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TOX-54: 1,4-Butanediol National Toxicology Program Toxicity Report Series Number 54 NTP Summary Report on the Metabolism, Disposition, and Toxicity of 1,4-Butanediol (CAS No. 110-63-4) Richard D. Irwin, Ph.D., Study Scientist National Toxicology Program Post Office Box 12233 Research Triangle Park, NC 27709 NIH Publication 96-3932 May 1996 United States Department of Health and Human Services Public Health Service National Institutes of Health NOTE TO THE READER The National Toxicology Program (NTP) is made up of four charter agencies of the U.S. Department of Health and Human Services (DHHS): the National Cancer Institute (NCI), National Institutes of Health; the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center for Toxicological Research (NCTR), Food and Drug Administration; and the National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control. In July 1981, the Carcinogenesis Bioassay Testing Program, NCI, was transferred to the NIEHS. The NTP coordinates the relevant programs, staff, and resources from these Public Health Service agencies relating to basic and applied research and to biological assay development and validation. The NTP develops, evaluates, and disseminates scientific information about potentially toxic and hazardous chemicals. This knowledge is used for protecting the health of the American people and for the primary prevention of disease. The studies described in this Report were performed under the direction of the NIEHS and were conducted in compliance 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 Health Service Policy on Humane Care and Use of Animals. Chemicals selected for NTP toxicology and carcinogenesis studies are chosen primarily on the bases of human exposure, level of production, and chemical structure. Selection per se is not an indicator of a chemical's carcinogenic 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 of this 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 Program Toxicity Report Series Number 54 NTP Summary Report on the Metabolism, Disposition, and Toxicity of 1,4-Butanediol (CAS No. 110-63-4) Richard D. Irwin, Ph.D., Study Scientist National Toxicology Program Post Office Box 12233 Research Triangle Park, NC 27709 NIH Publication No. 96-3932 May 1996 United States Department of Health and Human Services Public Health Service National Institutes of Health 2 1,4-Butanediol, NTP TOX 54 CONTRIBUTORS This summary NTP report on the metabolism, disposition, and toxicity studies of 1,4-butanediol is based partially on studies that took place from December 1988 through February 1989. National Toxicology Program Research Triangle Institute Evaluated and interpreted results and reported findings Provided absorption, distribution, metabolism, and excretion evaluation R.D. Irwin, Ph.D., Study Scientist J.R. Bucher, Ph.D. A.R. Jeffcoat, Ph.D., Principal Investigator L.T. Burka, Ph.D. J.M. Mathews, Ph.D., Study Director M.R. Elwell, D.V.M., Ph.D. D.B. Feldman, D.V.M. J. Mahler, D.V.M. P. Troxler G.S. Travlos, D.V.M. Biotechnical Services, Inc. Prepared Toxicity Study Report D.D. Lambright, Ph.D., Principal Investigator C.M. Bailey, B.S. Pharm. S.R. Gunnels, M.A. 1,4-Butanediol, NTP TOX 54 3 PEER REVIEW The draft summary report on the metabolism, disposition, and toxicity of 1,4-butanediol was evaluated by the reviewers 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 NTP studies are appropriate and ensure that this summary report of the metabolism, disposition, and toxicity studies presents the experimental results and conclusions fully and clearly. The comments of the reviewers were received and reviewed prior to the finalization of this document. Changes have been made such that the concerns of the reviewers have been addressed to the extent possible. Gary P. Carlson, Ph.D. Mary Jo Vodicnik, Ph.D. School of Health Sciences Lilly Research Laboratories Purdue University Toxicology Research Laboratories West Lafayette, IN Greenfield, IN Jay I. Goodman, Ph.D Department of Pharmacology and Toxicology Michigan State University East Lansing, MI 4 1,4-Butanediol, NTP TOX 54 TABLE OF CONTENTS ABSTRACT .......................................................................... 5 CHEMICAL ANDPHYSICAL PROPERTIES ................................................ 6 PRODUCTION, USE, AND HUMAN EXPOSURE ............................................. 6 NOMINATION ANDRECOMMENDATIONS ................................................ 7 PHARMACOLOGY .................................................................. 7 METABOLISM ANDDISPOSITION ...................................................... 11 TOXICITY ........................................................................ 15 CARCINOGENICITY ................................................................ 17 GENETIC TOXICITY ................................................................ 17 DISCUSSION ...................................................................... 8 CONCLUSION ..................................................................... 19 REFERENCES ..................................................................... 21 APPENDIXES Appendix A Metabolism and Disposition Studies of 1,4-Butanediol in Male F344/N Rats ............... A-1 Appendix B Survival and Mean Body Weight Results for F344/N Rats and B6C3F 1 Mice in the 16-Day and 13-Week Gavage Studies of -Butyrolactone .......................... B-1 1,4-Butanediol, NTP TOX 54 5 HO-CH2 -CH 2-CH 2-CH 2-OH 1,4-BUTANEDIOL CAS No. 110-63-4 Chemical Formula: C4 H 10 O 2 Molecular Weight: 90.14 Synonyms: Butanediol, butane-1,4-diol, 1,4-butylene glycol, 1,4-dihydroxybutane, 1,4-tetramethylene glycol, butylene glycol, tetramethylene 1,4-diol Trade names: Diol 14B, Sucol B ABSTRACT 1,4-Butanediol is an industrial chemical used in the manufacture of other organic chemicals. It was nominated by the National Cancer Institute and selected for evaluation by the NTP because of high production volume, the potential for worker exposure, the lack of adequate toxicological characterization, and the 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 rats 14 14 by the NTP confirmed the rapid and extensive conversion of 1-[ C]-1,4-butanediol to CO 2 . Because of this rapid and extensive conversion, the toxicological profile of 1,4-butanediol reflects that of -hydroxybutyric acid. -Hydroxybutyric acid is a naturally occurring chemical found in the brain and peripheral tissues which is 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 to function as a neuromodulator. -Hydroxybutyric acid readily crosses the blood-brain barrier, and oral, intraperitoneal, or intravenous administration elicits characteristic neuropharmacologic responses. These same responses are observed after administration of 1,4-butanediol. The lactone of -hydroxybutyric acid, -butyrolactone, is also rapidly converted to -hydroxybutyric acid by enzymes in the blood and liver of animals and humans. -Butyrolactone was previously evaluated by the NTP in 14-day and 13-week toxicology studies and 2-year toxicology and carcinogenesis studies in F344/N rats and B6C3F 1 mice. No organ-specific toxicity occurred in the toxicology studies. In the carcinogenesis studies, an equivocal response occurred in male mice, based on a marginal increase in the 6 1,4-Butanediol, NTP TOX 54 incidence 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 toxicologic responses to these chemicals are due to their metabolic conversion to -hydroxybutyric acid. Because the toxicity 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 is concluded that there is a high likelihood that 1,4-butanediol would be negative in a similar set of studies. For these reasons, it is the opinion of the NTP that 1,4-butanediol should be considered not carcinogenic in animals and no further evaluation of 1,4-butanediol is needed at this time. CHEMICAL AND PHYSICAL PROPERTIES 1,4-Butanediol is a colorless, viscous liquid with a molecular weight of 90.14, a density of 1.0154 at 25 C, and a boiling point of 228 C (Lewis, 1991). It is soluble in water, dimethyl sulfoxide,
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