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At least 19 recordsLinked to original sources
PubMed1977

Structural identification of p-dioxane-2-one as the major urinary metabolite of p-dioxane.

Analysis by gas chromatography (GC) of the volatile compounds present in the urine from rats administered dioxane, a hepatic carcinogen to this species, revealed a major metabolite. The appearance of the metabolite was pH-dependent, undetectable at high pH; reacidification of the urine sample brought about the reappearance of the metabolite. The amount excreted was dose-dependent and time-dependent, reaching a maximum between 20 and 28 h after dioxane administration. Diethylene glycol administered to rats gave rise to the same metabolite. When isolated and purified from lyophilized urine by preparative GC, the metabolite exhibited an intense carbonyl band at 1750 cm-1 in the infrared spectrum. Nuclear magnetic resonance spectrum showed two triplets and one singlet with equal intensity at delta 3.85, 4.48 and 4.37, respectively. GC-mass spectrometric studies indicated a parent peak at m/e 102. The metabolite was identified as p-dioxane-2-one. Synthetic reference compound exhibited identical IR, NMR, and GC-mass spectra as the metabolite. The tentative pathway and the biological significance of dioxane metabolism are discussed.

Animals↗
PubMedDate not supplied

Dose-dependent fate of 1,4-dioxane in rats.

A pharmacokinetic study was conducted to determine the fate of dioxane in rats at doses equivalent to those given in toxicological studies conducted previously. The results show that the fate of dioxane in rats is markedly dose-dependent because of a limited capacity to metabolize dioxane to beta-hydroxyethoxyacetic acid (HEAA). The pharmacokinetic data collected in support of these conclusions include plasma concentration-time curves for dioxane given to rats iv at dose levels of 3-1000 mg/kg and for an inhalation study of 50 ppm dioxane vapors for 6 h. The plasma curves at low doses by each route were linear with half-life values of about 1 h. As the dose was increased above 10 mg/kg the plasma clearance rate decreased, the fraction of the dose excreted as HEAA decreased, and the fraction of the dose excreted as dioxane per se in the urine and expired in the breath increased. These data could be described by a one-compartment open system model with parallel first-order (urinary and pulmonary excretion) and Michaelis-Menten (metabolism) elimination kinetics. At saturation, the maximum velocity of metabolism of dioxane to HEAA was about 18 mg/kg . h. Multiple daily oral doses of 1000 mg/kg, but not 10 mg/kg, were excreted more rapidly than equivalent single doses, indicating that at high daily doses dioxane induced its own metabolism. The correlation of the dose-dependent fate of dioxane with the results of toxicological studies in rats supports the conclusion that there is an apparent threshold for the toxic effects of dioxane that coincides with saturation of the metabolic pathway for its detoxification.

Aerosols↗
PubMedDate not supplied

The dose-dependent fate of 1,4-dioxane in rats.

A pharmacokinetic study was conducted to determine the fate of dioxane in rats at doses equivalent to those given in toxicological studies conducted previously. The results show that the fate of dioxane in rats is markedly dose-dependent due to a limited capacity to metabolize dioxane to beta-hydroxyethoxyacetic acid (HEAA). The pharmacokinetic data collected in support of these conclusions include plasma concentration-time curves for dioxane given to rats intravenously at dose levels from 3 to 1000 mg/kg and an inhalation study of 50 ppm dioxane vapors for 6 hr. The plasma curves at low doses by each route were linear, with half life values of about 1 hr. As the dose was increased above 10 mg/kg the plasma clearance rate decreased, the fraction of the dose excreted as HEAA decreased, and the fraction of the dose excreted as dioxane per se in the urine and expired in the breath increased. These data could be described by a one-compartment open system model with parallel first order (urinary and pulmonary excretion) and Michaelis-Menten (metabolism) type elimination kinetics. At saturation, the maximum velocity of the metabolism of dioxane ato HEAA was about 18 mg/kg/hr. Multiple daily oral doses of 1000 mg/kg, but not 10 mg/kg, were excreted more rapidly than equivalent single doses, indicating that at high daily doses dioxane induced its own metabolism. The correlation of the dose-dependent fate of dioxane with the results of toxicological studies in rats supports the conclusion that there is an apparent threshold for the toxic effects of dioxane which coincides with saturation of the metabolic pathway for its detoxification.

Administration, Oral↗
PubMed1979

Metabolism of dibenzo[1,4]dioxan by a Pseudomonas species.

Pseudomonas sp. N.C.I.B. 9816 strain 11, when grown on salicylate in the presence of dibenzo[1,4]dioxan, accumulated cis-1,2-dihydroxy-1,2-dihydrodibenzo[1,4]dioxan and 2-hydroxydibenzo[1,4]dioxan in the culture medium. Each metabolite was isolated in crystalline form and identified by a variety of conventional chemical techniques. Crude cell extracts prepared from the parental strain grown with naphthalene oxidized cis-1,2-dihydroxy-1,2-dihydrodibenzo[1,4]dioxan under both aerobic and anaerobic conditions to 1,2-dihydroxydibenzo[1,4]dioxan. Further degradation of this metabolite was not detected.

Chemical Phenomena↗
PubMedDate not supplied

[Toxicology of 1-4-dioxane].

Toxic parameters of 1-4 dioxan were estimated to be for white rats during 4 hr inhalation LC16 = 40 mg/l LC50 = 46 (42.2 +/- 50.1) mg/l; LC84 = 52 mg/l; for white mice during 2 hr inhalation LC16 = 61 mg/l; LC50 = 65 (61.3 +/- 68.2) mg/l; LC84 = 69.5 mg/l. As a result of single and repeated application, 1-4 dioxan did not induce skin changes, it was rapidly absorbed into the blood, and led to acute poisoning and irritation of the eye mucosa. A 24 hr exposure of white rats to 1-4 dioxan at concentrations of 4 and 20 mg/m3 for 90 days brought about their delayed weight gain, increased activity of glutamate-aspartate and glutamate-alanine transminases, prolonged duration of narcotic sleep, elevated content of protein in the urine, decreased diuresis, changed content of chlorides and altered motor chronaxia. The above concentrations proved to be effective. 1-4 dioxan at a concentrations proved to be effective. 1-4 dioxan at a concentration of 0.5 mg/m3 produced slight threshold changes.

Animals↗
PubMed1977

Rapid method for the simultaneous determination of 1,4-dioxan and its major metabolite, beta-hydroxyethoxyacetic acid, concentrations in plasma and urine.

1,4-Dioxan and its principle metabolite, beta-hydroxyethoxyacetic acid (HEAA), are determined by gas chromatography-mass spectrometry (GC-MS) on a 3% OV-17 column using selected ion monitoring, following the methylation of HEAA directly in plasma or urine without extraction. The recoveries of dioxan from plasma and urine are 98 and 94%, respectively, and the recoveries of HEAA from plasma and urine are 86 and 94%, respectively. The detection limits of 1,4-dioxan in plasma and urine are 0.07 ppm, and the detection limits of HEAA in plasma and urine are 0.5 and 0.1 ppm, respectively. Separate simultaneous measurements of 1,4-dioxan and HEAA methyl ester concentrations in urine and plasma are obtained after the methylation via GC-MS without additional preparation of the samples.

Acetates↗
PubMed1992

1,4-Dioxane: prediction of in vivo clastogenicity.

1,4-Dioxane was analyzed with the CASE program to determine the structural basis of its potential genotoxicity and carcinogenicity. These investigations led to the prediction that while 1,4-dioxane was not genotoxic in vitro, it was an inducer of micronuclei in the bone marrow of rats and a carcinogen for both rats and mice. If it is assumed that the induction of micronuclei is the result of DNA damage, then this potential and the previous report of the in vivo induction of DNA strand breaks in rat liver raise the possibility of a genotoxic action for 1,4-dioxane. However it is also conceivable that we have identified a structural feature which contributes to the induction of micronuclei by a non-genotoxic mechanism.

Animals↗
PubMed1990

Improved synthetic routes to the novel thromboxane receptor antagonist ICI 192605: activity of synthetic 1,3-dioxane intermediates.

A study of the synthetic routes to the thromboxane receptor antagonist ICI 192605 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid is described which led to an improvement in overall synthetic yield from 20 to 55%. Invitro thromboxane receptor antagonist data are reported for the novel 1,3-dioxane synthetic intermediates. These data indicated that shortening of the side chain in an appropriately substituted 2,2-dimethyl-1,3-dioxane (e.g. ICI 180080) from a heptenoic acid, to a hexenoic acid, had little effect on thromboxane receptor antagonist potency (pA2 = 7.5 rabbit thoracic aorta for the heptenoic acid ICI 180080 and pA2 = 6.9 for the corresponding hexenoic acid. Human platelet aggregation pA2 values were 6.7 and 7.0, respectively).

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1976

Substitued 5-nitro-1, 3-dioxanes: correlation of chemical structure and antimicrobial activity.

Various derivatives of 5-nitro-1, 3-dioxane were synthesized to determine the relative effect of chemical substitution in the 2-and 5-positions on broad spectrum antimicrobial activity. Each compound was evaluated quantitatively by calculation of a microbiocidal index, which measured the time to kill several different microorganisms. This test system indicated that 5-bromo-5-nitro substitution was essential for significant activity. Optimal activity was effected by 2-methyl substitution in the alkyl series and 2-hydroxy-phenyl substitution in the aryl series. The antimicrobial activity of the substituted dioxanes was not related directly to water solubility or hydrolysis to microbiocidal diols or aldehydes.

Anti-Infective Agents, Local↗
PubMed1991

Degradation of dioxane, tetrahydrofuran and other cyclic ethers by an environmental Rhodococcus strain.

By enrichment and isolation techniques bacterial strains with the capacity to grow on aliphatic cyclic ethers (dioxane, tetrahydrofuran, 1,3-dioxolane) have been isolated. Six strains that degrade tetrahydrofuran were classified as belonging to the genus Rhodococcus. One of two strains that degrade dioxane instead of or in combination with tetrahydrofuran was further characterized and a hypothetical catabolic pathway comprising an initial 2-hydroxylation and several oxidation steps is postulated.

Biodegradation, Environmental↗
PubMed1992

Solvation effects upon the thermodynamic substrate activity; correlation with the kinetics of enzyme catalyzed reactions. II. More complex interactions of alpha-chymotrypsin with dioxane and acetone which are also competitive inhibitors.

It is shown that the effects of the addition of various amounts of dioxane and acetone (solvent modifiers) upon the alpha-chymotrypsin-catalyzed hydrolysis of methylhippurate can be explained in terms of three factors. (A) The effects of the above modifiers on the chemical potential of the substrate. (B) The solvent modifiers dioxane and acetone also act as classical competitive inhibitors. The means of sorting out these contributions is presented. (C) The alterations of the chemical potentials or for free energies of the enzyme, enzyme-substrate complex, and/or other intermediates by the added modifiers appear to cancel out with the substrate used here.

Acetone↗
PubMed1977

The active site of beta-glucosidase from Botryodiplodia theobromae. Effects of pH and dioxan on enzyme-catalysed reactions.

1. The hydrolysis of o-nitrophenyl beta-D-glucopyranoside by the high-molecular-weight beta-glucosidase (beta-D-glucoside glucohydrolase, EC 3.2.1.21) of Botryodiplodia theobromae Pat in the absence or presence of added dioxan was found to be dependent on the ionization of two groups, which appeared to be a carboxyl group and an imidazole group. 2. Dioxan increased the Michaelis constant, Km, but decreased the maximum velocity, V.

Binding Sites↗
PubMed1992

Crystal structure of valinomycin-monohydrate cage complexes crystallized from dioxane.

Valinomycin, cyclo-[(L-Val-D-Hyv-D-Val-L-Lac)3-], was crystallized from aqueous dioxane solvent as a monohydrate complex in which water molecules were found within the ion-binding cavity of the ionophore: monoclinic P2(1), a = 14.377 (3), b = 41.554 (14), c = 14.080 (3) A, beta = 118.27 (2) degrees, Z = 4. There are two non-equivalent valinomycin-water complexes and three dioxane molecules in the asymmetric unit. The ionophore molecules adopt two similar but non-identical, octahedral, bracelet, cage conformations that are a consequence of two distinct ways in which the complexed water molecules can deform the normal octahedral coordinate geometry of the metal binding site. In the first complex the water molecule forms hydrogen donor bonds to the carbonyl oxygens of two L-valine residues on one facial side of the cavity, while in the second complex the water molecule is trigonal-planar coordinate and binds to two L-valine residues on one entrant face of the cavity plus a third D-valine residue from the opposite side of the cavity.

Binding Sites↗
PubMed1978

Metabolism of the antimicrobial agent nibroxane, 5-bromo-2-methyl-5-nitro-m-dioxane, in the rat.

1. The metabolism of nibroxane, a topically effective antimicrobial agent has been studied in the rat after oral and dermal administrations. 2. Plasma level studies in vitro and in vivo showed nibroxane to be rapidly debrominated to 2-methyl-5-nitro-m-dioxane. 3. Nibroxane is rapidly absorbed and extensively metabolized in the rat regardless of the route of administration. 4. Enzymic hydrolysis of the m-dioxane ring was of major importance in the biotransformation of nibroxane. The major eliminated metabolite in the rat was 2-nitropropan-1,3-diol.

Administration, Oral↗
PubMed1992

[Structure of macrocyclic K+, Rb+-complexon of meso-valinomycin monohydrate, cyclo[-(D-Val-Hyi-Val-D-Hyi)3-].H2O, in a crystalline complex with dioxane by x-ray structural data].

The crystal structure of a valinomycin analogue, cyclo[-(D-Val-Hyi-Val-D-Hyi)3-]x(C60H102N6O18) crystallized with dioxane and water molecules, has been solved by X-ray direct methods. The conformation found is analogous to one established for free meso-valinomycin crystallized from other organic solvents. It is characterized by a centrosymmetric bracelet form, stabilized by six intramolecular 4----1 type hydrogen bonds between amide N-H and C = O groups. One water molecule is fixed asymmetrically by hydrogen bonds in the internal negatively charged cavity of the complexon. The meso-valinomycin molecule "bracelets" in the crystal form stacks alternatively with dioxane molecules.

Cations, Monovalent↗
PubMed1991

Assay of 1,4-dioxane in commercial cosmetic products by HPLC.

The HPLC assay of 1,4-dioxane in a wide range of commercially available cosmetics containing polyethoxylated surfactants is described. After solid-phase extraction using Bakerbond CN- and Bakerbond C18-cartridges, samples were directly analysed on a LiChrospher CH-8 column with an acetonitrile water eluent and UV detection at 200 nm. Of the total cosmetic products investigated, 48% were found to contain 7.3-85.9 ppm of 1,4-dioxane.

Chromatography, High Pressure Liquid↗