(Group 3)

For definition of Groups, see Preamble Evaluation.

VOL.: 66 (1996) (p. 37)

CAS No.: 439-14-5
Chem. Abstr. Name: 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Diazepam is the most widely used of the benzodiazepine pharmaceuticals. Produced since the 1960s, it is prescribed for the treatment of anxiety and as a sedative, muscle relaxant, and anticonvulsant.

5.2 Human carcinogenicity data

Studies investigating unspecified hypnotics or tranquillizers as well as diazepam specifically have been included in this monograph because of the dominance of this benzodiazepine among those prescribed. The risk for a variety of cancers, especially of the breast, associated with diazepam use has been investigated in two cohort studies and in six distinct and three related case-control studies.

In none of the two cohort or five case-control studies on benzodiazepine or diazepam use in relation to breast cancer was a positive association found. One case-control study of ovarian cancer reported an increased risk for diazepam use, that was not confirmed by another study. This latter study reported no association between diazepam use and the risk of several other types of cancer.

5.3 Animal carcinogenicity data

Diazepam was tested for carcinogenicity in one experiment in mice, in one experiment in rats and in one experiment in hamsters by oral administration in the diet and also in one limited study in gerbils. An increase in the incidence of hepatocellular tumours occurred in male mice. No significant increase in the incidence of tumours was observed in rats, hamsters or gerbils.

In one study in mice, oral administration of diazepam enhanced the occurrence of hepatocellular tumours induced by N-nitrosodiethylamine. In two studies in rats initiated with 2-acetylaminofluorene or 3'-methyl-4-(dimethylamino)azobenzene, there was no promoting effect of diazepam. In gerbils initiated with N-nitrosodiethylamine, simultaneous administration of diazepam decreased the incidence of cholangiocarcinomas.

5.4 Other relevant data

Diazepam is absorbed rapidly and extensively in humans. A 30-fold range of peak plasma concentrations is obtained when the same dose is given to different subjects. Diazepam is metabolized initially to N-desmethyldiazepam (nordiazepam) and temazepam, both of which may be converted to oxazepam. Diazepam clearance shows marked inter-subject variability. The mean elimination half-life is about 32 h.

There is wide inter-species variability in diazepam metabolism. While formation of N-desmethyldiazepam and temazepam occurs to some extent in all species studied, hydroxylation in the 5-phenyl ring is the major pathway in rats.

Diazepam 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 diazepam to humans has not been observed.

The acute toxicity of diazepam to experimental animals can be considered as low. In subchronic toxicity assays in dogs, high doses of diazepam induced mild toxic effects in the blood, liver and gonads, while in rats, slight chemical-related histopathological changes were observed in the kidneys and thyroid gland. The effects of diazepam on the immune system have been investigated mainly in in-vitro experiments with conflicting results: both stimulatory and inhibitory effects have been demonstrated. There are no data on immunosuppressing or immunomodulating effects in humans.

In several cultured cell systems, diazepam inhibits cell proliferation.

No consistent association between orofacial clefts and diazepam has been identified in humans. No increase in the prevalence at birth of congenital abnormalities has been found associated with attempted maternal suicide using high doses of diazepam, in some instances during the first trimester. While excesses of anomalies associated with regular psychotherapeutic benzodiazepine use have been observed, the types of developmental defects involved have not been consistent between studies.

High doses of diazepam induce cleft palate in mice, but not in rats. In hamsters, exencephaly and limb defects are seen, as well as cleft palate.

In general, diazepam did not induce gene or chromosomal mutations in bacteria, yeast or cultured mammalian cells. In cultured mammalian cells, it induced micronuclei and aneuploidy, and inhibited gap-junctional intercellular communication. There are contradictory results on the induction of gene mutation in bacteria by the urinary metabolites of treated mice.

In general, diazepam did not induce micronuclei, chromosomal aberrations, aneuploidy, c-mitoses or polyploidy in bone marrow of mice in vivo. In rats in vivo, neither chromosomal aberrations in bone marrow, nor DNA strand breaks or alkali-labile sites in liver were found. In mouse spermatocytes, but not in oocytes, diazepam induced aneuploidy.

Mechanistic considerations

Diazepam does not cause gene mutations or chromosomal aberrations. One of its metabolites, oxazepam, increased the incidence of liver tumours (benign and malignant) (see Monograph on oxazepam). However, it is not clear that levels of oxazepam sufficient to induce hepatic effects are achieved in mice treated with diazepam.

5.5 Evaluation

There is evidence suggesting lack of carcinogenicity of diazepam to the breast and inadequate evidence for carcinogenicity at other sites in humans.

There is inadequate evidence in experimental animals for the carcinogenicity of diazepam.

Overall evaluation

Diazepam is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Previous evaluation: Suppl. 7 (1987) (p. 189)


Last Updated 05/21/97

    See Also:
       Toxicological Abbreviations
       Diazepam (PIM 181)