Regulatory risk assessments: Is there a need to reduce uncertainty and enhance robustness? Update on propylparaben in relation to its EU regulatory status
Over 10 years ago, propylparaben (propyl–p–hydroxybenzoate; PP) was withdrawn as a permitted food preservative in the EU based entirely on findings reported in a single dietary study in juvenile rats claiming to show adverse effects on male reproductive parameters [Oishi S. Effects of propyl paraben on the male reproductive system. Food Chem Toxicol 2002; 40(12): 1807 -1813]. Subsequent data reviews have cast serious doubt on the validity of the Oishi results, mainly in relation to aberrant concurrent-control values, and in two further comprehensive studies using neonatal and juvenile rats there were no adverse effects in males at oral doses up to 1000 mg/kg/day. By contrast, juvenile animal toxicity data on the two paraben preservatives currently permitted in the EU as food additives (methylparaben and ethylparaben) are non-robust and rudimentary. Although PP is a permitted preservative in cosmetics its use pattern is highly restricted based mainly on the results of a screening study in the rat using butylparaben as test material, and not taking into account the more recent data on PP. The European Medicines Agency has determined a permitted daily exposure of 2 mg/kg for PP, which applies to both adult and paediatric patients, based on an oral no-observed-adverse-effect level of 100 mg/kg/day in females, treatment-related changes suggestive of an estrogenic effect being noted at 1000 mg/kg/day. The weight of evidence strongly supports a toxicological re-evaluation of PP regarding its use in foodstuffs and cosmetics in the EU, with a view to reinstatement as a food additive, consistent with its status in other major jurisdictions.