For definition of Groups, see Preamble Evaluation.
VOL.: 79 (2001) (p. 145)
Chem. Abstr. Name: Butanedioic acid, compd. with N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]ethanamine (1:1); N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy] ethanamine, butanedioate (1:1)
5.1 Exposure data
Doxylamine succinate is an ethanolamine-based antihistamine used in the management of insomnia and, in combination with antitussives and decongestants, in the relief of cough and cold symptoms. It was widely used until the early 1980s in combination with other drugs to control nausea associated with pregnancy and is still registered for this use in at least one country.
5.2 Human carcinogenicity data
Two studies addressed the association between use of an anti-emetic drug containing doxylamine succinate during pregnancy and cancer during childhood in the offspring. The study in England showed no association with childhood cancer in general or with lymphohaematopoietic neoplasms, and no evidence of a dose–response relationship. The study from Canada and the USA on children with acute non-lymphoblastic leukaemia found an increased risk of borderline significance for self-reported use of a drug containing doxylamine succinate or other tablets for morning sickness during pregnancy and a trend of borderline significance with duration of use.
5.3 Animal carcinogenicity data
Doxylamine succinate was tested by oral administration in one study each in mice and rats. In mice, it increased the incidences of hepatocellular and thyroid follicular-cell adenomas in males and females, although the thyroid response was not dose-related in males. In rats, doxylamine succinate marginally increased the incidence of hepatocellular adenomas and carcinomas combined only in males.
5.4 Other relevant data
Doxylamine is converted to demethylated metabolites and their N-acetylated derivatives in humans, monkeys and rats. In rats, doxylamine is also metabolized via N-oxidation, aromatic hydroxylation and ether cleavage pathways. Doxylamine is a potent, phenobarbital-type inducer of cytochrome P450 enzymes in mice. No evidence of enzyme induction has been found in humans. Doxylamine succinate causes liver damage in mice; this effect may be related to its hepatocarcinogenicity. Doxylamine induces thyroxine glucuronidation in mice, with concomitant decreases in serum thyroxine and increases in serum thyroid stimulating hormone concentrations. This is the probable mechanism of action for the induction of thyroid tumours in animals. It has not been shown to be teratogenic in humans or experimental animals.
No data were available on the genetic and related effects of doxylamine succinate in humans. It did not induce micronucleus formation in mice when given transplacentally or in hamsters. It did, however, induce chromosomal aberrations in mice treated transplacentally. Doxylamine succinate induced DNA damage in primary rat hepatocytes and inhibited intercellular communication, but it did not induce sister chromatid exchange in mammalian cells in culture or induce mutations in bacteria. Doxylamine succinate is considered not to be genotoxic.
There is inadequate evidence in humans for the carcinogenicity of doxylamine succinate.
There is limited evidence in experimental animals for the carcinogenicity of doxylamine succinate.
Doxylamine succinate is not classifiable as to its carcinogenicity to humans (Group 3).For definition of the italicized terms, see Preamble Evaluation.
See Also: Toxicological Abbreviations