CHLORAL AND CHLORAL HYDRATE
(Chloral hydrate: Group 3)
For definition of Groups, see Preamble Evaluation.
VOL.: 84 (2004) (p. 317)
5.1 Exposure data
Chloral is a chlorinated aldehyde that found extensive use, beginning in the 1940s, as a precursor in the production of the insecticide DDT and, to a lesser extent, of other insecticides and pharmaceuticals. This use of chloral has declined steadily since the 1960s, especially in those countries where the use of DDT has been restricted. Chloral is readily converted to chloral hydrate in the presence of water. Chloral hydrate is used as a sedative before medical procedures and to reduce anxiety related to withdrawal from drugs. Wider exposure to chloral hydrate occurs at microgram-per-litre levels in drinking-water and swimming pools as a result of chlorination.
5.2 Human carcinogenicity data
Several studies were identified that analysed risk with respect to one or more measures of exposure to complex mixtures of disinfection by-products that are found in most chlorinated and chloraminated drinking-water. No data specifically on chloral or chloral hydrate were available to the Working Group.
5.3 Animal carcinogenicity data
Following administration in drinking-water, chloral hydrate increased the incidence of hepatocellular neoplasms in male mice in two studies. An increased trend with dose for hepatocellular carcinoma in one study with dietary-restricted male mice was reported. Chloral hydrate was not active in male or female rats in two studies. Chloral hydrate increased the incidence of adenomas in the pars distalis of the pituitary gland in female mice only at the highest dose in one gavage study, but did not induce tumours of the pars distalis in male mice.
5.4 Other relevant data
Chloral hydrate is a sedative and hypnotic with some clinical uses. These late effects are also evident in animal studies.
Chloral hydrate is metabolized to trichloroacetic acid, trichloroethanol (which is converted to trichloroethyl glucuronide) and dichloroacetic acid in humans and in rodents.
There is limited evidence from a single study that chloral hydrate affects sperm, but no evidence of actual reproductive or developmental toxicity has been shown.
Chloral hydrate is a well-established aneuploidogenic agent that also has some mutagenic activity. In vivo, it clearly induced aneuploidy and micronuclei in mammals, whereas chromosomal aberrations were not found in most studies. Conflicting results were obtained with regard to the induction of DNA damage in chloral hydrate-treated mammals. In human cells in vitro, chloral hydrate induced aneuploidy, micronuclei and gene mutations. Sister chromatid exchange and DNA strand-break studies yielded inconclusive and negative results, respectively. Chloral hydrate clearly induced micronuclei in Chinese hamster cells, whereas findings in mouse lymphoma cells were conflicting. It failed to induce DNA damage, but caused weak mutagenicity and a clear induction of aneuploidy, chromosomal aberrations and sister chromatid exchange in rodent cells in vitro. It induced the formation of micronuclei in erythrocytes of newt larvae in vivo. In fungi, chloral hydrate clearly induced aneuploidy, while mitotic recombination and gene conversion assays were inconclusive. Induction of somatic mutation (but not sex-linked mutation) by chloral hydrate was demonstrated in insects. In bacteria, the compound induced base-pair substitution mutations. When incubated with calf thymus DNA, chloral hydrate induced the formation of malonaldehyde-related DNA adducts.
There is inadequate evidence in humans for the carcinogenicity of chloral and chloral hydrate.
There is limited evidence in experimental animals for the carcinogenicity of chloral hydrate.
Chloral hydrate is not classifiable as to its carcinogencity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
· Anhydrous chloral
· Chloral monohydrate
· Trichloroacetaldehyde hydrate
· Trichloroacetaldehyde monohydrate
Last updated: 29 September 2004
See Also: Toxicological Abbreviations Chloral and Chloral Hydrate (IARC Summary & Evaluation, Volume 63, 1995)