Respiratory Support as a Source of Plasticizer Exposure in Premature Neonates

ABSTRACT

In the neonatal intensive care unit, premature neonates often are in need of respiratory support, which is provided via several plastic medical devices (PMDs). These devices can be a potential source of plasticizers (phthalates and alternative plasticizers [APs]), which increase the flexibility and durability of PMDs. The aim of this study was to investigate the contribution of respiratory support as a source of plasticizer exposure in neonates by analyzing the concentrations of nine phthalates and 11 APs in nine PMDs commonly used for invasive and noninvasive respiratory support administration using LC–MS/MS and GC–MS. Additionally, a pilot ex vivo experiment mimicking mechanical ventilation was set up to assess plasticizer content in breath condensate. First, we showed that tris‐(2‐ethylhexyl) trimellitate (TOTM), di‐(2‐ethylhexyl) terephthalate, and di‐(2‐ethylhexyl) phthalate (DEHP) are present in relevant amounts in PMDs used for respiratory support. Breath condensate collected after circulation through a ventilation circuit with three different endotracheal tubes containing either TOTM, DEHP, or no significant plasticizers all showed substantial concentrations for DEHP and diethyl phthalate. This work provides novel evidence that respiratory medical devices used in neonatal intensive care units can be a significant source of plasticizer exposure, and introduces an ex vivo leaching model that simulates in vivo ventilation conditions to assess clinical migration behavior of both phthalate and alternative plasticizers.

Short abstract

Premature neonates in intensive care often require respiratory support delivered through plastic medical devices (PMDs) containing phthalates or alternative plasticizers. We quantified nine phthalates and 11 alternatives in nine commonly used respiratory PMDs via LC–MS/MS and GC–MS, and conducted an ex vivo ventilation model to assess leaching into breath condensate. Devices frequently contained TOTM, DEHT, and DEHP, and condensate showed substantial DEHP and DEP. Ex vivo ventilation experiments confirm neonatal exposure to plasticizers via PMDs used for respiratory support.

Abbreviations

AP

alternative plasticizer

ATBC

acetyl tributyl citrate

ATEC

acetyl triethyl citrate

BBzP

butylbenzyl phthalate

BC

breath consendate

BPD

bronchopulmonary dysplasia

BTHC

butyryl trihexyl citrate

CDPHP

cresyl diphenyl phosphate

CMR

carcinogenic, mutagenic or toxic for reproduction

CPAP

continuous positive airway pressure

DBS

dibutyl succinate

DCM

DICHLOROMETHANE

DEHA

di‐(2‐ethylhexyl) adipate

DEHP

di‐(2‐ethylhexyl) phthalate

DEHTP

di‐(2‐ethylhexyl) terephthalate

DEP

diethyl phthalate

DF

detection frequency

DIBA

diisobutyl adipate

DiBP

diisobutyl phthalate

DIDP

di‐isodecyl phthalate

DINCH

cyclohexane‐1,2‐dicarboxylic di‐isononyl ester

DINP

di‐isononyl phthalate

DMP

dimethyl phthalate

DnBP

di‐n‐butyl phthalate

DPP

dipentyl phthalate

ECHA

European Chemical Agency

EDC

endocrine disrupting chemical

EFSA

European Food Safety Agency

EN

enteral nutrition

EtAc

ethyl acetate

ETT

endotracheal tube

GC

gas chromatography

IS

internal standard

IV

intravenous

LC

liquid chromatography

LOQ

limit of quantification

MDR

Medical Devices Regulation

MeOH

methanol

MS

mass spectrometry

MW

molecular weight

n‐Hex

n‐hexane

NICU

neonatal intensive care unit

PMD

plastic medical device

PP

polypropylene

PVC

polyvinyl chloride

QA

quality assurance

QC

quality control

THTM

tri‐n‐hexyl trimellitate

TOTM

tris‐(2‐ethylhexyl) trimellitate

UZA

University Hospital Antwerp

1. Introduction

Plastic polymers such as polyvinyl chloride (PVC) are commonly modified by the addition of plasticizers. These plasticizers are used to enhance softness, flexibility, and durability, with phthalates being the most widely used category of this class of additives. Exposure to phthalates is ubiquitous in humans and originates from a broad range of environmental sources, including food packaging, household items, pharmaceuticals, and indoor dust (Panneel et al. 2022). In addition to these exposure sources, plastic medical devices (PMDs) represent an important exposure pathway. Historically, di‐(2‐ethylhexyl) phthalate (DEHP) has been predominantly used as a plasticizer in PMDs (Malarvannan et al. 2019). The widespread use of DEHP is largely due to its low production cost, favorable properties, and ability to increase flexibility and stability to plastic materials. Consequently, DEHP is present in numerous invasive PMDs, such as blood bags, intravenous (i.v.) storage bags and infusion sets, as well as endotracheal and nasogastric tubes (Panneel et al. 2022).

Toxicological studies indicate that phthalates, including DEHP, exhibit endocrine‐disrupting and reprotoxic effects (Benjamin et al. 2017; Rowdhwal and Chen 2018; Schug et al. 2015; Zarean et al. 2016). These compounds are classified as carcinogenic, mutagenic, or toxic for reproduction (CMR 1b) (European Union 2008) and are also recognized as endocrine‐disrupting chemicals (EDC) (European Chemicals Agency 2006; European Chemicals Agency 2023). In response to these concerns, the European Union implemented the Medical Devices Regulation (MDR 2017/745) in May 2021 (European Union 2017), which requires justification and labelling for medical devices containing CMR 1a/b and/or EDC substances at concentrations exceeding 0.1 wt%. This resulted in the shift from phthalates to several alternative plasticizers (APs), including di‐(2‐ethylhexyl) terephthalate (DEHTP), diisononyl cyclohexane‐1,2‐dicarboxylate (DINCH), and di‐(2‐ethylhexyl) adipate (DEHA), which have been proposed as replacements for DEHP (Danish Ministry of the Environment—Environmental Protection Agency 2014; Den Braver‐Sewradj et al. 2020).

Plasticizers are not chemically bound to the PVC polymer matrix. This allows them to migrate from plastic products into surrounding environments and the human body. This has been documented through the detection of plasticizer metabolites in urine samples of critically ill adults (Huygh et al. 2015), pediatric populations (Verstraete et al. 2016), and neonates in the neonatal intensive care unit (NICU) (Panneel et al. 2022; Stroustrup et al. 2018). In the NICU setting, invasive PMDs may, therefore, contribute substantially to phthalate and AP exposure. Premature neonates are especially vulnerable as exposure occurs during a sensitive developmental phase. In the first weeks of life, their metabolic and elimination pathways are still underdeveloped (Gubhaju et al. 2014). Additionally, the perinatal period is a critical stage of lung development, particularly alveolarization, which is the final phase of pulmonary maturation (Woods and Schnitty 2016). Phthalates released from invasive and noninvasive respiratory support equipment may, therefore, affect the highly susceptible peripheral airways. Consequently, the EU Scientific Committee on Emerging and Newly Identified Health Risks has identified premature neonates as a risk population for plasticizer exposure (Testai et al. 2016).

The studies by Bernard, Cueff, Breysse, et al. (2015) and Bouattour et al. (2020) show that accurate plasticizers exposure assessment from both invasive and noninvasive respiratory support devices remain methodologically challenging. The experimental designs should closely reflect real‐life clinical conditions as the amount of plasticizer leaching from the plastic matrix is influenced by a range of variable clinical parameters.

Therefore, the primary objective of the present study was to evaluate the contribution of respiratory support to current phthalate and AP exposure in premature neonates. First, we identified and quantified the phthalates and APs in PMDs currently used for respiratory support in the NICU. Additionally, a pilot ex vivo study was conducted to measure the concentrations of phthalates and APs released from these devices by using breath condensate (BC) samples collected under clinically relevant conditions that simulated mechanical ventilation.

2. Materials and Methods

2.1. Chemicals and Reagents

Labeled butylbenzyl phthalate (BBzP‐d4) was purchased from AccuStandard. Labeled bis‐(2‐ethylhexyl) phthalate (DEHP‐d4) and labeled di‐n‐butyl phthalate (DnBP‐d4) were purchased from Sigma‐Aldrich (St. Louis, Missouri, USA) and were used as internal standards (ISs). Standards of phthalates DEHP, dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DiBP), DnBP, BBzP, dipentyl phthalate (DPP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP) and APs DEHTP, DINCH, tris‐(2‐ethylhexyl) trimellitate (TOTM), tri‐n‐hexyl‐trimellitate (THTM), DEHA, acetyl tributyl citrate (ATBC), acetyl triethyl citrate (ATEC), butyryl trihexyl citrate (BTHC), diisobutyl adipate (DIBA), cresyl diphenyl phosphate (CDPHP), and dibutyl succinate (DBS) were purchased from AccuStandard. All solvents were of chromatography grade. n‐Hexane (n‐Hex) was purchased from Acros Organics (Geel, Belgium). Ethyl acetate (EtAc), dichloromethane (DCM), and acetone were purchased from Merck (Darmstadt, Germany). Methanol (MeOH) was purchased from Fisher Scientific (Loughborough, UK).

2.2. Presence of Plasticizers in Plastic Medical Devices

2.2.1. Plastic Medical Devices

The concentrations of nine phthalates and 11 APs (Supporting Information Table S1) were analyzed in 19 individual samples obtained from nine plastic medical devices. The included PMDs reflected the full range of PMDs routinely used for respiratory support in a tertiary neonatal intensive care unit (NICU) at the Antwerp University Hospital (UZA), Edegem, Belgium. Unused plastic medical devices were extracted to ensure that the measured concentrations reflected material composition without the influence of clinical use. Each device was separated into multiple parts according to the specific plastic material used, as these PMDs were manufactured using soft plastics, hard plastics, or combinations of both.

2.2.2. Sample Preparation and Instrumental Analysis

Sample preparation was previously described by the study of Panneel et al. (2023). All device parts were first cut into pieces of approximately 2 mm. Afterward, 100 mg was weighed and transferred into polypropylene (PP) tubes that had been prerinsed with acetone. Prior to extraction, 50 μL of the internal standards (ISs) mix containing BBzP‐d4, DEHP‐d4, and DnBP‐d4 (10 ng/μL) was added to each sample. Extraction was performed using 5 mL of an n‐Hex:EtAc mixture (1:1, v/v). The samples were subsequently sonicated for 30 min, followed by vortex mixing at 2500 rpm for 30 min and centrifugation at 4000 rpm for 5 min. The supernatant was transferred to a clean PP tube, after which the extraction was repeated using 5 mL of fresh solvent. The supernatants obtained from both extraction steps were pooled and concentrated to dryness under a gentle nitrogen stream. The extract was reconstituted in 200 μL of MeOH. Targeted quantification of the analytes of interest (Table S1) was carried out using an Agilent 1200 Infinity liquid chromatography system coupled to an Agilent 6410 Triple Quadrupole mass spectrometer (MS/MS) (Agilent, Santa Clara, California, USA). Because DEHP and DEHTP coelute under the used LC–MS/MS conditions, these compounds were instead quantified using an Agilent 6890 gas chromatograph (GC) interfaced with an Agilent 5973 mass spectrometer (MS) operating in electron ionization (EI) mode (GC‐EI‐MS) (Agilent, Santa Clara, California, USA). Supporting information S1 contains chromatographic details for both instrumental analysis.

2.3. Clinical Simulation

2.3.1. Clinical Experiment Design

Few reports focus on the possible leaching of plasticizers from heated and humidified ventilation circuits (Panneel et al. 2022). Therefore, we set up ex vivo leaching experiments simulating real‐life mechanical ventilation, considering a hypothetical premature neonate of 1 kg supported via endotracheal intubation. The respiratory support equipment was set up identically as during clinical use in the UZA NICU, shown in Supporting Information Figure S1. Based on a target tidal volume of 5 mL and a respiratory rate of 60 breaths per min, a min volume of 300 mL/min was calculated. This target min volume was obtained using a continuous positive airway pressure (CPAP) modus with a pressure of 6 mbar using an SLE 6000 neonatal ventilator (SLE, Croydon, UK). The inspiratory limb was heated up to 37°C and humidified to 80% using a respiratory humidifier (Fischer and Pykel 950, East Tāmaki, Auckland, New Zealand). Condensate samples were collected after 6 h of simulated ventilation in a closed circuit. A polypropylene recipient, which was precleaned with acetone was placed at the distal end of the endotracheal tube and cooled at 5°C via Turbo‐DECCS (Medivac, Parma, Italy). Because different endotracheal tubes are clinically used, experiments were repeated in triplicate for each different type of endotracheal tube Vygon (Écouen, France), Portex (Hythe, UK), and Covidien (Dublin, Ireland). Samples collected after passage through the circuit were analyzed alongside a noncirculated control of sterile water for injection to determine the net contribution of the circuit to the measured concentrations.

2.3.2. Sample Preparation

Breath condensate samples were analyzed in the same manner as the plastic medical devices described in section “2.1.2 Sample preparation and instrumental analysis” with 1 mL of breath condensate used in sample preparation.

2.4. Quality Assurance and Quality Control

Analysis of three procedural blanks was performed along every batch of PMD and BC samples to check for background contamination. Additionally, a field blank was analyzed to detect and measure any contamination that might be introduced during the sampling, transportation, storage, or analytical processing. During compound quantification, average procedural blank levels were subtracted from the sample results, and a value equal to 10 times the standard deviation (SD) of the blank measurement was used as the limit of quantification (LOQ). Samples were spiked with 50 μL of the ISs, BBzP‐d4 (10 ng/μL), DEHP‐d4 (10 ng/μL), and DnBP‐d4 (10 ng/μL) to monitor sample preparation, instrument performance and for quantification purposes. Recoveries of the internal standard during sample preparation can be found in Supporting Information Figure S2. A quality control sample (QC) including all ISs and targeted native compounds (10 ng) was included in every batch during sample preparation, injected multiple times along the sequence and results were evaluated for the instrument performance on the same analytes. For analytes with nonsatisfactory results on QC accuracies, a correction factor was used for the calculation of the final plasticizer concentration. In addition, a solvent blank was injected during the sequence to control carry‐over effects. Traces of DEHP were found in solvent blank injections, as this compound is ubiquitously present. Subtraction of procedural and field blanks will compensate for this effect. Blank values, LOQs, and QC accuracies for all plasticizer compounds can be found in Supporting Information Table S2 and Table S3.

2.5. Statistical Analysis

Database set‐up and descriptive statistics were performed in JMP Pro 16 (JMP, Version 16. SAS Institute Inc., 1989–2023, Cary, North‐Carolina, USA). Tabulated descriptive statistics display raw concentrations.

3. Results

3.1. Plasticizers in Plastic Medical Devices

The concentrations of nine phthalates and 11 APs were analyzed in 19 individual samples obtained from nine plastic medical devices. Measured concentrations varied from approximately 10 ng/g to several mg/g. Due to this wide variability, results were reported as percentage weight per weight (% w/w) of the PMD material. Compounds detected at levels above 0.1% were classified as functional plasticizers, whereas those present below this threshold were regarded as trace components or impurities. An overview of the analyzed medical devices, including available labeling information, as well as the predominant plasticizers and minor compounds identified in each PMD, is presented in Table 1. The results showed a predominant use of TOTM, DEHTP, and DEHP as main plasticizers in PMD used for respiratory support manufactured in 2021–2023, with highest concentrations found for TOTM reaching 8.1% w/w in the side port of the endotracheal tube (ETT1) containing the pressure sensor disk. The main tube of this endotracheal tube contained 1.2% w/w TOTM. The second endotracheal tube (ETT2) showed no detection of the analyzed phthalates and APs included in this analytical method. The third endotracheal tube (ETT3) from a different manufacturer was labeled to contain phthalates and showed the presence of 2.7% DEHTP and 2.6% DEHP in the main tube.

TABLE 1.

Plasticizers detected in plastic medical devices used for neonatal respiratory support.

Product	Company (country)	Reference	Label	Production year	Sample part ( $\pm 100$ mg)	Predominant plasticizers (% w/w, ≥ 0.1)		Compounds < 0.1% w/w
						Compound 1	Compound 2
Sterile water for injection	Baxter (USA)	AE303	N/a	2022	Bag
					Water
Humidification chamber	FPH (New Zealand)	MR290	N/a	2021	Proximal tube	TOTM (1.2%)		DEHP
					Inside wall chamber			TOTM
					Outside wall chamber
					Distal tube
Breathing circuit (Evaqua)	FPH (New Zealand)	RT268	DEHP‐free	2022	Inspiratory proximal tube
					Inspiratory distal tube
					Expiratory tube
Endotracheal tube 1	Vygon (France)	5516.20	DEHP‐free	2022	Tube	TOTM (1.2%)		DEP, DEHA, DINCH
					Side port	TOTM (8.1%)		DEP, DEHA, DEHTP, DEHP
Endotracheal tube 2	Covidien (Ireland)	86,234	DEHP‐free	2023	Tube
Endotracheal tube 3	Smiths Medical—Portex (UK)	100/111/030	Contains phthalates	2021	Tube	DEHTP (2.7%)	DEHP (2.6%)
CPAP circuit	FPH (New Zealand)	RT132	N/a	2021	Inspiratory proximal tube
					Inspiratory distal tube
CPAP mask	Carefusion (USA)	777,002	PHT‐free	2022	Connection tube			DEHA
					CPAP prong
HFNC circuit	FPH (New Zealand)	OJR412	N/a	2022	Connection tube
					Prong

3.2. Plasticizers Leaching From Ex Vivo Circuits

Detection frequencies (%) of phthalates and APs found in breath condensate samples (n = 18) after ex vivo simulated invasive mechanical ventilation are shown in Supporting Information Table S4. Highest detection frequencies were found for DEHP (94%) and diethyl phthalate (DEP) (78%), followed by tris‐(2‐ethylhexyl) trimellitate (TOTM) (39%), acetyl tributyl citrate (ATBC) (33%) and dipentyl phthalate (DPP) (33%). For these compounds, concentrations found in BC varied depending on the used endotracheal tube as shown in Table 2 and Supporting Information Figure S3. The median concentrations of the five compounds were lower in the sterile water compared to the BC for all three ETT. For ETT1, showing the highest concentration of TOTM in its plastic polymer matrix, a median concentration of 2.5 ng/mL TOTM was found in the BC. This result was higher in comparison to the median concentration of 0.2 ng/mL TOTM found in sterile water, and BC from ETT2 and ETT3. However, in these latter BC samples, the median concentration of DEHP (25 ng/mL) and DEP (23 ng/mL) showed higher results. For ETT2, no compounds were detected in the plastic polymer matrix. The median concentrations of TOTM, ATBC, and DPP in BC showed the same results as for sterile water. The median concentrations of DEHP and DEP showed higher results in the BC from ETT2 compared to sterile water (28 vs. 8.3 ng/mL for DEHP, 5.2 vs. 2.4 ng/mL for DEP). For ETT3, DEHTP and DEHP were found in the plastic polymer matrix with concentrations of 2.7% and 2.6% w/w, respectively. The median concentrations of the BC showed highest results for DEHP (25 ng/mL), with median concentrations of the other plasticizers similar to those of sterile water.

TABLE 2.

Concentrations of all plasticizers with a DF > 30% collected in breath condensate after ex vivo simulated mechanical ventilation, depending on choice of endotracheal tube (ETT). Concentrations below the LOQ are replaced by LOQ x DF. All concentrations are expressed in ng/mL.

Plasticizer	Sterile water ( n = 3)			ETT 1 ( n = 6)			ETT 2 (n = 6)			ETT 3 (n = 6)
	P25	Median	P75	P25	Median	P75	P25	Median	P75	P25	Median	P75
DEHP	8.3	8.3	8.3	8.3	25	35	8.3	28	60	8.3	25	63
DEP	2.4	2.4	2.4	17.0	23	61	4.1	5.2	19	2.4	1.8	109
DPP	0.1	0.6	0.6	0.1	0.6	0.6	0.6	0.6	0.6	0.1	0.6	1.5
ATBC	3.8	3.8	3.8	3.8	3.8	5.8	3.8	3.8	7.2	3.8	3.8	6.9
TOTM	0.2	0.2	0.2	0.2	2.5	29	0.2	0.2	4.1	0.2	0.2	55

4. Discussion

Previous studies from our group reported TOTM and DEHP as the predominant plasticizers in PMDs used for neonatal enteral nutrition administration, with a maximum mass concentration of 0.45% w/w for both, present in gastric tubes (Cleys et al. 2025b). Additionally, ATBC and TOTM showed concentrations reaching up to 35.2% w/w ATBC in the pressure sensor disc of an extension set and 12.0% w/w TOTM in the tubing of an infusion set used for administration of parenteral nutrition in the NICU (Panneel et al. 2023). The present analysis of PMDs used for respiratory support in the NICU was in line with these findings, showing the presence of TOTM (8.1% w/w) in the side port of an endotracheal tube.

Bernard et al. (2023) analyzed 44 PMDs used in the NICU of two French academic hospitals. In this study, predominantly TOTM, DEHTP, and DEHP were found in the PMDs used for respiratory support, confirming the findings of our study. Additionally, TOTM was also found in most PMDs used in the French NICU centers. TOTM is, therefore, one of the predominant alternatives for DEHP in PMDs. Malarvannan et al. (2019) reported the predominant detection of DEHP in PMDs used in the pediatric intensive care unit (PICU) of two university hospitals. Indeed, DEHP was found in over half of the PMDs used in the PICU's of Leuven and Rotterdam, followed by DEHTP and DEHA. TOTM was found in about 20% of the PMDs. The shift in use of DEHP and consequent replacement by TOTM may be attributed to the implication of the EU Medical Devices Regulation (MDR 2017/745) (Danish Ministry of the Environment—Environmental Protection Agency 2014; Den Braver‐Sewradj et al. 2020). Biomonitoring studies from our group have shown the ongoing exposure of TOTM in this fragile NICU population, with possible negative health effects that are still insufficiently studied (Cleys et al. 2025a).

In our study, BC from ETT1 showed the highest concentration of DEHP and DEP, despite only being detected at low concentrations below 0.1% w/w in the plastic polymer matrix itself. On the other hand, low TOTM concentrations were found in the BC while the ETT contained up to 8.1% w/w. This adds to the hypothesis a lower migration potential of TOTM compared to DEHP and other phthalates from PVC medical devices (Eckert et al. 2016). Indeed, BC samples from all three ETTs contained DEHP while only ETT3 showed concentrations of DEHP above 0.1% w/w. This confirms the presence of significant amounts of DEHP in the infusion circuit used for mechanical ventilation in the NICU.

Leaching of DEHP from plastic medical devices has been studied for several decades. The study of Roth et al. (1988) showed that DEHP migrates from PVC respiratory tubing into condensate collected from water traps positioned in both inspiratory and expiratory tubes of ventilation circuits used in premature neonates intubated with an endotracheal tube (ETT). The DEHP concentrations in the condensates reached levels as high as 4100 μg/mL. In a later study by Latini and Avery (1999), unused ETTs were compared with those that had been clinically used. They reported a loss of 6%–12% in DEHP content in clinically used tubes. More recent studies suggested that the majority of DEHP release from ETTs occurs within the first 24 h of use (Chiellini et al. 2011). Morton et al. (2013) quantified the migration profile of phthalates by immersing ETTs in ultrapure water (UPW). They reported an increase in DEHP concentrations from 6.7 to 149 μg/L in the UPW over a five‐day period. It is important to note that these ex vivo experimental values may underestimate real clinical exposure, as plasticizer leaching potential is influenced by various additional factors following endotracheal intubation, such as airflow dynamics, temperature, and pH conditions.

More recently, the study of Bouattour et al. (2020) introduced an ex vivo experimental setup designed to replicate respiratory support using a PVC oxygen cannula. DEHP concentrations in air samples were analyzed using custom‐made cartridges, which were placed before and after the ventilation circuit. The model was used in clinically relevant conditions, such as a temperature of 23°C, airflow rates ranging from 2 to 4 L/min, and a simulation period of 6 days, to enhance its relevance to real‐life exposure scenarios. The highest DEHP concentrations were detected in samples collected on the first day of the experiment, and the estimated daily inhalation exposure to DEHP was calculated to be 10.6 μg/d.

Likewise, DEHP was recently shown to leach also significantly from nasal cannulas, more and more used in the NICU, reaching an estimated daily intake of up to 730 μg/kg/d (Wheeler and Smallwood 2020). The study of Bernard, Cueff, Chagnon, et al. (2015) proposed a migration model as a tool for the safety evaluation of the patients' exposure risk to plasticizers from PVC medical devices for infusion. However, comparison of exposure risk is difficult because the determination of plasticizer exposure through respiratory support is dependent on many parameters that still vary among studies.

5. Conclusions

In this study, we demonstrate that the plasticizers TOTM, DEHP, and DEHTP are present in concentrations above 0.1% w/w in PMDs used for respiratory support in neonates. An ex vivo leaching experiment simulating in vivo mechanical ventilation in premature neonates was set up to evaluate clinical exposure. Analysis of three endotracheal tubes showed the presence of TOTM, DEHP, or neither. Breath condensate after flow through different endotracheal tubes showed the highest concentrations for DEHP and DEP. The lower migration potential of TOTM, as opposed to phthalates, provides opportunities to reduce exposure to presumably less toxic plasticizers in ventilated neonates.

Our data demonstrate that premature neonates requiring invasive mechanical ventilation are still exposed to DEHP and, to a lesser extent, to the AP TOTM. As DEHP is being phased out of medical devices under European Union regulations due to its high leaching potential and documented adverse health effects, including endocrine disruption, a transition toward APs may be warranted. However, given the relatively recent introduction of these alternatives, limited data are available regarding their toxicological profiles and migration behavior, and their relative safety remains insufficiently characterized.

Funding

This work was supported by the Research Foundation–Flanders‐Belgium (FWO) under Grant Numbers 1S70820N and G074421N, providing Lucas Panneel and Paulien Cleys PhD fellowships at the University of Antwerp. This work was also supported by the Exposome Centre of Excellence of the University of Antwerp (BOF grant, Antigoon Database Number 41222).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Overview of analyzed phthalates and alternative plasticizers.

Data S1: Chromatographic details for analysis of phthalates and alternative plasticizers in plastic medical devices and condensate samples using LC–MS/MS and GC–MS.

Figure S1: Clinical setup of an ex vivo simulation experiment for the collection of breath condensate.

Figure S2: Recovery (%) of the internal standard during samples preparation of plastic medical devices (n = 19) and breath condensate (n = 21) for phthalates and alternative plasticizers.

Table S2: Blank values and limits of quantification (LOQs) for phthalates and alternative plasticizers with mean and standard deviation (Std. Dev.).

Table S3: Accuracies of quality control (QC) samples for phthalates and alternative plasticizers.

Table S4: Limit of quantification (LOQ) and detection frequencies (DF, %) of phthalates and alternative plasticizers found in condensate collected after ex vivo simulated invasive mechanical ventilation.

Figure S3: Concentrations of DEHP and TOTM collected in sterile water and breath condensate after ex vivo simulated mechanical ventilation, depending on choice of endotracheal tube.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.