Chloral hydrate: toxicities and applications

General Description

Chloral hydrate is a geminal diol with the formula C2H3Cl3O2. It is a colorless solid and derived from chloral (trichloroacetaldehyde) by the addition of one equivalent of water. ¹ It is a useful laboratory chemical reagent and was use as a sedative and hypnotic pharmaceutical drug. It is also Chloral hydrate has a fairly unique toxicity profile as compared to other sedative-hypnotics. Manifestations of toxicity include gastrointestinal toxicity and genotoxicity. Chloral hydrate is an irritant to the gastrointestinal tract. Ingestion of chloral hydrate may cause nausea, vomiting, and diarrhea. ²

^{Figure 1. Properties of chloral hydrate}

Toxicokinetic

Absorption

Studies in humans have shown that chloral hydrate is rapidly absorbed after oral administration, with peak concentrations in blood occurring within 1 hour after dosing. ³

Distribution

In humans, orally administered chloral hydrate enters the liver where it undergoes extensive metabolism. Only a limited amount enters the systemic circulation. Chloral hydrate in the blood is rapidly eliminated by metabolism, and a half-life of less than 1 hour. ³

Metabolism

Multiple studies in humans have reported that the metabolites of chloral hydrate include trichloroethanol, its glucuronide, and trichloroacetic acid. The terminal half-lives of trichloroethanol and trichloroacetic acid after oral exposure to chloral hydrate have been measured to be about 8-13 hours for trichloroethanol and 4-5 days for trichloroacetic acid. Trichloroethanol-glucuronide is excreted with bile into the intestine, where trichloroethanol is regenerated and reabsorbed in the gut. ³

Excretion

The primary known excretion route for chloral hydrate in humans is as the metabolites trichloroethanol-glucuronide and trichloroacetic acid in urine. ³

Chloral hydrate is an irritant to the gastrointestinal tract. Ingestion of chloral hydrate may cause nausea, vomiting, and diarrhea.

Gastric Perforation and Esophageal Stricture

Gastric perforation and esophageal stricture have been reported in cases of chloral hydrate overdose.

Erosive Gastritis and GI Bleeding

Gastrointestinal complications are common, including erosive gastritis and GI bleeding.

The single-cell gel electrophoresis assay in HepG2 cells was use to assess the DNA-damaging potential of chloral hydrate. A statistically significant increase (P < 0.01) in DNA damage was reported after treatment with chloral hydrate at 20 µM [3.3 µg/mL] for 4 hours, with cell viability exceeding 75%. Cell viability decreased below 75% at concentrations of 80 µM [13.2 µg/mL] and higher. ⁴

Mutations

The genotoxicity of chloral hydrate was studied in three short-term tests. Chloral hydrate can induce mutations in strain TA100 of S. typhimurium (fluctuation test). ⁵

Chromosomal effects

The potential of chloral hydrate to induce aneuploidy in mammalian germ cells has been of particular interest since first demonstrated that treatment of male mice with chloral hydrate results in statistically significant increases in the frequencies of hyperploidy in metaphase II cells. This hyperploidy was thought to have arisen from chromosomal nondisjunction in premeiotic/meiotic cell division, and may be a consequence of chloral hydrate interfering with spindle formation. Chloral hydrate also causes meiotic delay, which may be associated with aneuploidy. ⁶

Applications

Oral drugs

Chloral hydrate has been used as a hypnotic drug since the 1870s, principally for the short term treatment of insomnia. It was also used to allay anxiety and to induce sedation and/or sleep post-operatively, before electroencephalogram evaluations, and to treat the symptoms of withdrawal of alcohol and other drugs such as opiates and barbiturates. For many years chloral hydrate was widely used for the sedation of children before diagnostic, dental or medical procedures, but although still in use, it has largely been replaced by newer drugs with a lower risk of overdose. ⁷

Topical drugs

Externally,⁸

Chloral hydrate is also an ingredient in Hoyer’s solution, which is used in microscopy to mount organisms such as bryophytes, ferns, seeds, and arthropods. ⁹

Reference

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4. Zhang L, Xu L, Zeng Q, et al. Comparison of DNA damage in human-derived hepatoma line (HepG2) exposed to the fifteen drinking water disinfection byproducts using the single cell gel electrophoresis assay. Mutat Res. 2012, 741(1-2):89-94.

5. Miller BM, Adler ID. Aneuploidy induction in mouse spermatocytes. Mutagenesis. 1992, 7(1):69-76.

6. Giller S, Le Curieux F, Gauthier L, Erb F, Marzin D. Genotoxicity assay of chloral hydrate and chloropicrine. Mutat Res. 1995, 348(4):147-152.

7. Pershad J, Palmisano P, Nichols M. Chloral hydrate: the good and the bad. Pediatr Emerg Care. 1999, 15(6):432-435.

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9. Wilkinson LG, Tucker MR. An optimised clearing protocol for the quantitative assessment of sub-epidermal ovule tissues within whole cereal pistils. Plant Methods, 2017, 13:67.

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