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EC number: 204-616-2
CAS number: 123-30-8
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)
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.
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