Oral exposure to tire rubber-derived contaminant 6PPD and 6PPD-quinone induce hepatotoxicity in mice

Sci Total Environ. 2023 Apr 15:869:161836. doi: 10.1016/j.scitotenv.2023.161836. Epub 2023 Jan 28.


N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a widely used additive for protecting various rubber products, and its product of oxidation N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPDQ) has attracted extensive attention in aquatic toxicity. However, the toxicity of 6PPD and 6PPDQ in mammals has not been reported yet. In this study, the effects of 6PPD and 6PPDQ on the liver of C57BL/6 mice were assessed by orally administering different doses of 6PPD and 6PPDQ (10, 30, and 100 mg/kg) in mice for 6 weeks. 6PPD and 6PPDQ were found to bioaccumulate in the liver in a dose-dependent manner. Moreover, a high dose of 6PPD and 6PPDQ exposure increased not only the liver weights but also liver triglyceride levels, indicating that 6PPD and 6PPDQ exposure induced hepatotoxicity in mice. Furthermore, transcriptomic analysis revealed that 6PPD and 6PPDQ induced differential expression of genes mainly enriched in glycolipid metabolism, immune-related, and glutathione metabolism pathways. Therefore, 6PPD and 6PPDQ altered hepatic metabolism in mice. Furthermore, 6PPDQ could induce an immune response by upregulating the transcription of immune-related genes and promoting macrophage infiltration in the liver. In conclusion, our study revealed the toxic effects of 6PPD and 6PPDQ exposure on multi-endpoints in the liver of mice and improve our understanding of the health risks of 6PPD and 6PPDQ to mammals. The findings of our study may help formulate better safety regulations for the use and disposal of rubber products.

Keywords: 6PPD; 6PPDQ; Liver toxicity; Male mice; Transcriptomic analysis.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzoquinones* / administration & dosage
  • Benzoquinones* / toxicity
  • Chemical and Drug Induced Liver Injury* / etiology
  • Chemical and Drug Induced Liver Injury* / genetics
  • Gene Expression / drug effects
  • Liver* / drug effects
  • Liver* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phenylenediamines* / administration & dosage
  • Phenylenediamines* / toxicity
  • Rubber* / chemistry
  • Rubber* / toxicity


  • N-(1,3-dimethylbutyl)-N'-phenyl-1,4-phenylenediamine
  • Rubber
  • N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone
  • Benzoquinones
  • Phenylenediamines