A new study on use of PVC based on DEHP and alternate plasticizers is not decisive

For certain medical procedures such as blood transfusion, haemodialysis, parenteral nutrition or endotracheal tubing, the flexibility of certain parts of a medical device is essential.
Various substances are used to ensure this flexibility, among which DEHP [Di-(2-EthylHexyl) Phthalate] is the most frequently used plasticizer in PVC medical devices. DEHP
may migrate from the device to the human body, resulting in a certain degree of patient exposure. DEHP is classified by the US EPA as a probable human carcinogen (Class B2).
In 2000, the International Agency for Research on Cancer (IARC) changed its classification for DEHP from Group 2A ("possibly carcinogenic to humans") to Group 3 ("cannot be
classified as to its carcinogenicity to humans). Animal studies have found that DEHP is toxic to the male reproductive system. When DEHP is metabolized in the human body, it
produces compounds that are likely to be reproductive toxicants. DEHP can be released to the environment during its production, distribution and incorporation into PVC. DEHP
is also released when PVC material is heated or comes into contact with certain media. DEHP is not chemically bound into the polymer matrix and therefore can migrate out of
the polymer. It is especially likely to migrate out of the polymer in the presence of fatty solutions. Indoor releases of DEHP to the air from plastic materials, coatings, and flooring
in home and work environments can lead to higher indoor levels than are found in the outdoor air.
Alternative manufacturing processes to create flexible polymers can involve the replacement of DEHP with another plasticizer, or the use of a polymer or other material that does
not require the use of a plasticizer to achieve the same characteristics and performance. Compatibility with PVC and any other additives present (ability to create a stable single
phase compound) is a critical factor when considering alternative plasticizers. In addition, the alternative plasticizer should achieve the required level of flexibility (measured as
hardness) at a cost that is comparable to that of DEHP-plasticized PVC. In medical device applications there are additional performance criteria for the plasticized polymer.
Important considerations include the tendency of plasticizers to migrate out of the polymer matrix, and the ability of the plasticized polymer to be sterilized by different methods.
Additional concerns include:
For sheet applications tensile strength, cold flexibility (because solutions must be cold-storable) and clarity.
For tubing applications elastic recovery must be optimized to assure that tubing does not kink during use.
Some hospitals in Europe still recommend medical devices that are not made from PVC mainly because of environmental concerns. However, a new life cycle analysis that
compares a medical device made from PVC with two devices made from alternative plastic materials shows that PVC products based on DEHP plasticizer can be safely used in
healthcare products. The new Opinion of 2008 states clearly that there is limited evidence suggesting a relation between DEHP exposure and some effects in humans and so
far, there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans. The Opinion, however, states that even in the absence
of clinical or epidemiological evidence of harmful effects in humans, there is a reason for some concern for prematurely born male neonates for which the DEHP exposure may
be transiently above the dose inducing reproductive toxicity in animal studies. According to the Opinion other patient groups besides neonates are also at risk, namely, male
foetuses and male infants of pregnant women, lactating women exposed to DEHP and trauma patients who undergo massive infusion of blood. The reason for the concern for
these patient groups is that the level of DEHP exposure can exceed the exposure limits determined from doses that result in reproductive effects observed during animal studies.
The Opinion gives no clear answer to the question of whether or not DEHP in medical devices poses a risk. It suggests for further studies to confirm or reject the suggestions of
adverse effects of DEHP in humans.
The European Commission also wanted to know about possible alternative plasticizers that can be used to replace DEHP. Consequently, eight alternative plasticizers were
evaluated and among these were non phthalate plasticizers, as well as certain citrates and adipates. It was difficult for Scientific Committee on Emerging and Newly Identified
Health Risks (SCENIHR) to conclude anything decisive about the alternatives. For some of the alternatives, a complete evaluation could not be performed due to lack of data on
either toxicity or exposure. Regarding which plasticizers could be used as alternatives, the SCENIHR Opinion does not give a clear answer on this either, but asks manufacturers
to make a case- by-case evaluation of the risks and benefits of using a certain alternative. The latest report from the EU scientific committee does not help medical device
manufacturers much with regard to the use of DEHP in medical devices. It does not give a clear answer on whether or not DEHP poses a risk, nor does it say anything decisive
on the alternatives to DEHP. The only clear recommendation is that a case-by-case evaluation should be conducted if a company wishes to switch to another plasticizer.
The Swedish Life Cycle Assessment (LCA) expert, Hkan Stripple, of the Swedish Environmental Research Institute, tries to compare catheters manufactured in PVC,
thermoplastic polyurethane (TPU) and in a newly developed polyolefin based elastomer. The evaluation of the LCA results showed that the newly developed polyolefin based
elastomer catheter had in general low environmental impact. The article says that the impact is significantly lower than the TPU catheter material and in the same level as the
existing PVC bulk plastic material. Compared with the PVC plastic material the new polyolefin based elastomer showed an almost equivalent environmental performance. For the
first time, there is now a LCA analysis that compares examples of PVC medical devices with alternatives and shows that PVC is actually among the most favourable with regard
to environmental performance.
The Commonwealth of Massachusetts assessed five alternative plasticizers for use in medical devices.
Trioctyl trimellitate (TOTM) is a clear, oily liquid that is a high production volume plasticizer in the US. In the medical device industry, TOTM is currently used primarily in
blood and bag infusion sets.
Di (2-ethylhexyl) adipate (DEHA) has properties that make it a useful plasticizer for materials used to store medical solutions that must be kept cold.
Butyryl trihexyl citrate (BTHC) is a plasticizer specifically designed for use in medical articles, especially blood storage bags.
Di (isononyl) cyclohexane-1,2-dicarboxylate (DINCH) is the hydrogenated product of the corresponding di C9 phthalate ester (DINP).
Di isononyl phthalate (DINP) is currently used as a plasticizer in medical tubing devices.
TOTM, DEHA, BTHC, and DINCH are applicable for use in bag/sheet devices. Based on their elastic recovery properties, DEHA is also applicable for use in tubing, and DINP
was assessed for use in tubing only. For each of these alternatives, the Institute assessed health, environmental, technical, and cost criteria.
Health: All the alternatives are superior from the perspective of carcinogenity and reproductive toxicity, although there are grounds for concern about DINP and DEHA. The
alternatives are generally superior with regard to skin, eye, and respiratory irritation, with some exceptions.<br>
A key issue associated with potential health effects is the ability of a plasticizer to exude from the polymer matrix as well as its potential to produce metabolites of concern.
DEHP is lipid soluble and therefore is likely to exude out of the polymer when exposed to a lipid-soluble solution. TOTM, BTHC and DINCH appear to be less likely to migrate
out of the polymer in the presence of lipid-soluble medical solutions. DINP appears to be similar to DEHP in this regard, and the potential for DEHA to migrate is not well
defined.
Little information is available on the health effects of metabolites associated with the alternatives assessed. The exception is BTHC, which can be metabolized to butyric acid,
a chemical that is associated with negative impacts on the GI tract, liver and skin.
Environment: All the alternatives are equally or less persistent in sediment compared to DEHP (DINCH persistence is unknown). The alternative plasticizers studied are all
superior from the bioaccumulative and aquatic toxicity perspectives, with the exception of DINP, which has aquatic toxicity similar to that of DEHP. The aquatic toxicity of
BTHC is not known.
Technical criteria: Important criteria for both sheet/bag and tubing applications include flexibility when cold, clarity, compatibility with PVC, sterilizability, and plasticizer loss
during manufacture and use. In addition, elastic recovery is an important parameter for tubing applications. Some important differences between DEHP and alternatives are
noted below:
TOTM is inferior on measures of cold flexibility; DEHA is similar; and the other three alternatives are superior to DEHP on this measure.
DEHA is less compatible with PVC than DEHP.
BTHC is not steam sterilizable, while DINP tolerates steam sterilization better than DEHP. The sterilizability of DINCH is not known.
TOTM, BTHC, and DINCH are superior to DEHP on measures of plasticizer loss during use. DEHA and BTHC are inferior to DEHP on measure of plasticizer use during
manufacture.
Cost: Costs of DEHA and DINP are similar to those of DEHP, while the other alternatives are more expensive.
The Institute evaluated five alternative materials for medical devices: ethyl vinyl acetate (EVA), polyolefins (polyethylene and polypropylene), glass, silicone, and polyurethane.
Some of these could replace DEHP/PVC sheets, while others could replace DEHP/PVC tubing.
Ethyl vinyl acetate (EVA) is a copolymer blend of vinyl acetate, ethylene, and ethyl acetate that has been used for many years in medical sheet applications. EVA bags are
also used for custom mixing of drugs by pharmacies.
The polyolefins polyethyelene (PE) and polypropylene (PP) are widely used compounds that are valued for their flexibility, transparency and toughness.
Glass was commonly used to store medical solutions prior to the extensive use of plastics.
Silicone is a synthetic rubber that can be used in medical tubing. Silicone tubing is translucent, biologically inert, and inherently flexible.
Thermoplastic polyurethane (TPU) is used in tubing applications.
Materials that have been found to be appropriate alternatives to DEHP/PVC for medical bag devices include
Ethylene vinyl acetate (EVA), a copolymer used in medical film applications such as for parenteral and enteral solutions, and for custom mixing of pharmaceuticals
Polyolefins such as polyethylene and polypropylene stable and inert polymers which are widely used in medical device applications due to their flexibility, transparency and
toughness
Glass, which was historically used for solution storage purposes, though is now less commonly used due to handling concerns and cost.
Materials used in medical tubing applications must be able to be formed in a variety of configurations, have thin inner walls, be durable and strong with low coefficients of friction,
be highly resistant to chemicals and to temperature variations, be inert and be weldable to other components of the medical device. Appropriate alternative medical tubing
materials include EVA, polyolefins and glass, as well as :
Silicone, a naturally translucent, odorless and tasteless synthetic rubber
Thermoplastic polyurethane (TPU), formed by reacting alcohols with a diisocyanate or polymeric isocyanate.
In general, these materials exhibit equal or improved performance and environmental and human health characteristics over DEHP/PVC. The cost of the alternative materials
tends 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.