Toxicity of 1,4-Butanediol and its treatment

1,4-Butanediol (1,4-BD) is a clear, slightly viscous liquid with low vapor pressure. It is soluble in water, alcohol, esters and ketones, insoluble in aliphatic hydrocarbons, and can be used to make polyester glycols and polyurethanes. 1,4-BD is also the dihydroxy precursor of gamma-hydroxybutyric acid (GHB), a popular recreational drug that has been banned by the U.S. Food and Drug Administration (FDA) and regulated as a federal Class I drug. 1,4-BD is converted to GHB in the body through the enzymatic action of alcohol dehydrogenase (ADH). Overdose can cause coma, severe respiratory depression, bradycardia, hypothermia, seizures, and death.

Toxicity

1,4-Butanediol (1,4-BD) has low acute oral toxicity, with LD50 values of 1525 and 1780 mg/kg for rats, 1650 and 2062 mg/kg for mice, 1200 mg/kg for guinea pigs, and 2531 mg/kg for rabbits. Doses lethal to young rats within 6 hours (2-40 g/kg) result in rapid anesthesia, pupil constriction, and loss of reflexes, with death attributed to central nervous system (CNS) paralysis. The LD50 after dermal application is 1 g/kg. It is slightly irritating to rabbit skin and eyes, and no allergic contact dermatitis has been observed in guinea pigs.

In addition, 1,4-BD has low acute inhalation toxicity, with a 4-hour ALC of 15 mg/L in male rats. In a repeated dose study, groups of 10 male Cr1:CD rats were exposed to aerosol concentrations of 0, 0.20, 1.7, or 5.2 mg/l via the nose alone for 6 h per day, 5 days per week, for 2 weeks. Pathology, urinalysis, and clinical chemistry were performed on the rats after the last (tenth) exposure and after a 2-week recovery period. No adverse effects were observed in rats exposed to 0.20 or 1.1 mg/l. Rats exposed to 5.2 mg/l showed a significant decrease in body weight after the third exposure. After 10 exposures, these rats showed an increase in red blood cell counts and hematocrit, and a decrease in serum cholesterol concentrations. Pathological examination showed slight atrophy of thymic lymphocytes and a decrease in mean heart weight in these rats. No adverse effects were observed after a 2-week recovery period. Both 0.20 and 7.1 mg/l were no-adverse-effect concentrations. At 5.2 mg/l, rats showed nonspecific reversible systemic effects.

Subacute oral administration of 1,4-BD resulted in an overall low degree of systemic toxicity. At the highest dose of 500 mg/kg/day, slightly elevated sorbitol dehydrogenase and alanine aminotransferase activities were observed in male rats after 28 days of 1,4-BD administration, along with some disturbances in hematological parameters characterized by macrocytosis and thrombocytopenia. Treated animals developed mild to moderate hepatic inflammation characterized by bile duct proliferation and periportal infiltration of fibroblasts and mononuclear cells. 1,4-BD was also not determined to be developmentally toxic. Acute toxicity data showed moderate toxicity by the oral route, with the most common clinical signs being respiratory depression, lateral recumbency, and rigidity.

Treatment

There is currently no antidote for 1,4-Butanediol. We pretreated CD-1 mice with the ADH antagonist 4-methylpyrazole (4-MP) to determine whether blocking ADH could prevent or reduce toxicity caused by 1,4-BD overdose. After pretreatment with 4-MP, the toxic dose-50 (TD50) of 1,4-BD on the righting reflex of mice increased from 585 mg/kg (95% CI, 484-707 mg/kg) in the control group to 5,550 mg/kg (95% CI, 5,353-5,756 mg/kg) in the pretreated group. Pretreatment with 4-MP also increased the LD50 of 1,4-BD in the rotarod test from 163 mg/kg (95% CI, 136-196 mg/kg) in control mice to 4,900 mg/kg (95% CI, 4,812-4,989 mg/kg) in pretreated mice. Pretreatment with 4-MP significantly reduced the toxicity of 1,4-BD in CD-1 mice, possibly by inhibiting its bioconversion from ADH to GHB.

A case of a 43-year-old male who ingested 30 mL of a homemade 1,4-BD solution and developed generalized seizures and coma was reported. A loading dose of fomepizole 10 mg/kg was started intravenously on admission, followed by two injections of 10 mg/kg every 12 hours. The patient regained consciousness shortly after fomepizole administration. Initial plasma 1,4-butanediol and γ-hydroxybutyrate concentrations measured by gas chromatography-mass spectrometry were 24 and 222 mg/L, respectively. Subsequent 1,4-butanediol and γ-hydroxybutyrate assays showed further formation of γ-hydroxybutyrate after administration of fomepizole. This suggests that fomepizole appears to be safe in this patient with 1,4-BD poisoning. It is unclear whether fomepizole affected his clinical course, but the rapid awakening observed suggests that it may have been useful. However, further experience is needed to determine the efficacy of this detoxification therapy for 1,4-BD poisoning.

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