1. Chemical and Physical Data

1.2. Structural and molecular formula and molecular weight

2. Production, Occurrence, Use and Analysis

3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Humans

3.2. Other relevant data

(a) Experimental systems

(i) Absorption, distribution, excretion and metabolism

Dogs receiving a single oral administration of a wide range of doses of paracetamol excreted about 85% of the administered dose within the first 24 h (Savides et al., 1984).

A summary of the proposed metabolic pathways of paracetamol is shown in Figure 1. The major urinary metabolites (the glucuronide, sulfate and 3-mercapto derivatives) are observed in most species, although there is much species variation regarding the percentages of these conjugates excreted in the urine (Davis et al., 1976). Each of the other metabolites shown in Figure 1 has been identified in one species (see Gemborys & Mudge, 1981, for details). In rats, biliary excretion of the various metabolites of paracetamol increased from 20 to 49% as doses were increased from 37.5 to 600 mg/kg bw. The glucuronide conjugate was the major metabolite recovered in the bile at all doses (Hjelle & Klaassen, 1984). The putative reactive intermediates are not known but are thought to include benzoquinone (Hinson et al., 1977).

Fig. 1

Summary or metabolism of paracetamol based on data for different species^a

A minor but important metabolic pathway involves the conversion of paracetamol to a reactive metabolite by the hepatic cytochrome P450-dependent mixed-function oxidase system (Mitchell et al., 1973; Potter et al., 1973). The reactive metabolite is thought to be either N-acetyl-para-benzoquinoneimine (Corcoran et al., 1980) or the corresponding semiquinone free radical (De Vries, 1981; Nelson et al., 1981). With low doses of paracetamol, a conjugate of reduced glutathione with the reactive metabolite is further transformed to cysteine and mercapturic acid conjugates, which are excreted. As the dose of paracetamol increases, hepatic glutathione stores are diminished and the glucuronidation and sulfation pathways become saturated (Galinsky & Levy, 1981). A correlation has been demonstrated between species sensitivity to the hepatotoxicity of paracetamol and the balance between two pathways: (i) formation of glutathione conjugates and the corresponding hydrolysis products (indicative of the ‘toxic’ pathway) and (ii) metabolism via formation of glucuronide and sulfate esters (the ‘detoxification pathway’) (Gregus et al., 1988). Paracetamol-induced liver toxicity and depletion of glutathione may be partially prevented by provision of dietary methionine (Reicks et al., 1988; McLean et al., 1989). At sufficiently high doses of paracetamol, glutathione is depleted and the reactive metabolite binds covalently to cell macromolecules. It has also been noted that paracetamol and N-acetyl-para-benzoquinoneimine may exert their cytotoxic effects via disruption of Ca²⁺ homeostasis secondary to the depletion of soluble and protein-bound thiols (Moore et al., 1985). These data indicate that oxidative or free-radical reactions initiated by paracetamol have a role in the hepatotoxicity of this drug (Birge et al., 1988).

Radiolabel was bound covalently to hepatocellular proteins following incubation of mouse, rat, hamster, rabbit or guinea-pig liver microsomes with ³H-paracetamol; the degree of binding was correlated with the susceptibility of the species to hepatotoxicity in vivo (Davis et al., 1974). Similar covalent binding of radiolabel to liver proteins of rats 48 h after administration of [ring-¹⁴C]-paracetamol was proportional to the extent of liver damage (Davis et al., 1976). Covalent binding of radiolabel to liver plasma membranes and microsomes was demonstrated 2.5 h after oral administration of ³H-paracetamol at 2.5 g/kg bw to rats (Tsokos-Kuhn et al., 1988).

Paracetamol is activated in the kidney by an NADPH-dependent cytochrome P450 mechanism to an arylating agent which can bind covalently to cellular macromolecules (McMurty et al., 1978). Studies in several species have suggested that formation of para-aminophenol may be of importance with respect to paracetamol nephrotoxicity. prara-Aminophenol was identified as a urinary metabolite in hamsters (Gemborys & Mudge, 1981); the deacetylation of paracetamol to para-aminophenol has also been demonstrated in mouse renal cortical slices (Carpenter & Mudge, 1981). In comparison to acetyl-labelled paracetamol, ring-labelled paracetamol was preferentially bound to renal macromolecules in Fischer rats, which are sensitive to paracetamol nephrotoxicity, whereas binding of ring- and acetyl-labelled paracetamol to renal macromolecules was similar in non-susceptible Sprague-Dawley rats (Newton et al., 1985). This suggests that para-aminophenol may be responsible for paracetamol-induced renal necrosis in Fischer 344 rats (Newton et al., 1982).

(ii) Toxic effects

The single-dose oral LD₅₀ of paracetamol in male rats was 3.7 g/kg bw (Boyd & Bereczky, 1966); the 100-day LD₅₀ in rats was 400 mg per day (Boyd & Hogan, 1968).

Hepatic necrosis following administration of paracetamol was first reported in rats (Boyd & Bereczky, 1966). The main signs are hydropic vacuolation, centrilobular necrosis, macrophage infiltration and regenerative activity (Dixon et al., 1971). Paracetamol-induced hepatotoxicity varies considerably among species: hamsters and mice are most sensitive, whereas rats, rabbits and guinea-pigs are resistant to paracetamol-induced liver injury (Davis et al., 1974; Siegers et al., 1978). Toxic effects in dogs and cats given a single oral dose of paracetamol (maximal doses, 500 and 120 mg/kg bw, respectively) included hepatic centrilobular pathology in dogs, while cats, which do not glucuronidate exogenous compounds, had more diffuse liver pathological changes (Savides et al., 1984).

The hepatotoxic effects of paracetamol administered in the diet to mice have been examined histologically. After continuous exposure at 10 000 mg/kg diet for 72 weeks (Hagiwara & Ward, 1986), severe chronic hepatotoxicity was observed, with centrilobular hepatocytomegaly, cirrhosis, lipofuscin deposition and hepatocyte necrosis varying from focal to massive. With the same dose, Ham and Calder (1984) observed macroscopically and microscopically deformed livers with extensive lobular collapse, foci of hepatic necrosis and lymphoid aggregation in portal tracts after 32 weeks. At a lower dose (5000 mg/kg bw) and a shorter exposure time (24 weeks), histological changes were mild. Ultrastructural changes in the livers of rats administered paracetamol at 10 000 mg/kg diet for up to 18 months have been described (Flaks et al., 1985).

Histopathological review of liver sections from B6C3F1 mice of each sex fed paracetamol at 3000, 6000 or 12 500 mg/kg diet for 41 weeks and from NIH general-purpose mice of each sex fed paracetamol at 11000 mg/kg diet for 48 weeks indicated severe liver injury, characterized by centrilobular necrosis in animals receiving more than 10 000 mg/kg diet (Maruyama & Williams, 1988).

A single subcutaneous dose of paracetamol at 750 mg/kg bw to male Fischer 344 rats produced renal tubular necrosis restricted to the upper part of the proximal tubule (McMurty et al., 1978). Chronic cortical and medullary damage has been produced in uninephrectomized homozygous Gunn rats by single doses of various analgesic preparations containing paracetamol (Henry & Tange, 1984).

In fasted adult male mice given paracetamol at 600 mg/kg bw orally and killed within 48 h after treatment, degenerative and necrotic changes were detected in the bronchial epithelium and in testicular and lymphoid tissue, in addition to renal and hepatic effects (Placke et al., 1987).

When male rats were given paracetamol at 500 mg/kg bw per day orally for 70 days, a significant decrease in testicular weight was observed (Jacqueson et al., 1984).

(iii) Effects on reproduction and prenatal toxicity

In Sprague-Dawley rats administered paracetamol at 250 mg/kg bw orally on days 8 through 19 of gestation, embryo- and fetotoxic effects were not seen (Lubawy & Burriss Garret, 1977).

(iv) Genetic and related effects

Paracetamol was not mutagenic to Salmonella typhimurium at concentrations of up to 50 mg/plate in the presence or absence of an exogenous metabolic system (King et al., 1979; Wirth et al., 1980; Imamura et al., 1983; Dybing et al., 1984; Oldham et al., 1986; Jasiewicz & Richardson, 1987). It did not induce mutations in a liquid pre-incubation test with Escherichia coli in the presence or absence of an exogenous metabolic system (King et al., 1979). As reported in an abstract, paracetamol exhibited mutagenic activity towards S. typhimurium TA100 in the presence of an exogenous metabolic system (Tamura et al., 1980).

Feeding of male Drosophila melanogaster with a 40-mM solution of paracetamol did not induce sex-linked recessive mutations (King et al., 1979).

Treatment of Chinese hamster V79 cells with low concentrations (0.1–3.0 mM) of paracetamol inhibited DNA synthesis (Holme et al., 1988; Hongslo et al., 1988). Paracetamol at 10 mM had no effect on Reuber H4-II-E rat hepatoma cell DNA, as assayed by alkaline elution, but the toxic metabolite of paracetamol, N-acetyl-para-benzoquinoneimine, induced DNA strand breaks (Dybing et al., 1984). Treatment of Chinese hamster V79 cells induced DNA strand breaks at 3 and 10 mM but not at 1 mM (Hongslo et al., 1988). Analogous results were obtained with Chinese hamster ovary cells (Sasaki, 1986). Species specificity was observed in assays for unscheduled DNA synthesis in vitro. No unscheduled DNA synthesis was detected in Chinese hamster V79 cells (Hongslo et al., 1988), in Syrian hamster or guinea-pig primary hepatocytes (Holme & Soderlund, 1986) or in rat hepatocytes (Milam & Byard, 1985; Sasaki, 1986; Williams et al., 1989); however, a small but significant increase in unscheduled DNA synthesis was seen in rat primary hepatocytes and a marked increase in unscheduled DNA synthesis was observed in mouse hepatocytes (Holme & Soderlund, 1986).

Paracetamol did not induce mutations to ouabain-resistance in C3H/10T½ clone 8 mouse embryo cells (Patierno et al., 1989). It was reported in an abstract that paracetamol did not induce mutations at the hprt locus in Chinese hamster V79 cells (Sawada et al., 1985). It induced sister chromatid exchange in Chinese hamster V79 (Holme et al., 1988; Hongslo et al., 1988) and CHO cells (Sasaki, 1986). Micronuclei were induced by paracetamol in a rat kidney cell line (NRK-49F) at concentrations above 10 mM (Dunn et al., 1987). Paracetamol induced chromosomal aberrations in three different Chinese hamster cell lines (Sasaki et al., 1980; Sasaki, 1986; Ishidate, 1988) and in human lymphocytes (Watanabe, 1982). It weakly transformed C3H/10T½ clone 8 mouse embryo cells (Patierno et al., 1989).

Paracetamol given twice at a dose of 3 mM (450 mg/kg bw) either intraperitoneally or orally to NMRI mice did not induce micronuclei (King et al., 1979). Oral treatment of female Sprague-Dawley rats with paracetamol at 500 and 1000 mg/kg bw induced aneuploidy in 12-day embryos (Tsuruzaki et al., 1982). Oral treatment of Swiss mice with single or three consecutive daily doses of aqueous solutions of up to 2.5 mg/0.5 ml did not lead to chromatid breaks in bone-marrow cells (Reddy, 1984) or meiotic cells of male Swiss mice (Reddy & Subramanyam, 1985). [The Working Group noted that the description of the doses used in the two last studies was unclear.]

(b) Humans

(i) Pharmacokinetics

Following an oral dose, paracetamol is absorbed rapidly from the small intestine. The rate of absorption depends on the rate of gastric emptying (Clements et al., 1978). First-pass metabolism of paracetamol is dose-dependent: systemic availability ranges from 90% (with 1–2 g) to 68% (with 0.5 g). Plasma concentrations of paracetamol in fasting healthy subjects peaked within 1 h after treatment with 0.5 or 1.0 g but continued to rise up to 2 h after treatment with 2.0 g (Rawlings et al., 1977).

Paracetamol is rapidly and relatively uniformly distributed throughout the body fluids (Gwilt et al., 1963). Binding to plasma proteins is considered insignificant (Gazzard et al., 1973). The apparent volume of distribution of paracetamol in man is about 0.9 1/kg bw (Forrest et al., 1982). The decrease in paracetamol concentrations in plasma is multiphasic both after intravenous injections and after oral dosing with 500 and 1000 mg. When the data from six healthy volunteers were interpreted according to a two-compartment open model, the half-time of the first exponential ranged from 0.15 to 0.53 h and that of the second exponential from 2.24 to 3.30 h. The latter value was in agreement with that found after oral dosing. Mean clearance (± SEM) after intravenous administration of 1000 mg was 352 (± 40) ml/min (Rawlings et al., 1977). Renal excretion of paracetamol involves glomerular filtration and passive reabsorption, and the sulfate conjugate is subject to active renal tubular secretion (Morris & Levy, 1984). Both these metabolites have been shown to accumulate in plasma in patients with renal failure who are taking paracetamol (Lowenthal et al., 1976).

Paracetamol crosses the placenta in unconjugated form, and excretion in the urine of an exposed neonate was similar to that of a two- to three-day-old infant (Collins, 1981).

Paracetamol passes rapidly into milk, and the milk:plasma concentration ratio ranges from 0.7 to 1.1 (Berlin et al., 1980; Notarianni et al., 1987).

Paracetamol is metabolized predominantly to the glucuronide and sulfate conjugates in the human liver. A minor fraction is converted by cytochrome P450-dependent hepatic mixed-function oxidase to a highly reactive arylating metabolite, which is postulated to be N-acetyl-para-benzoquinoneimine (Miner & Kissenger, 1979). This metabolite is rapidly inactivated by conjugation with reduced glutathione and eventually excreted in the urine as acetyl cysteine and mercapturic acid conjugates. Large doses of paracetamol can deplete glutathione stores, and the excess of highly reactive intermediate binds covalently with vital cell elements, which may result in acute hepatic necrosis (Mitchell et al., 1973, 1974). Only 2–5% of a therapeutic dose was excreted unchanged in the urine. In young healthy subjects, about 55, 30, 4 and 4% of a therapeutic dose was excreted after hepatic conjugation with glucuronic acid, sulfuric acid, cysteine and mercapturic acid, respectively (Forrest et al., 1982).

The fractional recovery of mercapturic acid and cysteine conjugates after ingestion of paracetamol at 1500 mg was 9.3% in Caucasians compared with only 4.4–5.2% in Africans (Critchley et al., 1986). This may reflect different susceptibility to paracetamol hepatotoxicity.

(ii) Adverse effects

The toxic effects of paracetamol have been reviewed (Flower et al., 1985).

Reports on the acute toxicity, and in particular hepatotoxicity, of paracetamol have continued to appear since the reporting of the first two cases in 1966 (Davidson & Eastham, 1966). Initial symptoms of overdose are nausea, vomiting, diarrhoea and abdominal pain. Clinical indications of hepatic damage become manifest within two to four days after ingestion of toxic doses; in adults, a single dose of 10–15 g (200–250 mg/kg bw) is toxic. Serum transaminases, lactic dehydrogenase and bilirubin concentrations are elevated, and prothrombin time is prolonged (Koch-Weser, 1976). The severity of hepatic injury increases with the ingested dose and with previous consumption of other drugs that induce liver cytochrome P450 enzymes (Wright & Prescott, 1973). Biopsy of the liver reveals centrilobular necrosis with sparing of the periportal area (James et al., 1975). In nonfatal cases, the hepatic lesions are reversible over a period of months, without development of cirrhosis (Hamlyn et al., 1977).

Heavy alcohol consumption has been stated in several case reports to be related to more severe paracetamol hepatotoxicity than in non- or moderate drinkers (for review, see Black, 1984). Five cases of combined hepatocellular injury and renal tubular necrosis have been reported among patients with a history of chronic alcohol use who were receiving therapeutic doses of paracetamol (Kaysen et al., 1985).

(iii) Effects on reproduction and prenatal toxicity

No association of paracetamol use with congenital abnormalities or stillbirths was observed in a study on drug use in approximately 10 000 pregnancies in the UK (Crombie et al., 1970). In a case-control study of 458 mothers of malformed babies and 911 controls, there was no association of abnormalities with use of paracetamol during the first trimester (Nelson & Forfar, 1971). In the Collaborative Perinatal Project, in which drug intake and pregnancy outcome were studied in a series of 50 282 women in 1959–65, 226 women had been exposed to paracetamol during the first trimester of pregnancy. There were 17 malformed children in the exposed group, giving a nonsignificant standardized relative risk (RR) of 1.05 (Heinonen et al., 1977).

In a study of 280 000 women belonging to a prepaid health plan in Seattle, WA (USA), all drug prescriptions and all pregnancy outcomes were monitored between July 1977 and December 1979. Among the liveborn babies of 6837 women, 80(1.2%) had major congenital malformations. Three of the infants born to 493 women for whom paracetamol had been prescribed in the first trimester had major malformations (types not specified), giving a prevalence of 6 per 1000, which was not significantly different from the overall prevalence in the total population studied (12 per 1000). A second group of 328 women were exposed to paracetamol with codeine in the first trimester. Five of these had malformed babies, giving a prevalence of 15 per 1000, which was not significantly different from that in controls (Jick et al., 1981).

In a second study of the same population, covering the period January 1980 to June 1982, 6509 women had pregnancies ending in livebirths; 105 (1.5%) of the infants had major congenital malformations. Two of the infants born to 350 women for whom paracetamol had been prescribed in the first trimester had major malformations (types not specified), giving a prevalence of 6 per 1000 compared with an overall prevalence in the entire group of 16 per 1000. Three of 347 women exposed to paracetamol with codeine had malformed babies, giving a prevalence of 9 per 1000 (not significant) (Aselton et al., 1985).

(iv) Genetic and related effects

Eleven healthy volunteers were given paracetamol at 1000 mg three times over a period of 8 h. The frequency of chromatid breaks in peripheral blood lymphocytes was significantly increased after one day but returned to normal one week later (Kocisova et al., 1988).

4. Summary of Data Reported and Evaluation

5. References

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