LONDON – As the May 2020 deadline for complying with the EU Medical Device Regulation (MDR) looms large, companies have been handed a further requirement they must meet if their products contain certain phthalate plasticizers.

Phthalates are widely used to make polymers, in particular polyvinyl chloride (PVC), flexible. That allows it to be shaped into intubation tubes, catheters, blood bags, ventilator masks and other health care products. But the chemical bonds between phthalates and polymers are weak, and it is known they can leach into blood and other liquids, as well as be released into patients through mucous membranes.

Risk-benefit analysis required

Although banned in certain products, including children's toys and cosmetics, MDR allows the use of these phthalates if it can be shown there are no suitable alternatives. Companies will be required to conduct a risk-benefit analysis of continuing to use plastics containing phthalates that are known to be carcinogenic, mutagenic or endocrine disrupters, and publish the conclusions.

Last month, the European Commission published final guidelines detailing how to carry out risk-benefit analyses to justify the use of restricted phthalates. Limited use will be allowed if there are no suitable alternative additives, alternative materials or other medical treatments. Those analyses must not only weigh banned plasticizers head-to-head against alternatives in terms of their relative toxicities, but also assess the extent to which alternatives might reduce the performance characteristics of a device.

The guidelines were drawn up by the EU Scientific Committee on Health, Environmental and Emerging Risks. Medtech Europe raised several objections regarding the draft guidelines, including that it was not clearly stated that the overall purpose is to enable regulators to approve the use of phthalates in medical devices even if the substance is banned in other applications.

"While assuring customers and regulators that appropriate due diligence has been conducted [the guidelines] should not become an obstacle to placing innovative medical devices on the market," Medtech Europe said in its public comments. The trade body made other requests for alterations and clarifications. Following the publication of the final guidelines, Medtech Europe is now in the midst of an internal review and analysis and declined to comment at this time, saying the review may take some weeks.

While most people are exposed to small amounts of phthalates from environmental pollution, medical devices can subject patients to levels of these chemicals that are considered to be unsafe. In particular, EU safety committees have pointed to premature babies in special care units and adults undergoing chronic hemodialysis as being at particular risk.

Concerns revolve around serial exposure

Dorota Napierska, chemicals policy and projects officer at the patient advocacy group Health Care Without Harm Europe, told BioWorld MedTech that she expected to see the guidelines setting "a more pronounced" framework to support the use of alternatives to phthalates.

"One of our concerns is that the guidelines focus exclusively on a single medical device and the resulting exposure from its use. In real-life situations, many vulnerable patients, such as premature babies, are exposed to multiple medical devices simultaneously, sequentially, or intermittently, during periods of intense care," Napierska said.

The risk-benefit analyses conducted by manufacturers will not be based on the full extent of risks. Napierska noted that a committee of the U.S. National Academy of Sciences has made a similar case for considering risks from exposure to multiple phthalates from multiple sources. In addition, there currently are differing opinions between industry, risk assessors and scientists on what constitutes safe levels of exposure, especially for vulnerable patients.

That is because the adverse effects of endocrine disruptors are greater in utero, babies and during puberty, and also because current methods of testing for endocrine disrupting effects are not very sensitive.

Of particular concern is diethylhexyl phthalate (DEHP), which is the most widely used plasticizer in medical devices. In addition to suspicions that this substance is an endocrine disruptor, DEHP has been associated with autism, attention deficit hyperactivity disorder, breast cancer, obesity and asthma.

Blood bags are a potent example of why, despite its toxicity, DEHP has proved hard to replace. PVC blood bags contain up to 30% DEHP by weight. Apart from being lightweight, flexible and easy to handle, this material can be sterilized using heat or radiation. But it has a significant further advantage in that DEHP acts to preserve erythrocytes, meaning blood can be stored for longer.

Alternative plasticizers have been developed, but plastics manufacturers that contributed to the public consultation on the guidelines argued that there is not enough data to show blood bags made with these are of equivalent quality and safety to ones containing DEHP. Other phthalate plasticizers whose use must be justified are benzyl butyl phthalate, dibutyl phthalate, di-isobutyl phthalate and dicyclohexyl phthalate. Since 2012, these chemicals, along with DEHP, have been banned unless a special dispensation has been given.

In the face of mounting evidence of potential harm, a number of EU countries have imposed national bans and started to phase out materials containing these plasticizers. Napierska expects some manufacturers are likely to argue that there are no better alternatives and the benefits of using phthalates in medical devices outweigh the risks.

But she said, "attempts to justify continued use of hazardous substances" will be difficult, given extensive data on the danger they pose, the small cost differences of using safer alternatives, the greater safety of alternatives and the fact that phthalate-free or PVC medical devices already are available for "nearly all product categories" except blood bags.

No Comments