EMA publishes draft guideline on use of phthalates as excipients in human medicines
Also produces a draft reflection paper on the possible ‘endocrine-disrupting effects’ of parabens
The European Medicines Agency (EMA) could recommend new daily exposure limits for some phthalates, which are used as functional excipients in a number of oral medicines, after animal studies have shown that they can cause negative reproduction and development effects.
The EMA is proposing permitted daily exposure (PDE) values of 0.01, 4 and 2mg/kg/day for dibutyl phthalate (DBP), diethyl phthalate (DEP) and polyvinyl acetate phthalate (PVAP), respectively, in a new draft guideline.
‘These recommendations are precautionary measures aiming at reducing the phthalate content of medicines in order to ensure safety in all types of patient populations,’ the EMA said in the draft guidance.
However, the EMA also said that daily exposures above the PDEs ‘could be accepted as exceptions, on a case-by-case basis, taking into consideration the intended patient population, the disease seriousness and the presence or not of alternative treatment options.’
Other commonly used phthalates used in medicinal products include cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate phthalate (HPMCP).
These recommendations are precautionary measures aiming at reducing the phthalate content of medicines in order to ensure safety in all types of patient populations
In addition to the draft guidance, the EMA has also produced a draft reflection paper on the possible ‘endocrine-disrupting effects’ of parabens used as excipients in medicinal products, focusing on methyl- and propylparaben, which are predominantly used in oral pharmaceutical formulations.
The EMA said that methylparaben has ‘not been associated with adverse effects on the male reproductive organs in juvenile rats (applying doses up to 1g/kg) or in embryo-foetal development studies.
‘This allows concluding that the use of methylparaben in oral formulations up to 0.2% of the product (as within the recommended effective 290 concentrations as a preservative) is not a concern for humans including the paediatric population whatever the age group.’
However, for propylparaben, ‘certain oestrogenic activity has been seen in various experimental settings, but with approximately more than 10,000-fold lower activity than oestradiol in in vitro pharmacological models.
‘Based on the published results on the female reproductive system, a conservative NOEL of 250mg/kg has been determined for propylparaben,’ the EMA said.
For children below two years of age, ‘a PDE for propylparaben cannot be determined because of uncertainty related to the maturation of the enzymes that metabolise propylparaben as well as the limitation of the available animal data corresponding to the youngest children,’ the EMA said.
The use of propylparaben-containing medicines in this age group will therefore need to be justified on a case-by-case basis, by weighing the need for treatment against the potential risk, the EMA said.
The guideline on phthalates and the reflection paper on parabens are open for public consultation until October 2013.
