Medical devices as a source of phthalate exposure: a review of current knowledge and alternative solutions

Phthalates are the esters of 1,2-benzenedicarboxylic acid (o-phthalic acid) consisting of one benzene ring and two ester functional groups connected with two consecutive carbons on the ring (8, 9). They are produced by a reaction between phthalic anhydride and alcohols ranging from methanol and ethanol to tridecanol. These alcohols are the bases of linear or branched hydrocarbon chains which define their properties. At a room temperature, they are almost colourless and odourless oil-based lipophilic liquids with a low melting point and relatively high boiling point, which makes them very useful as plasticiser in the polymer industry. Linear phthalates provide superior flexibility at low temperatures and lower volatility (8).

Depending on their carbon chain length, phthalates are classified as low molecular weight (LMW) with 3–6 carbon atoms in their side chain or high molecular weight (HMW) with 7–13 carbon atoms in the side chain. The most common in the LMW group are dibutyl benzene-1,2-dicarboxylate (DBP), bis(2-methylpropyl) benzene-1,2-dicarboxylate (DiBP), 2-O-benzyl 1-O-butyl benzene-1,2-dicarboxylate (BBP), and bis(2-ethylhexyl) benzene-1,2-dicarboxylate (DEHP). The HMW group includes bis(8-methylnonyl) benzene-1,2-dicarboxylate (DiDP), bis(7-methyloctyl) benzene-1,2-dicarboxylate (DiNP), bis(2-propylheptyl) benzene-1,2-dicarboxylate (DPHP), bis(8-methylnonyl) benzene-1,2-dicarboxylate (DiUP), and (2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl phosphono hydrogen phosphate (DTDP), which are mostly used in industry and make 80 % of phthalate use in Europe. We shall, however, focus on LMW phthalates used in medical devices or for enteric coating and on the third group of phthalates with one or two carbon atoms in the side chain, namely dimethyl benzene-1,2-dicarboxylate (DMP) and diethyl benzene-1,2-dicarboxylate (DEP), which are used as solvents and fixatives in fragrances, additives in cosmetics, medical devices, and household and personal care products (8, 9). The amount of phthalates used in a certain product can reach up to 60 %, depending on the type and purpose (8). Annual phthalate consumption is more than one million tonnes in Western Europe and over three million tonnes around the world (10).

When used as plasticisers, phthalates bind to polymers non-covalently, which means that their bounds are temporary. Under certain conditions they tend to migrate from a material to the environment and – what is of particular concern – to patients during clinical treatment (1, 9, 10, 11, 12, 13). Patients can be exposed to phthalates through ingestion, inhalation, dermal absorption, and other parenteral routes (12). Studies have shown that phthalate migration depends on a number of factors, including flow rate, temperature, pH, contact time, and type of interaction between plasticisers and simulants (9, 11, 12, 14).

When phthalates enter the human body, their half-lives range from hours to several days before they are excreted in urine, sweat, or faeces (3, 9, 12). Parent compounds or their metabolites spread into the circulatory system, breast milk, amniotic fluid, semen, saliva, and adipose tissue. Phthalate metabolism usually includes two stages: hydrolysis and oxidation first to form hydrolytic monoesters and then conjugation to produce a number of hydrophilic glucuronide conjugates (3, 9). The higher the phthalate molecular weight, the lower its 24-hour excretion rate (9). Adults excrete phthalates conjugated to glucuronic acid via urine, but the conjugation pathway in infants is immature, especially in the premature ones, and their glomerular filtration rate is low (15).

Depending on the stage of development and sex, phthalates will affect different systems in a different way and not all phthalates will cause adverse effects in both sexes (9).

Certain medical procedures such as blood transfusion, intravenous (IV) drug or total parenteral infusion, enteral nutrition, haemodialysis, or cardiopulmonary bypass involve exposure to phthalates contained in medical devices made of polyvinyl chloride (PVC) (10, 15, 88, 89), DEHP in particular. Its release from medical devices, most often into the bloodstream, may exceed tolerable intake and cause serious harmful effects (22, 23). Different plastic materials of medical devices release phthalates differently: indwelling tubing can leak 21 % of total DEHP content in 24 h of use, especially in lipophilic solutions such as parenteral solution or blood (14, 90, 91).

Of particular concern is exposure in preterm neonates in intensive care units, who are in constant contact with feeding tubes, endotracheal tubes, and umbilical catheters (12, 13, 15, 50) and whose urinary phthalates concentrations are significantly higher than in full-term infants (92, 93, 94). Higher phthalate levels have also been reported in infants undergoing surgical repair of congenital heart defects. Gaynor et al. (94) reported higher preoperative levels than those maternal and even higher after surgery and expressed concern about the risk for exposed infants of developing neurobehavioral disorders later in life. The expert panel of the US National Toxicology Program’s Center for the Evaluation of the Risks to Human Reproduction assessed that, back in 2005, intensive care infant exposure to DEHP was two to three orders of magnitude higher than that of the general adult population and approached the lowest observed adverse effect levels (LOAEL) reported by animal studies (14–23 mg/ kg a day) (43). In adults and children on indwelling medical devices receiving intensive care urine and blood DEHP metabolite levels were reported to reach 10 μmol/L (95).

Several studies suggest that phthalate exposure is associated with the intensity and duration of invasive medical procedures (15, 88). In adults, the highest short-term phthalate exposure is associated with blood transfusion and extracorporeal membrane oxygenation (ECMO), whereas the highest chronic treatment exposure is associated with haemodialysis (96).

Besides medical devices, Messerlian et al. (92) have pointed to aqueous gel for obstetrical ultrasound in pregnancy as an unrecognised source of maternal and foetal exposure to phthalates. In utero exposure is likely, as phthalates cross the placental barrier and have been detected in the cord blood and amniotic fluid, but consequences of exposure in this critical period of development do not manifest themselves until later in life (12). Prenatal and early infancy exposure to HMW phthalates (most prevalent in neonatal intensive care units, DEHP in particular) can affect multiple domains of neurodevelopment, functional performance, attention, and motor reflexes and increase the risk of shortened anogenital distance and cardiac malformation. Exposure to DEHP during the third trimester has been associated with preterm birth, cognitive, motor, and executive function disorders and behavioural changes such as hyperactivity and autism spectrum disorders during middle childhood (12, 13, 94, 97). Iatrogenic exposure to DEHP in 4-year children after intensive care was specifically associated with impaired attention and, to a lesser extent, with impaired motor coordination (98). One study in a neonatal intensive care unit also showed improvement in hepatobiliary function following a switch to DEHP-free infusion systems (99).

While the European Commission has set specific migration limits for plastic materials and articles in contact with food (100), no such limits have been set for medical devices. One study (101) of plasticiser migration from infusion bags, however, showed higher DEHP levels than those set in the Regulation No. 10/2011//EC (100), even though the inner solution was a purely aqueous medium. Moreover, their levels in outdated bags kept for three years in conditions set by the International Conference of Harmonization (ICH) were even 10 times higher than usual (101).

ECMO is another medical intervention with a high risk of exposure to plasticisers. Blood is in contact with PVC lines with high flow rate (5 to 6 L/min) and mechanical strain at 37 °C for longer periods of time, which all are conditions favouring plasticiser migration (102). One study (103) showed considerable amounts of DEHP and its metabolite MEHP in a patient on ECMO. Their levels seem to correlate with runtime and amount of cannulas and membranes used during treatment. Another study (104) also suggests that high DEHP exposure is associated with high blood bilirubin, which points to liver dysfunction. Starting the ECMO treatment often triggers a complex and immediate inflammatory reaction, further aggravated by DEHP and phthalates in general, as they have pro-inflammatory properties and promote inflammation-related diseases such as asthma, obesity, type II diabetes, and coronary artery disease (90, 102). Fortunately, Bouattour et al. (88) report that air humidification may decrease volatile DEHP levels in ventilation air, probably due to DEHP low polarity, and that exposure to phthalates from respiratory medical devices may not be as high as from other devices.

Previous reports suggest that acute or chronic exposure to phthalates may affect wound healing, as phthalates interfere with key immune cells and induce pro-inflammatory response. A study in mice exposed to phthalates at levels observed in humans (90) showed greater inflammation reaction, cardiac dilation, and reduced cardiac function, suggesting that phthalates released from medical devices may impair post-surgery healing and that the post-surgical patients may be particularly sensitive to phthalate exposure.

Plasticisers, DEPH in particular, are used in the production of blood bags and tubings for blood collection, labile blood product (LBP) processing, and transfusion. DEPH is good for storing red blood cells, as it keeps their membranes intact but it migrates into LBP and eventually comes into contact with patients. Replacing it with alternative plasticisers for LBP storage is not a simple solution, as their metabolites can be cytotoxic and affect the quality of the red blood cells and platelets (105, 106, 107) (see the section Alternative plasticisers for more detail). Another, more common solution is mechanical rinsing of stored blood prior to transfusion, whose primary purpose is to clean the bags from electrolytes. The second positive effect of rinsing is that it reduces both DEHP and MEHP concentrations (108).

Another source of exposure are face masks, particularly prominent during the COVID-19 pandemic, as recent studies reported several phthalates in them and raised the issue of exposure, especially in vulnerable populations such as the elderly, children, and pregnant women (109, 110).

Several European documents regulate the use of certain phthalates as plasticisers in consumer goods and health products. Phthalates have been recognised and categorised as carcinogenic, mutagenic, or toxic to reproduction ever since the Council Directive 67/548/EEC of 27 June 1967 (111) dealing with the classification, packaging, and labelling of dangerous substances.

Phthalates in medical devices have first been addressed in Annex I of the Council Directive 93/42/EEC of 14 June 1993 (112), requiring that medical devices containing phthalates be labelled as such. Also, if such devices are intended to be used in children or pregnant or nursing women, the manufacturer must provide a specific justification for their use.

In 2005, the EU banned DEHP, DBP, BBP from toys and childcare items (113), and in 2009, these bans entered the REACH Annex XVII (as entries 51 and 52). As time went by, more and more phthalates were recognised as unsafe. Currently 14 phthalates are on the REACH Authorisation List, which means that their use will be banned unless the European Commission allows a specific company to continue their use (114).

The most common plasticiser in flexible PVC medical devices, DEHP, has been classified as carcinogenic, mutagenic, or toxic for reproduction (CMR 1b) by the EU Regulation 1272/2008 since 2008 (115). In 2015, the Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR) expanded the 2008 classification with an updated opinion that replacement of DEHP with alternative materials should be considered, taking into account their efficiency in the treatment and their toxicological profile and leaching properties (116). The new EU Regulations 2017/745 (6) on medical devices, in effect since 26 May 2021, and 2017/746 (7) on in vitro o diagnostic medical devices, in effect since 26 May 2022 specify that CMR and endocrine disrupting (ED) substances are allowed in concentrations above 0.1 % weight by weight (w/w) only when justified pursuant to Section 10.4.2 of Annex I Chapter II. The justification is to be based on the latest relevant Scientific Committee guidelines as well as on estimation of patient/user exposure and possible alternative substances, materials, or designs claiming that such substitutes are inappropriate.

The most common safer plasticiser alternatives to phthalates are tri-octyl trimellitate (TOTM), di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di-isononyl phthalate (DINP), di-(2-ethylhexyl) terephthalate (DEHT), di-(2-ethylhexy) adipate (DEHA) and acetyl tri-n-butyl citrate (ATBC) (89, 102, 117). A recent study by Malarvannan et al. (99), however, still reports the dominance of DEHP, followed by DEHA, DEHT, TOTM, and ATBC, sometimes within the same device. Other alternative plasticisers, such as DINCH, DINP, DPHP, and DiDP were detected in no more than 5 % of the investigated samples. Another study (117) showed predominance of TOTM in hospital devices, with DEHP present at trace levels.

TOTM seems to be poorly absorbed following oral exposure, but data on intravenous exposure are still scarce (118). According to Eckert et al. (10), its mean migration is about 350 times lower than that of DEHP and it has low absolute mass loss. One study of TOTM release during ECMO therapy (102) showed a weak leak at non-cytotoxic doses, lower than the derived no-effect level (DNEL). Another in vitro study on L929 cells (119) found no cytotoxic effects of TOTM and its corresponding metabolite MOTM.

Moreover, the toxicological profile of TOTM seems to be significantly more favourable than that of DEHP (10). Another interesting observation made by Eckert et al. (10) is that DEHP and TOTM migration was lower with devices kept in storage for several weeks before use. The authors wonder whether it would be better to use PVC medical devices stored for longer than the fresh ones in high-risk patients, especially for critical interventions such as cardiopulmonary bypass.

Acetyl triethyl citrate (ATEC) and ATBC were also investigated as alternatives for DEHP. One study (120) found the former a better alternative, as it is less likely to induce anti-androgenic effects.

Urine samples stored at the German Environmental Specimen Bank (ESB) from 1999 to 2017 showed increasing presence of di(2-ethylhexyl) terephthalate (DEHTP) (121), but DEHTP exposure gives no reason for immediate concern, yet it warrants close monitoring in the future.

An ex vivo study (122) showed high DEHA migration rates from haemofiltration systems and concluded that DEHA might not be the best alternative plasticiser for CVVH tubings, considering that its primary metabolite monoethylhexyladipate (MEHA) can reach cytotoxic levels in patients undergoing the procedure. This cytotoxic effect of MEHA was also reported by Eljezi et al. (119) at the concentration of 0.05 mg/mL. Another study reported 106 times higher DEHA migration than that of TOTM (117).

Another alternative plasticiser with a distinctly lower toxicological potential than DEHP, tri-2-ethylhexyl trimellitate (TEHTM), was found to have a comparatively low resorption rate and a rather slow metabolism (to DEHTM and MEHTM) and excretion rate (123). Eckert et al. (113), in turn, evidenced low TEHTM levels in the blood of children after cardiac surgery, whereas DEHP from blood bags was significantly higher.

Another interesting alternative to DEHP is DEHT because of its low migration from medical devices and lower toxicity. However, its metabolite 5-OH-MEHT has a potential endocrine-disrupting effect (124).

One study of DINCH and DINP primary unconjugated metabolites on a L929 cell line (125) has shown that at concentrations of 0.01–0.1 mg/mL they are more cytotoxic than their parent compounds, save for DINP’s MMeOP. Among the secondary DINCH and DINP metabolites, however, only 7-oxo-MMeOCH showed cytotoxicity at 0.1 mg/mL after seven days of exposure. Another study (126) showed DINCH-induced cytotoxicity in human kidney cell lines after 24 h of exposure and transient oxidative DNA damage in liver cells exposed for 3 h. However, a German study (127) based on data from urine analysis in samples collected from young adults concluded that the median daily DINCH intake calculated for 2017 was 4,310 times below the tolerable daily intake (TDI). Even though this finding seems reassuring, the constant increase in DINCH exposure between 1999 and 2017, calls for its close monitoring, according to the study authors.

There are several other studies that call for collecting larger datasets regarding phthalate leachability and safety (89, 117, 128, 129). These data, including migration, leaching, and route-specific toxicity of alternative plasticisers will help to better weigh the risks and benefits of their use in medical devices (118).

As alternatives go, one is the use of plasticiser-free silicone tubing. However, Eckert et al. (10) showed a considerable loss of silicone mass from tubing over time, probably owed to the migration of siloxanes.

It is clear that all medical devices included in this review are of vital importance for patients and that the benefits still outweigh the risks. However, we cannot ignore additional risks for vulnerable groups of patients, neonates, infants, and pregnant women. Here we would also like to acknowledge potential risks for healthcare professionals, which we did not include in this review, but which deserve more attention in the future.

Future research, we hope, shall also shed more light on the risks and benefits of phthalate replacement with safer alternatives in medical devices, but until that time, phthalates will remain in use.