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Paraldehyde
Paraldehyde
Paraldehyde
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Paraldehyde
Skeletal formula
Names
IUPAC name
2,4,6-Trimethyl-1,3,5-trioxane
Systematic IUPAC name
2,4,6-Trimethyl-1,3,5-trioxane
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.004.219 Edit this at Wikidata
EC Number
  • 204-639-8
KEGG
MeSH Paraldehyde
UNII
  • InChI=1S/C6H12O3/c1-4-7-5(2)9-6(3)8-4/h4-6H,1-3H3 checkY
    Key: SQYNKIJPMDEDEG-UHFFFAOYSA-N checkY
  • InChI=1/C6H12O3/c1-4-7-5(2)9-6(3)8-4/h4-6H,1-3H3
    Key: SQYNKIJPMDEDEG-UHFFFAOYAO
  • CC1OC(C)OC(C)O1
Properties
C6H12O3
Molar mass 132.159 g·mol−1
Appearance Colourless liquid
Odor Sweet
Density 0.996 g/cm3
Melting point 12 °C (54 °F; 285 K)
Boiling point 124 °C (255 °F; 397 K)[1]
soluble 10% vv at 25 Deg.
Vapor pressure 13 hPa at 20 °C[1]
−86.2·10−6 cm3/mol
Pharmacology
N05CC05 (WHO)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Flammable
GHS labelling:
GHS02: Flammable
Warning
H226
P210, P233, P303+P361+P353, P370+P378, P403+P235, P501
Flash point 24°C - closed cup
Explosive limits Upper limit: 17 %(V)
Lower limit: 1.3 %(V)
Lethal dose or concentration (LD, LC):
Oral - Rat - 1,530 mg/kg
Dermal - Rabbit - 14,015 mg/kg
Safety data sheet (SDS) [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Paraldehyde is the cyclic trimer of acetaldehyde molecules.[2] Formally, it is a derivative of 1,3,5-trioxane, with a methyl group substituted for a hydrogen atom at each carbon. The corresponding tetramer is metaldehyde. A colourless liquid, it is sparingly soluble in water and highly soluble in ethanol. Paraldehyde slowly oxidizes in air, turning brown and producing an odour of acetic acid. It attacks most plastics and rubbers and should be kept in glass bottles.

Paraldehyde was first observed in 1835 by the German chemist Justus Liebig; its empirical formula was determined in 1838 by Liebig's student Hermann Fehling.[3][4] The German chemist Valentin Hermann Weidenbusch (1821–1893), another of Liebig's students, synthesized paraldehyde in 1848 by treating acetaldehyde with acid (either sulfuric or nitric acid) and cooling to 0°C. He found it quite remarkable that when paraldehyde was heated with a trace of the same acid, the reaction went the other way, recreating acetaldehyde.[5][6]

Paraldehyde has uses in industry and medicine.

Preparation

[edit]

Paraldehyde can be produced by the direct reaction of acetaldehyde and sulfuric acid. The product of the reaction is dependent on the temperature. At room temperature and higher, the formation of trimer is preferred, but at lower temperatures, around  −10 °C, the tetramer metaldehyde is more likely to be produced.[7]

The reaction of sulfuric acid and acetaldehyde is exothermic, with the heat of reaction being −113 kJ·mol−1.[8]

Stereochemistry

[edit]

Paraldehyde is produced and used as a mixture of two diastereomers, known as cis- and trans-paraldehyde. For each diastereomer, two chair conformers are possible. The structures (1), (4) and (2), (3) are conformers of cis- and trans-paraldehyde, respectively. The structures (3) (a conformer of (2)) and (4) (a conformer of (1)) are high energy conformers on steric grounds (1,3-diaxial interactions are present) and do not exist to any appreciable extent in a sample of paraldehyde.[9][10]

stereochemistry of paraldehyd

Reactions

[edit]

Heated with catalytic amounts of acid, it depolymerizes back to acetaldehyde:[11][12]

C6H12O3 → 3CH3CHO

Since paraldehyde has better handling characteristics, it may be used indirectly or directly as a synthetic equivalent of anhydrous acetaldehyde (b.p. 20 °C). For example, it is used as-is in the synthesis of bromal (tribromoacetaldehyde):[13]

C6H12O3 + 9 Br2 → 3 CBr3CHO + 9 HBr

Medical applications

[edit]

Paraldehyde was introduced into clinical practice in the UK by the Italian physician Vincenzo Cervello (1854–1918) in 1882.[14][15][16]

It is a central nervous system depressant and was soon found to be an effective anticonvulsant, hypnotic and sedative. It was included in some cough medicines as an expectorant (though there is no known mechanism for this function beyond the placebo effect).

Paraldehyde was the last injection given to Edith Alice Morrell in 1950 by the suspected serial killer John Bodkin Adams. He was tried for her murder but acquitted.

As a hypnotic/sedative

[edit]

It was commonly used to induce sleep in sufferers from delirium tremens but has been replaced by other drugs in this regard. It was considered to have been one of the safest hypnotics and was regularly given at bedtime in psychiatric hospitals and geriatric wards until the 1970s [citation needed], but after it was confirmed that acetaldehyde is a confirmed category-1 human carcinogen, it could no longer be considered appropriately safe to use. Up to 30% of the dose is excreted via the lungs (the rest via the liver). This contributes to a strong unpleasant odour on the breath.

As anti-seizure drug

[edit]

Today, paraldehyde is sometimes used to treat status epilepticus. Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when no resuscitation facilities exist or when the patient's breathing is already compromised.[17] This makes it a useful emergency medication for parents and other caretakers of children with epilepsy. Since the dose margin between the anticonvulsant and hypnotic effect is small, paraldehyde treatment usually results in sleep.

Administration

[edit]
A 5 mL glass ampoule of paraldehyde.

Generic paraldehyde is available in 5 mL sealed glass ampoules. Production in the US has been discontinued, but it was previously marketed as Paral.

Paraldehyde has been given orally, rectally, intravenously and by intramuscular injection. It reacts with rubber and plastic which limits the time it may safely be kept in contact with some syringes or tubing before administration.

  • Injection. Intramuscular injection can be very painful and lead to sterile abscesses, nerve damage, and tissue necrosis. Intravenous administration can lead to pulmonary edema, circulatory collapse and other complications.
  • Oral. Paraldehyde has a hot burning taste and can upset the stomach. It is often mixed with milk or fruit juice in a glass cup and stirred with a metal spoon.
  • Rectal. It may be mixed 1 part paraldehyde with 9 parts saline or, alternatively, with an equal mixture of peanut or olive oil.

Industrial applications

[edit]

Paraldehyde is used in resin manufacture as an alternative to formaldehyde when making phenol formaldehyde resins. It has also found use as antimicrobial preservative, and rarely as a solvent. It has been used in the generation of aldehyde fuchsin.[18]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Paraldehyde

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from Grokipedia
Paraldehyde is an with the C₆H₁₂O₃, existing as a cyclic trimer of and known systematically as 2,4,6-trimethyl-1,3,5-trioxane. It appears as a clear, colorless liquid with a pleasant , possessing a of 12.6°C, of 124.5°C, and of 0.99 g/cm³, and it is moderately soluble in at 125 g/L. Historically introduced in the , paraldehyde served as one of the earliest synthetic sedative-hypnotic agents, acting as a to induce , , and effects. It was widely employed for treating convulsive disorders such as , managing symptoms of alcohol withdrawal including , and addressing nervous and mental conditions like and agitation in psychiatric settings. Administered orally, rectally, or via injection, its pharmacological action involves , believed to occur via reduction of release in response to neuronal , though the exact mechanism remains unclear. Despite its efficacy, paraldehyde's use has significantly declined since the mid-20th century due to the development of safer alternatives like benzodiazepines and the availability of more tolerable anticonvulsants. Common side effects include drowsiness, , gastric irritation, and a characteristic unpleasant breath , while serious risks encompass respiratory depression, dependence with prolonged use, and toxicity in overdose manifesting as or . It is contraindicated in patients with , gastrointestinal ulcers, or those using disulfiram, and it interacts additively with other CNS depressants. Regulatorily classified as a DEA Schedule IV due to its low potential for abuse relative to higher schedules, paraldehyde is now rarely prescribed and primarily retained for niche applications in resource-limited settings or . Additionally, it is recognized as a hazardous substance under EPA regulations for its flammability and irritant properties.

Introduction

Overview

Paraldehyde is an with the C6H12O3, recognized as the cyclic trimer of . It forms a six-membered ring structure consisting of three units linked via oxygen atoms, distinguishing it from its linear polymer forms. This compound appears as a colorless, volatile at , characterized by a strong, pungent and a disagreeable, burning taste. Paraldehyde exhibits limited in , approximately 12.5 g per 100 mL at 25°C, but is fully miscible with , , and fixed oils, which facilitates its handling in various formulations. Paraldehyde was first observed in 1835 by the German chemist during studies on , with its determined shortly thereafter; it was synthesized in pure form in 1848 by Valentin Hermann Weidenbusch using acid-catalyzed treatment of . As an older , paraldehyde retains niche applications today as a and in refractory seizures, alongside industrial roles in resin synthesis.

History

Paraldehyde was first observed in 1835 by the German chemist as a polymerization product of during experiments. This accidental discovery marked the initial recognition of the compound, though its structure and potential applications remained unexplored for over a decade. In 1848, Valentin Hermann Weidenbusch, another of Liebig's students, achieved the intentional synthesis of paraldehyde through acid-catalyzed trimerization of , establishing a reproducible method for its production. The compound's medical adoption began in 1882 when Italian physician Vincenzo Cervello introduced it into clinical practice in the as a safer alternative to for . It quickly gained popularity in the early for managing psychiatric conditions and epileptic seizures, valued for its rapid onset and relatively low toxicity compared to earlier sedatives. By the mid-, paraldehyde had become a staple treatment for severe cases of and , often administered rectally or intramuscularly in emergency settings due to its effectiveness in controlling agitation and convulsions. Its prominence waned in the 1970s as benzodiazepines, such as and chlordiazepoxide, emerged as preferred alternatives owing to their easier administration, broader safety profile, and reduced risk of adverse effects. Production in the United States ceased by the amid manufacturing challenges and the availability of superior options, leading to its withdrawal from mainstream Western markets. Nevertheless, as of 2025, paraldehyde persists in niche roles in some developing regions, particularly , where it remains a first-line intramuscular agent for control in resource-limited settings when benzodiazepines are unavailable.

Chemistry

Structure and stereochemistry

Paraldehyde features a six-membered ring formed by the cyclization of three molecules, with methyl substituents at the 2, 4, and 6 positions. This structure adopts a chair-like conformation analogous to that of , providing stability through minimized torsional strain. The molecule exists as two s: the cis , in which all three methyl groups occupy equatorial positions, and the trans , featuring two axial methyl groups and one equatorial. The cis form is thermodynamically more stable, as the trans configuration incurs significant steric repulsion from 1,3-diaxial interactions between the axial methyl groups. In typical syntheses and equilibrium mixtures, the cis predominates. Each possesses two interconvertible conformers via ring inversion. Structural analyses reveal an average C-O of approximately 1.42 Å within the ring, accompanied by C-C bond lengths around 1.51 Å and O-C-O bond angles near 110°. The ring exhibits puckering, with torsion angles reflecting the distortion typical of heterocyclic six-membered rings. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography provide confirmation of these structural features.

Physical and chemical properties

Paraldehyde is a clear, colorless at , with a of approximately 0.994 g/cm³ at 20 °C. Its melting point is 12.6 °C, and it boils at 124 °C under standard pressure. The compound exhibits a characteristic aromatic , often described as pleasant or sweet, accompanied by a disagreeable, burning . Paraldehyde shows moderate in , approximately 125 g/L at 25 °C, and is miscible with most organic solvents such as , , , and oils. It is volatile, with a ranging from 11 to 25 mmHg at 20–25 °C, facilitating easy evaporation. In terms of stability, paraldehyde oxidizes slowly upon exposure to air and light, decomposing to acetaldehyde and acetic acid, which can cause the liquid to turn yellow-brown over time. It remains chemically stable under standard ambient conditions but is incompatible with strong acids and oxidizers. Thermodynamically, the standard enthalpy of formation for liquid paraldehyde is -681.8 kJ/mol, while its heat of vaporization is approximately 41–46 kJ/mol.

Synthesis

Paraldehyde is synthesized through the acid-catalyzed cyclotrimerization of , a process first achieved in 1848 by German chemist Valentin Hermann Weidenbusch, who treated with hydrochloric or . This reaction involves the condensation of three molecules of (3\ceCH3CHO→\ceC6H12O33 \ce{CH3CHO} \rightarrow \ce{C6H12O3}), forming a cyclic trimer known as 2,4,6-trimethyl-1,3,5-trioxane, and is exothermic with a standard change of ΔH=−113 kJ/mol\Delta H = -113 \, \mathrm{kJ/mol}. The mechanism proceeds via of the carbonyl oxygen of , facilitating nucleophilic attack by another molecule to form intermediates, followed by cyclization and under acidic conditions. In laboratory settings, paraldehyde is typically prepared by adding concentrated (0.5–1% by weight) to anhydrous at (approximately 20 °C), with the reaction completing within 1–2 hours and yielding over 90% of the trimer, predominantly the cis isomer due to thermodynamic stability. The mixture is then neutralized with a base such as to quench the catalyst. Temperature plays a critical role in product distribution: at around 20 °C, the trimer (paraldehyde) predominates, while cooling to -10 °C favors formation of the tetramer () as a solid precipitate; the exists in reversible equilibrium, shifting toward upon heating above 80 °C. Purification involves under reduced pressure (typically 20–50 mmHg at 50–60 °C) to separate unreacted (boiling point 21 °C) and minor paracetaldehyde impurities (higher oligomers), yielding a clear, colorless product. Alternatively, can isolate the paraldehyde by solidifying impurities. Modern industrial variants employ heterogeneous catalysts such as cation-exchange resins (e.g., sulfonic acid-functionalized like Amberlyst-15) in fixed-bed reactors, allowing for continuous operation at 15–30 °C with reaction times of 1–5 hours and improved catalyst recyclability over traditional homogeneous acids like H₂SO₄ or HCl. These resin-based methods reduce and simplify while maintaining high selectivity for the trimer.

Reactivity

Paraldehyde, a cyclic trimer of , exhibits reactivity primarily through its acetal-like structure, which allows for ring opening and transformation under specific conditions. The most prominent reaction is , which reverses the formation of the trimer and yields . This occurs upon heating with dilute acids, such as at 100 °C, according to the equation: \ceC6H12O3−>[HCl,100∘C]3CH3CHO\ce{C6H12O3 ->[HCl, 100^\circ C] 3 CH3CHO} This acid-catalyzed process involves of the oxygen atoms in the ring, facilitating cleavage and reversion to the . is also observed with other mineral acids like and proceeds readily at elevated temperatures, highlighting paraldehyde's sensitivity to acidic environments. Hydrolysis of paraldehyde in water under acidic conditions proceeds slowly via ring opening, producing acetaldehyde and water. This reaction is analogous to the depolymerization but occurs in aqueous media, where the protonated acetal undergoes nucleophilic attack by water, leading to stepwise dissociation of the cyclic structure. At 25 °C in various aqueous acid solutions, the rate depends on the acidity, with stronger acids accelerating the process. Unlike neutral or basic aqueous conditions, where paraldehyde remains stable, acidic hydrolysis underscores its vulnerability to protonation. Oxidation represents another key reactivity pathway for paraldehyde. Exposure to air or light during prolonged storage leads to slow oxidation, forming peroxy compounds and ultimately acetic acid, which imparts a characteristic odor and discoloration. Paraldehyde also reacts vigorously with , first depolymerizing to and then undergoing α-bromination to yield bromal (tribromoacetaldehyde). The overall is: \ceC6H12O3+9Br2−>3CBr3CHO+9HBr\ce{C6H12O3 + 9 Br2 -> 3 CBr3CHO + 9 HBr} This transformation is typically conducted in solvents like and exemplifies paraldehyde's susceptibility to strong oxidants. Under basic conditions, paraldehyde is generally inert and does not undergo significant , distinguishing it from its acid-sensitive behavior. However, in the presence of and base, it can participate in reactions forming higher oligomers or resinous materials, leveraging its functionality for cross-linking. Overall, paraldehyde's stability to bases contrasts with its reactivity toward strong acids and oxidants, limiting its handling to inert conditions for storage and use.

Pharmacology

Mechanism of action

Paraldehyde functions as a (CNS) depressant, exerting its pharmacological effects through enhancement of inhibitory . Although its precise mechanism remains incompletely elucidated, evidence indicates that it inhibits the synaptosomal disposal of gamma-aminobutyric acid (GABA), the primary inhibitory in the , thereby prolonging GABA availability and amplifying its suppressive effects on neuronal activity. This action parallels the GABA_A receptor modulation seen with barbiturates, which facilitate conductance to hyperpolarize neurons and dampen excitability, but paraldehyde achieves CNS depression without equivalent direct receptor binding or pronounced respiratory suppression at therapeutic doses. In its role, paraldehyde stabilizes neuronal membrane potentials by curtailing the spread of hyperexcitable impulses, as evidenced by its ability to stop motor s in lithium-pilocarpine-induced models in immature rats. Animal studies further demonstrate dose-dependent reductions in release following neuronal , contributing to suppression without the specificity of modern antiepileptics. The properties of paraldehyde arise from its depression of the ascending reticular activating , promoting and while exerting negligible effects. As a non-selective CNS , it produces broad inhibitory effects with comparatively limited influence on cardiovascular or respiratory centers relative to , allowing therapeutic use in settings requiring without rapid ventilatory compromise. Historical research constraints have precluded detailed binding affinity studies, but EEG investigations consistently reveal paraldehyde-induced slowing and synchronization of brain waves, underscoring its dose-proportional impact.

Pharmacokinetics

Paraldehyde is rapidly absorbed from the following , with approximately 93% and peak plasma concentrations reached within 20-60 minutes. It is also quickly absorbed via rectal or intramuscular routes, though specific data for these are limited. The drug distributes widely to body tissues, including the and , owing to its lipophilic nature that enables easy passage across the blood-brain barrier. In adults, the volume of distribution is approximately 0.89 L/kg, reflecting extensive tissue penetration. Metabolism primarily occurs in the liver through depolymerization to acetaldehyde, followed by oxidation via aldehyde dehydrogenase to acetic acid, and further breakdown to carbon dioxide and water; cytochrome P450 enzymes are involved in the initial depolymerization step. About 70-90% of an administered dose undergoes hepatic metabolism, with no active metabolites produced. Elimination occurs mainly through pulmonary excretion, with 11-30% of the dose exhaled unchanged, accounting for the characteristic breath ; renal clearance is minimal, involving only 0.1-2.5% as unchanged . The plasma in adults ranges from 3.4 to 9.8 hours (mean approximately 7 hours), though it may be prolonged in neonates or with concurrent use of drugs like .

Medical applications

Sedative and hypnotic uses

Paraldehyde has been employed primarily as a sedative and hypnotic agent for managing acute agitation, insomnia among psychiatric patients, and delirium tremens during alcohol withdrawal. In clinical practice during the 19th and early 20th centuries, particularly in asylums and mental hospitals, paraldehyde was administered orally or rectally at doses of 5-10 g for adults, typically inducing sleep within 15-30 minutes. This agent provided reliable with minimal residual effects such as , making it a preferred alternative to s for short-term use before the , when concerns over barbiturate dependency arose. Historical evidence from clinical observations in psychiatric settings demonstrated its effectiveness in sedating manic or agitated patients, with reports indicating successful calming in a substantial proportion of cases, though no large-scale modern randomized controlled trials exist due to its declining use. By 2025, paraldehyde has become largely obsolete in developed countries, supplanted by safer benzodiazepines for , but it retains occasional application in resource-limited settings for agitation where alternatives are unavailable. A common includes a persistent garlic-like on the breath.

uses

Paraldehyde serves as an primarily for the management of , particularly in pediatric cases to first-line benzodiazepines, as well as for controlling seizures in and muscle spasms in . Its efficacy in these emergency settings stems from its rapid depressant action, which interrupts prolonged convulsive activity without requiring immediate intravenous access in all cases. The standard dosage for use is 0.1-0.15 mL/kg administered intramuscularly for children, or 0.3 mL/kg paraldehyde diluted 1:1 with oil administered rectally (total 0.6 mL/kg), often for rectal delivery to minimize irritation. Adults typically receive 5-10 mL or up to 10-12 mL rectally. occurs within 5-15 minutes following intramuscular or , with effects lasting 4-8 hours, allowing for repeat dosing as needed while monitoring for recurrence. A key advantage of paraldehyde in anticonvulsant therapy is its lack of significant respiratory depression at therapeutic doses, distinguishing it from benzodiazepines and making it valuable for neonates and in resource-limited environments where ventilatory support may be unavailable. This profile supports its application in high-risk populations, including infants with immature respiratory systems. As of 2025, paraldehyde is rarely used in developed countries due to commercial unavailability and preference for benzodiazepines, but remains an option in guidelines for refractory cases where IV access is difficult. In contrast, its use in Western countries remains limited under 2025 guidelines, which prioritize benzodiazepines such as or due to superior efficacy profiles and ease of administration. Clinical evidence from studies in the 1960s through 1980s, including retrospective analyses and case series, reported seizure control rates of 60-90% with paraldehyde in , often achieving cessation within the first hour of administration. More recent case reports highlight its utility in scenarios, such as benzodiazepine-resistant convulsions, where it provided rapid termination without additional immediate interventions.

Administration

Paraldehyde is administered via several routes to achieve therapeutic effects, primarily for and control, with route selection influenced by the need for rapid onset and patient condition. The primary routes include , rectal, , and, less commonly, intravenous (IV). involves dilution in or to minimize gastric irritation, while rectal use employs a 1:1 dilution with or for delivery to facilitate absorption. IM injections are given deeply into the gluteal muscle, avoiding nerve trunks, and IV administration requires dilution to prevent complications. Paraldehyde is supplied in 5 mL ampoules or vials to prevent adsorption or reaction with or rubber materials, which can degrade the . For IV use, it is diluted 1:10 with normal saline or 5% dextrose to form a 5% solution, and administration occurs slowly via tubing to avoid pulmonary issues. No more than 5 mL should be injected per IM site to reduce pain and tissue damage. Dosing guidelines vary by route, age, and indication, with repeats typically every 4-6 hours as needed. For oral in adults, 5-10 mL is used, diluted appropriately; children receive 0.15-0.3 mL/kg. Rectal dosing for seizures in children is 0.3 mL/kg paraldehyde diluted 1:1 with or (total volume 0.6 mL/kg of 50% solution), up to 10-12 mL in adults, providing rapid absorption. IM doses for adult are 5-10 mL, and for children with seizures, 0.1-0.15 mL/kg; doses in adults range from 5-10 mL. Maximum daily limits include 30 mL on the first day for alcohol withdrawal, reducing thereafter. Precautions emphasize safe handling and monitoring to mitigate risks. Store paraldehyde below 25°C in a cool, dark place, as it decomposes when exposed to or air, potentially turning brownish or developing a vinegar-like , rendering it unusable. Use only freshly opened ampoules, and discard after single use; if crystallized, warm gently to liquefy. Avoid aspiration during oral or to prevent chemical , and monitor for local reactions such as pain or sterile at IM sites. Historically, IV administration of paraldehyde declined after the 1970s due to risks of vein irritation, , and circulatory collapse, leading to a preference for rectal routes in emergencies for faster, safer delivery.

Safety and adverse effects

Side effects

Paraldehyde administration commonly results in a strong, fruity on the breath due to its pulmonary . This is a frequent and characteristic effect observed in most users. With oral use, gastrointestinal disturbances such as , , and stomach pain are typical adverse reactions. These effects arise from local in the digestive tract. Local reactions vary by administration route. often causes pain, redness, swelling, and sterile abscess formation at the site, potentially leading to skin sloughing or . Rectal administration may produce , tenesmus, pain, or bleeding. Intravenous use carries a risk of vein and . Respiratory issues can occur, particularly if paraldehyde is aspirated, leading to coughing, choking, or . is a rare complication. Other effects include symptoms such as , (manifesting as clumsiness or unsteadiness), drowsiness, and hangover-like sensations. Allergic reactions, including skin rash, occur infrequently.

Toxicity and contraindications

Paraldehyde overdose can lead to severe , manifesting as respiratory depression, , , , and potentially fatal cardiac failure. Doses exceeding typical therapeutic limits, such as more than 30 mL in adults, heighten the risk of these outcomes, with symptoms including , , drowsiness, and progressing to life-threatening complications. The oral LD50 in rats is 1.53 g/kg, indicating moderate compared to other sedatives. Management of acute overdose focuses on supportive care, including airway protection, for , vasopressors for , and monitoring for ; may be considered in severe cases to enhance elimination, though its efficacy for paraldehyde specifically remains unestablished. Chronic exposure to paraldehyde carries risks of dependence, tolerance, and organ damage, including toxic and with prolonged use. As paraldehyde undergoes hepatic metabolism to via enzymes, extended administration may induce liver enzyme activity, potentially altering the metabolism of co-administered drugs. The metabolite is classified by the International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B), raising concerns for long-term oncogenic potential through formation, though direct evidence for paraldehyde itself is limited. Despite this, paraldehyde exhibits relatively low acute environmental toxicity, with rapid volatilization and mitigating persistence in and . Paraldehyde is contraindicated in patients with severe respiratory diseases, such as bronchopulmonary disorders, due to the risk of exacerbated depression and aspiration. It is also contraindicated in severe hepatic impairment, where reduced can prolong exposure and worsen . Use during is contraindicated because paraldehyde readily crosses the , potentially causing respiratory depression in the neonate. Paraldehyde potentiates the effects of other depressants, including alcohol and opioids, leading to additive respiratory and risks that can precipitate overdose. Caution is advised with disulfiram, which inhibits and can elevate paraldehyde and levels, intensifying toxicity.

Non-medical applications

Industrial uses

Paraldehyde serves as a key intermediate and in the production of various , where it facilitates and by dissolving , waxes, and other components. It is incorporated into and coatings, acting as an indirect in adhesive compositions for materials. In these applications, paraldehyde's cyclic trimer provides lower volatility compared to monomeric aldehydes, enabling more controlled handling during synthesis and application. As a solvent, paraldehyde is employed in rubber accelerators and , where it substitutes for to minimize secondary reactions and improve safety due to its reduced and stability. It functions as a rubber additive, promoting vulcanization and acting as an in and production. Additionally, paraldehyde is used as a dyestuff intermediate and solvent for fats, oils, and processing, supporting the and chemical industries. Paraldehyde acts as a preservative in industrial formulations, leveraging the antimicrobial properties and chemical stability of its trimer form to inhibit microbial growth in products such as cosmetics and pharmaceuticals. Global production of paraldehyde reached approximately 18,400 metric tons in 2024, with major applications in chemical intermediates for resins and dyes accounting for over 9,000 tons. Usage in the rubber sector involves low thousands of tons annually, reflecting steady demand despite the rise of greener alternatives in solvent-based processes. Key advantages include its lower toxicity relative to , allowing safer industrial handling, and its ability to depolymerize under controlled conditions for in-situ acetaldehyde generation in reactions.

Other applications

In , paraldehyde has been employed as a and agent, particularly in laboratory animals for procedures involving or control. For instance, it is administered intramuscularly in combination with (50 mg/kg) to induce in rabbits at doses of 0.5 mL/kg. Similar applications include intraperitoneal administration in rats to terminate , typically at 0.3 mL/kg after prolonged activity. In experimental pigs, intraperitoneal paraldehyde facilitates during surgical interventions. has been explored in some contexts for rapid effects, though its use remains limited to research settings due to the availability of more modern alternatives. As a laboratory reagent, paraldehyde serves as a solvent in microscopy mounting media, such as Euparal, where it aids in preserving and embedding specimens for long-term observation by dissolving resins like sandarac and facilitating slide preparation. In analytical chemistry, it functions as a solvent for processing waxes, oils, and resins, and has been utilized in methods for detecting or quantifying related compounds like acetaldehyde in aqueous solutions. Historically, paraldehyde was recognized as a generally recognized as safe (GRAS) flavoring agent in food products, including baked goods, beverages, and candies, at low concentrations (e.g., up to 200 ppm in baked goods), contributing subtle notes derived from its acetaldehyde structure. This application extended to masking unpleasant odors or tastes in early pharmaceutical formulations, though such uses have largely diminished. Emerging as of 2025 explores paraldehyde's role in synthesizing biodegradable polymers, where it acts as a source of to form cyclic linkages in polyols for degradable polyurethanes, enabling acid-triggered breakdown for applications in sustainable materials and . Due to its pungent and the development of safer, less volatile alternatives, paraldehyde has been phased out from many non-medical applications, with its use now confined to niche and contexts.

Regulatory status

Availability

Production of paraldehyde is limited to a few manufacturers, primarily in and , including in , SE and Merck KGaA in , and Godavari Biorefineries in , with additional production from Chinese firms such as Nuote Chemical and Bojing Chemical. In the United States, production has been discontinued and the drug is no longer commercially available. Paraldehyde is supplied in forms such as 5 sealed ampoules for intramuscular or intravenous injection, oral solutions, and rectal preparations diluted in oil. Veterinary formulations exist in some countries for use in animals, particularly dogs. Globally, paraldehyde remains accessible in many developing nations for treating seizures, including status epilepticus, where it serves as an alternative anticonvulsant in resource-limited settings. As of 2025, bulk industrial quantities are available at around $5 per kg. Due to its incompatibility with plastics and rubbers, paraldehyde must be packaged in glass containers to prevent degradation. When stored in tight, light-resistant glass at temperatures not exceeding 25°C, it maintains stability with a shelf life of 2–3 years if unopened, though it decomposes rapidly after exposure to air. In the United States, paraldehyde is classified as a Schedule IV under the administered by the (DEA), reflecting its low potential for abuse relative to substances in Schedule III. Although commercial production was discontinued due to the availability of safer alternatives, it remains accessible through state-licensed pharmacies for human and veterinary applications or via importation under appropriate regulatory oversight. Internationally, paraldehyde is designated with the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification code N05CC05, categorizing it as an anxiolytic within the group of aldehydes and their derivatives. In the European Union and the United Kingdom, it is regulated as a prescription-only medicine, requiring authorization from a qualified healthcare professional for dispensing, and is often prepared as a "special" formulation or imported due to limited commercial availability. In Australia, paraldehyde is scheduled as a Schedule 4 substance under the Poisons Standard, classifying it as a prescription-only poison with restrictions on supply and possession to mitigate risks associated with its use. Paraldehyde's low abuse potential has generally precluded its inclusion in higher tiers of international drug scheduling under conventions, such as the 1971 , though it is occasionally monitored in contexts involving industrial chemical precursors due to its non-medical applications. As of 2025, however, paraldehyde has seen renewed inclusion in pediatric protocols for low-resource settings, particularly in parts of and where it remains unrestricted in emergency medical kits for managing convulsions when benzodiazepines are unavailable. Export controls on paraldehyde are minimal under UN frameworks, with no specific dual-use restrictions listed in the 1988 Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, though general chemical notifications may apply in cases of large-scale industrial shipments to prevent diversion. This regulatory landscape underscores its transition from a widely used sedative to a niche agent in resource-limited care.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Paraldehyde
  2. https://www.drugs.com/cons/paraldehyde.html
  3. https://www.sciencedirect.com/topics/neuroscience/paraldehyde
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