NTP Study Reports
Abstract for TOX-54 - 1,4-Butanediol
TOX-54
NTP Summary Report on the
Metabolism, Disposition and Toxicity of 1,4-Butanediol (CAS No. 110-63-4)
Chemical Formula: | C4H10O2 |
---|
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
g-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
g-hydroxybutyric acid. g-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 g-hydroxybutyric
acid in peripheral tissues is unknown, in the brain and neuronal
tissue it is thought to function as a neuromodulator. g-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 g-hydroxybutyric
acid, g-butyrolactone,
is also rapidly converted to g-hydroxybutyric
acid by enzymes in the blood and liver of animals and humans.
g-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 g-butyrolactone to
g-hydroxybutyric
acid, the evaluation of g-butyrolactone was in fact an
evaluation
of g-hydroxybutyric acid.
This summary report presents a review of the current literature which documents that both 1,4-butanediol and g-butyrolactone are rapidly metabolized to g-hydroxybutyric acid, and the pharmacologic and toxicologic responses to these chemicals are due to their metabolic conversion to g-hydroxybutyric acid. Because the toxicity and carcinogenicity of g-hydroxybutyric acid was fully evaluated in the NTP studies of g-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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