility of plastics in a wide array of consumer products. High-molecular-weight phthalates, such as butylbenzyl phthalate (BBzP), di-2-ethylhexyl phthalate (DEHP) and mixtures of di-n-octyl phthalates (DnOP), are most well-known for their use as plasticizers in polyvinyl chloride (PVC) materials such as food packaging, children’s toys, vinyl flooring, and medical devices ². Whereas low-molecular-weight phthalates, such as dibutyl phthalate (DBP), are used primarily as solvents in items such as shampoo and nail polish ³. More than 470 million pounds of phthalates are produced or imported in the United States each year ⁴. Human exposure to phthalates is nearly unavoidable ⁵. Phthalates are used in hundreds of products, such as toys, vinyl flooring and wall covering, detergents, lubricating oils, food packaging, pharmaceuticals, blood bags and tubing, and personal care products, such as nail polish, hair sprays, aftershave lotions, soaps, shampoos, perfumes and other fragrance preparations. By far the most common use of phthalates is in the production of polyvinyl chloride (PVC) products ⁶. Polyvinyl chloride (PVC) is the second most commonly used plastic in the world, and is present in pipes and tubing, construction materials, packaging, electrical wiring, and thousands of consumer goods ⁷. Biomonitoring samples collected from women of reproductive age as part of the National Human and Nutrition Examination Survey (NHANES) identified metabolites from >13 different phthalates and detected at least 1 phthalate metabolite in all available samples ⁸. The aggregated dietary exposure for di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), di-2-ethylhexyl phthalate (DEHP) and di-isononylphthalate (DINP) was estimated to be 0.9–7.2 and 1.6–11.7 μg/kg body weight per day for mean and high consumers, respectively, thus contributing up to 23% of the group‐tolerable daily intake (TDI) in the worst‐case scenario ⁹. For di-isodecylphthalate (DIDP), not included in the group‐tolerable daily intake (TDI), dietary exposure was estimated to be always below 0.1 μg/kg body weight per day and therefore far below the tolerable daily intake (TDI) of 150 μg/kg body weight per day.

Di-2-ethylhexyl phthalate (DEHP) is used primarily as a plasticizer for polyvinyl chloride (PVC) and can therefore be found in a variety of products such as floor and wall coverings, vinyl gloves, toys, child care articles, food packaging materials, and medical devices ¹⁰. DEHP is one of the most environmentally abundant endocrine‐disrupting chemicals that cause reproductive abnormalities in humans, and DEHP can leach out of plastic beverage or food containers and readily enter the blood following oral ingestion. After absorption, the parent diester phthalates are rapidly hydrolyzed to the corresponding monoesters, some of which are then further metabolized, with the metabolites excreted in urine and feces. In humans, phthalates are eliminated mostly within hours, with excretion complete by a day or two; half-lives in the body are in hours ¹¹. For phthalates with short alkyl chains, monoesters represent the major human metabolite, but in the case of phthalates with long alkyl chains, including DEHP, diisononyl phthalate (DINP) and diisodecyl phthalate (DIDP), the monoesters are further metabolized via omega- and omega-1-oxidation of the aliphatic side chain ¹².

Developmental exposures to DEHP has been associated with increased body fat and impaired glucose tolerance in rodents ¹³. DEHP has been shown to produce a wide range of adverse effects in experimental animals, notably liver toxicity and testicular atrophy ¹⁴. Although the toxic and carcinogenic effects of DEHP have been well established in experimental animals, the ability of this compound to produce adverse effects in humans is controversial. The specific mechanisms underlying the toxic effects of DEHP are an area that is largely unexplored. As a result, the ability of DEHP and other phthalate esters to produce adverse effects in humans has been a topic of active discussion and debate in the scientific and regulatory communities.

Despite indications that human exposures to DEHP are decreasing, exposure to other phthalates such as DINP, are increasing ⁸, there is a lack of in vivo data regarding metabolic impacts of developmental exposures to phthalates other than DEHP. Animal studies examining metabolic health outcomes resulting from exposures to phthalates other than DEHP are needed to understand whether other phthalates are also capable of interfering with metabolic processes.

Table 1. Phthalate parent compounds and their metabolites

Phthalate name	Abbreviation	Urinary metabolite	Abbreviation
Dimethyl phthalate	DMP	Mono-n-methyl phthalate	MnMP
Diethyl phthalate	DEP	Mono-ethyl phthalate	MEP
Di-isobutyl phthalate	DiBP	Mono-isobutyl phthalate	MiBP
Di-n-butyl phthalate	DnBP	Mono-n-butyl phthalate	MnBP
Di-n-octyl phthalate	DnOP	Mono-(3-carboxypropyl) phthalate	MCPP
Di-isononyl phthalate	DiNP	Mono-carboxyoctyl phthalate	MCOP
Di-isodecyl phthalate	DiDP	Mono-carboxynonyl phthalate	MCNP
Benzylbutyl phthalate	BzBP	Mono-benzyl phthalate	MBzP
Di-2-ethylhexyl phthalate	DEHP	Mono-2-ethylhexyl phthalate	MEHP
		Mono-(2-ethyl-5-hydroxyhexyl) phthalate	MEHHP
		Mono-(2-ethyl-5-oxohexyl) phthalate	MEOHP
		Mono-(2-ethyl-5-carboxypentyl) phthalate	MECPP

[Source ¹⁵ ]

Phthalates are or have been used in wall coverings, tablecloths, floor tiles, furniture upholstery, carpet backings, shower curtains, garden hoses, rainwear, pesticides, some toys, shoes, automobile upholstery, food packaging, medical tubing, and blood storage bags ¹⁶. Phthalates are not strongly bound in these products and can therefore leach out ¹⁷. Some phthalates are also present in cosmetics, nail polish, hair products, skin care products, and some medications ¹⁸. In recent years, di-nonyl phthalate (DiNP) and di-decyl phthalate (DiDP) have increasingly replaced DEHP in these applications ¹⁹. Alternatively, low-molecular weight phthalates, dimethyl phthalate (DMP), diethyl phthalate (DEP) and dibutyl phthalate (DBP), are primarily added to cosmetics and personal care products as solvents, fixatives and adhesives ²⁰. Due to non-covalent bonds between the phthalate chemicals and their parent materials, there can be significant leaching and volatilization leading to environmental contamination and thus ubiquitous exposures in the general population. In fact, a recent report showed that metabolite biomarkers of eight major phthalates have been detected in 89% to 98% of the United States (US) population ¹⁹.

Phthalates are used in many consumer products, including:

• Cosmetics and personal care products
• Plastic and vinyl toys
• Shower curtains
• Miniblinds and wallpaper
• Vinyl flooring
• Raincoats
• Food packaging and wraps
• Detergents
• Adhesives
• Plastic pipes
• Medical equipment and devices
• Polyvinyl chloride (PVC) plastics

Phthalates commonly enter(s) the body through:

• Ingestion (swallowing): Eating food or water packaged in plastic, or drinking water contaminated with phthalates; for children, chewing on soft vinyl toys or products made with phthalates
• Inhalation (breathing): Breathing dust in rooms with plastic miniblinds, wallpaper, or flooring that contain phthalates
• Skin contact: Touching or using products made with phthalates

For most phthalates, the major route of exposure is food ingestion ⁷. However, personal care product use and inhalation are major routes of exposure for certain phthalates ²¹. Some phthalates have been found at higher levels in fatty foods such as dairy products, fish, seafood, and oils ²². Phthalates in a mother’s body can enter her breast milk. Ingestion of that breast milk and infant formula containing phthalates may also contribute to infant phthalate exposure ²³. The phthalates that may be present in dust can be ingested by infants and children through hand-to-mouth activities ²⁴. Finally, infants and small children can be exposed to phthalates by sucking on toys and objects made with phthalate-containing plastics ¹⁷.

Other minor routes of phthalate exposure include inhalation, drinking contaminated water, and absorption through the skin ²⁵. Phthalates can be released in small amounts to the air people breathe inside homes or schools from the many consumer products that contain them ²⁶. People living near phthalate-producing factories or hazardous waste sites may be exposed to phthalates released into the air or ground water where they live ²². Individuals may be exposed to phthalates during the use of many personal care products containing phthalates, such as hair products, cosmetics, and lotions ²⁷. Phthalates in these products may be absorbed through contact with the skin or may be inhaled if some of the product is present in the air. In addition, certain medical devices, such as intravenous tubing or flexible bags containing blood, medications, or nutritional products, contain phthalates. These can be a source of phthalate exposure to children and women of child-bearing age when the tubing or bags are used to administer medications, nutritional products, or blood to the individual. This can be a very significant route of exposure, especially for premature infants in intensive care units ²⁸.

Phthalate exposures, assessed from urinary concentrations of phthalate metabolites (i.e., breakdown products), appear to be higher for children compared with adolescents and adults. Studies of phthalate metabolites in children’s urine are limited, but the few that have been published have found children’s urinary phthalate metabolite levels to be higher than levels in adults and to decrease with age (i.e., younger children had more phthalate metabolites in their urine than older children did) ²⁹. The exception is monoethyl phthalate (MEP), a metabolite of diethyl phthalate, which has been found to be present in higher levels in adult urine compared with children’s urine ²⁹. Levels of monoethyl phthalate (MEP) are most likely associated with use of consumer products that contain diethyl phthalate, such as detergents, soaps, cosmetics, shampoos, and perfumes ²⁹.

What are endocrine disruptors (endocrine disrupting chemicals)?

The Endocrine Society defined endocrine disrupting chemical as “an exogenous chemical, or mixture of chemicals, that interfere with any aspect of hormone action” ³⁰. In other words, the chemical substances that can affect the endocrine system resulting in adverse effects are called Endocrine Disruptor Chemicals ³¹. These chemicals often bind to the endogenous receptors (e.g., estrogen receptor, steroid receptor) and interfere with the normal function of brain, reproductive organs, development, immune system, and other organs ³². However, endocrine disrupting chemicals are not the same as hormones but they can mimic hormones, and produce ill effects in the body ³³.

Endocrine disruptors are found in many everyday products, including some plastic bottles and containers, liners of metal food cans, food, beverages, detergents, flame retardants, food, toys, cosmetics, pesticides and air. The common endocrine disrupting chemicals are bisphenol A (BPA), perchlorate, dioxins, phthalates, phytoestrogens, polychlorinated biphenyls (PCB), polybrominated diphenyl ethers (PBDE), triclosan, perfluoroalkyl and polyfluoroalkyl substances (PFAS), pesticides like dichlorodiphenyldichloroethylene (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE), organophosphorus compounds, alkylphenols(surfactants), parabens, methoxychlor, diethylstilbestrol (DES), fungicide vinclozolin, and natural hormones ³⁴. Among these, BPA (bisphenol A) is the most commonly encountered endocrine disrupting chemical, which has both estrogenic and antiandrogenic properties. endocrine disrupting chemicals are mostly lipophilic in nature and resistant to metabolism ³⁵. People who get exposed to any of these endocrine disrupting chemicals may have hormonal imbalance. Even a small amount of endocrine disrupting chemical consumed can result in hormonal imbalance especially in children ³¹. Sometimes they are stored in body fats, and transferred to the developing fetus via the placenta ³⁵.

Studies on animal models and humans reveal that the mechanisms through which the endocrine disrupting chemicals act involve many complex pathways. The endocrine disrupting chemical can act like endogenous hormones and thereby increase or decrease the cellular response. Also, they can block the effects of hormones and stimulate or inhibit the production of hormones. They can thus interfere with synthesis, transport, action, and degradation of hormones ³⁶. endocrine disrupting chemicals can act via nuclear receptors, nonsteroidal receptors, transcription coactivators, and certain enzymatic pathways ³⁴.

Endocrine disrupting chemicals can affect several systems in our body resulting in many ill health effects. There is evidence showing various diseases are linked to endocrine disrupting chemicals as shown in table below.

Endocrine disrupting chemicals	Main Sources	Possible Mechanism	Clinical condition
Alkylphenols	Detergents Shampoos Pesticide	Mimics estrogen	Breast cancer
Phthalates	Plastic products Personal care products (perfume, moisturizer)	Not yet known	Testicular and ovarian toxicants
Polychlorinated biphenyls (chlorinated/ halogenated/ TBBPA)	Paints Plastics Lubricants Electrical applications	Estrogenic and anti-androgenic activity Indirectly regulate circulating gonadal hormones. Inducers of CYP1A and CYPIIB Decreased NMDA receptor binding in striatum, frontal cortex and hippocampus, cerebellum Reduced glutamate and dopamine Acts at AhR signaling pathways resulting in cytotoxic effects	Neurobehavioral defects like cognitive deficits in children Neurotoxicity Thyroid toxicity Susceptibility to infections Cancers (especially Breast Cancer) Infertility

Abbreviations: TBBPA = Tetrabromobisphenol A; CYP = cytochrome P450 enzymes; NMDA = N-methyl-D-aspartate; AhR = aryl hydrocarbon receptor

The difference between hormone and endocrine disruptor chemicals

Hormones	Endocrine disrupting chemicals
1. Hormones are chemical substances produced by the body and transported via bloodstream to the cells and organs which carry receptors for the hormone and on which it has a specific regulatory effect.	1. Endocrine disrupting chemicals are exogenous substance that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or populations.
2. They act via specific receptors and produces class effects	2. They act via hormone and other receptors and produces abnormal functions and interactions.
3. No bio accumulation	3. Results in bioaccumulation
4. Non-linear dose response with saturable kinetics	4. Non-linear dose response with saturable kinetics
E.g.; steroid hormones, thyroid hormones	Eg; Perchlorate, Dioxins, Phthalates

Phthalates health effects

Some phthalates are suspected endocrine disruptors ³⁷. Endocrine disruptors act by interfering with the biosynthesis, secretion, action, or metabolism of naturally occurring hormones ³⁷. Given the importance of hormones in human physiology, there is concern in the scientific community over the potential for endocrine disruptors to adversely affect children’s health, particularly in reproduction, development, and behavior. Male laboratory animals exposed to high doses of some phthalates have been known to display elements of “phthalate syndrome,” which includes infertility, decreased sperm count, cryptorchidism (undescended testes), hypospadias (malformation of the penis in which the urethra does not open at the tip of the organ), and other reproductive tract malformations ⁷. A number of animal studies have reported associations between exposure to certain phthalates and changes in male hormone production, altered sexual differentiation, and changes to reproductive organs, including hypospadias ³⁸. These findings in animal studies, although typically occurring at exposure levels much higher than what the general population may be exposed to, suggest a potential concern for health effects in children as well. The National Research Council has concluded that prenatal exposure to certain phthalates produces reproductive tract abnormalities in male rats, and also concluded that the same effects could plausibly occur in humans ⁷.

There are only a limited number of human studies looking at the relationship between phthalate exposure and hormonal and reproductive health changes. In one study, prenatal exposure to some phthalates (DEP, diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP) and DEHP) at typical U.S. population levels was associated with changes in physical measures of the distance between the anus and the genitals (anogenital distance) in male infants, a marker of androgenization ³⁹. A shorter anogenital distance has been associated with decreased fertility in animal experiments ⁴⁰ and a recent human study reported that a shorter anogenital distance in men was associated with decreased semen quality and low sperm count ⁴¹. Another study reported an association between increased concentrations of phthalate metabolites in breast milk and altered reproductive hormone levels in newborn boys. The same study did not find an association between breast milk phthalate metabolite concentrations and cryptorchidism ⁴².

Exposure to some phthalates has been associated with neurodevelopmental problems in children in some studies. Two studies of a group of New York City children ages 4 to 9 years reported associations between prenatal exposure to certain phthalates and behavioral deficits, including effects on attention, conduct, and social behaviors ⁴³. Studies conducted in South Korea of children ages 8 to 11 years reported that children with higher levels of certain phthalate metabolites in their urine were more inattentive and hyperactive, displayed more symptoms of attention-deficit/hyperactivity disorder (ADHD), and had lower IQ compared with those who had lower levels ⁴⁴. The exposure levels in these studies are comparable to typical exposures in the U.S. population.

A handful of studies have reported associations between prenatal exposure to some phthalates and preterm birth, shorter gestational length, and low birth weight ⁴⁵; however, one study reported phthalate exposure to be associated with longer gestational length and increased risk of delivery by Cesarean section ⁴⁶.

In adult populations, various epidemiological studies support an association between phthalate exposure and markers of testicular function in men, particularly decreased semen quality ⁴⁷. There is also evidence linking endometriosis in women with high phthalate metabolite levels ⁴⁸. Increases in waist circumference and body mass index (BMI) have been linked to DEHP, BzBP, DBP and DEP exposure in men and DEP exposure in adolescent and adult females ⁴⁹. One of the replacements for the DEHP, DiNP, has recently been designated as a carcinogen in the State of California ⁵⁰.

Finally, some researchers have hypothesized that phthalate exposure in homes may contribute to asthma and allergies in children. Two research groups have conducted studies, primarily in Europe, and reported associations between surrogates for potential phthalate exposure in the home and risk of asthma and allergies in children ⁵¹. Examples of the exposure indicators and outcomes considered in these studies include an association between some phthalates in surface dust and increased risk of runny nose, eczema, and asthma ⁵² and increased risk of bronchial obstruction associated with the presence of PVC in the home ⁵³.

In 2006, the National Toxicology Program (NTP) concluded that there is “concern” for effects on reproductive tract development in male infants less than one year old exposed to DEHP. In addition, the National Toxicology Program also concluded that there is “some concern” (the midpoint on a five-level scale ranging from “negligible” to “serious” concern) for effects on reproductive tract development in male children older than one year old exposed to DEHP, and also that there is “some concern” for effects of prenatal DEHP exposure on reproductive tract development in males ⁵⁴. Concern was greater for males exposed to high levels of DEHP in the womb or early in life. These conclusions were based primarily on findings from animal studies, as human data are limited and were determined to be insufficient for evaluating the reproductive effects of DEHP ⁵⁵. Some studies have also reported associations of DEHP exposure with increased risk of asthma and bronchial obstruction, increased risk of ADHD symptoms, and altered pregnancy durations ⁵². Human health studies have reported associations between exposures to DBP and altered reproductive hormone levels in newborn boys, and shifts in thyroid hormone levels in pregnant women ⁵⁶. Signs of feminization in young boys (as measured by reduced anogenital distance), altered hormone levels in newborn boys, and increased risk of rhinitis and eczema are health effects that have been associated with BBzP exposure in some studies ⁵². The exposure levels in these studies are comparable to typical exposures in the U.S. population. It is important to note that while the following indicators present data on individual phthalate metabolites, evidence suggests that exposures to multiple phthalates may contribute to common adverse outcomes. The National Research Council has concluded that multiple phthalates may act cumulatively to adversely impact male reproductive development ⁷.

Phthalates in food

Given the increasing scientific evidence base linking phthalate exposure with harmful health outcomes, it is important to understand major sources of exposure. A recent and well-designed study by Koch et al. ⁵⁷ that monitored urinary phthalate excretion in individuals fasting for 48 hours, found that diet was the most significant pathway for exposures to DEHP, DiNP and DiDP while DMP, DEP, DiBP, DnBP and BBzP were primarily linked to non-food exposures. According to a review by Cao ⁵⁸, phthalates can migrate into food from plasticized PVC materials such as tubing typically used in the milking process, lid gaskets, food-packaging films, gloves used in the preparation of foods, and conveyor belts. These compounds are also found in printing inks and adhesives on food wrappers as well as coatings on cookware that have been contaminated by packaging ⁵⁹. Foods high in fat are contaminated by higher weight phthalates that are more lipophilic such as DEHP ⁵⁸. In the United States, phthalates have been approved by the Food and Drug Administration (FDA) as plasticizers in food packaging materials and food contact substances used during processing and storage while the European Commission and Chinese authorities have limited phthalates in food contact materials made of plastic since 2008–2009 ⁶⁰. Thus, there can be substantial variability in phthalate concentrations within food groups based on the region of food production, processing practices, presence and type of packaging and lipid content ⁶¹. With an ever increasing global market, phthalate contamination is a food safety issue that crosses international borders. Dietary phthalate exposure assessment has become a topic of great interest given the significance of the dietary pathway and health impacts associated with the specific phthalate species found in food.

The review of the literature revealed that poultry, some dairy products (cream) and fats are routinely contaminated with high concentrations of DEHP than other foods ¹⁵. Milk, yogurt, eggs, fruits, vegetables, pasta, noodles, rice, beverages and water were found to contain low concentrations of phthalates as a whole ¹⁵.

Foods with High DEHP Concentrations (>300 μg/kg)

• Poultry
• Cream
• Cooking Oils/Fats

Foods with Low DEHP Concentrations (<50 μg/kg)

• Yogurt, Eggs
• Pasta, Rice, Noodles
• Fruits/vegetables
• Beverages

Given the chemistry of high molecular weight phthalates like DEHP, higher concentrations in lipid rich foods were expected. There was significant variability in concentration observed between dairy products based on typical fat content. Among the dairy products tested, cream and cheese were more heavily contaminated across studies in comparison to yogurt ¹⁵. Poultry consistently had higher phthalate content than other meats, however it is unclear what factors impacted these results since details as to the fat content of products was not always reported. Noteworthy, phthalates in non-fatty foods including bread and cereal products were observed in variable concentrations. This is of importance since two recent studies conducted in Belgium ⁶² and Germany ⁶³ reported bread as a significant source of DEHP and highest contributor to total exposures in the general adolescent and adult population at 31.4% and 14.06%, respectively. Sources of contamination may be present in the processing of grains, though this is unclear. As a whole, food monitoring data also suggests that the consumption of fruit and vegetables is associated with limited phthalate exposures. However, processed fruit and vegetable products found in jars appear to contribute to greater exposures given the high concentrations reported.

Figure 1. Phthalates exposures through diet per capita

[Source ⁶⁴ ]

As expected, the epidemiology literature reported that dairy products, meats and discretionary fat intake, in fact, were associated with increases in DEHP urinary metabolite levels in adolescent and adult populations. Furthermore, consumption of these products were found to be associated with MnBP levels in one epidemiology study and elimination of some of these products from the diet (dairy and meat) led to a decrease in MnBP and DEHP metabolites in the Temple Stay intervention ⁶⁵. It is important to note that although results from Ji and others suggest that discontinuing meat and dairy from the diet may be largely responsible for decreases in metabolite levels, there may have been other factors in the environment that impacted results since details of the diet as well as daily practices in the Temple Stay program were not available ⁶⁶. It is possible that decreases in low molecular weight phthalates, given their primary source, could be attributed to reduced use of personal care products rather than changes in the diet ⁶⁶.

Results between food monitoring and epidemiological data were not completely consistent. Two epidemiology studies reported an association between fish consumption and MiBP; however the food monitoring data did not support this result as all DiBP levels in seafood were found to be low across studies. Additionally, increased levels of MMP (a metabolite of DMP) were associated with consumption of fruit while the food monitoring data did not show DMP at significant levels for this food group ⁶⁷. Finally, Colacino et al. ⁶⁸ as well as Trasande et al. ⁶⁹ reported positive associations between vegetables and MEP. However, the food monitoring data does not support this finding and two other epidemiology studies ⁷⁰, ⁷¹ suggest that diets with high consumption of fruits and vegetables may be associated with decreases in DEP exposure.

How much of the five phthalates is safe in food contact materials?

According to the 2019 experts opinion at the European Food Safety Authority ⁷² – a group Tolerable Daily Intake (TDI) – for four of the five phthalates (di-butylphthalate [DBP], butyl-benzyl-phthalate [BBP], di-2-ethylhexyl phthalate [DEHP] and di-isononylphthalate [DINP]) of 50 micrograms per kilogram of body weight (50 µg/kg body weight) per day based on their effects on the reproductive system. The Tolerable Daily Intake (TDI) is an estimate of the amount of a substance that people can ingest daily during their whole life without any appreciable risk to health ⁷². The key effect on which this group-Tolerable Daily Intake (TDI) is based is a reduction in testosterone in fetuses. The fifth phthalate in the assessment, di-isodecyl phthalate (DiDP), does not affect testosterone levels in fetuses, therefore the European Food Safety Authority experts set a separate Tolerable Daily Intake (TDI) of 150 µg/kg body weight per day based on its effects on the liver ⁷².

Nota that the European Food Safety Authority experts have set all these Tolerable Daily Intakes (TDIs) on a temporary basis due to uncertainties about health effects other than the reproductive ones and about the contribution of plastic food contact materials to overall consumer exposure of phthalates. The European Food Safety Authority experts have also added the need to address these uncertainties by considering the whole body of scientific evidence.

Are there any safety concerns of phthalates in food?

According to the 2019 European Food Safety Authority experts opinion at the current exposure to these five phthalates (di-butylphthalate [DBP], butyl-benzyl-phthalate [BBP], di-2-ethylhexyl phthalate [DEHP] and di-isononylphthalate [DINP]) from food is not a concern for public health ⁷². Dietary exposure to the group of DBP, BBP, DEHP and DINP for average consumers is 7 µg/kg body weight (7 micrograms per kilogram of body weight) or seven times below the safe level, while for high consumers it is 12 µg/kg bw, which is four times lower ⁷². For di-isodecylphthalate (DIDP), the dietary exposure for high consumers is 1,500 times below the safe level ⁷².

This 2019 assessment of the five phthalates (DBP, BBP, DEHP, DINP and DIDP) is in line with the 2005 European Food Safety Authority assessment in terms of their most sensitive effects and the individual tolerable daily intakes. The main differences concern an improved estimate of dietary exposure to phthalates and the introduction of the group-Tolerable Daily Intake (TDI) for four of the phthalates to account for combined exposure to several phthalates at the same time. This is a common occurrence and confirmed by data from studies with humans, e.g. traces found in urine.

Phthalates in cosmetics

Historically, the primary phthalates used in cosmetic products have been dibutylphthalate (DBP), used as a plasticizer in products such as nail polishes (to reduce cracking by making them less brittle); dimethylphthalate (DMP), used in hair sprays (to help avoid stiffness by allowing them to form a flexible film on the hair); and diethylphthalate (DEP), used as a solvent and fixative in fragrances. According to FDA’s latest survey of cosmetics, conducted in 2010, DBP and DMP are now used rarely. DEP is the only phthalate still commonly used in cosmetics ⁷³.

In 2002, the Cosmetic Ingredient Review Expert Panel ⁷⁴ reaffirmed its original conclusion (reached in 1985), finding that DBP, DMP, and DEP were safe as used in cosmetic products. Looking at maximum known concentrations of these ingredients in cosmetics, the Cosmetic Ingredient Review Expert Panel ⁷⁴ evaluated phthalate exposure and toxicity data, and conducted a safety assessment for dibutylphthalate in cosmetic products. The Cosmetic Ingredient Review Expert Panel ⁷⁴ found that exposures to phthalates from cosmetics were low compared to levels that would cause adverse effects in animals. The Cosmetic Ingredient Review Expert Panel is an industry-sponsored organization that reviews cosmetic ingredient safety and publishes its results in open, peer-reviewed literature. The FDA participates in Cosmetic Ingredient Review on a non-voting basis and may or may not accept Cosmetic Ingredient Review Expert Panel findings ⁷³.

The FDA reviewed the safety and toxicity data for phthalates, including the Centers for Disease Control and Prevention (CDC) data from 2001 ⁷⁵, as well as the Cosmetic Ingredient Review Expert Panel ⁷⁴ conclusions based on reviews in 1985 and 2002. While the Centers for Disease Control and Prevention (CDC) report noted elevated levels of phthalates excreted by women of child-bearing age, neither this report nor the other data reviewed by FDA established an association between the use of phthalates in cosmetic products and a health risk. Based on this information, FDA determined that there wasn’t a sound, scientific basis to support taking regulatory action against cosmetics containing phthalates ⁷³.

The FDA continues to monitor levels of phthalates in cosmetic products. The FDA have developed an analytical method for determining the levels of phthalates in cosmetic products and conducted surveys of products to determine these levels in cosmetics on the market.

What we know about infant exposure to phthalates

Infants, like all consumers, are exposed daily to phthalates from a number of sources, including air, drugs, food, plastics, water, and cosmetics.

The American Academy of Pediatrics has published an article stating that infants exposed to infant care products, specifically baby shampoos, baby lotions, and baby powder, showed increased levels of phthalate metabolites in their urine ⁷⁶.

Like the CDC report, this study did not establish an association between these findings and any health effects. In addition, levels of phthalates, if any, in the infant care products were not determined.

The FDA included 24 children’s products intended for infants and children in the survey we completed in 2006, and nearly 50 products for infants and children in the survey we completed in 2010. What the FDA have learned was that the use of phthalates in cosmetics intended for people of all ages, including infants and children, has decreased considerably since the surveys began in 2004.

How to know if there are phthalates in the cosmetics you use

Under the authority of the Fair Packaging and Labeling Act, the FDA requires an ingredient declaration on cosmetic products sold at the retail level to consumers. Consumers can tell whether some products contain phthalates by reading the ingredient declaration on the labels of such products.

However, the regulations do not require the listing of the individual fragrance ingredients; therefore, the consumer will not be able to determine from the ingredient declaration if phthalates are present in a fragrance. Also, because the Fair Packaging and Labeling Act does not apply to products used exclusively by professionals–for example, in salons–the requirement for an ingredient declaration does not apply to these products. Based on available safety information, DEP does not pose known risks for human health as it is currently used in cosmetics and fragrances. Consumers who nevertheless do not want to purchase cosmetics containing DEP may wish to choose products that do not include “Fragrance” in the ingredient listing.

Results of FDA’s 2010 Survey of Cosmetics for Phthalate Content

The products listed below represent a sample of cosmetics on the market at the time the survey was conducted, and products may have been reformulated since then. This survey was intended to monitor trends in the use of phthalates in cosmetics, not as a comprehensive analysis of all cosmetics on the market. The law does not require cosmetic firms to file their formulations with FDA. Also, note that some so-called “personal care products,” such as diaper creams and nipple creams, are regulated as drugs, or in some cases both cosmetics and drugs.

Table 2. 2010 Survey of Cosmetics for Phthalate Content

Product Type	Brand	Lot #	Phthalates (ppm)
			DMP	DEP	DBP
Nail Polish	Pure Ice – Spit Fire	991CP
	Dora the Explorer Mega Nail Polish Kit – Townley	WO90817
	Scherer Nail Polish CQ #143 Cabernet	Not visible
	Rimmel Lycra Wear 10 Days Nail Polish #303 Vintage	732318
	In a New York Color Minute 224B	8MBCK
	Sally Hansen Diamond Strength #45 Fuchsia	8MSHK
	Hard Candy Just Nails (Glitter)	9226
	Petites Pink Crush 270 – CQ	Not visible
	Revlon Nail Enamel Red Hot Tamale 908	Not visible
	Maybelline Express Finish Grape Times 608	WF224
	Nicole by OPI Razzle Dazzler	09295AAG
	Scherer Nail Polish CQ #107 Crystal Clear	Not visible
	LA Colors Nail Lacquer Red Stilettos CBLQ 389	Not visible
	LA Colors Art Deco Polish Silver Glitter CBNA 502	Not visible
	LA Colors Nail Hardener-Strengthener	9796
	Hot Topic Nail Polish Black	Not visible
	Hot Topic Nail Polish Green	Not visible
	Hot Topic Nail Polish Purple	Not visible
	Hot Topic Nail Polish (Skull) Green	Not visible			4,800
	Hot Topic Nail Polish (Skull) Black	Not visible			4.4
	Hot Topic Nail Polish (Skull) Yellow	Not visible			4
	Simple Pleasures Nail Polish “Peace” (Glitter)	Not visible
	Simple Pleasures Nail Polish “Love” (Pink)	Not visible
	WetnWild Wild Shine 410A	918201
	Sinful Colors Professional Nail Polish Enamel Pinky Glitter 830	Not visible
	Sinful Colors Under 18	Not visible
	Borghese Nail Lacquer Vernis Botticelli Nude	6KXJKC			3.4
	Sally Hansen High Definition 04 (Green)	9MHYK
	Cover Girl Boundless Base Coat Nail Color Red Revolution 553	7239HV
	Cover Girl Boundless Base Coat Nail Color Gold Rush 415	9139HV
	Sally Hansen Hard As Nails Xtreme Wear Hot Magenta 03	6MTXK
	Sally Hansen Salon Lacquer Nail Polish Orange You Cute? 450	8JFDK			6.6
	Sally Hansen Insta-Dri Rose-a-go-go 06	AKVDKN
	Sally Hansen Diamond Strength 33 Champagne Toast	8M8OK
	Avon Nailwear Pro Nail Enamel Polish Midnight Plum	VEK19
Skin Cream and Lotion	Red Velvet Body Lotion – Gift Pack	H8920109
	Dove Deep Moisture Nourishing Body Wash with NutrimMoisture	10079PP23S
	Eucerin Plus Intensive Repair Hand Crème with Dry Skin Therapy	90125515
	Aveeno Active Naturals Daily Moisturizing Lotion	1129LK
	Vaseline Sheer Infusion Vitamin Burst Body Lotion	08149UM42
	Palmer’s Cocoa Butter Formula Concentrated Cream	N9215A
	Jergens Ultra Healing Extra Dry Skin Moisturizer	Y225106ZZA
	Ponds Dry Skin Cream	08289HU87
	Dollar General Guarantee Skin Rescue Moisture Lock Lotion	C9A129
	Noxzema The Original Deep Cleansing Cream with Eucalyptus Oil	Rubbed out
	Suave Powder Fresh Body Lotion	10289JU41
	Celine Dion Sensational Shimmering Body Lotion	92251
	Scentsations by Body Source Cherry Blossom Body Lotion	M9290AL18
	Walgreens Advanced Care (Fragrance Free)	0401609
	Curel Continuous Comfort Original Formula Moisturizer	X140106ZZA
	Lubriderm Daily Moisture Lotion, Normal to Dry Skin, Fragrance Free	0118C
	Nivea Soft Refreshingly Soft Moisturizing Crème	73729160		100
	Bath, Body, etc… Organic Soothing Aloe Vera Body Lotion	29473		260
	J.R. Watkins Natural Apothecary Hand & Body Lotion	0374579
	Jergens Original Scent Cherry-Almond Moisturizer	W106125ZZ		110
	Palmer’s Cocoa Butter Formula with Vitamin E Skin Therapy Oil	Rubbed out
	St. Ives Hydrating Vitamin E Advanced Body Moisturizer	09327021103
	Vaseline for Men Hand Lotion	05279HU09
	Corn Huskers Heavy Duty Oil-Free Hand Treatment Lotion	2969G
	Malibu Hemp Moisturizer Body Lotion for Dry Skin	5434
	Keri Original Dry Skin Lotion	23654901
	Avon Haiku Perfumed Skin Softener	MK091
	Avon Jet Femme Body Lotion	MLP81
	Avon Candid Perfumed Skin Softener	MAN91
	Avon Moisture Therapy Intensive Extra Strength Cream	MIV91
Fragrance	Dove Go Fresh Body Mist	090495U49
	Jovan Island Gardenia Cologne Spray	9218		14,000
	Love’s Baby Soft Cologne Spray	0906D48
	A Little Sexy Body Spray by Parfums de Coeur	09324
	Axe Instinct Body Spray	03119KK09
	Curve Crush Body Mist	9JA02
	Bodycology Sweet Petals Body Mist	S9J27AK
	Cotton Candy Body Spray Prince Matchabelli	09267
	Degree Classic Romance Body Mist	4068
	Hannah Montana Cologne Spray	3169Y
	Wanna Play Body Spray Parfums de Coeur	09294		3,800
	Chantilly – Walmart Gift Pack	090723A		7,300
	Tabu – Walmart Gift Pack	090721A		6,200
	Heaven Sent – Walmart Gift Pack	090622B		1,300
	Navy – Walmart Gift Pack	090722C		40,000
	English Leather – Walmart Gift Pack	090721A		3,900
	British Sterling – Walmart Gift Pack	090526A		480
	Canoe – Walmart Gift Pack	0907248		2,000
	English Leather Black – Walmart Gift Pack	0907916
	Johnson’s Baby Cologne	1919COB128135
	Barbasol After Shave Pacific Rush	60161
	Aqua Velva Classic Ice Blue	R09K174		760
	Tattooed by Inky	Not visible
	BOD Really Ripped Abs	8TZ60		6,200
	i Carly	168961B
Baby Cream and Lotion	Johnson’s Baby Lotion	2519T
	Dollar General Sleepy Time Baby Lotion	8KF1025
	Baby Avalon Organics Protective A,D & E Ointment	6H01
	Huggies Naturally Refreshing (Green Tea & Cucumber) Lotion	CU6287282
	Baby Magic Gentle Baby Lotion	9237
	Burt’s Bees Baby Bee Buttermilk Lotion	0850801
	Aveeno Baby Soothing Relief Moisture Cream	0209D
	Parent’s Choice Baby Lotion	0034311
	Johnson’s Bedtime Lotion	1759G
	Johnson’s Head-to-Toe Fragrance Free Baby Lotion	0049LK
	Johnson’s Shea and Cocoa Butter Baby Cream	0069VB
	Susan Brown’s Baby Sensitive Baby Lotion-to-powder	10577A
	California Baby Calming Everyday Lotion	CB9303A2
Deodorant	Brut 24-Hour Protection deodorant	11029TR53		22
	Tom’s of Maine Natural Care Lavender Deodorant Stick	LD1370
	Old Spice High Endurance Deodorant	9307TN
	Axe Fresh Action Essence Deodorant	08129UR16
	Degree Men Deodorant Silver Ion Intense Sport	11209UR39	2.9
	Speed Stick Ocean Surf Deodorant	9270502
	Personal Care Clear Stick Deodorant	08123A
	Kiss My Face Active Enzyme Lavender Deodorant	KO73008B
	Dove Powder Invisible Solid	09229UR86
	Secret Powder Fresh	9068TN		34
Hair Products	Biosilk Rock Hard Gelee Firm Hold	C8200
	Garnier Fructis Style Body Boost Volumizing Gel	48F6030
	TRESemmé No Frizz Shine Spray	09308TA20SDSIL2506		22
	Suave Professionals Styling Foam Extra Hold	11129KK61		52
	Rave 4X Mega Unscented Hair Spray	11199HU63		16
	White Rain Unscented Extra Hold Hair Spray	287CP3475403SDSIL15001		61
	Short Sexy Hair Quick Change Shaping Balm	09219
	American Crew Forming Cream	F952CIOC		50
	Dep Sport Endurance Styling Gel	R2029932A2		6.8
	TRESemme Tres Two Extra Hold Hair Spray	09313AA1416		37
	John Frieda Collection Frizz-Ease Mousse	Y223DK17DDT2Q
	Aussi Catch the Wave Mousse & Conditioner	92755398F
	Catwalk Extra Strong Mousse	233748783122142		23
	Johnson’s No More Tangles Detangling Spray	0489VA
	Manic Panic Amplified Semi-Permanent Hair Color Cream	10922
	Color Fiend Blood Red Temporary Comb-In Color	RN0709
	Color Fiend Pink Pop Water Based Semi-Permanent Hair Color	Not visible
Shampoo	Johnson’s Baby Shampoo	2118T
	Suave Kids 2 in 1 Shampoo Smoothers Cowabunga Coconut	081491J18
	Ave Dual 2 in 1 Shampoo + Conditioner	01139TJ27		17
	Pantene Pro-v Moisture Renewal Hydration Quotidienne Shampoo	93005401E1
	Aveeno Baby Essential Moisture Shampoo	0099VA
	Big Sexy Hair Big Volume Shampoo	09205150		210
	Garnier Fructis Fortifying Shampoo Color Shield	EF036
	Dove Intense Damage Therapy Shampoo	08299JU39
	VO5 Normal Balancing Shampoo	09316020758		440
	Suave Professionals Sleek Shampoo	07109JU41
	Finesse Self Adjusting Moisturizing Shampoo	9234M
	Herbal Essences Hello Hydration Moisturizing Shampoo	93145395LF
	TRESemmé Smooth and Silky Touchable Softness	09231C1130
	Advance Techniques Color Reviving Shampoo	MK191		82
	Avon High School Musical Raspberry Roarin’ 2-in-1 Shampoo	MKW91
Body Wash	Caress Daily Silk Silkening Body Wash	10159UR022010
	Equate Tropical Fresh Body Wash with Exfoliating Pomegranate Seed	A50298-9328C1
	Caress Tahitian Renewal Silkening Body Wash	08069TJ37
	Olay Body Ultra Moisture with Shea Butter Body Wash	92595395WA
	Suave Naturals Cucumber Melon Rejuvenating Body Wash	11109J038
	Suave Men Body Wash Active Sport	09169CU05		10
	White Rain All Day Moisturizing Body Wash	093203
	Dove Sensitive Skin Beauty Body Wash	03049PP05
	Natural Concepts Sensitive Skin Body Wash	A48292926583		340
	Dial Clean and Soft Moisturizing Body Wash	Q89M0310806091102
	St. Ives Renewing Collagen Elastin Moisturizing Body Wash	09345181020141
	Natural Concepts Natural Blends Body Wash Violet & Pea	A40128-8353C1
	Avon Naturals Strawberry & Guava Shower Gel	Rubbed out
	Avon Bubble Bath Bain-mousse Vanilla Cream for Dry Skin	MLK91
	High School Musical Strawberry Sudsin’ Body Wash	MLC91
Nipple Cream	Lansinoh HPA Lanolin for Breastfeeding Mothers	39982
	Gerber Breast Therapy Moisturizing Balm	BK07A02UU
Children’s Makeup	Kiss Me 2 Gift Pack Blush – Markwins
	Kiss Me 2 Gift Pack Eye Shadow – Markwins	1090075
	Hard Candy in the Shadows Eye Shadow Collection	9260
	Claire’s Cosmetics Eye Shadow	11/09
	Claire’s Cosmetics Eye Glitter	DR911333
Diaper Cream	Butt Butter Organics Herbal Diaper Rash Treatment	31823
	Burts Bees Baby Bee Diaper Ointment	1070801
	Baby’s Bliss Diaper Cream	1386		130
	Lavera Baby & Kinder Neutral	2897
	Weleda Baby Calendula Baby Cream	902212
Wet Wipes	Pull-ups Flushable Moist Wipes	MK929202A
	Equate Flushable Wipes All Purpose	09295D209651416
	Pure’n Gentle Fragrance Free Wipes	09272C230400512
	Huggies Soft Skin Baby Wipes	MK914804A
	My Fair Baby Baby Wipes	38091679169
Infant Soap, Shampoo, Body Wash	Johnson’s Head to Toe Baby Wash	Rubbed out
	Body Sense Baby Wash with Shea & Cocoa butter	OU28781
	My Fair Baby Baby Wash with Camomile	608015001/A2		60
	Burts Bees Baby Bees Shampoo and Wash	2280801
	Avon Bubble Bath Bain-mousse for Kids	MKY91
	Aubrey Organics – Natural Baby & Kids Bath Soap	11249
Baby Oil	Johnson’s Baby Oil	2339G
	Equate Delicate Baby Oil	0031646
	Burt’s Bees Baby Bee Apricot Baby Oil	0460801
Face & Body Paint	Claire’s Cosmetics Body Glitter	07/09
	Claire’s Cosmetics Vanilla Glitter Body Mist	0929301		390
	Alex Face Paint Studio – Face Paint	9012LP
	Snazaroo Face Painting Kit	T190803
Glitter Gel	Hard Candy Glitteratzi Eye Glitter Gel	9301
	Claire’s Club Scented Body Glitter	4926		167
	Alex Face Paint Studio – Pink Glitter Gel	9B2351
Baby Powder	Johnson’s Baby Powder	2528RA
	Body Sense Baby Powder	9DG0797
	Burt’s Bees Baby Bee Dusting Powder	Not visible

[Source ⁷³ ]

DEHP

DEHP also known as di-2-ethylhexyl phthalate or bis(2-ethylhexyl)phthalate, which is a phthalate ester, is extensively used as a plasticizer in many products, especially for polyvinyl chloride (PVC) medical devices, furniture materials, cosmetics, and personal care products ¹⁴, ⁷⁷. DEHP is continuously released from plastic products and directly infiltrates food, water and air; thus, humans are exposed to DEHP daily via ingestion, inhalation, and skin absorption ⁷⁸. Patients undergoing medical procedures such as IV therapy, enteral and parenteral nutrition support, blood transfusion, hemodialysis and peritoneal dialysis, cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO) can be exposed to DEHP ¹⁴. The human body is reported to be exposed to DEHP at concentrations of up to 30 mg/kg/day, and occupational exposure levels of up to 600 mg/kg/day have been reported ⁷⁹, ⁸⁰. Estimates of mean daily intake in adults in the US population range from approximately 0.0006–0.002 mg/kg-day ⁸¹ to 0.011 mg/kg-day ⁸². However, intake is not necessarily reflective of biologically active dose, due to potential differences in pharmacokinetics ⁸³.

DEHP is an endocrine‐disrupting chemical that has been shown in animal studies to disrupt the function of reproductive system in both females and males ⁸⁴. DEHP disrupts normal mice reproductive and ovarian function ⁸⁵, alters follicular development during weaning and maturity ⁸⁶, impairs the steroidogenesis of ovarian follicular cells ⁸⁷ and induces premature ovarian failure ⁸⁸. In addition, prenatal exposure to DEHP exerts multigenerational and transgenerational effects on female mice reproduction ⁸⁹. This systematic review ⁸³ showed that prenatal exposure to diethylhexyl phthalate (DEHP) is associated with decreased anogenital distance in male offspring and DEHP is presumed to be a reproductive hazard to humans.

In recent years, DEHP and its active metabolic product, mono-2-ethylhexyl phthalate (MEHP), have been successively detected in many tissues, including the liver, blood, cord blood, breast milk, placenta, amniotic fluid, and early gestation villi ⁹⁰, ⁹¹. According to previous studies, DEHP is associated with liver, kidney and neural injures or diseases in mice ⁹², ⁹³, ⁹⁴. Developmental exposures to DEHP has been associated with increased body fat and impaired glucose tolerance in rodents ¹³. DEHP has been shown to produce a wide range of adverse effects in experimental animals, notably liver toxicity and testicular atrophy ¹⁴. Although the toxic and carcinogenic effects of DEHP have been well established in experimental animals, the ability of this compound to produce adverse effects in humans is controversial. As a result, the ability of DEHP and other phthalate esters to produce adverse effects in humans has been a topic of active discussion and debate in the scientific and regulatory communities.

Several animal studies have confirmed that the toxicity of DEHP is mediated by its effects on gonadal steroidogenesis and an accompanying decrease in reproductive function and fertility ⁷⁹. Prenatal exposure to DEHP induces premature reproductive senescence in male mice ⁹⁵. The average exposure of DEHP in humans ranges from 3 to 30 mg/kg body weight per day and occupational exposure levels have been calculated to even reach up to 300 to 600 mg/kg/day ⁸⁹. Based on epidemiological data, decreased conception rates, increased miscarriage rates, decreased estrogen levels, and abnormal ovulation are associated with the occupational exposure of female workers in India to DEHP ⁹⁶. Thus, the health risks of DEHP exposure in humans have attracted increasing attention.

The presence of DEHP metabolites in urine is associated with adiposity and insulin resistance in children ⁹⁷. Previous studies have reported that perinatal exposure to DEHP may induce obesity and metabolic disorders in mice ⁹⁸, ⁹⁹; however, the mechanisms underlying these associations are yet to be investigated.

The ovary is the primary reproductive organ in the female and it regulates female endocrinology and provides a microenvironment for follicle development ¹⁰⁰. DEHP and MEHP (mono-2-ethylhexyl phthalate) have been shown to induce a depletion of the primordial follicles and a decrease in sex hormone production in mice ¹⁰¹. Previous studies have also reported that DEHP is able to induce a dose-dependent decrease in mouse fertility ¹⁰² and affect reproductive outcomes in female mice ¹⁰³. The results from the female mice study ¹⁰³ indicate that prenatal DEHP exposure increased male-to-female ratio compared to controls. Prenatal DEHP exposure also increased preantral follicle numbers at postnatal day 21 compared to controls ¹⁰³. Furthermore, 22.2% of the 20 μg/kg/day treated animals took longer than 5 days to get pregnant at 3 months and 28.6% of the 750 mg/kg/day treated animals lost some of their pups at 6 months ¹⁰³. Therefore, prenatal DEHP exposure alters male-to-female sex ratio, increases preantral follicle numbers, and causes some breeding abnormalities in female mice ¹⁰³. However, the precise mechanisms by which DEHP affects female reproduction remain unclear. The human gastrointestinal tract contains 1013–1014 microbiota that consist of 1500 microbial species and are characterized by more than 3 million genotypes, and numerous studies have shown that the intestinal microbiota is inextricably linked to human health ¹⁰⁴. Approximately 1000 bacterial species and 7000 bacterial strains have been identified using the currently available advanced sequencing technology ¹⁰⁵. Recent studies have revealed the bidirectional relationship between the estrogen level and gut microbiota in females with diseases induced by abnormal estrogen levels; estrogens are potentially regulated by the gut microbiota through secretion of beta‐glucuronidase, which deconjugates estrogens into active forms, and estrogens regulate the gut microbiota through immunoregulation ¹⁰⁶. In addition, gut microbiota dysbiosis may increase intestinal permeability and alter the levels of host gut metabolites, allowing bacterial endotoxins, such as lipopolysaccharide, to be transported into the circulation and activate the inflammatory response to promote disease development in females ¹⁰⁷. Therefore, scientists hypothesized that women of child‐bearing age who are exposed to DEHP would exhibit abnormal follicular development and infertility that may be mediated by alterations in the gut bacterial composition and metabolite profiles ⁸⁴. In ths study ⁸⁴, DEHP exposure altered the estrous cycle and estrogen level, accelerated primordial follicle recruitment and induced follicular atresia. In terms of toxicological mechanisms, DEHP induces DNA damage and apoptosis of the ovarian somatic cells, and alters the ovarian oxidative stress status ¹⁰⁸. DEHP interferes with PI3K signaling and induces an acceleration of primordial follicle development; it also affects oocyte maturation and the embryogenesis process ¹⁰⁹. DEHP downregulates the expression of the germ cell markers Stra8, Dazl, and Nobox, delays the fetal oogenesis processes, inhibits the expression of the Gdf9 and Atm genes, and leads to abnormal follicular growth and cell division ¹¹⁰. Additionally, DEHP induces oxidative stress by promoting reactive oxygen species (ROS) generation and inhibits steroid synthesis by modulating the expression of steroidogenic responsive genes in rat ovarian granulosa cells; it also activates the Bax/Bcl‐2 and the caspase‐3‐mediated mitochondrial apoptotic pathway to induce apoptosis ¹¹¹. Thus, DEHP induces oxidative stress in ovary and alters ovarian function to induce female rodents reproductive toxicity. However, the specific mechanisms underlying the toxic effects of DEHP are an area that is largely unexplored.

In another mice study, no significant decline in fertility was exhibited by pregnant female mice treated with 0.05 mg/kg DEHP; however, the abortion rate was 100% in the 500 mg/kg DEHP dose group compared with 0% in the control and 0.05 mg/kg DEHP groups ¹³. These findings indicate that exposure to DEHP at the tolerable daily intake (TDI) level did not affect the reproductive outcomes of mice; however, a high dose of DEHP may damage the reproductive capacity ¹³. In addition, 0.05 mg/kg DEHP exposure did not significantly affect the food intake or reproductive outcome of female mice, although it did induce metabolic disorders in the offspring. Previous studies have reported a correlation between in utero exposure to endocrine-disrupting chemicals and the development of metabolic disorders in adulthood ⁹⁹. In the mice study, serum leptin, insulin, serum lipid, and glucose concentrations were significantly elevated in male and female offspring at postnatal week nine, indicating that in utero exposure to DEHP may influence metabolic function in adulthood ¹³.

Are children at increased risk for the adverse effects of DEHP, relative to adults?

The FDA’s Center for Devices and Radiological Health has examined this issue and has concluded that children undergoing certain medical procedures may represent a population at increased risk for the effects of DEHP ¹⁴. This decision is supported by three findings:

1. Children undergoing some medical procedures receive a greater dose of DEHP, on a mg/kg basis, than adults do,
2. Pharmacokinetic differences between children and adults may result in greater absorption of DEHP, greater conversion of DEHP to mono-2-ethylhexyl phthalate (MEHP) (the toxic
   metabolite of DEHP), and reduced excretion of MEHP in children compared to adults,
3. Children may be more pharmacodynamically sensitive to the adverse effects of DEHP than adults are.

This conclusion is consistent with that reached by the expert panel that was recently convened by the Center for the Evaluation of Risks to Human Reproduction of the National Toxicology Program. Specifically, the panel noted that: “The available reproductive and developmental toxicity data and the limited but suggestive human exposure data indicate that human exposures in this situation approach toxic doses in rodents, which causes the Panel serious concern that exposure may adversely affect male reproductive tract development.”

Dicyclohexyl phthalate

Dicyclohexyl phthalate (DCHP) is one of a family of synthetic compounds known as phthalates. Dicyclohexyl phthalate (DCHP) is as a plasticizer primarily used in adhesives and plastic and rubber products and resins ¹¹². Other uses of dicyclohexyl phthalate include:

• As a plasticizer in adhesive, paint and coating, plastic product, rubber product, and plastic resin manufacturing;
• As a phlegmatizer (to improve safety and stability) in a variety of peroxide curing agent mixtures used in industrial and commercial applications, such as roofing systems, road markings, coatings, adhesives and other composites;
• In industrial and commercial automobile and aerospace products;
• For laboratory chemicals; and
• In commercial and consumer products, such as adhesives and sealants, and plastic and rubber products.

Several animal studies about the effects of dicyclohexyl phthalate (DCHP) on mammalian development and reproductive system have been published ¹¹³, ¹¹⁴. Hoshino et al. ¹¹⁵ investigated the two-generation effects of dicyclohexyl phthalate (DCHP) exposure at doses of 240, 1200, and 6000 ppm (about 14.3, 69.8, and 349 mg/kg) per day in the diet from gestational day 1–21 of females in Sprague Dawley rats. They found that the atrophy of seminiferous tubules of male offspring occurred at 6000 ppm dose ¹¹⁵. When Sprague Dawley rats were exposed in utero to dicyclohexyl phthalate (DCHP) at 250, 500, and 750 mg/kg per day by gavage from gestational day 6 to 20, male fetuses at gestational day 21 had low body weight at 750 mg/kg and reduced anogenital distance at 500 and 750 mg/kg doses, suggesting that the anti-androgenic effect of dicyclohexyl phthalate (DCHP), since anogenital distance is the biomarker of androgen-dependent action ¹¹⁶. Previous study also demonstrated that dicyclohexyl phthalate (DCHP) directly inhibited the activities of two important Leydig cell androgen-biosynthetic enzymes, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1, encoded by Hsd3b1) and 17β-hydroxysteroid dehydrogenase 3 (HSD17B3, encoded by Hsd17b3) ¹¹⁷, suggesting that dicyclohexyl phthalate (DCHP) exerts its action at least in part via suppression of many androgen-biosynthetic enzyme activities. Lower androgen activity is one of the typical manifestations of phthalate-mediated testicular dysgenesis syndrome ¹¹⁸. Other phthalate-mediated manifestations of testicular dysgenesis syndrome include the abnormal aggregations of fetal Leydig cells and formation of multinucleated gonocytes ¹¹⁹. The term “testicular dysgenesis syndrome” was coined referring to a spectrum of reproductive disorders that originate in male fetal life ¹¹⁹. Testicular dysgenesis syndrome includes cryptorchidism (undescended testes) and hypospadias (abnormal formation of the urethral meatus) in newborn boys and testicular cancer and reduced fertility in adult males ¹¹⁹. The occurrence of multinucleated gonocytes, abnormal fetal Leydig cell aggregation, decreased intratesticular testosterone levels, and reduced insulin-like factor 3 (Insl3) mRNA/protein (INSL3) expression in the fetal testis have been well documented in some phthalates including DEHP and dibutyl phthalate (DBP) ¹²⁰. Therefore, these phthalate-mediated manifestions in rodents are similar to those of human testicular dysgenesis syndrome in human males, and are often referred as “phthalate syndrome” ¹¹⁹.

Di-n-pentyl phthalate (DnPP)

Di-n-pentyl phthalate (DnPP) is no longer in use in the United States, because DnPP (di-n-pentyl phthalate) has been shown to cause developmental and/or reproductive effects in laboratory animals ¹²¹.

Di-isononyl phthalate (DINP)

Di-isononyl phthalate (DINP) is used in the following products: adhesives and sealants, coating products, lubricants and greases and polymers. DINP is used in the following areas: building and construction work. The release to the environment of di-isononyl phthalate (DINP) is likely to occur from: indoor use (e.g. machine wash liquids/detergents, automotive care products, paints and coating or adhesives, fragrances and air fresheners), outdoor use, indoor use in close systems with minimal release (e.g. cooling liquids in refrigerators, oil-based electric heaters) and outdoor use in close systems with minimal release (e.g. hydraulic liquids in automotive suspension, lubricants in motor oil and break fluids).

How to reduce exposure to phthalates and other endocrine disrupting chemicals?

While you cannot completely avoid exposure to endocrine disrupting chemicals, you can take some simple steps to reduce exposure to them. This is especially important for women and men who plan to have children. Talk to your doctor when planning a family to discuss what precautions you can take to limit the risks of endocrine disrupting chemicals.

Here are some practical tips for reducing your exposure to endocrine disrupting chemicals:

• Washing fruit and vegetables and buying them from known (local) sources reduces your intake of pesticides, fungicides, herbicides and chemicals that may have been sprayed on the plants
  • eating fewer processed, canned, pre-packaged foodsreduces your intake of phthalates, BPA (bisphenol A) and plasticizers that coat the inside of cans or those absorbed from plastic wrappings or cling wrap.
• Limiting your intake of fatty meats reduces your consumption of persistent organic pollutants, pesticides, heavy metals and fat-soluble chemicals that can accumulate in animals.
• Avoiding handling sales receipts or storing them in your wallet. The thermal coating contains BPA (bisphenol A) to give them their shiny plastic texture.
• Drinking water/soft drinks out of glass or hard plastic bottles, not soft plastic bottles. BPA, phthalates and other plasticisers are used to make plastics in bottles flexible.
• Never heating food in soft plastic takeaway containers or those covered with cling wrap or foil. Instead, place food in a china or glass bowl and cover it with paper towel or a china plate before heating. When they are heated, phthalates and bisphenols in plastic can easily be absorbed into the food, especially if it is fatty. The heating process also releases dioxins from the plastics that can be absorbed into the food.
• Avoiding air fresheners, smoke, strong chemicals, heavily perfumed products, plastic smells and fumes.
• Airing your home frequently to reduce the amount of inhalable chemical particles.
• Avoiding use of pesticides and herbicides in your garden, at work or in the home. Instead, try using ‘green chemicals’, which use non-toxic agents to reduce pests and weeds.
• Avoiding potent household products like detergents, hand sanitizers, cleaning agents, and carpet cleaners or strong chemicals like glues, paints, and varnishes which have numerous chemicals classes in them. Use ‘green products’ which use alternative non-toxic agents.
• Reading the labels on all personal care products such as cosmetics, shampoos, conditioners, hair colorings and body washes etc and choosing those that are free of parabens. Try to avoid using heavily perfumed or scented products where possible.
• Reading the labels on all food products and avoid those with additives, preservatives and anti-bacterial agents.
• Being aware of marketing ploys – some products that are advertised as ‘BPA free’ for example often have replacement chemicals such (bisphenol S, commonly used in curing fast-drying epoxy resin adhesives) which can be just as harmful as BPA.

References

1. Schecter A, Lorber M, Guo Y, et al. Phthalate Concentrations and Dietary Exposure from Food Purchased in New York State. Environmental Health Perspectives. 2013;121(4):473-479. doi:10.1289/ehp.1206367. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620091
2. Phthalates. https://www.epa.gov/sites/production/files/2017-08/documents/phthalates_updates_live_file_508_0.pdf
3. SCHETTLER, T. (2006), Human exposure to phthalates via consumer products. International Journal of Andrology, 29: 134-139. https://doi.org/10.1111/j.1365-2605.2005.00567.x
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