User:Project Osprey/sandbox3

Natural occurrence

Various plants and microorganisms have been reported to naturally produce phthalate esters (endogenous phthalates).^[19][20] Biosynthesis is believed to involved a modified Shikimate pathway^[21][22] The extent of this natural production is not fully know, but it may create a background of phthalate pollution.

PVC Plasticisers

Among the common plastics, PVC is unique in its acceptance of large amounts of plasticiser with gradual changes in physical properties from a rigid solid to a soft gel. Between 90-95% of all phthalates are used as plasticisers for the production of flexible PVC.^[23][24] They were the first commercially important compounds for this role,^[25] a historic advantage that has lead to them becoming firmly embedded in flexible PVC technology.^[26] Compounds derived from alcohols with 7-13 carbon atoms occupy a privileged position as general purpose plasticisers, suitable for almost all flexible PVC applications.^[27][26] Compounds larger than this have limited compatibility in PVC, with di(isotridecyl) phthalate representing the practical upper limit. Conversely, compounds derived from alcohols with 4-6 carbon atoms are too volatile to be used on their own, but have been used alongside other compounds as secondary plasticisers, where they improve low-temperature flexibility. Phthalates derived from alcohols with 1-3 carbon atoms are not used as plasticisers in PVC at all, due excessive fuming at processing temperatures.^[26]

Historically DINP, DEHP, DIOP, DOTP and DIHP have been the most important phthalates, however many of these are now facing regulatory pressure and gradual phase-outs. Almost all phthalates derived from alcohols with 8 or fewer carbons are classed as toxic by ECHA. This includes Bis(2-ethylhexyl) phthalate (DEHP or DOT), which has long been the the most widely used phthalate, with commercial production dating back to the 1930's.^[28][29] In the EU, the use of DEHP is restricted under REACH and it can only be used in specific cases if an authorisation has been granted; similar restrictions exist in many other jurisdictions. Despite this, the phase-out of DEHP is slow and it was still the most frequently used plasticizer in 2018, with an estimated global production of 3.24 million tonnes.^[29] DINP and DIDP are used as a substitutes for DEHP in many applications, as they are not classified as hazardous.^[30] Non-phthalate plastisizers are also being increasingly used.

Almost 90% of all plasticizers are used in PVC, giving this material improved flexibility and durability.^[31] The majority is used in films and cable sheathing.^[29] Flexible PVC can consist of over 85% phthalate by mass, however unplasticized PVC (UPVC) should not contain any.

Non-PVC Plasticisers

Phthalates see use as plasticisers in various other polymers, with applications centred around coatings such as lacquers, vanishes and paints. The addition of phthalates imparts some flexibility to these materials, reducing their tendency to chip. Phthalates derived from alcohols with between 1-4 carbon atoms are used as plasticisers for cellulose-type plastics, such as cellulose acetate, nitrocellulose and cellulose acetate butyrate, with commonly encountered applications including nail polish. Most phthalates are also compatible with alkyds and acrylic resin, which are used in both oil and emulsion based paints.

Other polymer systems include polyvinyl butyral (particularly the forms used to make laminated glass), PVA and its co-polymers like PVCA. They are also compatible in nylon, polystyrene, polyurethanes, and certain rubbers; but their use in these is very limited.^[33] Phthalates have also been used for producing plastic explosives such as Semtex.

Phthalates can plasticise ethyl cellulose, polyvinyl acetate phthalate (PVAP) and cellulose acetate phthalate (CAP), all of which are used to make enteric coatings for tablet and capsule medications. These coatings protect drugs from the acidity of the stomach, but allow their release and absorption in the intestines.

Other uses

Relatively minor amounts of some phthalates are used in non-plasticizer applications. Phthalates find use in personal-care items such as eye shadow, moisturizer, nail polish, liquid soap, and hair spray.^[34][35][36] Low molecular weight phthalate like dimethyl phthalate and diethyl phthalate are used as fixatives for perfumes.^[37] Dimethyl phthalate has been also used as an insect repellent and is especially useful against ixodid ticks responsible for Lyme disease.^[38] and species of mosquitoes such as Anopheles stephensi, Culex pipeins and Ades aegypti.^[39][40][41]

Diallyl phthalate is used to prepare vinyl ester resins with excellent electrical insulation properties and is used to manufacture of electronic parts.Alkyds are sometimes classes as phthalates, as they meet the technical definition, being polymeric esters of phthalic acid however their properties and applications are very different.

Prevalence and human exposure

Due to the ubiquity of plasticized plastics, the majority of people are exposed to some level of phthalates. For example, most Americans tested by the Centers for Disease Control and Prevention have metabolites of multiple phthalates in their urine.^[48] In studies of rodents exposed to certain phthalates, high doses have been shown to change hormone levels and cause birth defects.^[49]

Endocrine disruption

Phthalates enter the bloodstream and disrupt sex hormone production, interfering with sexual development in infants and sexual behaviour in adults. Levels of phthalates have been dose-dependently linked to reduced anogenital distance^[50] decreased sexual desire and satisfaction in women,^[51] and malformed genital development in rats.

Phthalates act by mimicking the female hormone estrogen, which in turn inhibits production of the male hormone testosterone. As such, phthalates are considered to be endocrine disruptors^[52][53][54]—a substance that interferes with the normal hormonal mechanisms that allow a biological organism to interact with its environment, and has sparked demands to ban or restrict its use in baby toys.^[52]

Endocrine disruptors exhibit numerous behaviors that can make studying them a challenge. There can be a lag between when someone is exposed to an endocrine disruptor and any symptoms manifesting themselves–in particular fetal and early childhood exposure may have consequences later in adulthood.^[52][55] Many studies refer to this period of fetal and postnatal development as particularly important to development, but studying this is difficult; it is obviously a huge challenge to measure endocrine disruptor exposure during fetal development and then decades later diagnosing any health problems. Additionally, endocrine disruptor exposure can transmit epigenetically to one's offspring without them being directly exposed to the endocrine disruptors.^[56] Finally, particularly low levels of exposure may still have significant effects, and exposure to multiple endocrine disruptors across a variety of compounds (not just phthalates) may synergistically combine to cause a greater effect.^[52][55] Evaluating the actual effects of a specific compound such as a particular phthalate requires examining cumulative exposure across multiple compounds, rather than evaluating one compound in isolation.^[55]

A widespread concern about phthalate exposure is the possibility (though not conclusive) that it is the cause of a worldwide drop in male fertility.^[57][58][59] Studies have shown that phthalates cause abnormalities in the reproductive systems of animals,^[60] with the greatest effects when the animal is exposed during gestation and immediately thereafter.^[61] Numerous studies on adult male humans show the similar result that phthalate exposure correlates with worsening metrics of male fertility, such as semen quality, the quantity of damaged DNA in sperm, decreased sperm motility, decreased semen volume, and other metrics.^[53][61][62] Phthalates causing harm to the male reproductive system is plausible,^[63] and continues to be researched.

The effect of phthalates on the female reproductive system is also not fully understood yet. Current studies indicate phthalates have negative effects on folliculogenesis and steroidogenesis.^[64]

Early research also shows phthalate exposure may be associated with diabetes and insulin resistance, breast cancer, obesity,^[65] metabolic disorders, and immune function.^[54]

There are possible (though not conclusive) associations between phthalate exposure and adverse child neurodevelopment,^[66][67] including the development of ADHD and autistic behaviors and lower cognitive and motor development.^[68] Most common associations found in medical reports link the phthalates exposure to hyperactivity, aggression, and other adverse behaviors.^[68] Some studies have found the childhood exposure to be as early as in utero.^[69]

In many cases, there are studies that show connections between phthalates and these negative outcomes, as well as studies that show no connection; this is likely due to the research challenges outlined above, and when resolved, could show that phthalate exposure does not cause health effects, or even that they have a much greater effect than currently predicted.^[55] In all cases, larger studies are needed to demonstrate incontrovertibly what effect phthalate exposure has on human health.

A Nature Reviews Endocrinology review paper from 2017^[55] gives some advice for avoiding exposure to phthalates for concerned people; while they make pains to state that there is no evidence that shows this advice will positively affect one's health, they suggest (1) eating a balanced diet to avoid ingesting too many endocrine disruptors from a single source, (2) eliminating canned or packaged food in order to limit ingestion of DEHP phthalates leached from plastics, and (3) eliminating use of any personal product such as moisturizer, perfume, or cosmetics that contain phthalates.^[55] Eliminating personal products containing phthalates can be particularly difficult or impossible due to some countries such as the United States not requiring them to be disclosed in a list of ingredients.^[70]

Endocannabinoid system disruption

Phthalates block CB₁ as allosteric antagonists.^[71]

Other effects

This section needs more reliable medical references for verification or relies too heavily on primary sources. (April 2022)

There may be a link between the obesity epidemic and endocrine disruption and metabolic interference. Studies conducted on mice exposed to phthalates in utero did not result in metabolic disorder in adults.^[72] However, "in a national cross-section of U.S. men, concentrations of several prevalent phthalate metabolites showed statistically significant correlations with abnormal obesity and insulin resistance."^[72] Mono-ethylhexyl-phthalate (MEHP), a metabolite of DEHP, has been found to interact with all three peroxisome proliferator-activated receptors (PPARs).^[72] PPARs are members of the nuclear receptor superfamily. The author of the study stated "The roles of PPARs in lipid and carbohydrate metabolism raise the question of their activation by a sub-class of pollutants, tentatively named metabolic disrupters."^[72] Phthalates belong to this class of metabolic disruptors. It is a possibility that, over many years of exposure to these metabolic disruptors, they are able to deregulate complex metabolic pathways in a subtle manner.^[72]

Large amounts of specific phthalates fed to rodents have been shown to damage their liver and testes,^[49] and initial rodent studies also indicated hepatocarcinogenicity. Following this result, di(2-ethylhexyl) phthalate was listed as a possible carcinogen by IARC, EC, and WHO. Later studies on primates showed that the mechanism is specific to rodents; humans are resistant to the effect.^[73] The carcinogen classification was subsequently withdrawn.

Canada

In 1994, a Health Canada assessment found that DEHP and another phthalate product, B79P, were harmful to human health. The Canadian federal government responded by banning their use in cosmetics and restricting their use in other applications.^[85]

A more recent assessment in 2017 found that B79P and DEHP may cause environmental damage. As of 2019, regulations to protect the environment against DEHP and B79P have not yet been put into place.^[86]

European Union

The use of some phthalates has been restricted in the European Union for use in children's toys since 1999.^[87] DEHP, BBP, and DBP are restricted for all toys; DINP, DIDP, and DNOP are restricted only in toys that can be taken into the mouth. The restriction states that the amount of these phthalates may not be greater than 0.1% mass percent of the plasticized part of the toy.

Generally, the high molecular weight phthalates DINP, DIDP, and DPHP have been registered under REACH and have demonstrated their safety for use in current applications. They are not classified for any health or environmental effects.

The low molecular weight products BBP, DEHP, DIBP, and DBP were added to the Candidate list of Substances for Authorisation under REACH in 2008-9, and added to the Authorisation list, Annex XIV, in 2012.^[4] This means that from February 2015 they are not allowed to be produced in the EU unless authorisation has been granted for a specific use, however they may still be imported in consumer products.^[88] The creation of an Annex XV dossier, which could ban the import of products containing these chemicals, was being prepared jointly by the ECHA and Danish authorities, and expected to be submitted by April 2016.^[89]

In 2006 the Dutch office of Greenpeace UK sought to encourage the European Union to ban sex toys that contained phthalates.^[90]

United States

During August 2008, the United States Congress passed and President George W. Bush signed the Consumer Product Safety Improvement Act (CPSIA), which became public law 110-314.^[91] Section 108 of that law specified that as of February 10, 2009, "it shall be unlawful for any person to manufacture for sale, offer for sale, distribute in commerce, or import into the United States any children's toy or child care article that contains concentrations of more than 0.1 percent of" DEHP, DBP, or BBP and "it shall be unlawful for any person to manufacture for sale, offer for sale, distribute in commerce, or import into the United States any children's toy that can be placed in a child's mouth or child care article that contains concentrations of more than 0.1 percent of" DINP, DIDP, DnOP. Furthermore, the law requires the establishment of a permanent review board to determine the safety of other phthalates. Prior to this legislation, the Consumer Product Safety Commission had determined that voluntary withdrawals of DEHP and diisononyl phthalate (DINP) from teethers, pacifiers, and rattles had eliminated the risk to children, and advised against enacting a phthalate ban.^[92]

In another development in 1986, California voters approved an initiative to address their growing concerns about exposure to toxic chemicals. That initiative became the Safe Drinking Water and Toxic Enforcement Act of 1986, better known by its original name of Proposition 65.^[93] In December 2013 DINP was listed as a chemical "known to the State of California to cause cancer"^[94] This means that, starting December 2014, companies with ten or more employees manufacturing, distributing or selling the product(s) containing DINP are required to provide a clear and reasonable warning for that product. The California Office of Environmental Health Hazard Assessment, charged with maintaining the Proposition 65 list and enforcing its provisions, has implemented a "No Significant Risk Level" of 146 μg/day for DINP.^[95]

Further reading