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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↗
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↗
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↗
PubMed1975

Synthesis of potential adrenergic blocking agents: 2-substituted aminomethylnaphthol(2,3-b)-1,4-dioxans.

Eleven 2-substituted aminomethylnaphtho(2,3-b)-1,4-dioxans were synthesized. The nucleophilic displacement of 2-tosyloxymethylnaphtho(2,3-b)-1,4-dioxan by appropriate amines was carried out using dimethyl sulfoxide as the solvent. Preliminary pharmacological evaluation revealed a potentiation of norepinephrine at low doses and a noncompetitive antagonism at high doses in the rat vas deferens and a dose-related hypotensive action of short duration in the anesthetized rat.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

The disposition of l-3-[(dimethylamino)-(m-dioxan-5-yl)methyl]pyridine in man.

l-3-[(Dimethylamino)-(m-dioxan-5-yl)methyl]pyridine hydrochloride (LY 108380) is being evaluated in man as a potentially useful, nonaddicting analgesic agent. This substituted dioxane is structurally different from any currently known analgesic. Following im administration of the 14C-labeled compound to healthy volunteers, the drug was absorbed rapidly (t1/2(abs) = 2--20 min). Pharmacokinetic analyses suggested that LY 108380 was widely distributed and extensively bound in tissues. The drug was not bound to plasma proteins in vitro or in vivo. In the blood, radioactivity was distributed in both red cells and plasma; a cell/plasma radioactivity ratio of 0.5 was maintained for about 1 hr. The t1/2 for elimination of LY 108380-14C from plasma was about 1.3 hr, although radioactivity persisted in plasma for over 100 hr. At the time of peak radioactivity, the parent compound was the major constituent in plasma; quaternary N-glucuronide and N-desmethylated metabolites were also detected in plasma. Levels of radioactivity in saliva were 2--5 times higher than those in plasma shortly after drug administration. About 82% of the radioactivity was eliminated in the urine, 6% in expired air (as 14CO2), and 1% in feces. The major metabolite of LY 108380 (55% of the dose) was a quaternary amine formed by glucuronidation at the pyridine nitrogen. Less than 10% of the dose was N-demethylated to secondary and primary amines, and about 2% was excreted unchanged.

Adult↗
PubMed1978

Mortality follow-up of workers exposed to 1,4-dioxane.

As a result of recent interest in the carcinogenic effect of dioxane, a mortality study was conducted on employees exposed to this compound at a major chemical company plant. Standard follow-up techniques were used to ascertain the vital status of a total of 165 employees ever exposed to dioxane since 1954. Observed deaths from overall cancer were not significantly different from the expected number of deaths. The observations were based on small numbers of deaths of employees who were apparently exposed at low levels and for relatively short exposures.

Adult↗
PubMed1977

An analysis of the bovine genome by density gradient centrifugation: fractionation in Cs2SO4/3,6-bis(acetatomercurimethyl)dioxane density gradient.

The fractionation of calf thymus DNA by centrifugation in density gradients of Cs2SO4/BAMD, where BAMD = 3,6-bis(acetatomercurimethyl)dioxane, is described. A large-scale separation of (dG+dC)-rich DNA fractions has been obtained, allowing the relative amounts of minor and satellite components in the bovine genome to be precisely assessed.

Animals↗