Phthalates

New European Regulation

The European Directive 2007/47/EC makes several amendments to the Medical Devices Directive (MDD) 93/42/EEC that was implemented in 1995. One of the amendments requires the device manufacturer to now label products that incorporate phthalates and, where appropriate, to provide additional related information.

Across the medical device industry phthalate plasticizers are incorporated in plastic materials, particularly PVC (polyvinyl chloride), to enhance flexibility and other performance characteristics. The most commonly used phthalate is DEHP [bis(2-ethylhexyl) phthalate] and, if used in the material formulation of the device and meeting specific criteria of the Directive 93/42/EEC, will be identified on the packaging with the following symbol:

Considerations
In 2002 the EU Scientific Committee on Medicinal Products and Medical Devices (SCMPMD) published an opinion¹ on DEHP in medical devices. It was the committee’s view that overall, the advantages of using DEHP outweighed the disadvantages. This opinion was based on the absence of reports of adverse effects in humans (even in neonates or other groups of patients with relatively high levels of exposure) and on the benefits that DEHP provided, as an efficient plasticizer. In addition it was the committee’s view that safety data on most of the alternatives to DEHP-plasticized PVC were very limited and that these materials could pose an unknown (and thus possibly higher) risk.

1. European Commission Doc: SANCO/SCMPMD/2002/0010 Final “Opinion on Medical Devices Containing DEHP Plasticized PVC.”

On 15 October 2007 the EU Scientific Committee on Emerging and Newly-Identified Health Risks (SCENIHR) published its report² on “The safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk”. The SCENIHR report takes into account new scientific data and the committee considers that, despite a lack of clinical evidence for harmful effects on humans, the high exposure of patients to phthalates during medical treatment may present a cause for concern. The risk of exposure to DEHP is chiefly attributed to the composition of materials, the type of procedure and the time in contact with the patient. Departing from these current well-identified points and the potential risk of DEHP reprotoxicity in prepubescent children (SCENIHR), the population for whom the risk of exposure is heightened has been identified as: premature infants, hospitalised newborns in neonatal care, prepubescent children and adolescents hospitalised in intensive care, on haemodialysis or in long-term treatment. DEHP penetrates skin and placental barriers and concentrates itself easily in breast milk. The risk therefore includes women who are pregnant or breast-feeding in intensive care, on haemodialysis or in long-term treatment.

2. European Commission - Scientific Committee on Emerging and newly-Identified Health Risks – Scientific Opinion on the safety of medical devices containing DEHP-plasticized PVC or other plasticizers on neonates and other groups possibly at risk, 6 February 2008.

The United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) (www.mhra.gov.uk) has reviewed the SCENIHR report and has concluded that the evidence does not support a change from DEHP to other plasticizers. Click here for further information.

Physiological considerations
The key factors influencing the risks to individual patients, arising from the use of DEHP used in medical devices are:

Background exposure
Exposure dose (leaching from each medical device used)

Vulnerability of patients (including the time of the exposure)The general population is exposed to DEHP through a variety of routes with food being the primary source. Several metabolite excretion studies suggest a non-negligible exposure to DEHP in the whole general population. In general, DEHP exposure assessments from probabilistic calculations from DEHP measurements in environmental media and dose reconstructions from urinary metabolite levels agree within an order of magnitude. Most recent studies suggest a current median exposure of 2 to 5 μg/kg bw/day [body weight/day], whereas the 95th percentile is estimated to be between 6 and 17 μg/kg bw/day. Children may have somewhat higher body burden of DEHP than adults. There are indications that exposure to DEHP in the general population has decreased during the last few years.

Medical procedures using PVC medical devices can lead to DEHP exposures much higher than the background levels, although such exposure is typically of limited duration. Even voluntary medical treatments such as an aphaeresis procedure to donate blood products, may result in exposure to DEHP. The extent of exposure largely depends on the type and duration of medical treatment. Premature neonates in intensive care can receive even higher DEHP exposures than adults relative to their body weight (up to 35 mg/kg body weight over a 10 day period). This exposure may be even higher than the doses observed to induce reproductive toxicity in animals. In effect, this means that there is no margin of exposure (MoE) for certain procedures however, this is justified by the beneficial effects of these procedures.

Treatment categories involving a potential exposure include:

Multiple procedures in pre-term neonates
Total Parenteral Nutrition (TPN) in neonates
ECMO in neonates
Exchange transfusion in neonates
Haemodialysis patients
Enteral nutrition in neonates and adults
Heart transplantation or coronary artery bypass graft surgery
Massive infusion of blood into trauma patient
Transfusion in adult undergoing ECMO

The animal and epidemiological studies enable the likely sensitive patient groups to be identified. Animal studies have identified two lead effects; liver tumours and changes in the male reproductive system. The NOAEL (no-observed-adverse-effect-level) for the reproductive toxicity is 4.8 mg/kg bw/day. In respect to the liver tumours, there is good scientific evidence from mechanistic and other studies to indicate that DEHP is unlikely to cause this effect in humans. However, for the effect in the male reproductive system both mechanistic and epidemiological findings indicate a potential hazard for men. Immature young animals are more susceptible to testicular toxicity from DEHP than older mature animals. The EU (European Union) risk assessment for DEHP (ECB 2006) identified the most critical effects as on the testes, fertility, development (anogenital distance), and kidney (repeated dose). The sensitivity for such endocrine effects is highest during gestation and the first month after birth when the most sensitive organs are developing. It has to be considered that there is the potential exposure for infants to other phthalates that are toxic to reproduction, which may have similar mechanisms of action as DEHP.

The summary of epidemiological findings on DEHP and other phthalates is as follows:

Fetal development and adverse pregnancy outcomes: limited evidence
Hypospadias and cryptorchism: no evidence for potential endocrine disrupting effects
Anogenital distance: limited indications based on one study
Birth weight and gestational age: insufficient evidence based on one study
Pubertal development of young females: insufficient evidence based on one study
Phthalate ester levels affect the severity of endometriosis: insufficient evidence
Male fertility: no association between exposure and time to pregnancy
Testicular cancer: no association between this cancer and exposure to PVC plastics
Respiratory health: phthalate exposure correlates weakly with obstructive respiratory symptoms and asthma

Although epidemiological studies on DEHP, as assessed within a report commissioned by Smiths Medical, do not, by themselves, establish a cause-and-effect relationship for harmful effects on humans, these studies give rise to concern for potential reproductive effects in males.

From analysing the animal and human data, and related studies as a whole, it can be concluded that male foetuses of pregnant women and male neonates have to be considered as the most sensitive groups.

Although, the exposure levels from the use of PVC medical devices with certain medical procedures may result in DEHP levels that could produce toxicity to immature male reproductive systems, consideration must be given to the treatment needed and the availability of suitable alternatives for each medical treatment.

DEHP Alternatives
Sufficient toxicological data is available for some compounds to indicate a lower hazard compared to DEHP. However, a risk assessment of these alternative plasticizers could not be performed due to a lack of human exposure data. For other compounds, information on the toxicological profile is inadequate to identify the hazard. This limits the proper evaluation of the potential to replace DEHP by alternative plasticizers. The risk and benefit is continually evaluated for each individual medical device and each medical procedure in which the alternative needs to be used.

Updated: 2014/02/06 (YYYY/MM/DD)