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                                   TOX-54

     NTP Summary Report on the Metabolism, Disposition and Toxicity of
                     1,4-Butanediol (CAS No. 110-63-4)
                         Chemical Formula: C4H10O2
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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 gamma-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 gamma-hydroxybutyric acid. Gamma-
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 gamma-hydroxybutyric acid 
in peripheral tissues is unknown, in the brain and neuronal tissue it is 
thought to function as a neuromodulator. gamma-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 gamma-hydroxybutyric acid, gamma-butyrolactone, is also 
rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and 
liver of animals and humans. gamma-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 gamma-butyrolactone to gamma-hydroxybutyric 
acid, the evaluation of gamma-butyrolactone was in fact an evaluation of 
gamma-hydroxybutyric acid.

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

Synonyms: 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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