(Group 2B)

For definition of Groups, see Preamble Evaluation.

VOL.: 66 (1996) (p. 115)

CAS No.: 604-75-1
Chem. Abstr. Name: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Oxazepam is a benzodiazepine used extensively since the 1960s for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal. It is a metabolite of diazepam, prazepam and temazepam, among the benzodiazepines considered in this volume.

5.2 Human carcinogenicity data

In one case-control study evaluating benzodiazepine use, subjects using oxazepam were included, but were too few to analyse as a separate category.

5.3 Animal carcinogenicity data

Oxazepam was tested for carcinogenicity in three experiments in two strains of mice by oral administration in the diet. Significant increases in the incidence of benign and malignant liver tumours were found in two of the studies. The incidence of an uncommon malignant liver tumour, hepatoblastoma, was also increased in one strain of mice. In the third study, an increased incidence of liver adenomas was found. In one of the studies, a small increase in the incidence of thyroid gland adenomas was observed in females of one strain of mice.

Oxazepam promoted liver tumour development in one two-stage model in mice and in one of three studies in rats.

5.4 Other relevant data

Oxazepam is rapidly and completely absorbed in humans and is largely eliminated in urine conjugated with glucuronic acid. The half-life averages 5-6 h.

Oxazepam is also extensively metabolized in animals. In some species (miniature swine), conjugation predominates, while in others (rats) oxidative metabolism is the major route.

Oxazepam has low acute and chronic toxicity for humans at therapeutic concentrations. The main adverse effects of chronic administration are psychological and physical dependence and withdrawal phenomena; specific organ toxicity of oxazepam to humans has not been observed.

The acute toxicity of oxazepam to experimental animals is also low. Short-term, high-dose administration of oxazepam to mice and rats resulted in increased liver weights. A transient increase in cell proliferation was observed in oxazepam-treated mice.

Perinatal death and neurodevelopmental retardation have been reported in the offspring of women who were exposed to oxazepam during pregnancy (see the monograph on diazepam for further discussion relating to cleft palate). However, confounding factors could not be controlled adequately in these studies.

Malformations have been observed following high doses of oxazepam in mice, but not at moderate doses in this species or in rats or rabbits.

Oxazepam is inactive in most genetic toxicity assays, although it has been shown to cause micronuclei and neuploidy in vitro and to inhibit gap-junctional intercellular communication in human hepatoma cells in vitro. No data were available on humans.

Mechanistic considerations

There is no evidence that oxazepam interacts with DNA. Evidence of mutagenic activity is limited to aneuploidy in cell culture systems.

The induction of hepatocellular proliferation and hepatic cytochromes P450 by oxazepam was observed in mice at doses that were carcinogenic following long-term exposure. These adaptive effects are typical of several non-genotoxic compounds with promoting activity that are carcinogenic in mouse liver. Oxazepam has demonstrated promoting activity. Furthermore, the formation of hepatocellular tumours and hepatoblastomas by oxazepam does not involve the H-ras codon 61 pathway. Similarities have been observed between the hepatic effects of oxazepam and those of phenobarbital, which also promotes development of hepatocellular tumours in mice. Taken together, these data support the conclusion that liver tumours are produced in mice by a promoting mechanism.

The implications of these findings with respect to potential cancer risk of oxazepam exposure in humans are unclear. Specifically, information on the relevant effects of oxazepam in human groups or systems is not available. In general, the sensitivity of human liver to tumour formation, even if induction of cytochromes P450 and hepatocellular proliferation at levels comparable to those in mice were to occur, has not been established.

Levels of thyroid-stimulating hormone were increased in mice fed oxazepam at doses that induced adenomas and hyperplasia following long-term exposure. Sustained thyroid stimulation has been implicated as a mechanism of thyroid tumorigenesis in rodents.

5.5 Evaluation

There is inadequate evidence in humans for the carcinogenicity of oxazepam.

There is sufficient evidence in experimental animals for the carcinogenicity of oxazepam.

Overall evaluation

Oxazepam is possibly carcinogenic to humans (Group 2B).

In making the overall evaluation, the Working Group took into account that:
(i) uncertainty exists regarding the formation of mouse liver tumours by oxazepam as a relevant end-point for evaluation of carcinogenic risks to humans.
(ii) appropriate mechanistic information in humans is lacking.

For definition of the italicized terms, see Preamble Evaluation

Previous evaluation: Suppl. 7 (1987) (p. 69)


Last updated 05/22/97

    See Also:
       Toxicological Abbreviations
       Oxazepam (PIM 677)