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PubMed1998

Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide, and nalidixic acid in dioxane-water.

In earlier work, a nonlinear enthalpy-entropy compensation was observed for the solubility of phenacetin in dioxane-water mixtures. This effect had not been earlier reported for the solubility of drugs in solvent mixtures. To gain insight into the compensation effect, the behavior of the apparent thermodynamic magnitudes for the solubility of paracetamol, acetanilide, and nalidixic acid is studied in this work. The solubility of these drugs was measured at several temperatures in dioxane-water mixtures. DSC analysis was performed on the original powders and on the solid phases after equilibration with the solvent mixture. The thermal properties of the solid phases did not show significant changes. The three drugs display a solubility maximum against the cosolvent ratio. The solubility peaks of acetanilide and nalidixic acid shift to a more polar region at the higher temperatures. Nonlinear van't Hoff plots were observed for nalidixic acid whereas acetanilide and paracetamol show linear behavior at the temperature range studied. The apparent enthalpies of solution are endothermic going through a maximum at 50% dioxane. Two different mechanisms, entropy and enthalpy, are suggested to be the driving forces that increase the solubility of the three drugs. Solubility is entropy controlled at the water-rich region (0-50% dioxane) and enthalpy controlled at the dioxane-rich region (50-100% dioxane). The enthalpy-entropy compensation analysis also suggests that two different mechanisms, dependent on cosolvent ratio, are involved in the solubility enhancement of the three drugs. The plots of deltaH versus deltaG are nonlinear, and the slope changes from positive to negative above 50% dioxane. The compensation effect for the thermodynamic magnitudes of transfer from water to the aqueous mixtures can be described by a common empirical nonlinear relationship, with the exception of paracetamol, which follows a separate linear relationship at dioxane ratios above 50%. The results corroborate earlier findings with phenacetin. The similar pattern shown by the drugs studied suggests that the nonlinear enthalpy-entropy compensation effect may be characteristic of the solubility of semipolar drugs in dioxane-water mixtures.

Acetaminophen↗
PubMed2001

Hydroboration. 97. Synthesis of new exceptional chloroborane--Lewis base adducts for hydroboration. Dioxane--monochloroborane as a superior reagent for the selective hydroboration of terminal alkenes.

Several less volatile oxygen-containing Lewis bases, such as tert-butyl methyl ether, dioxane, anisole, ethyl acetate, beta-chloroethyl ether, and monoglyme, were examined as prospective mono- and dichloroborane carriers. Dioxane, ethyl acetate, and beta-chloroethyl ether form relatively stable boron trichloride adducts, but the boron trichloride adduct of monoglyme is not very stable and must be used immediately. On the other hand, tert-butyl methyl ether and anisole fail to form stable boron trichloride adducts and the corresponding ether-cleaved products are obtained. Among the selected oxygen-containing Lewis bases, only dioxane forms stable and reactive mono- and dichloroborane adducts. Monoglyme and beta-chloroethyl ether give stable dichloroborane adducts requiring excess of diborane. Convenient methods for the preparation of mono- and dichloroborane adducts of dioxane from dioxane-BCl(3) and NaBH(4) in the presence of catalytic amounts of tri- or tetraglyme were developed. The dioxane--monochloroborane adduct hydroborates representative olefins cleanly and rapidly. The corresponding alcohols were obtained in quantitative yields after oxidation. Also, the hydroboration of several terminal olefins with dioxane--monochloroborane were highly regioselective and the primary alcohols were obtained almost exclusively (>99.5%), after oxidation. Accordingly, dioxane-monochloroborane should serve as a reagent of choice for such hydroborations. The dioxane--dichloroborane adduct showed remarkable selectivity toward 2-substituted terminal olefins, such as 2-methyl-1-butene and beta-pinene, when compared to simple terminal and hindered olefins, giving a unique tool for selective hydroborations. Dichloroborane adducts of monoglyme and beta-chloroethyl ether also showed high reactivity, even at room temperature, toward simple unhindered olefins. However, hydroboration of hindered olefins is slow and requires either higher temperatures or the addition of 1 equiv of boron trichloride to liberate free dichloroborane, as in the case of the previously known dichloroborane adducts of methyl sulfide and diethyl ether.

Journal Article↗
PubMed2006

Quantitative determination of 1,4-dioxane and tetrahydrofuran in groundwater by solid phase extraction GC/MS/MS.

Groundwater contamination by cyclic ethers, 1,4-dioxane (dioxane), a probable human carcinogen, and tetrahydrofuran (THF), a co-contaminant at many chlorinated solvent release sites, are a growing concern. Cyclic ethers are readily transported in groundwater, yet little is known about their fate in environmental systems. High water solubility coupled with low Henry's law constants and octanol-water partition coefficients make their removal from groundwater problematic for both remedial and analytical purposes. A solid-phase extraction (SPE) method based on activated carbon disks was developed for the quantitative determination of dioxane and THF. The method requires 80 mL samples and a total of 1.2 mL of solvent (acetone). The number of steps is minimized due to the "in-vial" elution of the disks. Average recoveries for dioxane and THF were 98% and 95%, respectively, with precision, as indicated by the relative standard deviation of <2% to 6%. The method quantitation limits are 0.31 microg/L for dioxane and 3.1 microg/L for THF. The method was demonstrated by analyzing groundwater samples for dioxane and THF collected during a single sampling campaign at a TCA-impacted site. Dioxane concentrations and areal extent of dioxane in groundwater were greater than those of either TCA or THF.

Chemistry Techniques, Analytical↗
PubMed2000

Mineralization of 1,4-dioxane in the presence of a structural analog.

A mixed culture with the ability to aerobically biodegrade 1,4-dioxane in the presence of tetrahydrofuran (THF) was enriched from a 1,4-dioxane contaminated aquifer. This consortium contained 3-4 morphologically different types of colonies and was grown in mineral salts media. Biodegradation of 1,4-dioxane began when THF concentrations in batch experiments became relatively low. No biodegradation of 1,4-dioxane was observed in the absence of THF and the measured cell yield was similar during degradation of 1,4-dioxane with THF or with THF alone. However, when the consortium was grown in the presence of 14C-1,4-dioxane plus THF, 2.1% of the radiolabeled 1,4-dioxane was present in the particulate fraction. The majority of the 14C (78.1%) was recovered as 14CO2, while 5.8% remained in the liquid fraction. This activity is interesting since the non-growth substrate is mineralized, yet only minimally assimilated into biomass. Using THF as the growth substrate, the consortium also degraded 1,3-dioxane, methyl t-butyl ether, ethyl t-butyl ether and t-amyl methyl ether.

Biodegradation, Environmental↗
PubMed2006

Estimating health risk from exposure to 1,4-dioxane in Japan.

Exposure to 1,4-dioxane from the atmosphere around high-emission plants and from consumer products used in daily life that contain the substance may have adverse health effects; however, its emission into the atmosphere is not regulated. In this study, the health risk posed by 1,4-dioxane is assessed to investigate whether measures should be undertaken to reduce exposure to 1,4-dioxane. The notion of the margin of exposure (MOE), given by the ratio of no observed adverse effect level (NOAEL) to actual or projected exposure level, is used to assess risk. In exposure assessment, two types of exposure channel are considered: (a) the use of consumer products that contain 1,4-dioxane and (b) the inhalation of air around high-emission plants. To estimate exposure via channel (a), we measured the concentration of 1,4-dioxane in consumer products and estimated the interindividual variability of exposure by Monte Carlo simulation that reflects the measured data. To estimate exposure via channel (b), we employed a local-level atmospheric dispersion model to estimate the concentration of 1,4-dioxane immediately around high-emission plants. For hazard assessment, we derived the inhalatory and oral NOAELs for liver adenomas and carcinomas and the uncertainty factor. The results suggest that measures are not needed to reduce exposure to 1,4-dioxane from consumer products. As for inhalation exposure around high-emission plants, some residents may be exposed to health risks if certain conservative analytical conditions are assumed. Even in this case, we conclude that it is not necessary for Plant A to stop the use of 1,4-dioxane immediately and that medium- to long-term emission reduction measures should be sufficient.

Chemical Industry↗
PubMed1990

Development of a physiologically based pharmacokinetic model for risk assessment with 1,4-dioxane.

A six compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the disposition of diethylene-1,4-dioxide (dioxane) and its principal metabolite beta-hydroxyethoxyacetic acid in rats, mice, and humans. The model was developed from experimentally measured partition coefficients (reported here for the first time) as well as pharmacokinetic data previously reported. The completed PB-PK model adequately described data from gavage and intravenous studies in rats, as well as inhalation studies in rats and humans. Substantial nonlinearities were observed in the kinetic behavior of dioxane under high exposure conditions (water concentrations greater than 0.1% dioxane and atmospheric concentrations greater than 300 ppm dioxane). The PB-PK model was subsequently used to prepare quantitative estimates of the "plausible upper bounds" on carcinogenic risk for human populations exposed to dioxane in air or water. Based on these quantitative estimates, it appears that human populations continuously exposed to 740-3700 ppb dioxane in air or 20,000-120,000 ppb dioxane in water would be unlikely to experience increased frequencies of tumors.

Animals↗
PubMed1990

Cancer risk assessment for dioxane based upon a physiologically-based pharmacokinetic approach.

A cancer bioassay conducted in 1974 (Kociba et al.) indicated that rats given drinking water containing dioxane at a dose of 1184 mg.kg-1.d-1 produced an increased incidence of liver tumors. Applying the linearized multistage extrapolation model to these data, the administered dose estimated to present a human cancer risk of 1 in 100,000 (10(-5)) was 0.01 mg.kg-1.d-1. As in customary regulatory policy, this estimate assumed that humans were about 5.5 times more sensitive than rats on a mg/kg basis. However, this approach did not consider that the metabolism of dioxane is saturable at high doses. Based on experience with similar chemicals, it is known that the conventional risk extrapolation method may overestimate the most likely human cancer risk. In order to determine more accurately the likely human response following lifetime exposure to dioxane, a physiologically-based pharmacokinetic (PB-PK) model was developed. The objective of this study was to establish a quantitative relationship between the administered dose of dioxane and the internal dose delivered to the target organ. Using this PB-PK model, and assuming that the best dose surrogate for estimating the liver tumor response was the time-weighted average lifetime liver dioxane concentration, the cancer risk for humans exposed to low doses of dioxane was estimated. The dose surrogate in humans most likely to be associated with a tumorigenic response of 1 in 100,000 is 280 mumol/l, equivalent to an administered dose of about 59 mg.kg-1.d-1. The 95% lower confidence limit on the dose surrogate at the same response level is 1.28 mumol/l, equivalent to an administered dose of 0.8 mg.kg-1.d-1. This PB-PK analysis indicated that conventional approaches based on the administered doses in the rodent bioassay, if uncorrected for metabolic and physiological differences between rats and humans, will overestimate the human cancer risk of dioxane by as much as 80-fold.

Animals↗
PubMed2005

Impurity analysis of 1,4-dioxane in nonionic surfactants and cosmetics using headspace solid-phase microextraction coupled with gas chromatography and gas chromatography-mass spectrometry.

1,4-Dioxane impurity in nonionic surfactants and cosmetics were analyzed using solid-phase microextraction (SPME) coupled with gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Experimental results show that there is no significant difference using SPME-GC and SPME-GC-MS for analysis of 1,4-dioxane in three types of nonionic surfactants at the 95% confidence level. The relative standard deviation (R.S.D.) values of each analytical method were smaller than 3%. The amount of 1,4-dioxane was found to vary from 11.6 +/- 0.3 ppm to 73.5 +/- 0.5 ppm in 30% of nonionic surfactants from manufacturers in Taiwan. These methods were linear over the studied range of 3-150 ppm with correlation coefficients higher than 0.995. The recoveries of 1,4-dioxane for these nonionic surfactants following SPME were all higher than 96 +/- 1% (n = 3). The detection limits of 1,4-dioxane for these nonionic surfactants following SPME were from 0.06 ppm to 0.51 ppm. The experimentally determined level of 1,4-dioxane in cosmetics from manufacturers in Taiwan varied from 4.2 +/- 0.1 ppm to 41.1 +/- 0.6 ppm in 22% of daily used cosmetics following SPME coupled with GC and GC-MS. Conventional solvent extraction takes around 1 h for extraction and reconcentration but SPME takes only around 10 min. SPME provides better analyses of 1,4-dioxane in nonionic surfactants and cosmetics than conventional solvent extraction and head space pretreatments in term of simplicity, speed, precision, detection limit, and solvent consumption.

Calibration↗
PubMed1999

Distribution of 1,4-dioxane in relation to possible sources in the water environment.

The distribution of 1,4-dioxane was investigated in surface and groundwater in relation to possible sources. Water samples from river, coastal sea, and groundwater were collected and examined in Kanagawa Prefecture, Japan, from 1995 to 1998. Almost all samples were contaminated by 1,4-dioxane. On annual changes, the concentrations did not vary significantly in river water. However, some samples were still heavily polluted in groundwater. The highest correlation was between the concentration of 1,4-dioxane and 1,1,1-trichloroethane in the polluted groundwater samples. Soil and groundwater that was polluted by 1,1,1-trichloroethane in the past is still a possible source of 1,4-dioxane. In regard to a survey of other sources, effluents from the combined collection treatment from apartment houses, river basin sewage systems, and chemical plants were examined. The load unit of 1,4-dioxane from the treated effluent of domestic wastewater was assumed to be approximately 0.25 mg/person/day. This was derived from commonly used household chemicals, which contained 1,4-dioxane as a by-product. In river basin sewage systems, the concentrations in effluents varied significantly. High concentration inflows were probably not degraded and released. Although 50-60% of removal was recognized in acclimatized activated sludge from a chemical plant, 1,4-dioxane was easily desorbed with water from sludge.

Dioxanes↗
PubMed1996

Nonlinear enthalpy-entropy compensation for the solubility of phenacetin in dioxane-water solvent mixtures.

The solubility of phenacetin was determined at five temperatures in solvent mixtures of aprotic-amphiprotic mixtures of dioxane and water. Enthalpy-entropy compensation analysis is used to study the effect of changing polarity of the medium on the solute. The apparent heats of solution and free energies of solution are nonlinear functions of the cosolvent (dioxane) ratio. The free energy curve goes through a minimum at 80-90% dioxane in water, whereas the apparent heat of solution displays a maximum at low cosolvent ratio (40% dioxane) and a minimum at high cosolvent ratio (90% dioxane). A plot of delta H against delta G shows a nonlinear compensation effect. Two different mechanisms (entropy and enthalpy) are suggested to be the driving forces to increase solubility. These two mechanisms can be related to the nonlinearity of the compensation effect. The slope changes from positive to negative at 40% dioxane. The overall nonlinear function can also be considered as two linear relationships that intersect at 40% dioxane. The results support the usefulness of enthalpy-entropy compensation analysis for a better understanding of the solubility of drugs in aqueous mixtures as related to the role of cosolvents.

Dioxanes↗
PubMed1994

Degradation of 1,4-dioxane by an actinomycete in pure culture.

An actinomycete capable of sustained aerobic growth on 1,4-dioxane was isolated from a dioxane-contaminated sludge samples. The actinomycete, CB1190, grows on 1,4-dioxane as the sole carbon and energy source with a generation time of approximately 30 h. CB1190 degrades 1,4-dioxane at a rate of 0.33 mg of dioxane min-1 mg of protein-1 and mineralizes 59.5% of the dioxane to CO2. CB1190 also grows with other cyclic and linear ethers as the sole carbon and energy sources, including 1,3-dioxane, 2-methyl-1,3-dioxolane, tetrahydrofuran, tetrahydropyran, diethyl ether, and butyl methyl ether. CB1190 is capable of aerobic autotrophic growth on H2 and CO2.

Actinomycetales↗
PubMed2003

An updated evaluation of the carcinogenic potential of 1,4-dioxane.

This paper presents a critical review of the information pertaining to the potential carcinogenicity of 1,4-dioxane. The primary target organs for cancer via the oral route are the liver and the nasal cavity, however, the relevance of nasal cavity tumors to human exposures has been questioned. Liver tumors were accompanied by degenerative changes and appear only to occur at high doses where clearance mechanisms are saturated and liver toxicity is significant. Genetic toxicity data suggests that 1,4-dioxane is a very weak genotoxin. An increase in hepatocyte cell proliferation was reported and 1,4-dioxane was shown to act as a tumor promoter in rat liver and mouse skin carcinogenicity assays. Two reports are available from the literature regarding physiologically based pharmacokinetic (PBPK) modeling approaches to assess the risk of liver cancer for 1,4-dioxane. A comparison of cancer risk estimates from linear and nonlinear models in the presence or absence of PBPK modeling suggests that USEPAs current cancer slope factor significantly overestimates the potential cancer risk from 1,4-dioxane. This critical review of the scientific literature indicates that a formal reevaluation of the carcinogenic potency of 1,4-dioxane is warranted.

Animals↗
PubMed1999

Novel 1,3-dioxanes from apple juice and cider.

Extracts obtained by XAD solid-phase extraction of apple juice and cider were separated by liquid chromatography on silica gel. Several new 1,3-dioxanes including the known 2-methyl-4-pentyl-1,3-dioxane and 2-methyl-4-[2'(Z)-pentenyl]-1,3-dioxane, were identified in the nonpolar fractions by GC/MS analysis and confirmed by chemical synthesis. The enantioselective synthesis of the stereoisomers of the 1,3-dioxanes was performed using (R)- and (R,S)-octane-1,3-diol and (R)- and (R,S)-5(Z)-octene-1,3-diol as starting material. Comparison with the isolated products indicated that the natural products consisted of a mixture of (2S,4R) and (2R,4R) stereoisomers in the ratio of approximately 10:1, except for 1,3-dioxanes generated from acetone and 2-butanone. It is assumed that the 1, 3-dioxanes are chemically formed in the apples and cider from the natural apple ingredients (R)-octane-1,3-diol, (R)-5(Z)-octene-1, 3-diol, (3R,7R)- and (3R,7S)-octane-1,3,7-triol, and the appropriate aldehydes and ketones, which are produced either by the apples or by yeast during fermentation of the apple juice.

Beverages↗
PubMed1997

The crystal structure of subtilisin Carlsberg in anhydrous dioxane and its comparison with those in water and acetonitrile.

The x-ray crystal structure of the serine protease subtilisin Carlsberg in anhydrous dioxane has been determined to 2.6-A resolution. The enzyme structure is found to be nearly indistinguishable from the structures previously determined in water and acetonitrile. Small changes in the side-chain conformations between the dioxane and water structures are of the same magnitude as those observed between two structures in different aqueous systems. Seven enzyme-bound dioxane molecules have been detected, each potentially forming at least one hydrogen bond with a subtilisin hydrogen-bond donor or bound water. Two of the bound dioxane molecules are in the active-site region, one in the P2 and another bridging the P1' and P3' pockets. The other five dioxane molecules are located on the surface of subtilisin at interprotein crystal contacts. The locations of the bound solvent in the dioxane structure are distinct from those in the structures in acetonitrile and in water.

Acetonitriles↗
PubMed2006

Modifications on collagen structures promoted by 1,4-dioxane improve thermal and biological properties of bovine pericardium as a biomaterial.

Collagen is a widely used raw material for biomaterial manufacture, which generally depends on chemical modifications of this fibrillar protein with cross-linking agents to improve biocompatibility and mechanical properties. However, cross-linking reduces the natural properties of collagen, such as low immune response, low toxicity as well as the ability to promote cellular growth and attachment. In this work, the modifications promoted by 1,4-dioxane solvent on the collagen present in native bovine pericardium (NBP) matrix routinely used in bioprosthesis manufacture, with or without subsequent cross-linking by glutaraldehyde, has been studied. The structural changes of NBP evaluated by scanning electron microscopy show that 1,4-dioxane induces a more homogeneous material by increasing aggregation of collagen fibers, while transmission scanning electron microscopy shows that natural collagen fibril arrangement, integrity, and the D-periodicity pattern are maintained by solvent treatments. Measurements of thermal stability and resistance to collagenase enzymatic digestion of NBP matrices treated with 1,4-dioxane show an increase in melting temperature and decrease in biodegradability, as compared to native pericardium. Cross-linking with glutaraldehyde improves all the analyzed NBP properties, which are not impaired by previous treatment with 1,4-dioxane. Histological evaluation of NBP submitted to 1,4-dioxane treatment shows lower lipid and cell contents and improvement in other morphologic characteristics compared to native pericardium. Altogether, these results suggest the use of 1,4-dioxane organic solvent as an alternative non-cross-linking treatment for direct utilization on rich collagen matrices, resulting in materials with improved biocompatibility and physicochemical properties suitable for tissue engineering.

Animals↗
PubMedDate not supplied

Occurrence of 1,4-dioxane in cosmetic raw materials and finished cosmetic products.

Surveys of cosmetic raw materials and finished products for the presence of the carcinogen 1,4-dioxane have been conducted by the U.S. Food and Drug Administration since 1979. Analytical methods are described for the determination of 1,4-dioxane in ethoxylated cosmetic raw materials and cosmetic finished products. 1,4-Dioxane was isolated by azeotropic atmospheric distillation and determined by gas chromatography using n-butanol as an internal standard. A solid-phase extraction procedure based on a previously published method for the determination of 1,4-dioxane in cosmetic finished products was also used. 1,4-Dioxane was found in ethoxylated raw materials at levels up to 1410 ppm, and at levels up to 279 ppm in cosmetic finished products. Levels of 1,4-dioxane in excess of 85 ppm in children's shampoos indicate that continued monitoring of raw materials and finished products is warranted.

1-Butanol↗
PubMed2001

The stability constants of copper(II) complexes with some alpha-amino acids in dioxan-water mixtures.

In this study, the overall stability constants of copper(II) complexes with some alpha-amino acids (glycine, dl-alanine, dl-valine, l-leucine, l-asparagine, l-glutamine) were determined by potentiometric titration in water, 25% dioxan-75% water, 35% dioxan-65% water, 50% dioxan-50% water, and 60% dioxan-40% water. The titrations were performed at 25 degrees C, under nitrogen atmosphere, and the ionic strength of the medium was maintained at 0.10 M by using sodium perchlorate. The formation curves of their complexes (n-p[L]) were obtained by means of the titration data. Then the stability constants were determined in relation to these curves. The mol ratio of copper(II) to alpha-amino acid was also determined and it was found that the complexes were CuL(2) type. Another important result obtained was that the tendency of amino acids to form complexes with copper(II) was greater in dioxan-water mixtures compared to water.

Amino Acids↗
PubMed2004

Inactivation kinetics of beta-N-acetyl-D-glucosaminidase from prawn (Penaeus vannamei) in dioxane solution.

beta-N-Acetyl-D-glucosaminidase (NAGase, EC 3.2.1.52) catalyzes the cleavage of N-acetylglucosamine polymers. It is in the composition of the chitinases and cooperates with endo-chitinase and exo-chitinase to disintegrate chitin into N-acetylglucosamine. In this work, the effects of dioxane on the enzyme activity for the hydrolysis of p-nitrophenyl-N-acetyl-beta-D-glucosaminide from the prawn (Penaeus vannamei) have been studied. The results show that appropriate concentrations of dioxane can lead to reversible inactivation of the enzyme, and the IC(50) is estimated to be 1.1 M. The kinetics of inactivation of NAGase in the appropriate concentrations of dioxane solution has been studied using the kinetic method of the substrate reaction. The rate constants of inactivation have been determined. The results show that the free enzyme molecule is more fragile than the enzyme-substrate complex in the dioxane solution. It is suggested that the presence of the substrate offers marked protection of this enzyme against inactivation by dioxane.

Acetylglucosaminidase↗