For definition of Groups, see Preamble Evaluation.
VOL.: 73 (1999) (p. 401)
Chem. Abstr. No.:
Chem. Abstr. Name: N-(4-Hydroxyphenyl)acetamide
Paracetamol (acetaminophen) is widely used as an analgesic and antipyretic at daily doses up to 4000 mg, with minor uses as an intermediate in the chemical and pharmaceutical industries. Occupational exposure may occur during its production and its use.
5.2 Human carcinogenicity data
In the previous monograph on paracetamol, a positive association with cancer of the ureter (but not of other sites in the urinary tract) was observed in an Australian case–control study. None of the other three case–control studies showed an association with cancer in the urinary tract. Nine new—mainly population-based—case–control studies of cancers of the urinary tract have been published, many of which addressed more than one subsite.
None of six studies from Australia, Europe and North America, including a very large international study, found a consistent association between renal-cell cancer and regular intake of paracetamol at any level. In one study from the United States which included patients with renal cancer (type not specified), the risk increased with increasing cumulative intake of paracetamol, to reach statistical significance at the highest exposure; however, this result was not adjusted for intake of other analgesics.
In one study from Australia which included patients with cancer of the renal pelvis, a nonsignificant twofold increase in risk was seen among people in the highest exposure category, with no excess risk in the two lower exposure categories. Another, large case–control study of cancer of the renal pelvis and ureter from the United States showed no association with regular intake of paracetamol.
Of the three new studies that included patients with urinary bladder cancer, that conducted in Sweden showed an elevated risk without providing details. The other two (both from the United States) showed only a slight or no association.
5.3 Animal carcinogenicity data
Paracetamol was tested for carcinogenicity by oral administration in mice and rats. An early study indicated an increased incidence of liver adenomas and carcinomas at a markedly toxic dose in mice of one strain; however, this result was not corroborated in a later study in mice, also at a dose greater than the maximal tolerated dose. A more recent, well-conducted study showed no evidence of a carcinogenic effect in mice. Paracetamol had no carcinogenic effect in rats of several strains, but in rats of one inbred strain, increased incidences of liver and bladder neoplasms were recorded in males at the high dose and an increased incidence of bladder tumours in females at the low dose. A more recent, well-conducted study showed no treatment-related carcinogenic effect in rats. Paracetamol did not promote urinary bladder carcinogenesis in rats and reduced the incidence of intestinal tumours in a two-stage model of intestinal carcinogenesis in rats. It enhanced the incidence of renal adenomas induced by one renal carcinogen but not those induced by another.
5.4 Other relevant data
Activation of a relatively small percentage of paracetamol to N-acetyl-para-benzoquinone imine by cytochrome P450, predominantly CYP 2E1, has been found to be involved in the mechanism of hepatic and, perhaps, renal toxicity. Most paracetamol is metabolized by glucuronidation, sulfation and conjugation with glutathione, which protects the liver at therapeutic doses. Doses of 300 mg/kg bw per day paracetamol and higher saturate conjugation reactions, deplete glutathione and result in binding of the benzoquinone imine to cellular proteins; this has been proposed to be the mechanism of hepatocellular injury in rodents and humans. Several protein adducts have been found in humans and rodents in vivo after exposure to paracetamol. DNA adducts were not observed in mice.
In humans, an association was reported in two case–control studies between daily use of paracetamol and renal disease; however, a causal relationship has not been established. Humans and rodents exposed to doses of paracetamol well above the therapeutic range have experienced centrilobular hepatotoxicity and nephrotoxicity involving the proximal renal tubule. In experimental animals, hepatic, renal and testicular damage occurred only at oral doses that exceeded 300 mg/kg bw per day in rats and 900 mg/kg bw per day in mice. At lower doses, toxic effects in rodents are minimal or absent.
Paracetamol does not present a teratogenic risk to humans at doses associated with severe maternal toxicity. It did not affect reproductive performance of mice in a continuous breeding protocol, although growth and birth weights were reduced. Sperm abnormalities have been observed in mice.
The results of studies of the cytogenetic effects of paracetamol in humans are inconclusive. Paracetamol induced sister chromatid exchange in human cells in vivo, and it was aneugenic and induced chromosomal aberrations but not micronuclei in mammalian cells in vivo. It induced DNA single-strand breaks in mice treated in vivo. Paracetamol induced sister chromatid exchange and chromosomal aberrations in human cells in vitro. It weakly induced cell transformation in a mouse cell line. It induced chromosomal aberrations, micronuclei and sister chromatid exchange in mammalian cells in vitro. It did not induce gene mutation, and the results of tests in mammalian cells in vitro for unscheduled DNA synthesis and DNA damage were inconclusive. Overall, paracetamol was genotoxic in mammalian cells in vivo and in vitro. It was not mutagenic to insects but was clastogenic in plant cells. It was not mutagenic in any standard assay in bacteria.
There is inadequate evidence in humans for the carcinogenicity of paracetamol.
There is inadequate evidence in experimental animals for the carcinogenicity of paracetamol.
Paracetamol is not classifiable as to its carcinogenicity to humans (Group 3).For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Vol. 50 (1990)Synonyms
See Also: Toxicological Abbreviations Paracetamol (ICSC) Paracetamol (PIM 396)