1,4-BUTANEDIOL

1,4-BUTANEDIOL

1,4-Butanediol, colloquially known as BD, is a primary alcohol, and an organic compound, with the formula HOCH2CH2CH2CH2OH. 1,4-Butanediol is a colorless viscous liquid. It is one of four stable isomers of butanediol. 1,4-Butanediol is used industrially as a solvent and in the manufacture of some types of plastics, elastic fibers and polyurethanes. In organic chemistry, 1,4-butanediol is used for the synthesis of γ-butyrolactone (GBL). In the presence of phosphoric acid and high temperature, it dehydrates to the important solvent tetrahydrofuran.

CAS No. : 110-63-4
EC No. : 203-786-5

Synonyms:
Butane-1,4-diol; Tetramethylene glycol; BE; BD; 1,4-Butanediol; 1-4-butanediol; 1.4-butanediol; 1,4 butanediol; 1,4-Butandiol; 1-4-butandiol; 1.4-butandiol; 1,4 butandiol; 1,4-Butanediyol; 1-4-butanediyol; 1.4-butanediyol; 1,4 butanediyol; 1,4-BUTANEDIOL; 1,4-butynediol; 1,4-BUTANEDIOL; Butane-1,4-diol; 110-63-4; 1,4-Butylene glycol; 1,4-BD; Tetramethylene glycol; 1,4-Dihydroxybutane; 1,4-Tetramethylene glycol; Tetramethylene 1,4-diol; Sucol B; 1,4-BD; DIOL 14B; Agrisynth B1D; EINECS 203-786-5; 1,4-Butanediol, homopolymer; 4-hydroxybutanol; 1,4butanediol; 1.4-butanediol; Dabco BDO; 1,4-butandiol; 1,4-butane diol; 1,4-Butanediol; 1,4-butane-diol; 1,4-BD; butane 1,4-diol; butane diol-1,4; butane-1-4-diol; 1,4- butandiol; Butan-1.4-diol; 1.4 - butanediol; 1,4 butylene glycol; [O]CCCCO; but-1-ene-1,4-diol; ACMC-1BRE8; 1,4-Butanediol, 99%; EC 203-786-5; 4-01-00-02515 (Beilstein Handbook Reference); 1,4-Butanediol 4 M solution; 1,4-BUTANEDIOL; 1,4-Butanediol, for synthesis, 98%; 1,4-Butanediol, ReagentPlus(R), 99%; 1,4-Butanediol, ReagentPlus(R), >=99%; 1,4-Butanediol, Vetec(TM) reagent grade, 98%; UNII-TMS4MGA0H4 component WERYXYBDKMZEQL-UHFFFAOYSA-N; 1,4-Butanediol solution; 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material; 1,4-BD; 1,4-BD; 1,4-butanediol; 1,4-butylene glycol; 1,4-dihydroxybutane; 1,4-tetramethylene glycol; 2(3H)-Furanone di-dihydro; BD; BDO; Butane-1,4-diol; Butanodiol; Butylèneglycol; Butylene Glycol; Butylène Glycol; Glycol Butylique; One Comma Four; One Four BDO; One Four Bee; Tetramethylene Glycol; Tetramethylene-1,4-diol

1,4-Butanediol

Synthesis of 1,4-Butanediol
In its industrial synthesis, acetylene reacts with two equivalents of formaldehyde to form 1,4-butynediol. This type of acetylene-based process is illustrative of what is known as "Reppe chemistry", after German chemist Walter Reppe. Hydrogenation of 1,4-butynediol gives 1,4-butanediol. It is also manufactured on an industrial scale from maleic anhydride in the Davy process, which is first converted to the methyl maleate ester, then hydrogenated. Other routes are from butadiene, allyl acetate and succinic acid.

A biological route to BD has been commercialized that uses a genetically modified organism. The biosynthesis proceeds via 4-hydroxybutyrate.

Industrial use of 1,4-Butanediol
1,4-Butanediol is used industrially as a solvent and in the manufacture of some types of plastics, elastic fibers and polyurethanes. In organic chemistry, 1,4-butanediol is used for the synthesis of γ-butyrolactone (GBL). In the presence of phosphoric acid and high temperature, it dehydrates to the important solvent tetrahydrofuran. At about 200 °C in the presence of soluble ruthenium catalysts, the diol undergoes dehydrogenation to form butyrolactone.

Almost half of it is dehydrated to tetrahydrofuran to make fibers such as Spandex. 
Toxicity of 1,4-Butanediol
When mixed with other drugs, misuse of 1,4-butanediol has resulted in addiction and death.

Use as a recreational drug

FDA warning against products containing GHB and its prodrugs, such as 1,4-butanediol.
1,4-Butanediol is also used as a recreational drug known by some users as "One Comma Four", "Liquid Fantasy", "One Four Bee" or "One Four B-D-O". It exerts effects similar to γ-hydroxybutyrate (GHB), which is a metabolic product of 1,4-butanediol.

Pharmacokinetics
1,4-Butanediol is converted into GHB by the enzymes alcohol dehydrogenase and aldehyde dehydrogenase, and differing levels of these enzymes may account for differences in effects and side effects between users. While co-administration of ethanol and GHB already poses serious risks, co-administration of ethanol with 1,4-butanediol will interact considerably and has many other potential risks. This is because the same enzymes that are responsible for metabolizing alcohol also metabolize 1,4-butanediol so there is a strong chance of a dangerous drug interaction. Emergency room patients who overdose on both ethanol and 1,4-butanediol often present with symptoms of alcohol intoxication initially and as the ethanol is metabolized the 1,4-butanediol is then able to better compete for the enzyme and a second period of intoxication ensues as the 1,4-butanediol is converted into GHB.

Pharmacodynamics
1,4-Butanediol seems to have two types of pharmacological actions. The major psychoactive effects of 1,4-butanediol are because it is metabolized into GHB; however there is a study suggesting that 1,4-butanediol may have potential alcohol-like pharmacological effects on its own. The study arrived at this conclusion based on the finding that 1,4-butanediol co-administered with ethanol led to potentiation of some of the behavioral effects of ethanol. However, potentiation of ethanol's effects may simply be caused by competition for the alcohol dehydrogenase and aldehyde dehydrogenase enzymes with co-administered 1,4-butanediol. The shared metabolic rate-limiting steps thus leads to slowed metabolism and clearance for both compounds including ethanol's known toxic metabolite acetaldehyde.

Another study found no effect following intracerebroventricular injection in rats of 1,4-butanediol. This contradicts the hypothesis of 1,4-butanediol having inherent alcohol-like pharmacological effects.

Like GHB, 1,4-butanediol is only safe in small amounts. Adverse effects in higher doses include nausea, vomiting, dizziness, sedation, vertigo, and potentially death if ingested in large amounts. Anxiolytic effects are diminished and side effects increased when used in combination with alcohol.

Legality of 1,4-Butanediol
While 1,4-butanediol is not currently scheduled federally in the United States, a number of states have classified 1,4-butanediol as a controlled substance. Individuals have been prosecuted for 1,4-butanediol under the Federal Analog Act as substantially similar to GHB. A federal case in New York in 2002 ruled that 1,4-butanediol could not be considered an analog of GHB under federal law, but that decision was later overturned by the Second Circuit. However, a jury in Federal District Court in Chicago found that 1,4-butanediol was not be an analog of GHB under federal law, and the Seventh Circuit Court of Appeals upheld that verdict. In the United Kingdom, 1,4-butanediol was scheduled in December 2009 (along with another GHB precursor, gamma-butyrolactone) as a Class C controlled substance. In Germany, the drug is not explicitly illegal, but might also be treated as illegal if used as a drug. It is controlled as a Schedule VI precursor in Canada.

2007 contamination of Bindeez toy
A toy called "Bindeez" ("Aqua Dots" in North America) was recalled by the distributor in November 2007 because of the presence of 1,4-butanediol. The toy consists of small beads that stick to each other by sprinkling water. 1,4-Butanediol was detected by GC-MS. The production plant seems to have intended to cut costs by replacing less toxic 1,5-pentanediol with 1,4-butanediol.

Properties of 1,4-Butanediol
Chemical formula C4H10O2
Molar mass 90.122 g·mol−1
Density 1.0171 g/cm3 (20 °C)
Melting point 20.1 °C (68.2 °F; 293.2 K)
Boiling point 235 °C (455 °F; 508 K)
Solubility in water Miscible
Solubility in ethanol Soluble
Magnetic susceptibility (χ) -61.5·10−6 cm3/mol
Refractive index (nD) 1.4460 (20 °C)

1,4-Butanediol is completely metabolized in rabbits. No free 1,4-butanediol could be detected in the urine after oral administration of 4 mmol 1,4-butanediol/kg bw (equivalent to 361 mg/kg). About 1% of the administered dose was found to be conjugated with glucuronic acid, while 7% was excreted as succinic acid.

1,4-Butanediol was rapidly metabolized to 4-hydroxybutyric acid in humans and monkeys. The appearance of 4-hydroxybutyric acid as a metabolite was faster in man than in monkey.

 This chemical appeared to have two types of pharmacologic actions, one attributable to its conversion to gamma-hydroxybutyric acid and the other an inherent property of the diol itself. It is generally accepted that gamma-hydroxybutyric acid crosses the blood-brain barrier and shows neuropharmacologic responses same as 1,4-butanediol. Therefore, neurotoxic effect of 1,4-butanediol is considered to be caused by the metabolite, gamma-hydroxybutyric acid. Recently, a metabolism and disposition study conducted in F344/N rats by the NTP confirmed the rapid and extensive conversion of 1-(14C)-1,4-butanediol to 14CO2. Based on this information, it is considered that 1,4-butanediol is rapidly absorbed and metabolized to gamma-hydroxybutyric acid in animals as well as humans.

Here we show that in vivo injection of 1,4-butanediol into adult Drosophila leads to GHB synthesis (GHB was detectable 5 min after 1,4-butanediol injection and increased dramatically 1-2 hr later). This synthesis of GHB was accompanied by an impairment of locomotor activity that was mimicked by a direct injection of GHB into flies. We propose Drosophila as a model to study the molecular actions of 1,4-butanediol and GHB.

1,4-Butanediol is a gamma hydroxybutryic acid (GHB) analogue that can be used as a substitute for GHB. When ingested, 1,4-butanediol is metabolized to GHB and produces similar effects.

IDENTIFICATION of 1,4-Butanediol: 
1,4-Butanediol is a colorless, oily liquid with almost no odor. It mixes easily with water. 

USE: 1,4-Butanediol is used as a solvent and in the manufacturing of plastics and pharmaceuticals. It is used in personal care products and is an illicit drug in place of gamma-hydroxybutyric acid (GHB). 

EXPOSURE of 1,4-Butanediol: 
Workers that produce or use 1,4-butanediol may breathe in mists or have direct skin contact. The general population may be exposed dermally to consumer products or via its use as an illicit drug. If 1,4-butanediol is released to the environment, it will be broken down in air by reaction with hydroxyl radicals. It will not be broken down in the air by sunlight. It will not volatilize into air from soil and water surfaces. It is expected to move easily through soil. It will be broken down by microorganisms rapidly, and is not expected to build up in fish. RISK: 1,4-Butanediol is a sedative when ingested or administered intravenously, and can cause feelings of intoxication. Additional effects associated with sedative doses include restlessness, muscle spasms, shortness of breath, low respiratory rate, vomiting, seizures, unconsciousness, coma and even death. 1,4-Butanediol is addictive, so people who use it recreationally may experience symptoms of withdrawal. No evidence of infertility, abortion or birth defects were observed in laboratory animals following oral exposure to 1,4-butanediol before and/or during pregnancy. Decreased birth weights were observed in offspring at high doses that also caused maternal toxicity (decreased weight gain, mild kidney and liver effects, and death in some animals). Data on the potential for 1,4-butanediol to cause cancer in laboratory animals were not available. However, there is evidence that its main breakdown product (GHB) causes cancer in laboratory animals exposed over time, suggesting a low potential for 1,4-butanediol to cause cancer in laboratory animals. The potential for 1,4-butanediol to cause cancer in humans has not been assessed by the U.S. EPA IRIS program, the International Agency for Research on Cancer, or the U.S. National Toxicology Program 14th Report on Carcinogen.

1,4-Butanediol is a versatile intermediate for the chemical industry. The most important area of application is the production of polyurethanes and poly(butylene terephthalate). Among the polyurethanes produced from 1,4-butanediol, cellular and compact elastomers are of prime importance.

1,4-Butanediol is made on a large industrial scale by continuous hydrogenation of the 2-butyne-1,4-diol over modified nickel catalysts. The one-stage flow process is carried out at 80 - 160 °C and 300 bar. An aqueous solution of 2-butyne-1,4-diol (30 - 50%), together with carbon monoxide-free hydrogen and recycled reaction mixture, which acts as medium for dissipation of heat, is lead over a reduced nickel - copper - manganese catalysts on silica gel strands. The initial temperature in the reactor is 80 °C; the temperature must not exceed 170 °C. In order to obtain a better distribution of the liquid, hydrogen is also circulated. The raw product contains methanol, propanol, and butanol as byproducts as well as traces of 2-methyl-1,4-butanediol, hydroxybutyraldehyde, acetals, and triols. The reactor effluent is worked up to pure 1,4-butanediol by fractional distillation.

Mitsubishi uses a three-step process: the catalytic reaction of butadiene and acetic acid yields 1,4-diacetoxy-2-butene; subsequent hydrogenation gives 1,4-diacetoxybutane; and hydrolysis leads to 1,4-butanediol.

According to a process practiced by Toyo Soda chlorine first adds to butadiene to form a mixture of 1,4-dichloro-2-butene and 3,4-dichloro-1- butene. This mixture reacts with sodium acetate to form 1,4-diacetoxy-2- butene, which is subsequently hydrogenated directly to 1,4-butanediol.

1,4-Butanediol can be stored indefinitely. The product is noncorrosive and therefore can be transported in cast iron containers. When it is stored for longer periods, storage tanks of steel or aluminum are necessary in order to avoid traces of iron in the product. In this case, a cover of dry nitrogen also is recommended.

1,4-Butanediol is an indirect food additive for use only as a component of adhesives.

From June 1999 through December 1999, cases of toxic effects of 1,4-butanediol involving patients who presented to emergency departments with a clinical syndrome suggesting toxic effects of gamma-hydroxybutyrate and a history of ingesting 1,4-butanediol and patients discovered through public health officials and family members /were identified/. Gas chromatography-mass spectrometry /was used/ to measure 1,4-butanediol or its metabolite, gamma-hydroxybutyrate, in urine, serum, or blood. Nine episodes of toxic effects in eight patients who had ingested 1,4-butanediol recreationally, to enhance bodybuilding, or to treat depression or insomnia /were identified/. One patient presented twice with toxic effects and had withdrawal symptoms after her second presentation. Clinical findings and adverse events included vomiting, urinary and fecal incontinence, agitation, combativeness, a labile level of consciousness, respiratory depression, and death. No additional intoxicants were identified in six patients, including the two who died. The doses of 1,4-butanediol ingested ranged from 5.4 to 20 g in the patients who died and ranged from 1 to 14 g in the nonfatal cases. The health risks of 1,4-butanediol are similar to those of its counterparts, gamma-hydroxybutyrate and gamma-butyrolactone. These include acute toxic effects, which may be fatal, and addiction and withdrawal.

IDENTIFICATION AND USE of 1,4-Butanediol: 
1,4-Butanediol is a colorless, oily liquid. It is used as an industrial solvent, intermediate in organic synthesis, and polymer feedstock. Two studies have been identified concerning the experimental use of 1,4-butanediol as a sedative. 

HUMAN STUDIES of 1,4-Butanediol: It was reported that sleep is induced by intravenous administration or by infusion. Undesirable side-effects which may occur include restlessness and clonic spasms of the muscle of the extremities. Cases of abuse and fatal intoxication have been reported. 

ANIMAL STUDIES of 1,4-Butanediol: Gauze patches with undiluted 1,4-butanediol were applied to the intact and abraded skin of rabbits with occlusive dressing for 24 hours. After 1, 24, 48 and 72 hours, no reaction was observed on the intact and abraded skin. The main signs of toxicity seen in mice and rats were accelerated breathing, dyspnea, spasmodic breathing, bradycardia, exsiccosis, exophthalmus, apathy, hyperreflexia, hyporeflexia, areflexia, ataxia, atonia, twitching, reduced motility, analgesia, lying on the side, loss of righting reflexes, sedation, narcosis, hair loss and ruffled fur. Death occurred within 24 hours. Respiratory failure was thought to be the cause of death. Signs of intoxication appeared more quickly after rectal than after oral administration. In rat developmental studies, administration was conducted by gavage at doses of 200, 400 or 800 mg/kg/day from 14 days before mating to 14 days after mating in males and from 14 days before mating to day 3 of lactation in females. The parental animals exhibited no alteration in reproductive parameters including the copulation index, fertility index, gestation length, numbers of corpora lutea or implantation, implantation index, gestation index, delivery index, and behavior at delivery and lactation. Although neither the pup viability nor the incidence of morphological abnormalities was changed by administration of the compound, pup body weight was slightly but significantly decreased in the 800 mg/kg group. In a gene mutation assay using CHO cells, 1,4-butanediol did not induce any reproducible statistically or biologically significant increase in the mutant frequency of the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus with and without metabolic activation. A gene reverse mutation test was negative in S. typhimurium TA 100, TA 98, TA 1535, TA 1537 and E.coli WP2 uvrA with and without metabolic activation. 

ECOTOXICITY STUDIES of 1,4-Butanediol: Toxicity of this chemical to aquatic organisms seems to be low, because all toxicity data obtained were higher than 85 mg/L or 1000 mg/L which were the maximum concentrations of exposure. No fish died, and no toxic symptoms were observed in fish exposed to 92.5 mg/L of this chemical throughout 14 day test period. Also, any reproduction impairment was not observed in D. magna exposed to 85 mg/L.

 Ingestion of plastic toys is common in children and usually does not result in harm. We report a case of coma in a 20-month-old child after an ingestion of a toy containing 1,4-butanediol, an industrial solvent used to manufacture plastics. When ingested, 1,4-butanediol is metabolized to gamma-hydroxybutyrate, which can have significant systemic effects including death. Health care providers should suspect the possibility of a toxic component when a presumed nontoxic object causes unusual symptoms.

Acute Exposure/ 1,4-Butanediol was administered to the right conjunctival sac of rabbits as a single dose of 0.1 mL. Slight reddening of the conjunctiva and small amounts of discharge were observed in all four rabbits 1 hour after ocular application. The changes diminished after 24 and 48 hours and no abnormalities were observed thereafter. In another study, there was also very slight conjunctival irritation but no corneal injury. ... Ineffective concentration of 1,4-butanediol with respect of ocular mucosa was determined 500 mg/L.

1,4-Butanediol's production and use as a solvent and chemical intermediate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.0105 mm Hg at 25 °C indicates 1,4-butanediol will exist solely as a vapor in the atmosphere. Vapor-phase 1,4-butanediol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 10 hours. 1,4-Butanediol does not contain chromophores that absorb at wavelengths >290 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight. If released to soil, 1,4-butanediol is expected to have very high mobility based upon an estimated Koc of 1. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.2X10-9 atm-cu m/mole. 1,4-Butanediol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Utilizing the Japanese MITI test, 83% of the Theoretical BOD was reached in 2 weeks indicating that biodegradation is an important environmental fate process in soil and water. If released into water, 1,4-butanediol is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to 1,4-butanediol may occur through inhalation and dermal contact with this compound at workplaces where 1,4-butanediol is produced or used. Monitoring data indicate that the general population may be exposed to 1,4-butanediol via dermal contact with personal care products and inhalation of cigarette smoke condensate. Limited general exposure may occur with its use as an illicit drug.

1,4-Butanediol's production and use as a solvent, humectant, cross-linking agent in polyurethane elastomers, and an intermediate for plasticizers, and in the manufacture of pharmaceuticals, tetrahydrofuran, and terephthalate plastics may result in its release to the environment through various waste streams.

According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere, 1,4-butanediol, which has a vapor pressure of 0.0105 mm Hg at 25 °C, is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,4-butanediol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 10 hours, calculated from its rate constant of 3.67X10-11 cu cm/molecule-sec. 1,4-Butanediol does not contain chromophores that absorb at wavelengths >290 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight.

The rate constant for the vapor-phase reaction of 1,4-butanediol with photochemically-produced hydroxyl radicals has been reported as 3.67X10-11 cu cm/molecule-sec at 25 °C. This corresponds to an atmospheric half-life of about 10 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm. 1,4-Butanediol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions. 1,4-Butanediol does not contain chromophores that absorb at wavelengths >290 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 16,811 workers (3870 of these are female) were potentially exposed to 1,4-butanediol in the US. Occupational exposure to 1,4-butanediol may occur through inhalation and dermal contact with this compound at workplaces where 1,4-butanediol is produced or used. Monitoring data indicate that the general population may be exposed to 1,4-butanediol via dermal contact with personal care products and inhalation of cigarette smoke condensate. Limited exposure may occur with its use as an illicit drug.

1,4-Butanediol is a chemical. 1,4-Butanediol is used industrially to make floor stripper, paint thinner, and other solvent products. It is sometimes used in supplements as a substitute for illegal substances such as gamma butyrolactone (GBL) and gamma hydroxybutyrate (GHB). Unfortunately, butanediol is just as dangerous as GBL and GHB.

1,4-Butanediol is used for muscle strength, obesity, insomnia, and to increase the production of growth hormone, but there is no good scientific evidence to support any use.

How does 1,4-Butanediol work ?
1,4-Butanediol is converted to gamma hydroxybutyrate (GHB) in the body. GHB slows down the brain, which can cause loss of consciousness along with dangerous slowing of breathing and other vital functions. It also stimulates growth hormone secretion.