Cumulative exposure to phthalates from phthalate-containing drug products: a Danish population-wide study

Br J Clin Pharmacol. 2018 Aug;84(8):1798-1805. doi: 10.1111/bcp.13614. Epub 2018 Jun 3.


Aims: Up to 50-fold higher levels of urinary phthalate metabolites have been observed in users of phthalate-containing drug products compared with non-users. This is of concern, as phthalates are suspected endocrine disrupters and have been associated with cancer development. This study aims to quantify annual cumulated phthalate exposure from drug products among users of phthalate-containing oral medications in Denmark throughout the period of 2004-2016.

Methods: We conducted a Danish nationwide cohort study using The Danish National Prescription Registry and an internal database held by The Danish Medicines Agency. These databases hold information on drug products; date of dispensing, and the type and quantity of excipients in drugs with Danish marketing permission. We present the number of users over time and their distribution of exposure to enteric phthalate polymers and ortho-phthalates.

Results: The annual number of individuals exposed to phthalate-containing products declined during 2004-2016. The total number of individuals exposed to dibutyl phthalate declined from 21 499 in 2004 to 5400 in 2016. However, among those exposed, the median dibutyl phthalate exposure remained above European regulatory limit of exposure ranging between 380-1710 mg/year throughout the study period. Lithium-products constituted the majority of dibutyl phthalate exposure. Diethyl phthalate exposure, mainly caused by erythromycin, theophylline and diclofenac products, did not exceed the EMA regulatory limit.

Conclusion: While the number of individuals exposed to phthalates from oral medications during 2004-2016 declined, the use of phthalate-containing drugs is still considerable.

Keywords: drug utilization; pharmacoepidemiology; pharmacovigilance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Cohort Studies
  • Denmark
  • Drug Prescriptions / statistics & numerical data
  • Endocrine Disruptors / chemistry
  • Endocrine Disruptors / toxicity
  • Endocrine Disruptors / urine*
  • Excipients / analysis*
  • Excipients / chemistry
  • Excipients / toxicity
  • Humans
  • Neoplasms / chemically induced
  • Neoplasms / prevention & control
  • Pharmaceutical Preparations / administration & dosage*
  • Pharmaceutical Preparations / chemistry
  • Phthalic Acids / chemistry
  • Phthalic Acids / toxicity
  • Phthalic Acids / urine*
  • Registries / statistics & numerical data


  • Endocrine Disruptors
  • Excipients
  • Pharmaceutical Preparations
  • Phthalic Acids