Medical Plasticizers & Materials Evolving to Meet the Challenge!

Plasticizers are the largest category of additives accounting for 54% of the total market volume. The global plasticizer market is an $11 billion industry.

These additives are compounded into certain types of plastics and elastomers to render them more flexible. Plasticizers work by:

• Embedding themselves between the chains of polymers
• Spacing them apart (increasing the "free volume")
• Enabling the chains to more readily slip over each other
• Thus significantly lowering the plastic's glass transition temperature and making it softer

Demand for most downstream plasticizer markets is greatly influenced by general economic conditions.

Polyvinyl chloride (PVC) polymers are one of the most widely plasticized types. Approximately 90% of the plasticizers produced are consumed in vinyl based formulations. Medical device development is indicative of leading edge PVC plasticizer evolution across application segments.

Use of PVC in Medical Industry

PVC-based materials are widely used in medical device applications chiefly because of their:

• Physical properties
• Ease of fabrication, and
• Compatibility with intravenous (IV) solutions and blood

PVC products commonly used in medical care, such as IV blood bags and tubing, artificial kidney connective tubing, bubble-type oxygenators, and enema and urinary drainage bags. These products chiefly contain the plasticizer di (2-ethylhexyl) phthalate (DEHP), which imparts flexibility to the products. One of the most cost effective and broadly used plasticizers, DEHP, serves to make PVC soft and pliable.

Launched in medical applications in 1950, DEHP is the primary plasticizer in many other medical devices, including:

• Cardiac catheters
• Endotracheal tubes, and
• Certain implanted heart valves and devices

Benefits of Plasticized PVC in Medical Applications

Initially developed as replacements for natural rubber and glass, medical products made from plasticized PVC are easier to sterilize, transparent, chemically stable and cost-effective.

• Plasticized PVC products are convenient to use
• Their softness and flexibility allow trauma to sensitive tissue and discomfort to the patient to be avoided
• Furthermore, the collection of whole blood is improved through the prevention clotting and the range of blood treatment options available is broadened
• Sterilizable, plasticized PVC tubes and catheters do not 'kink' thereby ensuring the uninterrupted flow of fluids critically important whether for the treatment of infants, or open-heat surgery patients
• Plasticized PVC's transparency also reduces mistakes and allows healthcare workers to see immediately if a fluid is running low or its flow interrupted, while the smooth inner surface prevents blood clots or other disruptions
• Labels can also be printed directly onto the plasticized PVC surface and cannot be worn off, providing an additional safety feature

Medical Plasticizer Challenge

Plasticizers serve to increase a polymer's flexibility, elongation or ease of processing (workability). While various plasticizers can be used to soften PVC, the most frequently used are phthalate esters. DEHP (also referred to as di-octylphthalate or DOP) is a phthalate ester produced from the reaction of 2-ethyl hexanol and phthalic anhydride.


Even though the health effects of DEHP have been questioned, it is still the plasticizer of choice for PVC medical and surgical products due to its plasticizing performance and cost. Because DEHP and other phthalate plasticizers used with PVC  are not covalently bonded to the polymer, they may leach out in contact with certain media.

• Insoluble in water, phthalate plasticizers are readily miscible with organic solvents such as plasma and saliva and may result in patient ingestion or absorption during common medical procedures such as blood transfusion, use of tubing for respiration, or in the use of catheters
• Once absorbed it is believed the plasticizer is stored in the fatty tissue, and can thus be teratogenic (able to disturb the growth and development of an embryo or fetus)
• The body's ability to metabolize phthalates once ingested or absorbed is not well understood. DEHP is suspected to be an endocrine disrupter, affecting reproductive health and being linked to male reproductive tract abnormalities

Lately, the risk of phthalates leaching out of the PVC and into individuals has been increasingly debated. While it is still unclear as to what hazards these chemicals pose to humans, research on various other species has shown mixed results.

DEHP, the most widely used phthalate, has been associated with a range of adverse effects in laboratory animals including a carcinogenic effect in vivo. Safety issues related to reproductive risks have been expressed for high direct/indirect exposure patients groups, such as neonates, infants, pregnant and breast feeding women exposed to DEHP.

Legislation Evolving

California Assembly Bill AB 1879

California signed into legislation two of the most wide-ranging of any U.S. state laws to evaluate, label, and potentially ban industrial chemicals linked to cancer, hormone disruption, and other toxic effects on human health. Instead of taking a product-by-product approach, these new laws covering 80,000 chemicals currently in use, concentrate on the most hazardous, widespread substances first, controlling them at the manufacturing stage, before they leach into the air, water or human skin.

California Assembly Bill AB 1879 implemented in early 2011 requires the adoption of regulations to establish a process by which materials in products may be identified and prioritized for consideration as being chemicals of concern. In concert with the Assembly bill, California Senate Bill SB 509 calls for a Toxics Information Clearinghouse to be established for the collection, maintenance, and distribution of specific chemical hazard traits and environmental and toxicological end-point data and is currently underway.

EU Issues Updated Report on Safety of Plasticized PVC in Medical Devices

The EU Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR) has issued and updated its report on "The safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and others possibly at risk." The MHRA (Medicines and Healthcare products Regulatory Agency) examined the SCENIHR report and concluded that in relation to the regulation of DEHP in medical devices, no additional regulatory measures are necessary to assist the phasing out of DEHP-plasticized PVC in medical devices.

The Medical Devices Directive provisions are adequate to ensure that any material identified as presenting a toxic hazard is replaced as soon as alternatives with a more positive risk-to-benefit balance are available. As no new evidence indicates that medical devices plasticized with DEHP present an unacceptable health risk to humans, and in view of the proven clinical benefits of PVC medical devices plasticized with DEHP it would be premature to recommend a change to other plasticizers.

Eastman 168™ Non-orthophtalate Plasticizer - the Classic Benchmark!

Eastman recognized that customers needed options when it came to plasticizer formulation products. For those customers who require an alternative plasticizer for most flexible PVC applications, Eastman offers its novel Eastman 168™ non-orthophthalate plasticizer. Marketed and safely used for more than 30 years, Eastman 168™ has an extensive toxicological profile that demonstrates its suitability in sensitive applications such as toys, childcare articles, food contact materials, and medical devices such as tubing, film, IV bags, gloves, and inhalation masks.


Eastman 168™ plasticizer is an excellent phthalate alternative plasticizer for PVC, with performance equal or better than most ortho™ - phthalate plasticizers. DOTP (dioctyl terephthalate), a non ortho-phthalate is a para-phthalate; one of the isomeric forms of benzenedicarboxylic acid esters is not adversely listed. It offers good performance properties, excellent low temperature flexibility, resistance to extraction by soapy water and excellent non-migration properties.

In plastisols, Eastman 168™ non-phthalate plasticizer results in low initial viscosity and excellent keeping viscosity. Eastman Chemical has also commercialized in the EU Eastman DBT (dibutyl terephthalate), a high solvating, non ortho-phthalate plasticizer for PVC plastisols and water-based adhesives.

Eastman has announced that in addition to existing FCN (Food Contact Notification) clearance from the FDA, its Eastman 168™ non ortho-phthalate plasticizer is now listed in EU Commission regulation No 975/2009 amending Annex III (list of additives which may be used in the manufacture of plastic materials) and articles of Directive 2002/72/EC relating to plastic materials/articles intended to come into contact with foodstuffs. All of these attributes and more are what make Eastman 168™ the preferred alternative to phthalate plasticizers.

Other Alternative Plasticizers

The most commonly used alternative plasticizers to DEHP in medical devices include trioctyl trimellitate (TOTM), di (2-ethylhexyl) adipate (DEHA), and butyryl trihexyl citrate (BTHC). Di (isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di isononyl phthalate (DINP) represent possible alternatives.

Important technical criteria for both sheet/bag and tubing applications include flexibility when cold, clarity, PVC compatibility, sterilizability, and plasticizer loss during manufacture/use. In addition, elastic recovery is an important parameter for tubing applications.

• TOTM: In the medical device industry, TOTM is used primarily in blood and bag infusion sets. It is inferior to DEHP in terms of cold flexibility.
• DEHA: It is a useful plasticizer for materials used to store refrigerated medical solutions however it is less compatible with PVC than DEHP and is slightly more difficult to process compared to DEHP.
• BTHC: This plasticizer is specifically designed for use in medical articles, especially blood storage bags; however it is not steam sterilizable.
• DINP: Currently used as a plasticizer in medical tubing devices, tolerates steam sterilization better than DEHP.
• DINCH: The hydrogenated product of the corresponding di C9 phthalate ester (DINP).

The costs of DEHA and DINP are similar to DEHP while TOTM, BTHC and DINCH are more expensive. Idealized plasticizer cost comparisons based on numerous industry sources are shown in Table 1 as follows:

Plasticizer	Plasticizer Cost Estimate ($/lb)	Substitution Factor (SF)	Normalized Cost (raw cost x SF)
DEHP	$0.70	1	$0.70
TOTM	$0.95	1.17	$1.11
DEHA	$0.73	0.94	$0.70
BTHC	$1.15	0.975	$1.12
DINCH	$0.91	Unknown	$0.91
DINP	$0.74	1.06	$0.77

These materials are said to be superior to DEHP in terms of carcinogenicity and reproductive toxicity, although there are some concerns regarding DINP and DEHA. However, their acceptance across the health care industry is progressing more slowly in part due to the need to develop information concerning the health effects of the alternatives and their metabolites.

Medical Specialty Materials Based in Phthalate Alternatives

AlphaGary's 'Superkleen' Specialty Vinyl Compounds

AlphaGary's 'Superkleen' specialty vinyl compounds are a new generation of technically advanced specialty materials formulated with an FDA-recognized phthalate alternative plasticizer system.

This family of compounds makes use of citrate-based plasticizers, an ATC-IV Alpha additive package based on a derivative of a naturally occurring tribasic monohydroxy acid, which, according to the manufacturer, makes them ideal for molding medical devices, infant toys, and other regulated products.

Odorless, tasteless, and biocompatible, these gamma radiation stable compounds meet USP Class VI and WI-38 biological tests. They are available in hardnesses of 55 to 95A, are functionally equivalent to conventional vinyl, and exhibit similar processing in molding.

PolyOne's Geon HC Vinyl Compounds for the Healthcare Industry

PolyOne's Geon HC vinyl compounds for the healthcare industry are fully commercialized. Gamma and EtO (ethylene oxide) sterilizable, the materials, which include phthalate alternative grades, feature flexible injection molding/extrusion grade vinyl compounds with a wide Shore A hardness durometer range.


These compounds are offered from a low 60 Shore A through nearly rigid grades, with many having USP (United States Pharmacopeia) Class 6 standing and FDA (Food & Drug Administration, U.S.) regulatory approval.

New Approach to Flexible PVC with Zero Migration of Plasticizer

Researchers at the Institute of Polymer Science & Technology in Madrid are developing technology to prevent potentially harmful plasticizers such as DEHP (DOP) from migrating from PVC. The advance could lead to a new generation of PVC plastics that are potentially safer than those now used in:

• Packaging
• Medical tubing
• Toys, and
• Other products

The permanent plasticizer effect will also ensure PVC flexibility is maintained with the possibility of extending useful product life. The functionalized plasticizer DOP-SH [di(2-ethylhexyl) 4-mercaptophthalate] was developed with physiochemical properties similar to those of commercial DOP, but with an additional functional group able to establish a covalent bond to the polymeric backbone.

The percentage of plasticizer that could be covalently linked to the PVC backbone was similar to plasticizer amounts usually commercially employed. The approach completely suppressed plasticizer migration. While the plasticizer efficiency of the novel plasticizers is less than conventional DEHP (DOP) the glass transition temperature of modified PVC is largely reduced and is around 0°C for the highest modified samples.

This approach may open new ways to prepare flexible PVC with permanent plasticizer effect and zero migration.

Plastication with Suppressed Migration Extraction of Plasticized PVC Sheets with Heptane at Room Temperature (Source: Institute of Polymer Science & Technology Madrid)

Alternative Non-Plasticized Compounded Materials

Materials that are either inherently flexible, or that fulfill the function of the DEHP/PVC material without being plasticized are also available. PolyOne GLS Thermoplastic Elastomers' Versaflex CL E95 designed for markets requiring a clear, sterilizable, low-extractable material with no phthalates, is a thermoplastic elastomer (TPE) developed to eliminate the need for plasticizers altogether.

This FDA approved TPE material is stable under gamma and autoclave sterilization, and offers a unique balance of superior clarity, low hardness, and excellent flexibility at low temperatures as compared to competitive products. Target applications include medical tubing, drug storage and delivery, face masks, and infant-care products.

TPE with No Phthalates for Medical Devices (Source: PolyOne GLS)

Other materials that can replace DEHP/PVC for medical devices are:

• Ethyl vinyl acetate (EVA)
• Polyolefins (PE-polyethylene, PP-polypropylene)
• Polyurethane
• Silicone, and
• TPU (thermoplastic polyurethane)
• As well as blends and multilayer laminates of these materials

A key consideration for these materials is their shelf life in a medical situation - that is their capacity to retain flexible characteristics without leaching harmful chemicals. Materials used in medical tubing applications must be capable of being formed in a variety of arrangements, have thin inner walls, be durable and strong with low coefficients of friction, and be highly resistant to chemicals and to temperature variations. They must also be weldable to other components of the medical device.

• Ethylene vinyl acetate (EVA): A copolymer blend used for many years in medical film applications such as for parenteral and enteral solutions and for custom mixing of pharmaceuticals


• Polyethylene: Stable polymer widely used in medical device applications particularly medical tubing due to its flexibility, transparency and toughness. Lighter than PVC, PE is relatively inexpensive and is easy to mold. However, it is less clear and less flexible than PVC


• Silicone: A naturally translucent, odorless and tasteless synthetic rubber, it is biologically inert and its inherent lubricity and flexibility eases medical procedures. Conventional silicone elastomers can have fairly high ultimate elongations, but only low-to-moderate tensile strengths. Consequently, the toughness of most biomedical silicone elastomers is not particularly high


• Thermoplastic polyurethane (TPU): formed by reacting alcohols with a diisocyanate or polymeric isocyanate. Conventional TPU generally has excellent physical properties, combining high elongation and high tensile strength to form tough elastomers

In general, these materials exhibit equal or improved performance and environmental and human health characteristics over DEHP/PVC. However, their costs tend to be greater than that of the DEHP/PVC. In addition, gas permeability of EVA and polyolefins and manufacturability of silicone and TPU are worse than DEHP/PVC. There is an environmental and human health concern associated with the manufacture of TPU, potentially making it less favorable as an alternative from that perspective.

Medical Plasticizer and Alternative Material Technology Sources

Company/Organization	Description
Plastics Institute of America	www.plasticsinstitute.org
Kaiser Permanente	www.kaiserpermanente.org
Eastman Chemical	Eastman 168™ Plasticizer
Institute of Polymer Science & Technology Madrid	www.ictp.csic.es
PolyOne GLS Thermoplastic Elastomers	Versaflex CL E95; Global manufacturer of high-performance TPEs has introduced TPE with no phthalates for medical device applications www.glstpes.com
AlphaGary Corporation	Superkleen; Custom compounder specializing in the design and development of PVC, TPE, and TPO compounds. Manufactures Superkleen vinyl compounds formulated with FDA-recognized non-DEHP, nonphthalate plasticizer system www.alphagary.com
PolyOne Corporation	Geon HC; A global supplier of specialized polymer materials offering a vinyl compound-based product line for the healthcare industry www.polyone.com
BASF Alcohols, Solvents and Plasticizers	Hexamoll; DINCH plasticizer combines excellent toxicological profile with very low migration rate. Used as plasticizer for medical devices made with soft PVC products such as tubes for enteral feeding and hemodialysis, bags, respiratory tubes, catheters, gloves and breathing masks www.hexamoll.com
Phthalate Esters Panel	Established in 1973, Panel members sponsor health, safety and environmental research on phthalate esters. Results are shared with government agencies around the globe to support a comprehensive/ thorough assessment of the safety of panel member products www.phthalates.org
Toxic Uses Reduction Institute, University of Massachusetts, Lowell	Research, test and promote alternatives to toxic chemicals used in Massachusetts industries and communities. Studies include alternatives for significant uses of DEHP www.turi.org

Conclusion

PVC has an extensive history of use in various medical products, including IV bags, and catheters. These medical devices have undergone strict regulatory review by numerous government and independent health agencies around the world, including the FDA. In use for more than 40 years, the safety of these materials has been confirmed through 5-7 billion patient days of acute exposure and 1-2 billion patient days of chronic exposure with no indication of adverse effects.

The degree to which alternative materials can effectively replace the need for DEHP (or DEHP-containing PVC) across the broad spectrum of current uses remains to be determined. Such alternative materials must also be evaluated on the basis of toxicological evidence and standards of safety typically used and accepted for these applications, and should demonstrate an equivalent degree of safety.