Phthalates, a group of chemicals commonly used as plasticizers, have long been scrutinized for their potential health risks. Recent updates to the guidelines by the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) have introduced more stringent requirements for assessing the safety of phthalates in medical devices, particularly those with carcinogenic, mutagenic, or reproductive toxic (CMR) properties, or those with endocrine-disrupting (ED) effects. While phthalates play a critical role in ensuring the functionality of medical devices, their potential to leach into patients during use has raised significant safety concerns, especially for vulnerable populations such as neonates, pediatrics, and pregnant women.
Understanding Phthalates and Their Risks
Phthalates are a class of chemical compounds commonly used as plasticizers to improve the flexibility, durability, and workability of polymers like polyvinyl chloride (PVC). Their widespread application spans industries, including medical devices, where they are critical for ensuring the functionality of tubing, infusion sets, and blood bags. However, growing evidence has highlighted potential health risks associated with certain phthalates, particularly those classified as CMR (Carcinogenic, Mutagenic, or Reproductive toxicants) or ED (Endocrine Disruptors).
Key Health Risks Linked to Phthalates
1. Carcinogenicity
Some phthalates, such as Di(2-ethylhexyl) phthalate (DEHP), are classified as Group 2B carcinogens by the International Agency for Research on Cancer (IARC), meaning they are 'possibly carcinogenic to humans.' This classification is based on animal studies showing an association between DEHP exposure and liver and other cancers, while human data remains inconclusive and inadequate. The experimental studies suggest that DEHP affects biological processes that may contribute to animal tumor development.
2. Mutagenicity
Phthalates like di-n-butyl phthalate (DBP) have been shown in experimental studies to cause genetic mutations. Mutagenicity refers to the ability of a substance to alter DNA, potentially leading to genetic instability. This instability is a precursor to various health issues, including cancer and hereditary conditions. The mutagenic effects are especially concerning in germ cells, as these can lead to heritable genetic changes.
3. Reproductive Toxicity
Among the most critical concerns, phthalates such as DEHP, DBP, and butyl benzyl phthalate (BBP) are well-documented reproductive toxicants. They can interfere with normal reproductive development and function, leading to:
- Reduced sperm count and motility in males.
- Hormonal imbalances affecting ovulation and fertility in females.
- Developmental toxicity, including impaired fetal growth, congenital abnormalities, and low birth weight when exposed during pregnancy.
4. Endocrine Disruption
Some phthalates are classified as endocrine-disrupting chemicals (EDCs) due to their ability to mimic or block the action of natural hormones. For example:
- Phthalates can bind to Estrogen and androgen receptors, leading to altered hormone levels.
- In children, exposure to phthalates has been linked to delayed puberty, altered growth patterns, and neurodevelopmental disorders.
- In adults, they may contribute to conditions like obesity, diabetes, and thyroid dysfunction through hormonal imbalances.
Population-Specific Concerns
Neonates and Pediatrics: Infants and children are particularly vulnerable due to their developing organ systems and higher exposure relative to body weight. Phthalates leaching from medical devices during prolonged medical treatments, such as neonatal intensive care, pose significant risks.
Pregnant Women: Exposure during pregnancy can affect fetal development, with potential long-term impacts on the child’s reproductive and neuroendocrine systems.
Chronic Patients: Individuals requiring regular and prolonged use of medical devices, such as dialysis patients, are at increased risk of cumulative exposure.
Background
Regulatory bodies, including the EU MDR (2017/745) and the updated Scientific Committee on Health, Environmental, and Emerging Risks (SCHEER) - Guidance on the use of phthalates in medical devices (2024), have taken steps to address these risks. By requiring comprehensive safety assessments, patient exposure calculations, and exploration of safer alternatives, these frameworks aim to mitigate the health risks associated with phthalates in medical devices.
Understanding these risks is critical for manufacturers, regulators, and healthcare providers to ensure patient safety and align with evolving safety standards.
A Part of a Broader Series
This blog is the third publication in a series focused on the safety assessment of medical devices, with the following preceding contributions:
I: How Can You Mitigate Risks in Medical Device Development: The eBook explored risk-based frameworks for assessing medical device safety and functionality through TRA.
II: Decoding EU Regulation 2024/1860: Key Changes and Their Impact on EU MDR and IVDR Compliance: The blog provided an in-depth analysis of the updated regulatory landscape.
Building on these foundations, this paper narrows its focus to Phthalates, offering a detailed benefit-risk evaluation approach aligned with the SCHEER 2024 guidance on phthalates and alternatives.
Case Study: DEHP-Containing PVC in Ambulatory Infusion System and Administration Sets
A medical device manufacturer sought approval for their infusion set and associated medical devices in the European Union (EU) market. The device was constructed with PVC containing Di(2-ethylhexyl) phthalate (DEHP), a plasticizer integral to the device's functionality and flexibility. However, DEHP’s potential health risks, including its carcinogenic, reproductive, and endocrine-disrupting properties, raised significant concerns. In light of the recent updates to the SCHEER guidelines, which emphasize minimizing patient exposure to harmful substances, the manufacturer faced challenges in meeting the EU’s stringent safety standards for medical devices.
The manufacturer sought guidance to evaluate the risks associated with DEHP in their infusion set and to explore safer alternatives. The challenge was to balance the need for performance, flexibility, and durability with the imperative to ensure patient safety and compliance with the updated SCHEER guidelines.
The solution provided to the manufacturer is outlined in the following case study, along with the detailed assessment and recommendations we developed to ensure compliance and enhance patient safety:
|
Device Name
|
Infusion System along with Administration Sets
|
|---|---|
|
Classification
|
Class II
|
|
Patient population
|
Pediatric
|
|
Contact Duration
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Prolonged (>24h to 30d)
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I. Description and Characterization of Composition
The Ambulatory Infusion System and its administration sets are Class II medical devices designed for infusion therapy. They are used across diverse healthcare settings, including homecare, oncology infusion suites, and acute care hospitals, catering to a pediatric population. The administration sets are sterile, disposable components facilitating fluid delivery from an infusion container to the patient’s catheter.
The target Infusion Pump is a compact, lightweight device for infusion delivery. It features a curvilinear peristaltic pump mechanism, enhancing its compactness. The pump's initiation is facilitated via a color LCD and a keypad. Commands are issued to the microprocessor by activating the user interface, and then it operates under the guidance of software preserved within the pump's memory.
The pump consists of the user interface, sensors, communication ports, power ports, structural (housing) components, electronics, pumping mechanism, watchdog timer, pump battery and circuitry, real-time clock, onboard memory, and pump log. Exterior surface components include the pump housing, platen (door assembly), LCD lens, keypad, and labels. Materials used to construct these components are widely used within the medical industry.
The pump is designed to deliver measured drug therapy to patients in home care, infusion suites, oncology, and other alternate site locations as appropriate. The pump also has applicability in the acute care market, specifically in small hospitals (300 beds or less), Labor and Delivery Units, and other areas of the hospital where pain management is required. The pump is designed to be used with administration sets, which provide a sterile pathway for delivering the infuscate fluid from the infusion container (e.g., IV reservoir bag) to the distal connection, which connects to the patient’s catheter/delivery site.
II. Key Material Composition
a) Component breakdown and contribution to total weight
|
Component
|
Material
|
Total Set Weight (%)
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DEHP Content (% w/w) and (g)
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Weight Contribution (g)
|
|---|---|---|---|---|
|
PVC Tubing
|
PVC with DEHP
|
65
|
9.75 and 1.58
|
16.25
|
|
Drip chamber
|
PVC with DEHP
|
10
|
1.2 and 0.03
|
2.50
|
|
Roller Clamp
|
Acrylonitrile Butadiene Styrene (ABS)
|
N/A
|
N/A
|
N/A
|
|
Luer Lock connectors
|
Polypropylene (PP)
|
N/A
|
N/A
|
N/A
|
|
Needle
|
Stainless steel
|
N/A
|
N/A
|
N/A
|
|
Air Filter/Port
|
Polypropylene with PTFE
|
N/A
|
N/A
|
N/A
|
|
Adhesive Components
|
Adhesive pads
|
N/A
|
N/A
|
N/A
|
b) Estimated total weight of the whole tubing set
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The overall weight of the complete infusion set, including all components (total weight)
|
25 g
|
|---|---|
|
PVC tubing
|
16.25 g
|
|
Drip Chamber, Connectors, and Clamps (combined weight)
|
5.0 g
|
|
Needle, Air Filter, and Adhesives (Minor components)
|
1.75 g
|
c) Length and dimensions of the tubing set
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Tubing Length: The standard length for infusion set tubing in clinical settings.
(This length ensures sufficient length for reach from the fluid source to the patient) |
180 cm (1.8 m)
|
|---|---|
|
Outer diameter (Tubing width)
|
3.5 mm
|
|
Inner diameter
|
2.8 mm
|
d) Total DEHP content in the Infusion set
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Total DEHP Content = DEHP from PVC tubing + DEHP from drip chamber = 1.61 g
|
|---|
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Total weight of infusion set = 25 g
|
|
Total DEHP content percentage = 1.61g/25g= 6.44%
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III. Use and Function of the DEHP in the Infusion set
In the presented infusion set, DEHP (Di(2-ethylhexyl) phthalate) is used as a plasticizer in PVC (polyvinyl chloride) components, such as the tubing and drip chamber. The primary function of DEHP is to make the PVC more flexible and easier to handle. Without DEHP, the PVC would be rigid, making it unsuitable for medical applications that require frequent bending, manipulation, and patient comfort. This functionality is crucial for maintaining the structural integrity and usability of the device during intravenous (IV) therapy, where precision and adaptability are essential.
a) Functionality/Performance provided by the Presence of CMR/ED Phthalate
The inclusion of DEHP in the PVC of the infusion set provides several critical functional and performance benefits:
- Flexibility: DEHP softens the PVC, allowing the tubing and other parts to be highly flexible. This ensures that the tubing can be easily bent and adjusted without kinking or breaking, maintaining the smooth flow of fluids during IV administration.
- Durability: DEHP also enhances the toughness of the PVC material, making it more resistant to cracking or degradation over time, even under repeated handling or stress during medical procedures.
- Clarity: The plasticized PVC retains a high degree of optical clarity, which allows medical professionals to visually monitor fluid flow and detect any air bubbles or obstructions during the infusion process.
b) The benefit in terms of material properties and/or clinical outcome of the presence of CMR/ED phthalate in the medical device
The inclusion of DEHP in the infusion set provides material and clinical benefits that are significant for both device performance and patient outcomes:
- Reduced Risk of Kinks and Obstructions: The flexibility provided by DEHP in the tubing minimizes the chance of kinks that could obstruct the flow of fluids, ensuring continuous and reliable delivery of medications or fluids to the patient.
- Improved Patient Comfort: The softness of the DEHP-plasticized PVC minimizes patient discomfort, especially during long-term use, as the tubing and components are less rigid and less likely to cause irritation or injury.
- The clear tubing, made flexible with DEHP, allows visual monitoring. This ensures that medical staff can quickly detect issues such as air bubbles, improving patient safety and the efficacy of treatments.
IV. Risk Assessment of DEHP
a) Patient Exposure Analysis (Realistic worst-case scenario):
For pediatric patients (target population), prolonged exposure (>24h to 30d) to DEHP leached from the administration set during infusion is assessed.
|
Infusion rate
|
1 mL/min (60 mL/hour)
|
|---|---|
|
Daily Infusion Volume
|
1440 mL
|
|
DEHP leaching rate
|
5 µg/mL
|
|
Daily DEHP exposure 1440 mL/day × 5 µg/mL = 7.2 mg/day
|
|
|
Body Weight-Based Dose
|
|
|---|---|
|
For a 10 kg pediatric patient
|
7.2 mg/10 kg = 0.72 mg/kg/day
|
|
DEHP Tolerable Intake (TI)
|
0.6 mg/kg/day
|
|---|---|
|
Pediatric exposure exceeds the TI by 1.2-fold, indicating a significant risk of endocrine disruption and reproductive toxicity in this vulnerable population
|
|
b) Biocompatibility findings:
The biocompatibility test reports were conducted according to the ISO 10993 series of standards following Good Laboratory Practices, and the final finished (administration sets) tested device met the acceptance criteria. For the administration sets classified as external communicating with indirect-blood path and prolonged use, the below-mentioned endpoints have been evaluated:
|
Endpoint
|
Method
|
Standard Reference
|
Biological Risk Assessment
|
|---|---|---|---|
|
Cytotoxicity
|
Cytotoxicity Study Using the ISO Elution Method
|
ISO (10993-5)
|
Non-cytotoxic
|
|
ISO Guinea Pig Maximization Sensitization Test
|
ISO Guinea Pig Maximization Sensitization Test
|
ISO (10993-10)
|
Non-sensitizer
|
|
Irritation or Intracutaneous Reactivity
|
ISO Intracutaneous Irritation Study - Extract
|
ISO (10993-10)*
|
Non-irritant
|
|
Acute systemic toxicity
|
ISO Acute Systemic Toxicity Study in Mice
|
ISO (10993-11)
|
Non-toxic
|
|
Material Mediated Pyrogenicity
|
USP Rabbit Pyrogen Study, Material Mediated
|
USP, General Chapter 151; ISO (10993-11)
|
Non-pyrogenic
|
|
Subacute/Subchronic toxicity
|
ISO Two Week Toxicity Study in Rats, Repeated Parenteral Administration of Two Extracts
|
ISO (10993-11)
|
Non-Toxic
|
|
Hemocompatibility
|
ASTM Hemolysis Study - Extract Method
|
ASTM F756; ISO (10993-4)
|
Non-hemolytic
|
*Upon review of the transition between ISO 10993-10 and ISO 10993-23, no substantive gaps or deviations were identified that would compromise the relevance or adequacy of the original irritation testing conducted under ISO 10993-10. The testing methodology, procedures, and outcomes remain consistent with the current requirements outlined in ISO 10993-23, ensuring the irritation aspect of the subject device’s biocompatibility remains compliant with the latest standards.
|
Specific CMR/ED Hazard Data
|
|---|
|
DEHP is a Category 1B Reproductive Toxicant (EU REACH Regulation)
|
|
Endocrine Disruption: Alters hormone signaling pathways, particularly during critical windows of development (e.g., pediatric and neonatal stages)
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c) Toxicological Risk Characterization:
|
Pediatric patient risk
|
Exposure to 0.72 mg/kg/day exceeds the TI of 0.6 mg/kg/day for DEHP, posing risks of testicular toxicity, impaired fertility, and hormonal dysregulation.
|
|---|---|
|
Clinical Impact
|
Risk of long-term developmental and reproductive health issues due to cumulative DEHP exposure during prolonged infusion therapy.
|
V. Framework for Assessment of Possible Alternatives:
a) Alternative Materials:
Two non-DEHP plasticizers are proposed as alternatives for evaluation: TOTM (Tris(2-ethylhexyl) trimellitate) and DEHT (Di(2-ethylhexyl) terephthalate.
- Material and clinical comparisons:
|
Parameter
|
DEHP
|
TOTM
|
DEHT
|
|---|---|---|---|
|
Leaching rate
|
5 µg/mL
|
<1 µg/mL
|
~1–2 µg/mL
|
|
Flexibility
|
Excellent
|
Excellent
|
Excellent
|
|
Durability
|
High
|
High
|
High
|
|
TI
|
0.6 mg/kg/day
|
2 mg/kg/day
|
7.632 mg/kg/day
|
|
Endocrine Disruption
|
Yes
|
No
|
No
|
|
Reproductive Toxicity
|
Yes
|
No
|
No
|
- Clinical exposure analysis:
|
Alternative
|
Daily Exposure
|
Risk
|
|---|---|---|
|
TOTM
|
0.14 mg/kg/day (i.e., <7% of TI)
(based on 1 µg/mL leach rate for 1440 mL/day infusion) |
Negligible
|
|
DEHT
|
~0.28 mg/kg/day (i.e., <3.67% of TI)
(based on 2 µg/mL leach rate for 1440 mL/day infusion) |
Negligible
|
- Risk mitigation: Transition to TOTM or DEHT as plasticizers for PVC tubing and drip chambers to eliminate DEHP-related risks:
|
Implementation considerations
|
Regulatory compliance with EU MDR 2017/745
Validation of alternative materials through ISO 10993 testing and clinical evaluation |
|---|---|
|
TOTM
|
Preferred due to its minimal leaching, high thermal stability, and established use in pediatric medical devices.
|
|
DEHT
|
Also viable, particularly for cost-sensitive applications, with a comparable safety profile to TOTM.
|
b) Alternative polymers:
In alignment with SCHEER guidelines, replacing PVC entirely with alternative polymers provides an effective strategy to eliminate the risks associated with phthalates like DEHP. Below is a detailed comparison, recommendations, and benefit-risk analysis of alternative materials for infusion sets:
|
Material
|
Safety and SCHEER Recognition
|
Durability
|
Functionality & Clinical Outcomes
|
Trade-offs
|
|---|---|---|---|---|
|
Thermoplastic Polyurethane (TPU)
|
No CMR or ED classification; Excellent biocompatibility; Recognized as a primary alternative for PVC
|
High tensile strength (25–50 MPa); Suitable for prolonged use (>30 days)
|
High flexibility and resistance to kinking, critical for infusion tubing; Eliminates phthalate exposure, enhancing patient safety
|
Slightly higher manufacturing cost compared to PVC
|
|
Polyolefins (PE, PP)
|
Completely inert with no plasticizer requirement; Supported for medical tubing and connectors due to high safety
|
Moderate tensile strength (20–40 MPa); Sufficient for most infusion applications
|
Transparent, lightweight, and compatible with standard sterilization; Reduces harmful chemical leaching for safer use
|
Slightly less flexibility than TPU
|
|
Ethylene Vinyl Acetate (EVA)
|
Excellent biocompatibility with no toxic leaching; Recognized for use in infusion bags and flexible tubing applications
|
Lower tensile strength (10–20 MPa); Adequate for short-term use
|
Soft, flexible, and ideal for delicate applications; Prevents contamination and supports safe drug delivery
|
Best suited for short-term or low-stress applications
|
c) Integrating both alternative materials and polymers into the comparative framework
PVC + Safer Plasticizers (DEHT or TOTM) vs. Alternative Polymers:
|
Criteria
|
PVC with DEHT/TOTM
|
TPU
|
PE/PP
|
EVA
|
|---|---|---|---|---|
|
Safety
|
No CMR/ED classification; low migration
|
Free of phthalates, highly biocompatible
|
No plasticizers; inherently safe
|
No toxic leaching; excellent safety
|
|
Performance
|
Flexible, transparent, and durable
|
Excellent flexibility and kink resistance
|
Chemically resistant but less flexible
|
Soft and flexible; suited for IV bags
|
|
Clinical outcomes
|
Reduced phthalate exposure, suitable for pediatric use
|
Eliminates phthalate risks entirely
|
Safe for all patient groups
|
Ideal for short-term infusion use
|
|
Cost
|
Moderate; DEHT is cheaper than TOTM
|
Higher manufacturing costs
|
Cost-effective alternative
|
Lower material cost but limited use
|
|
Regulatory alignment
|
Meets SCHEER guidance for safer plasticizers
|
Fully compliant, recommended by SCHEER
|
Supported for tubing/connectors
|
Recognized for medical applications
|
VI. Summary and Conclusion of Risk-Benefit Analysis
The benefit-risk assessment of phthalates in medical devices, such as DEHP in infusion sets, underscores the complexity of balancing material performance with patient safety. While DEHP offers unparalleled functionality, its associated health risks highlight the need for safer alternatives, particularly in pediatric populations.
Recommendations
- Short-Term Compliance: Substituting DEHP with TOTM or DEHT eliminates critical risks to pediatric patients while maintaining the infusion system's performance and reliability.
- Long-Term Transition: Transition to phthalate-free polymers like TPU or Polyolefins to eliminate reliance on plasticizers and future-proof devices against evolving regulations. TPU is the primary recommended alternative, aligning with SCHEER's updated guidance for safer medical devices.
- Lifecycle Analysis: Continuously assess material performance, cost implications, and regulatory alignment to ensure safe and effective device use.
By adopting these strategies, manufacturers can ensure compliance with the 2024 SCHEER guidance while prioritizing patient safety.
Partnering for Safer Medical Devices
The SCHEER guidelines represent a significant advancement in ensuring the safety of phthalates in medical devices. Manufacturers can better manage phthalate risks and protect patient health by adhering to these updated guidelines.
At Evalueserve, we offer comprehensive support to medical device manufacturers navigating these regulatory updates. Our expertise includes:
- Risk Assessment and Management: Conducting detailed risk assessments and recommending appropriate mitigation strategies.
- Regulatory Compliance: Ensure your products meet the latest safety guidelines and regulations.
- Material and Design Recommendations: Assisting in the selection of safer materials and design modifications.
For more information on how we can help you stay compliant and safeguard your products, contact us at Evalueserve IP and R&D.
