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Dimethylacetamide
Dimethylacetamide
Dimethylacetamide
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Dimethylacetamide
Skeletal formula of dimethylacetamide
Skeletal formula of dimethylacetamide
Ball and stick model of dimethylacetamide
Ball and stick model of dimethylacetamide
Names
Preferred IUPAC name
N,N-Dimethylacetamide
Identifiers
3D model (JSmol)
Abbreviations DMA, DMAC, DMAc[1]
1737614
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.004.389 Edit this at Wikidata
EC Number
  • 204-826-4
MeSH dimethylacetamide
RTECS number
  • AB7700000
UNII
  • InChI=1S/C4H9NO/c1-4(6)5(2)3/h1-3H3 checkY
    Key: FXHOOIRPVKKKFG-UHFFFAOYSA-N checkY
  • CN(C)C(C)=O
Properties
C4H9NO
Molar mass 87.122 g·mol−1
Appearance Colorless liquid
Odor Ammoniacal
Density 0.937 g/mL
Melting point −20 °C (−4 °F; 253 K)
Boiling point 165.1 °C; 329.1 °F; 438.2 K
Miscible
log P −0.253
Vapor pressure 300 Pa
UV-vis (λmax) 270 nm
1.4375
Viscosity 0.945 mPa·s [2]
Thermochemistry
178.2 J/(K·mol)
−300.1 kJ/mol
−2.5835–−2.5805 MJ/mol
Hazards
GHS labelling:
GHS07: Exclamation mark GHS08: Health hazard
Danger
H312, H319, H332, H360
P280, P308+P313
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g. diesel fuelInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
2
0
Flash point 63 °C (145 °F; 336 K)
490 °C (914 °F; 763 K)
Explosive limits 1.8–11.5%
Lethal dose or concentration (LD, LC):
2.24 g/kg (dermal, rabbit)
4.3 g/kg (oral, rat)
4.8 g/kg (oral, rat)
4.62 g/kg (oral, mouse)[4]
2475 ppm (rat, 1 h)[4]
NIOSH (US health exposure limits):
PEL (Permissible)
 TWA 10 ppm (35 mg/m3) [skin][3]
REL (Recommended)
 TWA 10 ppm (35 mg/m3) [skin][3]
IDLH (Immediate danger)
 300 ppm[3]
Related compounds
Related compounds
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 ?)

Dimethylacetamide (DMAc or DMA) is the organic compound with the formula CH3C(O)N(CH3)2. This colorless, water-miscible, high-boiling liquid is commonly used as a polar solvent in organic synthesis. DMA is miscible with most other solvents, although it is poorly soluble in aliphatic hydrocarbons.

Synthesis and production

[edit]

DMA is prepared commercially by the reaction of dimethylamine with acetic anhydride or acetic acid. Dehydration of the salt of dimethylamine and acetic acid also furnishes this compound:[5]

CH3CO2H·HN(CH3)2 → H2O + CH3CON(CH3)2

Dimethylacetamide can also be produced by the reaction of dimethylamine with methyl acetate.[6]

One route to dimethylacetamide

The separation and purification of the product is carried out by multistage distillation in rectification columns. DMA is obtained with essentially quantitive (99%) yield referred to methyl acetate.[6]

Reactions and applications

[edit]

The chemical reactions of dimethylacetamide are typical of N,N-disubstituted amides. Hydrolysis of the acyl-N bond occurs in the presence of acids:

CH3CON(CH3)2 + H2O + HCl → CH3COOH + (CH3)2NH2+Cl−

However, it is resistant to bases. For this reason DMA is a useful solvent for reactions involving strong bases such as sodium hydroxide.[7]

Dimethylacetamide is commonly used as a solvent for fibers (e.g., polyacrylonitrile, spandex) or in the adhesive industry.[5] It is also employed in the production of pharmaceuticals and plasticizers as a reaction medium.

A solution of lithium chloride in DMAc (LiCl/DMAc) can dissolve cellulose. Unlike many other cellulose solvents, LiCl/DMAc gives a molecular dispersion, i.e. a "true solution". For this reason, it is used in gel permeation chromatography to determine the molar mass distribution of cellulose samples.

Dimethylacetamide is also used as an excipient in drugs, e.g. in Vumon (teniposide), Busulfex (busulfan) or Amsidine (amsacrine).

Toxicity

[edit]

Dimethylacetamide, like most simple alkyl amides, is of low acute toxicity. Chronic exposure can cause hepatotoxicity.[8][9][10][11] At high doses (400 mg/kg body mass daily), dimethylacetamide causes effects on the central nervous system (e.g. depression, hallucinations and delusion).[8][12][13]

Dimethylacetamide may be incompatible with polycarbonate or ABS. Devices (e.g. syringes) that contain polycarbonate or ABS can dissolve when coming into contact with dimethylacetamide.[14]

Regulation

[edit]

In 2011, dimethylacetamide was identified in the EU as a Substance of very high concern (SVHC) because of its reproductive toxicity.[15] In 2014, the European Commission has started an investigation to restrict the use of dimethylacetamide in the EU according to REACH.[16]

In 2015, the CNESST (Committee on Standards, Equity, Health and Safety at Work in Quebec) has adopted a tightened classification of dimethylacetamide:[17]

Description Category GHS hazard statement
Reproductive toxicity 2 Suspected of damaging fertility or the unborn child (H361)
Specific target organ toxicity – repeated exposure 2 May cause damage to organs through prolonged or repeated exposure (H373)
Serious eye damage/eye irritation 2 Causes serious eye irritation (H319)
Acute toxicity – inhalation 3 Toxic if inhaled (H331)
Specific target organ toxicity – single exposure – narcotic effects 3 May cause drowsiness or dizziness (H336)
Flammable liquid 4 Combustible liquid (H227)

See also

[edit]

References

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

Dimethylacetamide

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from Grokipedia
N,N-Dimethylacetamide (DMAc), with the molecular formula C₄H₉NO, is a colorless serving as a in and industrial manufacturing. It exhibits high solvency for a wide range of organic and inorganic compounds, a of approximately 165 °C, and with and most organic solvents, accompanied by a faint ammonia-like odor. Industrially produced through the reaction of with acetic acid or , DMAc finds extensive use in dissolving polymers for fiber production (such as and ), formulating pharmaceuticals and agrochemicals, and manufacturing coatings, adhesives, and photoresists. Despite its effectiveness, DMAc poses significant health risks, including developmental toxicity, male reproductive effects, and potential carcinogenicity as recognized under California's Proposition 65; animal studies indicate and fetotoxicity at occupational exposure levels. Exposure occurs primarily via absorption or , prompting regulatory limits such as OSHA's of 10 ppm over 8 hours. Its environmental persistence and bioaccumulative potential further underscore the need for substitution efforts in sensitive applications like and membrane production.

Chemical and Physical Properties

Molecular Structure and Basic Characteristics

Dimethylacetamide, systematically named N,N-dimethylacetamide, has the molecular formula CH₃CON(CH₃)₂ (or C₄H₉NO) and a molecular weight of 87.12 g/mol. This compound features a tertiary amide functional group, characterized by a carbonyl (C=O) bonded to a nitrogen atom substituted with two methyl groups, which restricts rotation around the C–N bond due to partial double-bond character from resonance delocalization of the nitrogen lone pair into the carbonyl π-system. The amide structure confers significant polarity, with a dipole moment of approximately 3.72 D, arising from the electronegative oxygen and the electron-rich nitrogen. As a polar aprotic solvent, dimethylacetamide solvates ions and polar species effectively through its electronegative oxygen acceptor site but lacks acidic protons on nitrogen, preventing hydrogen bond donation and enhancing its utility in reactions sensitive to proton activity. Relative to analogous solvents, dimethylacetamide displays polarity comparable to N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), evidenced by its polarity index of 6.5—marginally above DMF's 6.4 but below NMP's 6.7—stemming from similar dielectric constants around 37–38 that support dissolution of diverse substrates without protic interference. This intrinsic molecular architecture underpins its role as a versatile medium for solvation-driven processes.

Thermodynamic and Solubility Properties

Dimethylacetamide (DMAc) is a existing as a under ambient conditions, with a of -20 °C and a of 166 °C at standard pressure. Its measures 0.942 g/cm³ at 20 °C, while the dynamic is 0.92 mPa·s at 25 °C, contributing to its flow characteristics in industrial applications.
PropertyValueConditions
Heat of vaporization53.2 kJ/mol25 °C
Octanol-water log P-0.7725 °C
DMAc demonstrates complete with , as well as with oxygen- and nitrogen-containing organic solvents such as ethers, esters, ketones, and aromatics; however, decreases in aliphatic hydrocarbons. This broad profile stems from its functionality, enabling strong interactions and bonding capabilities. The negative log P value underscores its hydrophilic nature relative to nonpolar solvents. Relevant to safe handling, DMAc has a of approximately 70 °C (open cup) and a of 0.33 kPa at 20 °C, indicating low volatility at but potential flammability risks under elevated conditions. The heat of vaporization reflects the energy required for , influencing processes in purification.

Stability and Reactivity

Dimethylacetamide (DMAc) exhibits high chemical stability under standard ambient conditions, remaining unreactive with air, , or common materials at . It is thermally stable up to its of approximately 165°C, allowing without significant decomposition, and maintains integrity under heating to around 200°C in inert atmospheres as evidenced by empirical tests in solvent recovery processes. As a , DMAc resists in neutral or mildly basic aqueous environments, with degradation rates below 0.02% observed at 95°C and pH 9.36 over extended periods, reflecting the robust acyl-N bond characteristic of tertiary . This stability extends to strong bases such as or , where DMAc solvates metal cations effectively without undergoing nucleophilic attack, enabling its use in base-promoted reactions unlike protic solvents that protonate bases. However, exposure to strong acids catalyzes , yielding acetic acid and via protonation of the carbonyl oxygen, which facilitates nucleophilic water attack on the . Under extreme thermal or hydrolytic conditions exceeding 200°C or in concentrated acids/bases, DMAc decomposes primarily to acetic acid, , and trace carbon oxides or species, as identified in controlled degradation studies. Unlike ethers such as or THF, DMAc does not form explosive peroxides upon prolonged air exposure or contact with oxidants, due to the absence of alpha-hydrogens prone to in its structure. Hazardous is not observed, and reactivity ratings in standard hazard classifications confirm low general reactivity (NFPA reactivity 0).

Synthesis and Production

Industrial Manufacturing Processes

Dimethylacetamide (DMAc) is primarily manufactured on an industrial scale through the reaction of with or acetic acid. The route involves direct amidation, proceeding exothermically under controlled conditions to form DMAc and acetic acid as a , which can be recycled in integrated processes. This method benefits from the availability of as a bulk chemical intermediate, enabling high-purity product isolation via . An alternative continuous process reacts with in solution, typically using 0.1 to 10 mol% as a basic catalyst at temperatures of 50–150 °C. This ester aminolysis achieves space-time yields of 0.1–0.85 kg DMAc per liter of reactor volume per hour, with excess methyl ester ensuring high conversion and recovery to minimize waste. Catalysts such as oxides or have also been employed in ester-based routes for enhanced selectivity. Carbonylation routes, such as the (I)-catalyzed reaction of or with and derivatives, represent emerging alternatives but remain less dominant industrially due to higher catalyst costs and complexity in handling gases. These processes manage byproducts like methyl iodide through recycling, though energy inputs for pressurization exceed those of conventional aminolysis. Global production capacity exceeds 20,000 tons annually as of early 2000s data, with major producers including BASF SE, , and . Economic viability hinges on feedstock costs, with routes gaining favor for utilizing byproducts from production.

Laboratory-Scale Preparation

In laboratory settings, N,N-dimethylacetamide (DMAc) is commonly prepared via the of with under anhydrous conditions to minimize of the reactive . The procedure typically involves dissolving or bubbling into an inert solvent such as at low temperature (e.g., 0–5°C) to control the , followed by slow dropwise addition of with vigorous stirring. An inert atmosphere, such as , is employed to exclude moisture and oxygen, preventing side reactions like HCl gas evolution without salt formation or decomposition. The resulting precipitates and is filtered off, yielding a crude filtrate that is purified by under reduced pressure, collecting the fraction boiling at 164–166.5°C to achieve >99% purity. Yields for this method range from 84% in early procedures to up to 98.5% with optimizations like nanoscale solid alkali catalysts, offering higher purity than industrial routes that prioritize volume over refinement. Unlike large-scale production favoring for cost, lab-scale reactions enable precise control and easier byproduct removal, though they require rigorous exclusion of water to avoid degradation to acetic acid. Modern variants may incorporate catalysts for enhanced efficiency, contrasting historical solvent-free or basic anhydride methods that often yielded lower purity without .

Industrial and Commercial Applications

Use as a Solvent in Polymers and Fibers

Dimethylacetamide (DMAc) functions as a in the wet and dry spinning processes for synthetic fibers, enabling the dissolution of polymers such as (PAN) for acrylic fibers and for , due to its high solvency power and thermal stability. In production, PAN is dissolved in DMAc to form viscous spinning dopes typically at concentrations of 5-25 wt%, which are then extruded through spinnerets into baths for fiber formation. This process accounts for a significant portion of industrial DMAc consumption, with approximately 15% of global production directed toward solvents for acrylic fibers and related resins. For spandex production, such as Lycra, DMAc dissolves the polyurethane prepolymer, facilitating chain extension and dry spinning where the solvent is evaporated to yield elastic fibers with high stretch recovery, essential for apparel applications requiring breathability and durability. The solvent's ability to maintain polymer solution homogeneity supports high-speed extrusion, contributing to efficient large-scale manufacturing, as seen in processes developed by companies like . DMAc also dissolves (PVC) for and film applications, though less commonly than for PAN or polyurethanes, and aids in processing where it promotes uniform dope formation for advanced with thermal resistance. Post-spinning, DMAc is recovered through from aqueous or mixed streams, achieving purities suitable for reuse and minimizing waste in closed-loop systems typical of plants. This recovery step enhances economic viability, as solvent costs represent a substantial fraction of production expenses in industries.

Role in Pharmaceutical and Fine Chemical Synthesis

Dimethylacetamide (DMAc), a with a constant of 37.8 at 25°C, promotes reactions involving ionic or polar transition states in pharmaceutical synthesis by stabilizing charged species and enhancing reactant without participating in proton transfer. Its high of 166°C allows for elevated reaction temperatures, facilitating processes like (SNAr) of activated aryl halides, where dipolar aprotic solvents such as DMAc constitute nearly 50% of usage in nucleophilic substitutions according to process development surveys. In SNAr applications for fine chemicals, DMAc enables efficient displacement by nucleophiles like amines or thiols, often outperforming protic solvents due to reduced hydrogen bonding interference. DMAc supports palladium-catalyzed Heck couplings in API production, serving as the medium for aryl halide-alkene cross-couplings with Pd-supported catalysts, where it maintains catalyst activity and minimizes Pd leaching under typical conditions of 100-140°C. For amide formations essential to peptide linkages and antibiotic scaffolds, DMAc dissolves derivatives and amines, enabling steps in the synthesis of compounds like beta-lactams, with its properties contributing to cleaner reaction profiles compared to less polar media. In solid-phase , DMAc is routinely applied as a swelling and coupling for resin-bound , often in DMF-DMAc blends to improve deprotection and coupling efficiencies for sequences up to 50 residues. As a co-solvent for poorly soluble drug intermediates, DMAc enhances in multi-step syntheses, leading to reported yield increases of up to 20% in API pathways by better solubilizing hydrophobic substrates during key transformations. The International Council for Harmonisation (ICH) Q3C(R8) guideline permits DMAc residuals in pharmaceuticals at concentrations corresponding to a permitted daily exposure of 3.1 mg/day, classifying it as a Class 2 solvent acceptable for use when manufacturing controls ensure levels below 0.109% in substances. This regulatory threshold supports its routine application in processes, balanced against purification steps to minimize carryover into final products.

Applications in Electronics and Other Sectors

Dimethylacetamide (DMAc) is employed as a in stripping for fabrication, where it effectively dissolves post-exposure residues while preserving substrate integrity. Patented formulations combining DMAc with monoethanolamine (20-60 wt%) and additional solvents enable stripping of crosslinked s at elevated temperatures, achieving residue-free surfaces essential for high-yield microelectronic devices. This application leverages DMAc's high solvency for organic polymers, minimizing defects in processes like and . In advanced battery electrolytes, DMAc acts as a non-flammable solvent and stabilizer, enhancing thermal stability and electrochemical performance in lithium-ion and sodium-based systems. For example, DMAc-integrated localized high-concentration electrolytes regulate Li+ solvation to form robust solid-electrolyte interphases, supporting stable cycling in high-voltage lithium metal batteries. Hybrid water/DMAc electrolytes for sodium batteries exhibit improved reversibility, with dipole interactions mitigating water-related degradation. DMAc-based non-flammable formulations with sodium triflate achieve an electrochemical stability window of 2.65 V, addressing safety concerns in electric vehicle applications. DMAc plays minor roles in agrochemical synthesis as a reaction medium for pesticides and herbicides, facilitating efficient intermediate processing. In dyes and coatings production, it dissolves precursors for films and pigments, contributing to durable formulations in industrial finishes. Demand from , including semiconductors and batteries, has driven DMAc market expansion since 2020, with global volumes projected to grow amid high-tech sector scaling.

Health Effects and Toxicology

Acute Exposure Effects

Dimethylacetamide (DMAc) demonstrates low acute systemic via oral exposure, with an LD50 of 4,300 mg/kg in rats, indicating minimal at doses below this threshold. exposure yields an LC50 exceeding 2,475 ppm (1-hour exposure) in rats, consistent with limited immediate but potential for sensory at lower concentrations, such as 1,658 ppm in mice. Dermal LD50 in rabbits is approximately 2,240 mg/kg, reflecting moderate absorption potential without rapid fatality. Immediate symptoms from acute or include , , , and , observed in overexposure scenarios without specified ppm thresholds in animal models but correlating with airborne concentrations prompting . contact causes serious eye , manifesting as redness and pain, while exposure results in mild and defatting, exacerbated by DMAc's rapid dermal penetration— volunteer studies report equivalent vapor uptake via at 6.1 ppm, comparable to routes. First-aid measures emphasize prompt removal from exposure: provide fresh air for inhalation cases, where symptoms typically resolve with supportive care; irrigate eyes with water for at least 15 minutes; and wash skin thoroughly with soap and water to mitigate absorption and irritation, with full recovery expected in non-complicated acute incidents based on reversible irritant effects in toxicity profiles.

Chronic and Reproductive Toxicity Data

Dimethylacetamide (DMAC) is classified as a reproductive toxicant Category 1B under the EU due to evidence from indicating serious effects on development, presumed to produce such effects in humans. Inhalation developmental toxicity studies in pregnant rats exposed to 100–600 ppm DMAC (approximately 356–2136 mg/m³, based on molecular weight of 87.12 g/mol) identified a no-observed-adverse-effect level (NOAEL) of 100 ppm for maternal , with higher concentrations inducing fetal skeletal abnormalities, reduced fetal weight, and increased resorptions, suggesting interference with embryonic differentiation via solvent-induced metabolic disruption. Oral gavage studies in rats established a NOAEL of 65 mg/kg body weight/day for both maternal and developmental , with adverse outcomes at 200 mg/kg/day including delayed and visceral variations, linked to DMAC's role in altering cellular processes. Chronic inhalation studies in rats and mice exposed to 0–350 ppm DMAC for up to two years reported non-neoplastic liver effects such as and increased organ weights at concentrations exceeding 25 ppm, with a NOAEL of 25 ppm (equivalent to approximately 6.4 mg/kg/day in rats) for systemic , attributed to dose-dependent interference with hepatic and induction. No oncogenic potential was observed in these long-term rodent bioassays, consistent with negative results in dominant lethal assays and micronucleus tests. Reproductive fertility endpoints in multi-generation studies showed no adverse effects up to 400 ppm, indicating that gametogenic is not a primary concern, though developmental endpoints drive the reprotoxic classification. DMAC demonstrated no genotoxicity in the Ames bacterial reverse mutation test across multiple Salmonella and E. coli strains, with and without metabolic activation, supporting a non-mutagenic profile and aligning with negative outcomes in chromosomal aberration assays. In vitro and in vivo studies further confirmed absence of clastogenic or aneugenic potential, suggesting chronic risks stem from epigenetic or cytotoxic mechanisms rather than direct DNA damage.

Human Epidemiological Evidence and Exposure Limits

Epidemiological studies of occupational exposure to dimethylacetamide (DMAc) have primarily identified as the principal adverse effect in humans, with elevated liver enzymes observed in cohorts of workers in fiber production and chemical manufacturing. In a study of 178 employees at a spandex-fiber , toxic attributable to DMAc was diagnosed in seven workers (approximately 4%), correlating with dermal and inhalational exposure during initial plant operations without adequate controls. Cohort analyses in elastane fiber workers reported hepatic injury incidence below 5% among new employees exposed to airborne concentrations under 10 ppm, with reversibility upon exposure cessation and implementation of ventilation. No hepatotoxicity was detected in workers exposed to average levels around 3 ppm, and associations weakened at higher but controlled exposures exceeding 9 ppm when factors like alcohol consumption were accounted for. These findings underscore that hepatotoxic risks are dose-dependent and predominantly occupational, with minimal evidence of effects in non-professional settings lacking direct handling. Dermal absorption contributes significantly to systemic uptake, estimated at 40% of total exposure in human volunteers during controlled vapor contact, necessitating notation in exposure guidelines alongside respiratory limits. The National Institute for Occupational Safety and Health (NIOSH) recommends a (REL) of 10 ppm (35 mg/m³) as an 8-hour time-weighted average, with a designation to account for penetration that bypasses monitoring. This benchmark aligns with observations that exposures below 10 ppm yield low incidence, while proper (PPE) such as gloves and respirators reduces effective uptake to negligible levels in compliant workplaces. Regarding carcinogenicity, human evidence remains inadequate, with no confirmed excess cancer incidence in exposed cohorts despite retrospective reviews of workers handling DMAc alongside other solvents. The International Agency for Research on Cancer (IARC) classifies DMAc as Group 2B (possibly carcinogenic to humans), based on limited mechanistic data rather than robust epidemiological links, contrasting with sufficient animal evidence but highlighting the absence of clear causal patterns in occupational populations. Alarmist interpretations exaggerating consumer risks lack empirical support, as effects are confined to high-exposure industrial scenarios mitigable by and PPE, yielding near-zero incidence under standard protocols.

Environmental Fate and Impact

Persistence, Bioaccumulation, and Mobility

Dimethylacetamide (DMAc) degrades rapidly in the atmosphere through reaction with hydroxyl radicals, with an estimated half-life of 1 day under typical environmental conditions. In water, abiotic hydrolysis proceeds slowly, with a predicted half-life exceeding 300 days at neutral pH, though biotic degradation contributes to overall shorter environmental residence times, as evidenced by inherent biodegradability (77–83% degradation after 14 days in tests). Soil persistence aligns with aquatic behavior, lacking significant adsorption or rapid transformation, but regulatory assessments classify DMAc as non-persistent overall due to biodegradation half-lives below 60 days in water and sediment. DMAc demonstrates negligible bioaccumulation potential, with a calculated factor (BCF) of 0.008 in aquatic organisms, driven by its hydrophilic nature and log Kow of -0.77. This low partitioning into ensures minimal uptake and retention in biological tissues, falling well below thresholds for concern (BCF > 5000). Experimental and modeled data consistently support the absence of risk across trophic levels. High aqueous (miscible with water) and low soil organic carbon-water (Koc ≈ 9) confer substantial mobility to DMAc in environmental compartments. Upon release to , it exhibits minimal adsorption to or particulates, facilitating leaching into aquifers and with limited retardation. Volatilization from or water surfaces is negligible due to low and Henry's law constant.

Ecological Toxicity and Wastewater Management

Dimethylacetamide (DMAC) exhibits low to aquatic organisms, with 96-hour LC50 values exceeding 500 mg/L for such as Leuciscus idus, 48-hour values exceeding 500 mg/L for , and 72-hour values exceeding 500 mg/L for algae such as Scenedesmus subspicatus. These thresholds indicate minimal risk of immediate lethal effects under typical environmental exposure scenarios, as predicted no-effect concentrations remain well below observed environmental levels. Chronic toxicity data are limited, but experimental assessments suggest potential sublethal effects on at concentrations around 100 mg/L, highlighting greater sensitivity in primary producers compared to vertebrates or . No widespread evidence of long-term population-level impacts has been reported from controlled studies. Field incidents involving DMAC spills are rare and poorly documented, attributable in part to its high facilitating rapid dilution in receiving waters rather than persistence or . In industrial wastewater management, DMAC is effectively remediated through aerobic biodegradation in systems, achieving (DOC) removal efficiencies of up to 95% under optimized conditions. Multi-stage biological processes, including of degradation intermediates like , can yield near-complete (over 99%) (TOC) removal, with influent concentrations up to 3346 mg/L fully degraded. Distillation-based recovery is also employed prior to biological treatment to reclaim the solvent, minimizing effluent discharge volumes and enhancing overall process efficiency in sectors like polymer production.

Regulations and Risk Management

Global Regulatory Frameworks

In the United States, dimethylacetamide (DMAc) is included on the Toxic Substances Control Act (TSCA) inventory as an active chemical substance subject to commercial reporting, with no federal bans on production, import, or use as of pre-2025 assessments. The (OSHA) enforces a (PEL) of 10 ppm (35 mg/m³) as an 8-hour time-weighted average, accompanied by a skin notation to account for dermal absorption risks. These measures prioritize monitoring and over outright prohibitions, reflecting evaluations of occupational hazards without evidence warranting broader restrictions under TSCA. In , DMAc appears on the Domestic Substances List (DSL) and underwent a screening-level published on August 22, 2009, under the Chemicals Management Plan. The assessment highlighted developmental concerns, supported by animal indicating potential effects on fetal development at exposure levels relevant to industrial scenarios, leading to recommendations for enhanced exposure screening in high-risk sectors like chemical manufacturing. Despite these findings, no significant use bans were imposed, as general exposure was estimated as low and not posing unacceptable risks. The classifies DMAc under the Classification, Labelling and Packaging ( as a reproductive in category 1B (Repr. 1B), based on harmonized criteria denoting suspected damage to the unborn (H360D) from sufficient evidence in , including teratogenic effects observed in models at doses around 50-150 mg/kg/day. This mandates specific labeling, safety data sheets, and risk communication for mixtures containing ≥0.3% DMAc, but pre-2025 REACH evaluations did not trigger substance-wide restrictions, allowing regulated applications in solvents and polymers with exposure mitigation. Pre-2025 global frameworks thus centered on harmonized hazard classifications and occupational limits to inform , with international trade volumes—exceeding 10,000 metric tons annually in key markets—proceeding without interdictions tied to DMAc content. These regulations drew from empirical toxicology data, such as developmental endpoints in guideline studies, emphasizing causal links between exposure and outcomes over precautionary bans absent direct human evidence of widespread harm.

Recent Restrictions and Compliance Challenges

In June 2025, the adopted Regulation (EU) 2025/1090, amending Annex XVII to Regulation (EC) No 1907/2006 to restrict N,N-dimethylacetamide (DMAC) due to its classification as a reproductive category 1B. This update prohibits the placing on the market of DMAC as a substance on its own, as a constituent of other substances, or in mixtures at concentrations equal to or greater than 0.3% by weight after December 23, 2026, extending prior consumer-use bans to broader industrial applications. Derogations allow continued use for essential applications if manufacturers demonstrate adequate control of risks to human health and the environment through measures such as exposure monitoring, adherence to derived no-effect levels (DNELs) for long-term (e.g., 14.5 mg/m³ for workers), and submission of exposure scenarios to authorities. Compliance requires supply-chain substitution audits to identify and replace DMAC where feasible, with enforcement relying on national authorities' inspections and reporting under REACH Article 117, though as of October 2025, no widespread post-restriction enforcement data exists given the future applicability date. Challenges include verifying concentration thresholds in complex mixtures and documenting risk mitigation for derogations, particularly in sectors like electronics where DMAC's properties are hard to replicate without trade-offs. Parallel restrictions apply to 1-ethylpyrrolidin-2-one (NEP) under the same Annex XVII entries 80 and 81, mirroring DMAC's 0.3% threshold and derogation framework due to shared concerns from animal studies. These measures adopt a precautionary approach, prioritizing hazard-based over empirical epidemiological , which indicate low incidence of reproductive effects in occupationally exposed workers when exposure is managed below certain thresholds, as evidenced by cohort studies showing primarily hepatic and irritant outcomes rather than causal reproductive harm. Such restrictions aim to reduce modeled risks but lack direct pre-post causal evidence of incidence reductions, given reliance on developmental extrapolated to humans.

Economic and Practical Implications of Regulations

Regulations on dimethylacetamide (DMAC) impose substantial compliance costs on industries reliant on the , particularly in and production, where it serves as a critical aid. The European man-made fibers sector, represented by CIRFS, estimates that substituting DMAC could exceed €500 million in capital and operational expenditures, reflecting investments in alternative processes, equipment retrofits, and validation testing. These costs arise from the need to reformulate processes without viable drop-in replacements, potentially elevating overall production expenses by significant margins and straining smaller operators in affected supply chains. Practical implementation favors targeted risk management over outright bans, enabling firms to retain jobs and operations through engineering controls such as enclosed systems, ventilation enhancements, and exposure monitoring via biological markers like urinary N-methylacetamide. Industry feedback highlights that stringent derived no-effect levels (DNELs) for dermal and inhalation routes—such as 0.53 mg/kg/day dermal—necessitate refined handling protocols but avert total phase-outs, as evidenced by ongoing use in authorized applications like medical membranes. Empirical workplace data supports this approach, demonstrating that exposures remain controllable below thresholds with existing measures, thus preserving innovation in sectors like elastane fiber production without triggering widespread relocations or unemployment. Causal trade-offs underscore the tension between safety imperatives and economic vitality: while regulations mitigate reproductive risks, disproportionate restrictions risk offshoring production to less-regulated regions, undermining EU competitiveness and job retention estimated in thousands across chemical-dependent . Proponents of calibrated oversight argue that verified low-incidence events under controlled conditions justify prioritizing exposure reduction over substitution, yielding net socioeconomic benefits by balancing with sustained industrial output.

Alternatives and Future Outlook

Substitute Solvents and Green Chemistry Approaches

(GVL) serves as a bio-derived dipolar aprotic capable of replacing dimethylacetamide (DMAc) in dissolution processes, particularly for () separation from blends, where Hansen solubility parameters indicate strong compatibility without dissolving the component. In applications, GVL enables selective elastane recovery with dissolution efficiencies approaching those of DMAc, preserving fiber integrity for reuse. Cyrene (dihydrolevoglucosenone), produced from lignocellulosic waste via and , functions as a sustainable DMAc alternative in processing and , offering high boiling points and polarity for effective while demonstrating yield retention of over 90% in reactions like amide couplings traditionally reliant on DMAc or analogous solvents. Lifecycle analyses of Cyrene reveal a 77% lower compared to petroleum-based aproptics like DMAc, due to its renewable feedstock and biodegradability under aerobic conditions. 1,3-Dimethyl-2-imidazolidinone (DMI) provides another option for DMAc substitution in polymer formulations, exhibiting similar solvency for polyurethanes and maintaining processing yields in fiber spinning without significant adjustments to formulation ratios. (DMSO) hybrids, blending DMSO with co-solvents, have been tested for partial DMAc replacement in dissolution tasks, but DMSO's membrane-disrupting toxicity at concentrations above 10% v/v necessitates careful dosing to avoid cellular damage in biological evaluations or worker exposure risks. Post-2022 European initiatives in sustainable chemistry have emphasized empirical validation of these substitutes through performance benchmarking, such as in production where GVL and Cyrene blends retain 90-95% of DMAc's dissolution capacity while reducing emissions by up to 50% in lifecycle assessments. In electronics coating applications, industry trials with Cyrene have achieved defect-free polyimide film deposition equivalent to DMAc baselines, enabling partial process shifts without yield losses.

Barriers to Replacement and Ongoing Research

Dimethylacetamide's (DMAc) efficacy as a derives from its strong dipolar aprotic character, enabling effective dissolution of polar polymers through disruption of intermolecular forces like hydrogen bonding, a property not easily replicated by substitutes. Polarity mismatches in alternatives, such as lower moments or insufficient Lewis basicity, often result in substantially reduced , requiring process adjustments that compromise efficiency or yield. Economic barriers further impede replacement, as solvents like certain bio-based options incur 1.5-2 times higher costs due to limited scale and expenses, rendering full substitution uneconomical for high-volume applications without equivalent performance. Recent research from 2024-2025 has focused on ionic liquids (ILs) and deep eutectic solvents (DESs) to address gaps, with pilot-scale studies demonstrating partial success in polymer processing via tunable donor-acceptor interactions. ACS publications highlight DES formulations achieving viable dissolution rates in membrane fabrication, though and recovery challenges persist in industrial trials. These efforts emphasize iterative optimization over outright displacement, prioritizing hybrids that mitigate while preserving DMAc-like . Prospects for comprehensive replacement remain limited, as incremental enhancements via ILs/DESs fail to achieve parity or toxicity equivalence without extensive validation, potentially sustaining DMAc use in regulated niches pending regulatory evolution. Full-phaseout hinge on proving substitutes' long-term stability and , areas where current indicate persistent deficits.

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