Lactone metabolite common to the carcinogens dioxane, diethylene glycol, and N-nitrosomorpholine: aqueous chemistry and failure to mediate liver carcinogenesis in the F344 rat.

Abstract

1,4-Dioxan-2-one, 1, was synthesized, and the equilibrium constant between it and the hydrolysis product 2-(2-hydroxyethoxy) acetic acid, 2, was determined as K(O) = 70 ± 4 in acidic aqueous media, 25 °C, ionic strength 1 M (KCl), and 5% by volume acetonitrile. The carboxylic acid dissociation constant of 2 was determined under the same conditions to be pK(a) = 3.31 ± 0.02. On the basis of these two determinations, the equilibrium constant between 1 and carboxylic acid anion, 3, and the proton was calculated to be K(OA) = 0.034 ± 0.002 M. The stability of 1 was determined in the range of pH between 1 and 8.5 in buffered aqueous solutions under the conditions above by UV spectrophotometric methods and exhibited simple first order kinetics of decay. On the basis of buffer dilution plots, the values of k(o), the rate constant for solvent mediated decomposition, were determined. The plot of log k(o) against pH is consistent with a three term rate law for solvolysis with a hydrogen ion catalyzed rate constant k(H+) = 1.1 (±0.1) M(-1) min(-1), a water catalyzed rate constant, k(w) = 9.9 (±0.5) × 10(-4) min(-1), and a hydroxide ion catalyzed rate constant, k(OH) = 4.1 (±0.3) × 10(4) M(-1) min(-1). The t(1/2) for decay at pH 7.0, at 25 °C, is ∼2 h. Treatment of F344 rats with aflatoxin B(1) (AFB(1)) (positive control) elicited the expected preneoplastic foci in the livers of each rat tested, while subsequent administration of 1 (a total of 1.32 g over 12 weeks) failed to statistically increase focal number or focal volume percent. In 8 rats administered 1 (1.32 g, 12 weeks) alone, no increase above background foci was detected. This study does not support compound 1 as a common carcinogen.

• Authors: Niangoran Koissi, Niti H Shah, Brandon Ginevan, William S Eck, Bill D Roebuck, James C Fishbein
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 25 Issue 5 Pg. 1022-8 (May 21 2012) ISSN: 1520-5010 [Electronic] United States
• PMID: 22458541 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carcinogens
• Dioxanes
• Ethylene Glycols
• Lactones
• Nitrosamines
• N-nitrosomorpholine
• diethylene glycol
• 1,4-dioxane

Topics

• Animals
• Carcinogens (chemistry, metabolism)
• Dioxanes (chemistry, metabolism)
• Ethylene Glycols (metabolism)
• Lactones (chemistry, metabolism)
• Liver (metabolism)
• Liver Neoplasms (metabolism)
• Male
• Nitrosamines (metabolism)
• Rats
• Rats, Inbred F344