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Administrative data

Key value for chemical safety assessment

Additional information

p-Aminophenol induces clastogenic effects under standard test conditions at high doses in the presence of other toxic effects. The biological significance of these and relevance to exposed humans must be considered in light of the fact that p-aminophenol is metabolized to acetaminophen (paracetamol) to a significant extent when given dermally and also when given orally. Paracetemol (acetaminophen) has also been shown to be clastogenic in vitro and in vivo in standard genotoxicity tests. However, the potential mechanisms of paracetamol-induced genotoxicity have been concluded to involve a dose threshold (Bergman et al. 1996; Mutation Reseach, 349:263 -288).  Paracetemol has been extensively used in patient populations for more than 50 years without any correlation to carcinogenicity even though these genotoxic effects have been shown. Bergman et al., 1996

in their reviewed indicated, as with para-aminophenol that there was clear evidence that paracetamol causes chromosomal damage in vitro in mammalian cells at high concentrations and indicating that similar effects occur in vivo at high dosages. Available data point to three possible mechanisms of paracetamol-induced genotoxicity: (1) inhibition of ribonucleotide reductase; (2) increase in cytosolic and intranuclear Ca2+ levels; (3) DNA damage caused by NAPQI after glutathione depletion. All mechanisms involve dose thresholds. Studies of the relationship between genotoxicity and toxic effects in the rat (induction of micronuclei in rat bone marrow including dose-response relationship, biotransformation of paracetamol at different dosages, concomitant toxicity and biochemical markers) have employed doses ranging from the dose resulting in human therapeutic peak plasma levels to highly toxic doses, give convincing evidence that genotoxic effects of paracetamol appear only at dosages inducing pronounced liver and bone marrow toxicity and that the threshold level for genotoxicity is not reached at therapeutic dosage. Reliable studies on the ability of paracetamol to affect germ cell DNA are not available. However, Bergman et al., 1996 concluded that based on the amount of drug likely to reach germ cells and the evidence of thresholds, paracetamol is not expected to cause heritable damage in man.

The data for para-aminophenol also indicates a threshold as indicated by two studies in which para-aminophenol was given at moderate doses repeatedly (Molinier, B, 1995 and Volkner, W., 1999) which did not indicate chromosomal effects while higher dose studies indicated clastogenic effects. Additionally for para-aminophenol, as indicated in section 7.7, it is not carcinogenic at repeated oral doses of 30 mg/kg/day for a lifetime in laboratory animals.


Short description of key information:
Both the key and supporting studies for Ames are negative. Positive chromosome aberrations and mouse micronucleus assays would suggest that the substance is clastogenic.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Classified as a Muta-2 compound; the relevance of this finding for human health has not been established and is most likely a threshold effect based on data on its metabolite, paracetemol.