Carcinogenic substance discovered in batches of paracetamol

The Chinese company Anqiu Lu’an Pharmaceutical, has been selling the active pharmaceutical ingredient (API) of paracetamol that is contaminated with a carcinogenic substance. Anqiu Lu’an Pharmaceutical is the world’s largest producer of the raw material of paracetamol. In recent years it has supplied the raw material used in much of the paracetamol sold in chemists, supermarkets and pharmacies throughout the Netherlands.

This information was uncovered by NRC, a Dutch newspaper, and the television programme Zembla. NRC and Zembla took samples from three batches of this temperature-lowering pain reliever that had been produced by Anqiu Lu’an to a certified laboratory in Germany for analysis. The three contaminated batches, which were manufactured in spring 2019, were enough to make 36 million pills. It is not known where in the world this contaminated paracetamol was sold.

Laboratory analysis revealed that all three batches were contaminated with 4-chloroaniline, known by its abbreviation, PCA. According to the European Medicines Agency (EMA) and the European Food Safety Authority (EFSA), this substance, which is formed during the production of paracetamol, is a genotoxic carcinogen. PCA can cause liver tumours in test animals by damaging their genetic material.

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There seems to be a difference of opinion among European regulators with regard to the risks posed by PCA. If you assess concentrations of PCA according to the EMA’s guidelines, someone who takes no more than six contaminated tablets per day would not exceed the ‘tolerable daily intake’. The ‘margin of exposure’ applied by the EFSA, however, takes a more protective approach due to the fact that PCA can damage DNA. The concentrations detected were a factor of eighteen above the level considered safe by the EFSA. In other words, while the EMA considers it acceptable to take up to six contaminated pills per day, the EFSA approach finds that taking more than one contaminated pill per day may already lead to an unacceptable risk of cancer.

‘Take these pills off the market’
Toxicologists in the Netherlands and Belgium who spoke to NRC and Zembla agreed with the EFSA’s strict safety margin. Professor Jan Tytgat (KU Leuven) said ‘Above this margin, there is a substantiated risk that PCA is carcinogenic. PCA does not belong in a painkiller that is used by so many people’. Tytgat called on the regulatory bodies to trace the contaminated batches and withdraw them from the market.

‘I agree with the EFSA’, said Martin van den Berg, emeritus professor of toxicology (Utrecht University), after studying the analysis results. ‘I think that the EFSA is right to apply the precautionary principle. The basic premise is that there is no safe limit because of the damage it may cause to DNA’. According to both professors, the batches of paracetamol API from factories that use the same production methods as Anqiu Lu’an should also be tested for PCA.

Paracetamol is one of the most commonly-used pain relievers and fever reducers in the world. Two billion pills, powders and drinks containing paracetamol are consumed every year in the Netherlands alone. About half of these are produced in Leiden by the pharmaceutical company Apotex, a subsidiary company of the Indian group Aurobindo. Sources close to the company have confirmed that Anqiu Lu’an has been Apotex’s main supplier of API in recent years. Apotex produces paracetamol for the own brands of Albert Heijn, Etos, Jumbo, Trekpleister, DA and Kruidvat, among others. Aurobindo did not wish to comment.

Low levels of contamination in a medicine may sometimes be acceptable if there is no safe alternative. But this does not apply to paracetamol. There is an alternative, as the American pharmaceutical company Mallinckrodt manufactures paracetamol using a different process that does not produce carcinogenic PCA. As far as we know, this paracetamol is not available in the Netherlands.

No action from the regulators 
NRC and Zembla informed the Inspectorate for Health and Youth Care (IGJ) and the Medicines Evaluation Board (CGB) ̶ who monitor the quality of medicines ̶ of the contaminated paracetamol. The inspectorate replied in an e-mail, stating that it saw ‘no role for itself’ in this matter for the time being. Neither did it feel any need to discuss it with NRC and Zembla. The Medicines Evaluation Board (CBG) was willing to listen to our findings, but did not see any reason to trace the contaminated batches or to investigate the matter more widely. They found that the analysed batches fell ‘well below’ the threshold set by the European Medicines Agency. The CGB did not mention genotoxicity and apparently, PCA is only ‘possibly carcinogenic’.

By Joep Dohmen, Jos van Dongen and Annette Schätzle