Many factors impact migration rates
When lipid-containing fluids (i.e. fluids which contain fats) are stored in plasticised PVC containers or conveyed through PVC tubing, some of the plasticiser will migrate into the fluid. The rate of migration is highly dependent on the properties of the fluid, storage time, storage temperature and the type of plasticiser used. Due to the low solubility of plasticisers in water, aqueous medical solutions extract practically no plasticiser from containers or tubing. Data collected on DEHP (the most commonly used plasticiser in medical devices) exposure in patients undergoing medical treatment have shown that even the highest exposures of DEHP provide a significant safety margin when compared with levels of exposure which have been seen to produce no effect in animal studies.
EU scientific committee opinion on DEHP
However, responding to public concerns, the EU Commission has asked a scientific committee to look into the issue. This committee, the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), published a revised Opinion in 2016.The Opinion concluded as follows:
"The Tolerable Daily Intake (TDI) value of DEHP was previously established at 48 μg per kg body weight per day, based on a NOAEL of 4.8 mg/kg/d for reproductive toxicity in rats and applying an assessment factor of 100. Based on the same studies, the European Food Safety Agency rounded the TDI to 50 μg/kg bw/d (EFSA 2005). SCENIHR supports the previously derived TDI value, considering that the new studies are in line or not sufficiently robust to justify the derivation of a new TDI.
Notably, the TDI is a value set up for a lifelong continuous exposure, in contrast with transient acute or subacute exposure produced by DEHP-containing medical devices. Therefore, the use of TDI value for risk assessment associated to exposure via medical device represents a conservative approach, being exposure to medical devices generally limited over time (corresponding to acute/sub-acute/subchronic scenarios from a toxicological point of view, depending on the medical device used). The exception is the group of dialysis patients, whose regimen of treatment can be considered chronic.
Exposure to DEHP may significantly exceed the TDI in some specific groups, among which adult patients undergoing haemodialysis: their median exposure levels reported in various studies exceed the TDI by 2-12 fold with peak values (up to 2200 μg/kg/d) >40 fold higher than the TDI. The exposure values have a small Margin of Safety (MoS) (lower than 100) also considering the NOAEL in rodents for induction of kidney toxicity (around 30 mg/kg/day), which is particularly relevant for that kind of patients. Therefore patients subject to haemodyalisis procedure may be at risk of DEHP induced effects.
Premature neonates in intensive care units (NICU), being dependent on multiple medical procedures, may receive DEHP levels (6000 μg/kg bw/d) similar to the No Observed Adverse Effect Level (NOAEL) (4.8 mg/kg/d) for reproductive toxicity and for this group of patients there is no MoS. In infants and neonates, ECMO is the medical treatment which may give the highest daily exposure over repeated exposure for a short period of time (up to 35000 μg/kg over 10 days treatment in 4 kg bw infants: assuming an equal distribution over time, this would correspond approximately to 3500 μg/kg bw/d). Therefore, premature neonates in NICU and infants subjected to ECMO represent a high-risk population to DEHP exposure."
The SCENIHR adds that “It should be realised that the benefit of medical devices must also be considered: the survival of premature infants often depends on the availability of the same medical devices that result in a relatively high DEHP exposure due to treatment. Whenever possible, material with low release potential should be used.”
This is why the development of alternatives to DEHP is very important. The progress in this field has been acknowledged by the revision of the European Pharmacopoeia.