Permitted Daily Exposures (PDE) values of 0.01, 4 and 2 mg/kg/day for dibutyl phthalate (DBP), diethyl phthalate (DEP), polyvinyl acetate phthalate (PVAP), respectively, are proposed in the draft guideline released Wednesday.
The EMA’s decision for new exposure levels follows the US FDA’s final guidance released in December that calls on the pharmaceutical industry to avoid using DBP and di(2-ethylhexyl) phthalate (DEHP) as excipients. The FDA also notes the limited human data that preceded its decision to recommend against using the excipients.
Phthalates are used as functional excipients in a large number of oral formulations. They are most commonly used as plasticizing agents in enteric film-coating materials or as a matrix binder for tablets, capsules, beads and granules. Due to their plasticizer properties, phthalates can be included in soft gelatine formulations, or may control the viscosity of certain liquid formulations, according to the EMA.
“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 its draft guideline. But the EMA also said that daily exposures above the recommended 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 in medicinal products licensed in the EU are cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose acetate phthalate (HPMCP).
EU Reflection Paper on Parabens
In addition to the draft guidance released Wednesday, the EMA also offered a reflection paper on the possible “endocrine-disrupting effects” of methyl- and propylparaben, which are the parabens predominantly used as excipients in oral formulations.
More specifically, the EMA said that methylparaben “has not been associated with adverse effects on the male and female reproductive organs in juvenile rats 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 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 [No Observable Effects Limit] of 25O mg/kg has been determined for propylparaben," the EMA said.
And 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 metabolize propylparaben as well as the limitation of the available animal data corresponding to the youngest children,” the EMA concluded.
The comment period for both the concept paper and the draft guideline ends October 31.