1,4-Butanediol - Erowid
National Toxicology ProgramToxicity Report SeriesNumber 54NTP Summary Reporton the Metabolism, Disposition,and Toxicity of1,4-Butanediol(CAS No. 110-63-4)Richard D. Irwin, Ph.D., Study ScientistNational Toxicology ProgramPost Office Box 12233Research Triangle Park, NC 27709NIH Publication 96-3932May 1996United States Department of Health and Human ServicesPublic Health ServiceNational Institutes of Health
NOTE TO THE READERThe National Toxicology Program (NTP) is made up of four charter agencies of the U.S. Department of Health andHuman Services (DHHS): the National Cancer Institute (NCI), National Institutes of Health; the NationalInstitute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center forToxicological Research (NCTR), Food and Drug Administration; and the National Institute for OccupationalSafety and Health (NIOSH), Centers for Disease Control. In July 1981, the Carcinogenesis Bioassay TestingProgram, NCI, was transferred to the NIEHS. The NTP coordinates the relevant programs, staff, and resourcesfrom these Public Health Service agencies relating to basic and applied research and to biological assaydevelopment and validation.The NTP develops, evaluates, and disseminates scientific information about potentially toxic and hazardouschemicals. This knowledge is used for protecting the health of the American people and for the primary preventionof disease.The studies described in this Report were performed under the direction of the NIEHS and were conducted incompliance with NTP laboratory health and safety requirements and must meet or exceed all applicable federal,state, and local health and safety regulations. Animal care and use were in accordance with the Public HealthService Policy on Humane Care and Use of Animals.Chemicals selected for NTP toxicology and carcinogenesis studies are chosen primarily on the bases of humanexposure, level of production, and chemical structure. Selection per se is not an indicator of a chemical'scarcinogenic potential.These NTP Technical Reports are available for sale from the National Technical Information Service,U.S. Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161 (703-487-4650). Single copies ofthis Technical Report are available without charge while supplies last from NTP Central Data Management,NIEHS, P.O. Box 12233, MD A0-01, Research Triangle Park, NC 27709 (919-541-3419).
National Toxicology ProgramToxicity Report SeriesNumber 54NTP Summary Reporton the Metabolism, Disposition,and Toxicity of1,4-Butanediol(CAS No. 110-63-4)Richard D. Irwin, Ph.D., Study ScientistNational Toxicology ProgramPost Office Box 12233Research Triangle Park, NC 27709NIH Publication No. 96-3932May 1996United States Department of Health and Human ServicesPublic Health ServiceNational Institutes of Health
21,4-Butanediol, NTP TOX 54CONTRIBUTORSThis summary NTP report on the metabolism, disposition, and toxicity studies of 1,4-butanediol is based partially onstudies that took place from December 1988 through February 1989.National Toxicology ProgramResearch Triangle InstituteEvaluated and interpreted results and reported findingsProvided absorption, distribution, metabolism, and excretionevaluationR.D. Irwin, Ph.D., Study ScientistJ.R. Bucher, Ph.D.L.T. Burka, Ph.D.M.R. Elwell, D.V.M., Ph.D.J. Mahler, D.V.M.G.S. Travlos, D.V.M.A.R. Jeffcoat, Ph.D., Principal InvestigatorJ.M. Mathews, Ph.D., Study DirectorD.B. Feldman, D.V.M.P. TroxlerBiotechnical Services, Inc.Prepared Toxicity Study ReportD.D. Lambright, Ph.D., Principal InvestigatorC.M. Bailey, B.S. Pharm.S.R. Gunnels, M.A.
31,4-Butanediol, NTP TOX 54PEER REVIEWThe draft summary report on the metabolism, disposition, and toxicity of 1,4-butanediol was evaluated by thereviewers listed below. These reviewers serve as independent scientists, not as representatives of any institution,company, or governmental agency. In this capacity, reviewers determine if the design and conditions of these NTPstudies are appropriate and ensure that this summary report of the metabolism, disposition, and toxicity studiespresents the experimental results and conclusions fully and clearly. The comments of the reviewers were receivedand reviewed prior to the finalization of this document. Changes have been made such that the concerns of thereviewers have been addressed to the extent possible.Gary P. Carlson, Ph.D.School of Health SciencesPurdue UniversityWest Lafayette, INJay I. Goodman, Ph.DDepartment of Pharmacology and ToxicologyMichigan State UniversityEast Lansing, MIMary Jo Vodicnik, Ph.D.Lilly Research LaboratoriesToxicology Research LaboratoriesGreenfield, IN
41,4-Butanediol, NTP TOX 54TABLE OF CONTENTSABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5CHEMICAL AND PHYSICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6PRODUCTION, USE, AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6NOMINATION AND RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7PHARMACOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7METABOLISM AND DISPOSITION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11TOXICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15CARCINOGENICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17GENETIC TOXICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21APPENDIXESAppendix AAppendix BMetabolism and Disposition Studies of 1,4-Butanediol in Male F344/N Rats . . . . . . . . . . . . . . .A-1Survival and Mean Body Weight Results for F344/N Rats and B6C3F 1 Micein the 16-Day and 13-Week Gavage Studies of -Butyrolactone . . . . . . . . . . . . . . . . . . . . . . . . . .B-1
51,4-Butanediol, NTP TOX 54HO-CH2-CH2-CH2-CH2-OH1,4-BUTANEDIOLCAS No. 110-63-4Chemical Formula: C4H10O2Molecular Weight: 90.14Synonyms: Butanediol, butane-1,4-diol, 1,4-butylene glycol, 1,4-dihydroxybutane, 1,4-tetramethylene glycol, butylene glycol,tetramethylene 1,4-diolTrade names: Diol 14B, Sucol BABSTRACT1,4-Butanediol is an industrial chemical used in the manufacture of other organic chemicals. It wasnominated by the National Cancer Institute and selected for evaluation by the NTP because of highproduction volume, the potential for worker exposure, the lack of adequate toxicological characterization, andthe lack of evaluation for carcinogenic potential.As documented in the scientific literature, 1,4-butanediol is rapidly absorbed and metabolized to-hydroxybutyric acid in animals and humans. A metabolism and disposition study conducted in F344/N ratsby the NTP confirmed the rapid and extensive conversion of 1-[ 14C]-1,4-butanediol to 14CO2. Because of thisrapid and extensive conversion, the toxicological profile of 1,4-butanediol reflects that ofacid.-hydroxybutyric-Hydroxybutyric acid is a naturally occurring chemical found in the brain and peripheral tissues whichis converted to succinate and processed through the tricarboxylic acid cycle. Although the function of-hydroxybutyric acid in peripheral tissues is unknown, in the brain and neuronal tissue it is thought tofunction as a neuromodulator.-Hydroxybutyric acid readily crosses the blood-brain barrier, and oral,intraperitoneal, or intravenous administration elicits characteristic neuropharmacologic responses. Thesesame responses are observed after administration of 1,4-butanediol.The lactone of -hydroxybutyric acid, -butyrolactone, is also rapidly converted toenzymes in the blood and liver of animals and humans.-hydroxybutyric acid by-Butyrolactone was previously evaluated by theNTP in 14-day and 13-week toxicology studies and 2-year toxicology and carcinogenesis studies in F344/Nrats and B6C3F 1 mice. No organ-specific toxicity occurred in the toxicology studies. In the carcinogenesisstudies, an equivocal response occurred in male mice, based on a marginal increase in the
61,4-Butanediol, NTP TOX 54incidence of pheochromocytomas of the renal medulla. Because of the rapid and extensive conversion of-butyrolactone to -hydroxybutyric acid, the evaluation of-butyrolactone was in fact an evaluation of- hydroxybutyric acid.This summary report presents a review of the current literature which documents that both 1,4-butanediol and-butyrolactone are rapidly metabolized to-hydroxybutyric acid, and the pharmacologic and toxicologicresponses to these chemicals are due to their metabolic conversion to-hydroxybutyric acid. Because thetoxicity and carcinogenicity of -hydroxybutyric acid was fully evaluated in the NTP studies of-butyrolactone, and a lack of organ-specific toxicity or carcinogenic potential was demonstrated, it isconcluded that there is a high likelihood that 1,4-butanediol would be negative in a similar set of studies. Forthese reasons, it is the opinion of the NTP that 1,4-butanediol should be considered not carcinogenic in animalsand no further evaluation of 1,4-butanediol is needed at this time.CHEMICAL AND PHYSICAL PROPERTIES1,4-Butanediol is a colorless, viscous liquid with a molecular weight of 90.14, a density of 1.0154 at 25C,and a boiling point of 228 C (Lewis, 1991). It is soluble in water, dimethyl sulfoxide, acetone, and 95%ethanol.PRODUCTION , USE, AND HUMAN EXPOSUREIndustrial synthesis of 1,4-butanediol is accomplished in three steps. In the first step, formaldehyde andacetylene are condensed in the presence of a catalyst to produce 1,4-butynediol. This acetylenediol intermediateis then catalytically reduced to 1,4-butanediol in a reactor containing a fixed bed catalyst. In the last step,1,4-butanediol is refined by column distillation ( Kirk-Othmer, 1978; HSDB, 1994).2 H2C O HC CHHO-CH2-C C-CH2-OHHO-CH2-CH2-CH2-CH2-OH1,4-Butanediol is available in grades ranging from greater than 96% pure to 99% pure with a water content ofless than 0.1%.From 1978 to 1985, domestic production of 1,4-butanediol ranged from 138.2 to 353.5 million poundsannually (USITC, 1982a,b, 1983a,b, 1984a,b, 1985, 1986; Chemical Economics Handbook , 1993), while thequantity imported for the same period ranged from 2.0 to 27.7 million pounds annually.
71,4-Butanediol, NTP TOX 541,4-Butanediol is primarily used in the manufacture of tetrahydrofuran,-butyrolactone, andpolyvinylpyrrolidinone. 1,4-Butanediol is also used as a chain extender for polyurethanes and in themanufacture of poly-(butylene terephthalate) ( Kirk-Othmer, 1978; HSDB, 1994).Occupational exposure to 1,4-butanediol was examined in a National Occupational Hazard Survey conductedby the National Institute of Occupational Safety and Health (NIOSH) covering the years from 1972 to 1974.During this time, an estimated 21,169 workers in 369 facilities were potentially exposed to 1,4-butanediol(NIOSH, 1976). These estimates were based on direct observations of actual use of 1,4-butanediol, onobservations of the use of trade-name products containing 1,4-butanediol, and on observations of the use ofgeneric products suspected to contain the chemical. In a second survey of workplace exposure (NationalOccupational Exposure Survey) covering the years from 1981 to 1983, and based only on direct observationof the actual use of 1,4-butanediol, 16,809 workers were potentially exposed (NIOSH, 1995). Thirteen1,4-butanediol-containing products with industrial applications are listed in the NIOSH Tradename IngredientData Base (NIOSH, 1976).No information about the presence of 1,4-butanediol in consumer products was found in the literature. Thedatabase maintained by the U.S. Consumer Product Safety Commission contained no listings for1,4-butanediol at the time of publication; however, these data have not been updated since 1988 (USCPSC,1988).NOMINATION AND RECOMMENDATIONS1,4-Butanediol was nominated by the National Cancer Institute and selected for evaluation by the NTPbecause of high production volume, the potential for worker exposure, the lack of adequate toxicologicalcharacterization, and the lack of evaluation for carcinogenic potential.PHARMACOLOGYEarly investigations of 1,4-butanediol (Sprince et al., 1966) indicated a pronounced pharmacologic effect onthe central nervous system (CNS). Administration of 496 mg/kg 1,4-butanediol to male Sprague-Dawley orHoltzman rats caused CNS depression and induced a state resembling sleep or anesthesia characterized byloss of righting reflex, struggle response, and voluntary motor activity, but retention of the ability to respondto pain and tactile stimuli (Sprince et al., 1966). Very similar neuropharmacologic responses were observedafter administration of -hydroxybutyric acid, except that sleep induction time and sleeping time were longerafter administration of 1,4-butanediol than after administration of-hydroxybutyric acid (Sprince et al.,
81,4-Butanediol, NTP TOX 541966). After administration of -butyrolactone, the -lactone of -hydroxybutyric acid, sleep induction wassimilar to that observed with -hydroxybutyric acid but sleeping time was more similar to that observed with1,4-butanediol. Since previous work (Giarman and Roth, 1964; Roth and Giarman, 1966; Roth et al., 1966)had indicated that the CNS depressant effects of-butyrolactone were due to its metabolism to-hydroxybutyric acid, it was suggested that the CNS depressant activity of 1,4-butanediol was the result ofbiotransformation to -hydroxybutyric acid (Sprince et al., 1966; Menon et al., 1973; Snead et al., 1982).-Hydroxybutyric acid is a naturally occurring chemical found in the brain and peripheral tissue (Roth, 1970;Roth and Giarman, 1970). In the brain,-hydroxybutyric acid is present in micromolar concentrations. Inperipheral tissues (liver, heart, kidney),-hydroxybutyric acid concentrations are 5 to 10 times higher than inthe brain; however, neither the source (precursors) nor physiological function ofperipheral tissues is known with certainty (Mamelak, 1989; Cash, 1994).-hydroxybutyric acid in the-Hydroxybutyric acid readilycrosses the blood-brain barrier, and oral, intraperitoneal, or intravenous administration elicits characteristicneuropharmacologic responses. Current evidence suggests it may function as a neuromodulator (Mandelet al., 1987; Vayer et al., 1987).-Hydroxybutyric acid is synthesized and released in specific neuronalpathways (Rumigny et al., 1981; Maitre et al., 1983) and its actions are mediated by a set of specific, highaffinity receptors which are heterogeneously distributed within the cerebral cortex and hippocampus (Hechleret al., 1992). Administration of exogenous-hydroxybutyric acid induces a state described as behavioralarrest characterized by specific dose-dependent changes in the electroencephalogram which have been wellcharacterized in the rat, cat, and monkey (Snead, 1992). Administration of low doses (12.5 mg/kg) of-hydroxybutyric acid to male Wistar rats had no effect on behavior or on the electroencephalogram(Godschalk et al., 1977). At doses of 150 mg/kg or greater,-hydroxybutyric acid induces a statecharacterized by behavioral arrest, facial myoclonus, vibrissal twitching, and loss of righting reflex. Thebehavioral changes are accompanied by bilaterally synchronous electroencephalogram patterns characterizedby spike-wave discharge similar to that observed during seizures in humans with nonconvulsive or absent(petit mal) epilepsy (Snead, 1992). Administration of anti-petit mal drugs such as ethosuximide,trimethadione, or n-propylacetate to male Wistar rats prior to administration of-hydroxybutyric acidantagonizes the induction of the hypersynchronous electroencephalogram pattern and eliminates the loss ofthe righting reflex (Godschalk et al., 1977). Essentially the same results have been observed in cats (Wintersand Spooner, 1965), chicks (Osuide, 1972), and humans (Yamada et al., 1967). Because of these findings,the -hydroxybutyric acid-treated animal has been proposed as an animal model for petit mal epilepsy(Snead, 1988, 1992).More direct evidence that -hydroxybutyric acid is responsible for the CNS action of 1,4-butanediol wasobtained by Roth and Giarman (1968), who found that the length of sleeping time in rats administered
91,4-Butanediol, NTP TOX 541,4-butanediol was proportional to the concentration of-hydroxybutyric acid in brain tissue. Within15 minutes after intravenous administration of 520 mg 1,4-butanediol per kilogram body weight to SpragueDawley rats, blood and brain concentrations of-hydroxybutyric acid (determined using gaschromatography) were significantly increased, and these concentrations continued to increase to a maximumthat occurred approximately 60 minutes (blood) or 90 minutes (brain) after administration. This increase in-hydroxybutyric acid blood and brain concentrations was accompanied by sleep onset 30 minutes afteradministration, and sleep continued until the-hydroxybutyric acid concentration returned to normal(approximately 150 minutes after administration). Concomitant administration of 1,4-butanediol and2 g -hydroxybutyric acid/kg, a compound which antagonizes-hydroxybutyric acid sleep induction, resultedin antagonized sleep induction, shortened sleeping time, and lower brain-hydroxybutyric acid concentrationthan that observed in rats after administration of 1,4-butanediol alone. In addition, both blood and brain-hydroxybutyric acid concentrations were lower in animals that received-hydroxybutyric acid than in thosegiven only 1,4-butanediol.Zabic et al. (1974) examined the dose response for behavioral effects of 1,4-butanediol in male SpragueDawley rats. Spontaneous motor activity was reduced at doses as low as 50 mg/kg with 100% cessation ofmotor activity at 300 mg/kg. Rotorod performance was unaffected at 100 mg/kg, but was significantlyimpaired at 200 mg/kg, while loss of righting reflex occurred at 300 mg/kg.-Butyrolactone, in the form of an unhydrolyzed, cyclic ester, does not produce behavioral arrest or spikewave discharge in the electroencephalogram of male Sprague-Dawley rats (Snead, 1991, 1992). However,the pharmacologic activity of -butyrolactone is essentially identical to that of 1,4-butanediol and-hydroxybutyric acid (Giarman and Roth, 1964; Sprince et al., 1966; Snead, 1992) after metabolicconversion to -hydroxybutyric acid.and liver to -hydroxybutyric acid.-Butyrolactone is rapidly hydrolyzed by an enzyme found in the blood-Butyrolactone has a half-life (t 1/2) of less than 1 minute in thisconversion (Roth and Giarman, 1965; Fishbein and Bessman, 1966).-Butyrolactone is less polar andtherefore better absorbed after oral administration than its hydrolyzed, free acid form,-hydroxybutyric acid.-Butyrolactone is converted to -hydroxybutyric acid so rapidly after absorption thatbioavailability is actually greater after administration of-hydroxybutyric acid-butyrolactone than after administration of anequivalent dose of -hydroxybutyric acid (Lettieri and Fung, 1978; Vree et al., 1978).Maxwell and Roth (1972) examined the ability of various rat tissues to metabolize [14C]-1,4-butanedio
annually (USITC, 1982a,b, 1983a,b, 1984a,b, 1985, 1986; Chemical Economics Handbook, 1993), while the quantity imported for the same period ranged from 2.0 to 27.7 million pounds annually. 1,4-Butanediol, NTP TOX 54 7 1,4-Butanediol is primarily used in the manufacture of tetrahydrofuran, -butyrolactone, and
Chemical Economics Handbook , 1993), while the quantity imported for the same period ranged from 2.0 to 27.7 million pounds annually. 1,4-Butanediol, NTP TOX 54 7 ; 1,4-Butanediol is primarily used in the manufacture of tetrahydrofuran, -butyrolactone, and polyvinylpyrrolidinone. 1,4-Butanediol is also used as a chain extender for polyurethanes .
responses by Shulgin and his research group and active dose work-ups of various substances. It covers the time frame of 1983 to 1984. The Creation of This Document: The project to undertake the transcribing of Shulgin’s Lab Books was started in 2008 by a team of volunteers and staff at Erowid, along with members of Team Shulgin.
Boric acid, aqueous 10 043353 A Bromine 7726956 C A Bromobenzene 108861 C A Hydrobromic acid 10 035106 C A Butanediol(1,3), aqueous 107880 A Butanediol(1,4) 110634 A Butanol 71363 A Butanon(2) see Ethyl methyl ketone Butyne(2)-diole(1,4) 110656 A Butyric acid 107926 CB A Butyric acid ethyl ester see Ethyl butyrate Butyl acetate 123864 C A
detection can be substituted for the GHB analysis, but comparatively poor sensitivity towards GBL and 1,4-butanediol is observed. Note that GHB (as GHB ) shows no column retention with this buffer system. Standard Solution Preparation: Prepare a mixed standard of GHB sodium salt (1-10 mg per mL), GBL (5-10 mg/mL), and 1,4-butanediol (1-10
216 G.L. Gessa / Alcohol 20 (2000) 215–216 However, abuse liability in alcoholic patients taking GHB for
providing an introduction to some of the more technical aspects of winemaking. However, the technical . wine is made by crushing the grapes and then fermenting the juice, the pulp, the skins and the seeds together for several days. Near the end
native London armed with hundreds of copies of the updated Book of the Dead and five thousand doses of LSD (which he procured from Czech government laboratories in Prague)." And communism did collapse, though not right then, and acid did have quite a bit to do with
Affected Publication: API Recommended Practice 2GEO/ISO 19901-4, Geotechnical and Foundation Design Considerations, 1st Edition, April 2011 ADDENDUM 1 Page 1, 1 Scope, replace the final bullet, and insert an additional bullet as follows: design of pile foundations, and soil-structure interaction for risers, flowlines, and auxiliary subsea structures. Page 1, 2 Normative References .
