Abstract for TOX-54

Summary Report on the Metabolism, Disposition and Toxicity of 1,4-Butanediol 

CASRN: 110-63-4
Chemical Formula: C4H10O2
Molecular Weight: 90.14
Synonyms/Common Names: Butanediol; butane-1,4-diol; 1,4-butylene glycol; 1,4-dihydroxybutane, 1,4-tetramethylene glycol; butylene glycol; tetramethylene 1,4-diol
Report Date: May 1996

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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 γ-hydroxybutyric acid in animals and humans. 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. Because of this rapid and extensive conversion, the toxicological profile of 1,4-butanediol reflects that of γ-hydroxybutyric acid. γ-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 γ-hydroxybutyric acid in peripheral tissues is unknown, in the brain and neuronal tissue it is thought to function as a neuromodulator. γ-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 γ-hydroxybutyric acid, γ-butyrolactone, is also rapidly converted to γ-hydroxybutyric acid by enzymes in the blood and liver of animals and humans. γ-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 B6C3F1 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 incidence of pheochromocytomas of the renal medulla. Because of the rapid and extensive conversion of γ-butyrolactone to γ-hydroxybutyric acid, the evaluation of γ-butyrolactone was in fact an evaluation of γ-hydroxybutyric acid.

This summary report presents a review of the current literature which documents that both 1,4-butanediol and γ-butyrolactone are rapidly metabolized to γ-hydroxybutyric acid, and the pharmacologic and toxicologic responses to these chemicals are due to their metabolic conversion to γ-hydroxybutyric acid. Because the toxicity and carcinogenicity of γ-hydroxybutyric acid was fully evaluated in the NTP studies of γ-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.