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Morpholine

Morpholine is an organic heterocyclic compound with the molecular formula C₄H₉NO, characterized by a six-membered ring incorporating one oxygen atom and one nitrogen atom positioned para to each other, functioning as both an amine and an ether.^[1]^[2]
This colorless, hygroscopic liquid exhibits a characteristic amine odor, boils at 128–129 °C, and is miscible with water and most organic solvents, rendering it versatile as a solvent and intermediate in chemical synthesis.^[3]^[1]
Morpholine finds primary industrial application as a corrosion inhibitor in steam boiler systems, where it neutralizes carbonic acid to prevent equipment degradation, and as a reagent in the production of rubber accelerators, pharmaceuticals, and herbicides.^[2]^[4]
Its reactivity stems from the basic nitrogen, enabling salt formation and nucleophilic substitutions, though it poses hazards as a flammable, corrosive substance capable of causing severe skin burns, eye damage, and respiratory irritation upon exposure.^[1]^[5]^[6]

Chemical and Physical Properties

Molecular Structure and Formula

Morpholine possesses the molecular formula C₄H₉NO and a molar mass of 87.12 g/mol.^[1]^[7] Its systematic IUPAC name is tetrahydro-4H-1,4-oxazine, reflecting its saturated six-membered ring structure with heteroatoms oxygen and nitrogen positioned at the 1 and 4 loci, respectively.^[7]^[1] The molecular architecture features a cyclic arrangement of four -CH₂- units interrupted by adjacent O and NH groups, endowing it with dual ether and secondary amine functionalities within a single heterocycle.^[1]^[8] This configuration distinguishes morpholine from related heterocycles such as piperazine, which incorporates two nitrogen atoms in place of the oxygen-nitrogen pair, or tetrahydrofuran, a five-membered cyclic ether lacking the amine moiety.^[1]^[8]

Physical Characteristics

Morpholine is a colorless, hygroscopic liquid with a characteristic weak fishy or ammonia-like odor.^[1]^[9]^[10] It exhibits a melting point of -5 °C and a boiling point of 129 °C at standard atmospheric pressure.^[11]^[12] The density is 1.0 g/cm³ relative to water at 20 °C.^[11] Morpholine is miscible with water and most organic solvents, such as alcohols and ethers.^[11]^[10] Its vapor pressure measures 1.06 kPa (approximately 8 mmHg) at 20 °C.^[11] Relevant to fire safety, the flash point is 35 °C (closed cup), and the autoignition temperature is 310 °C.^[11]^[12]

Chemical Reactivity and Stability

Morpholine exhibits basic properties characteristic of a secondary amine, with the pKa of its conjugate acid (morpholinium ion) reported as 8.49 at 25°C, enabling protonation and salt formation with acids such as hydrochloric or nitric acid.^[1] This basicity (pKb ≈ 5.5) facilitates rapid reactions with carbon dioxide to form carbamates, as the nitrogen lone pair attacks the electrophilic carbon of CO2, yielding morpholine-1-carboxylate species that are relatively unstable compared to those from primary amines.^[13]^[14] As a nucleophile, morpholine's nitrogen lone pair, moderated by the electron-withdrawing ether oxygen in the ring, participates in substitution and addition reactions typical of secondary amines, including acylation with benzoyl halides and Michael additions to activated olefins like benzylideneacetylacetone.^[15] The ether moiety reduces electron density on nitrogen relative to piperidine, lowering nucleophilicity but enhancing solubility in polar media for synthetic applications.^[3] Morpholine demonstrates good thermal stability up to approximately 150°C under neutral conditions, with degradation accelerating above 175°C, particularly in the presence of CO2 or oxygen, leading to products like formamides or oxidized derivatives.^[16] It is incompatible with strong oxidizers, which can promote ring oxidation or cleavage, and prolonged exposure to concentrated acids or bases risks ether hydrolysis or protonation-induced decomposition, though the ring remains intact under mild aqueous conditions.^[1]^[17] Storage requires avoidance of acids, acid anhydrides, and isocyanates to prevent exothermic reactions or salt precipitation.^[13]

History

Discovery and Early Research

Morpholine was first prepared in 1898 via the dehydration of diethanolamine using concentrated sulfuric acid, marking the initial synthesis of this heterocyclic compound.^[18] This method emerged from advancements in amine chemistry during the late 19th century, when diethanolamine itself had become accessible through reactions involving ethylene oxide and ammonia. The name "morpholine" originated with German chemist Ludwig Knorr in the 1890s, during his structural elucidation of morphine, the principal alkaloid from opium.^[19] Knorr erroneously concluded that morpholine constituted a key fragment of morphine's structure, a misattribution stemming from degradation experiments on the alkaloid, though subsequent analyses disproved this linkage.^[20] Early investigations, conducted primarily in German laboratories amid the era's rapid progress in heterocyclic compounds, focused on morpholine's fundamental attributes as a six-membered ring containing nitrogen and oxygen. Researchers observed its strong basicity, attributable to the secondary amine moiety (pKa of conjugate acid approximately 8.3), and its miscibility with water and organic solvents, traits that distinguished it from simpler aliphatic amines.^[18] These empirical findings positioned morpholine within the expanding field of cyclic ethers and amines, influencing subsequent explorations in organic synthesis without immediate industrial intent.

Commercialization and Patent Developments

Morpholine entered commercial production in the United States by 1935, transitioning from its initial synthesis as a heterocyclic compound to an industrially viable intermediate.^[21] Early adoption focused on its role in manufacturing rubber chemicals, where it served as a precursor for vulcanization accelerators, enabling more efficient cross-linking in elastomer processing.^[1] Patents from this era, such as those exploring morpholine derivatives for enhancing rubber plasticity and curing, underscored its value in the burgeoning synthetic rubber sector amid rising automotive and tire demands. Post-World War II petrochemical advancements drove production scale-up, with morpholine output expanding in the 1950s to support corrosion inhibition in industrial systems, aligning with infrastructure growth and boiler maintenance needs.^[4] Recovery processes, exemplified by U.S. Patent 2,776,972 granted in 1956, optimized extraction from aqueous solutions derived from diethanolamine dehydration, improving yield and economic feasibility for larger-scale operations.^[22] By the 1960s, patent activity highlighted morpholine's integration into optical brighteners, with formulations incorporating morpholino groups for enhanced whitening in textiles and detergents, responding to manufacturing demands for brighter consumer goods. These developments, including U.S. Patent 3,038,949 for dithiodimorpholine in latex vulcanization, reflected diversified market entry while prioritizing efficient synthesis routes.^[23]

Production

Synthetic Routes

The primary laboratory and scalable synthetic route to morpholine involves the acid-catalyzed dehydration of diethanolamine (DEA), an intermediate derived from the reaction of ethylene oxide with aqueous ammonia under controlled conditions to yield primarily DEA alongside monoethanolamine and triethanolamine.^[20] In the dehydration step, DEA is heated with concentrated sulfuric acid (approximately 1.8 equivalents) or alternative catalysts like solid acids at 150–200°C, promoting intramolecular cyclization via elimination of water to form the six-membered ring.^[24] ^[25] Optimized processes achieve yields of up to 91.6%, with the reaction driven by the thermodynamic stability of the product ring, which adopts a low-strain chair conformation akin to cyclohexane, releasing two molecules of water per cycle.^[26] An alternative pathway proceeds via nucleophilic substitution of bis(2-chloroethyl) ether with excess anhydrous ammonia in a sealed vessel at around 50°C for 24 hours, followed by venting excess ammonia, filtration of ammonium chloride byproduct, and distillation of morpholine.^[27] ^[8] This method likely involves initial formation of the linear intermediate 2-(2-chloroethoxy)ethylamine, followed by intramolecular SN2 cyclization displacing chloride, favored by the entropic gain from ring closure in a medium-sized heterocycle and the leaving group ability of chloride under basic conditions.^[28] Efficiencies typically range from 80–90% in laboratory settings, though purification is required to separate from polymeric byproducts.^[20]

Industrial Manufacturing Processes

Morpholine is produced industrially on a large scale primarily through the vapor-phase catalytic hydrogenation of diethylene glycol with excess ammonia, in the presence of hydrogen gas and metal catalysts such as nickel or cobalt-promoted variants.^[4] This process, which gained prominence in the 1980s, yields morpholine via dehydration and cyclization, with water as the main by-product.^[20] Operations typically employ continuous fixed-bed reactors in petrochemical plants, maintaining temperatures of 150–400 °C and pressures of 3–40 bar to achieve selectivities above 80%, minimizing side products like piperazine and N-hydroxyethyl ethylenediamine.^[4] Diethylene glycol feedstock is derived from ethylene oxide, itself produced via ethylene oxidation, linking production costs to petrochemical market volatility; ethylene price fluctuations, such as those exceeding 20% annually in response to crude oil variations, directly impact raw material expenses comprising over 60% of total costs.^[29] Energy demands are significant, with high-temperature vaporization and compression requiring substantial steam and electrical inputs, often optimized through heat recovery systems in integrated facilities. By-product management focuses on water removal via azeotropic distillation or dehydration columns, followed by multi-stage fractional distillation to purify morpholine (boiling point 129 °C) from higher-boiling impurities, enabling recycle of unreacted ammonia and glycol for yield improvements up to 90%.^[30] Global production capacity exceeds 300,000 metric tons annually, concentrated in Asia with key facilities in India (e.g., capacities over 60,000 tons) and China, reflecting regional advantages in feedstock access and lower energy costs.^[31] Approximately 40% of output supports rubber chemicals manufacturing, driving scale-up in continuous processes to meet demand stability in that sector.^[4] Process engineering emphasizes catalyst longevity and reactor design for uninterrupted operation, with modern plants incorporating online monitoring to handle corrosion from ammonia traces and ensure product purity above 99%.^[32]

Applications

Industrial and Corrosion Inhibition Uses

Morpholine functions as a critical intermediate in the synthesis of rubber accelerators and vulcanizing agents, such as sulfenamides and dithiodimorpholine derivatives, which account for approximately 40% of its global industrial consumption. These compounds promote efficient sulfur crosslinking during the vulcanization of natural and synthetic rubbers, resulting in improved tensile strength, elasticity, and resistance to aging and heat—key factors in the longevity of products like tires, hoses, and conveyor belts. For instance, 4,4'-dithiodimorpholine acts as a sulfur donor, releasing sulfur at curing temperatures around 140–160°C to form polysulfide bonds without excessive scorching.^[4]^[33]^[34] In corrosion inhibition, morpholine is applied as a neutralizing amine in boiler water treatment, representing about 30% of its usage, where it volatilizes with steam to evenly distribute and maintain condensate pH between 8.5 and 9.5. This neutralizes carbonic acid from dissolved CO2, preventing acidic corrosion on ferrous metals in steam lines and economizers, particularly in fossil fuel-fired systems where combustion gases exacerbate acidity. Its efficacy stems from forming a passive iron oxide film on metal surfaces, reducing corrosion rates by up to 90% in controlled tests compared to untreated water, though it requires dosages of 10–50 ppm based on CO2 levels for optimal performance.^[4]^[35]^[36] Morpholine also finds use in waxes, polishes, and textile auxiliaries, comprising roughly 5% of applications, where it serves as an emulsifier for oleic acid-based formulations. In industrial waxes and polishes, it stabilizes emulsions for floor and metal coatings, enhancing adhesion and abrasion resistance to extend service life under mechanical stress. For textiles, morpholine derivatives act as lubricants and finishing agents, reducing friction during processing and improving fabric durability against wear, with typical incorporation rates of 1–5% in auxiliary blends.^[4]^[1]^[2]

Organic Synthesis and Pharmaceuticals

Morpholine serves as a versatile nucleophilic reagent in organic synthesis, particularly for the formation of enamines from carbonyl compounds, which are key intermediates in alkylation reactions such as the Stork enamine synthesis.^[37] Its secondary amine functionality enables efficient reaction with aldehydes and ketones under mild conditions, often with azeotropic removal of water to drive equilibrium toward the enamine product.^[38] Additionally, morpholine participates in Mannich reactions to generate β-amino carbonyl compounds, leveraging its basicity to facilitate carbon-carbon bond formation.^[21] In pharmaceutical applications, morpholine acts as a privileged scaffold that enhances aqueous solubility and metabolic stability of drug candidates due to its polar oxygen and nitrogen atoms, which form hydrogen bonds without introducing excessive lipophilicity.^[39] It is incorporated as a building block in the synthesis of antibiotics like linezolid, where morpholine derivatives serve as precursors in multi-step assemblies to construct the oxazolidinone core.^[40] Similarly, anticoagulants such as rivaroxaban utilize morpholine moieties to optimize pharmacokinetic properties, including oral bioavailability.^[41] These structural integrations often stem from morpholine's ability to mimic piperazine or ethylene glycol units while providing conformational flexibility in active sites.^[42] Morpholine derivatives constitute approximately 5% of its industrial consumption in the production of optical brighteners and dyes, where its reactivity supports conjugation to chromophores for enhanced fluorescence or color stability.^[2] In optical brighteners, morpholine acts as an intermediate to link stilbene or triazine units, improving solubility in detergent formulations.^[35] For dyes, it functions as a solvent or reactant to dissolve resins and facilitate coupling reactions, capitalizing on its miscibility with both polar and nonpolar media.^[43] As a solvent in organic reactions, morpholine's polarity (dielectric constant around 7) and amphiphilic nature—combining ether-like oxygen and amine basicity—enable it to stabilize polar transition states in nucleophilic additions or substitutions requiring aprotic environments, while its low cost supports large-scale processes.^[44] This solvating capability arises causally from its ability to donate and accept hydrogen bonds, preventing aggregation of reactants without proton donation that could protonate nucleophiles.^[45] Morpholine functions as an emulsifying agent in post-harvest wax coatings for fruits, including apples and citrus, where it facilitates the formation of microemulsions with carnauba wax and fatty acids like oleic or linoleic acid to create protective films that reduce desiccation, enhance gloss, and inhibit mold growth.^[18] ^[46] These coatings extend shelf life by minimizing water loss and microbial proliferation, thereby reducing post-harvest food waste, with empirical studies showing effective desiccation prevention on coated apples under refrigerated storage.^[47] Residue analyses indicate morpholine concentrations in fruit peels typically range from 0.03 to 0.3 ppm, with no detectable levels in pulp, as confirmed by gas chromatography-mass spectrometry methods applied to apples and oranges.^[48] ^[46] In fungicide applications, morpholine derivatives such as dodemorph, tridemorph, and fenpropimorph serve as ergosterol biosynthesis inhibitors, effectively controlling powdery mildew on cereal crops and other foliar diseases without documented broad-spectrum resistance in field trials.^[49] ^[9] Morpholine itself contributes to post-harvest protectant formulations in fruit waxes, providing fungistatic effects against surface molds during storage and transport.^[18] A 2000 USDA Agricultural Marketing Service technical report evaluated morpholine's use in such contexts, concluding minimal persistence in treated commodities due to its volatility and low application rates, supporting its role in reducing spoilage without significant accumulation.^[35] Regulatory assessments highlight benefits like decreased food loss from desiccation and fungal decay, balanced against concerns over its synthetic nature and potential in vivo formation of N-nitrosomorpholine, a carcinogen, though exposure modeling at detected residue levels indicates negligible dietary risk per USDA evaluations.^[48] ^[18] The European Union has imposed bans on morpholine in food coatings, establishing no maximum residue limits, reflecting precautionary approaches to volatile amine residues despite lower detected levels in recent analyses compared to 1980s data.^[50] ^[46]

Health and Safety

Acute and Chronic Toxicity

Morpholine exhibits moderate acute toxicity via oral, dermal, and inhalation routes, primarily manifesting as irritation and corrosion due to its basic nature (pKa of conjugate acid approximately 8.36), which enables protonation and disruption of biological membranes and lipid barriers in tissues.^[51] In rats, the oral LD50 ranges from 1,050 to 1,900 mg/kg body weight, indicating lethality requires doses around 1 g/kg, with symptoms including severe burns to the mouth, esophagus, and gastrointestinal tract upon ingestion.^[52] ^[51] Dermal exposure in rabbits yields an LD50 of approximately 500 mg/kg, causing skin corrosion and necrosis, while inhalation LC50 in rats is about 7.8 mg/L over 4 hours, leading to respiratory distress, pulmonary edema, and irritation of mucous membranes.^[53] ^[54] These effects stem from morpholine's reactivity as a secondary amine, promoting saponification of fats and proteins in contact tissues, though empirical dose-response data show threshold irritation below lethal levels, with no evidence of systemic neurotoxicity or genotoxicity in acute models.^[4] Chronic exposure studies in animals reveal target organ effects primarily on the kidneys and liver at high doses, with histopathological evidence of tubular degeneration and necrosis in rats administered 100-500 mg/kg/day orally over extended periods, though no-observed-adverse-effect levels (NOAELs) exceed 100 mg/kg/day in subchronic assessments lacking neoplastic changes.^[5] ^[4] Inhalation studies at concentrations up to 50 ppm for 6 months in rats induced mild renal hypertrophy without progression to failure, underscoring dose-dependent causality rather than inherent organ specificity absent confounding factors like nitrosation. Morpholine lacks strong carcinogenic potential, classified by the International Agency for Research on Cancer (IARC) as Group 3 (not classifiable as to carcinogenicity to humans), based on inadequate evidence from rodent bioassays showing no tumors at exposures up to 200 mg/kg/day, countering concerns from its nitrosamine-forming reactivity which requires exogenous nitrosating agents not inherent to pure morpholine exposure.^[55] ^[56] Human data from controlled thresholds align with animal findings, indicating chronic risks emerge only above irritancy limits, with empirical reversibility upon cessation.^[57]

Exposure Risks and Occupational Health

In industrial manufacturing and handling of morpholine, the primary routes of occupational exposure are inhalation of vapors and dermal absorption through skin contact, with potential for eye exposure during spills or splashes.^[58] These routes predominate in settings involving mixing, transfer, or application as a corrosion inhibitor or solvent, where vapors can accumulate in poorly ventilated areas and the liquid's corrosiveness facilitates rapid skin penetration.^[5] Exposure to morpholine vapors above 20 ppm, the OSHA permissible exposure limit (PEL) as an 8-hour time-weighted average, can cause acute symptoms including irritation of the eyes, nose, throat, and respiratory tract, as well as headaches and nausea.^[58] ^[59] Workers handling the substance for several hours at low vapor levels have reported transient visual disturbances, such as foggy vision with halos around lights, attributable to the amine's irritant properties.^[60] Dermal exposure without barriers leads to severe skin burns and potential systemic effects via absorption, underscoring the "[skin]" notation in regulatory limits.^[58] Effective mitigation relies on engineering controls like local exhaust ventilation to maintain airborne concentrations below the NIOSH recommended exposure limit of 20 ppm (time-weighted average) and 30 ppm (short-term), combined with personal protective equipment (PPE) such as butyl rubber gloves, chemical-resistant clothing, and full-face shields for splash protection.^[58] Respiratory protection, including air-purifying respirators with organic vapor cartridges, is advised when ventilation is inadequate or during high-risk operations.^[5] Grounding equipment during handling prevents static-induced sparks, given morpholine's flammability.^[6] Morpholine's occupational risks align with those of similar aliphatic amines, where adherence to these exposure limits—established based on irritation thresholds rather than severe toxicity—has enabled safe industrial use without widespread reports of uncontrolled incidents when controls are implemented.^[61] Monitoring via air sampling and biological indicators, per NIOSH methods, ensures compliance and minimizes health impacts in controlled environments.^[62]

Regulatory Classifications for Human Health

Morpholine has been evaluated by the International Agency for Research on Cancer (IARC) as Group 3, not classifiable as to its carcinogenicity to humans, based on inadequate evidence of carcinogenicity in humans and experimental animals.^[55]^[63] The U.S. National Toxicology Program does not list morpholine as a known human carcinogen or reasonably anticipated to be one, reflecting the absence of sufficient data establishing causal links to cancer in bioassays or epidemiology.^[18] Similarly, the American Conference of Governmental Industrial Hygienists (ACGIH) assigns it an A4 classification, indicating it is not classifiable as an occupational carcinogen due to limited evidence.^[52] Under the European Union's Classification, Labelling and Packaging (CLP) Regulation (EC) No 1272/2008, morpholine is classified for human health hazards as Acute Toxicity Category 4 (oral, dermal, and inhalation; harmful if swallowed, in contact with skin, or inhaled), Skin Corrosion Category 1B (causes severe skin burns and eye damage), and Specific Target Organ Toxicity (single exposure) Category 3 (respiratory tract irritation).^[64] These classifications stem from empirical data on its irritant and corrosive effects observed in acute exposure studies, including LD50 values around 1-2 g/kg orally in rodents, prioritizing direct toxicological observations over precautionary extrapolations.^[1] Health Canada conducted a 2017 assessment of morpholine's use as an emulsifier in wax coatings for fruits and vegetables, determining it poses no health risk at typical residue levels (below 5-10 mg/kg in peel), supported by margin-of-exposure calculations exceeding 1000 based on no-observed-adverse-effect levels from repeated-dose studies.^[65] This evidence-based conclusion contrasts with isolated advocacy for restrictions citing potential nitrosamine formation, though verifiable data show morpholine itself exhibits low genotoxic potential and no tumor promotion in standard assays.^[66] Occupational guidelines, such as NIOSH's skin notation, emphasize systemic absorption risks from dermal exposure leading to liver and kidney effects in high-dose animal models, but human epidemiology lacks confirmed chronic health outcomes beyond irritation.^[57]

Environmental Considerations

Environmental Fate and Persistence

Morpholine demonstrates limited environmental persistence, primarily due to its susceptibility to atmospheric photo-oxidation and biodegradation in aqueous and soil environments, rather than hydrolysis. In the atmosphere, reaction with hydroxyl radicals proceeds rapidly, yielding an estimated half-life of less than one day based on structure-activity modeling.^[27] This short atmospheric lifetime minimizes long-range transport and aerial deposition as a persistent pollutant. In surface waters, morpholine resists hydrolysis across neutral to alkaline pH ranges, lacking labile functional groups that would facilitate rapid aqueous breakdown, though indirect photo-oxidation may contribute under illuminated conditions with a modeled half-life of approximately 0.9 hours.^[67] Biodegradation dominates in water, with aerobic microbial consortia, including mycobacteria isolated from contaminated sites, degrading it at rates exceeding 0.8 mM/hour under optimal conditions, often within 13 hours.^[68] In soils, morpholine's low organic carbon partition coefficient (Koc ≈ 7.4) indicates high mobility and potential for leaching to groundwater, but its persistence is curtailed by volatilization from dry surfaces and aerobic biodegradation akin to aquatic pathways.^[1] Volatilization from moist soils or water bodies occurs slowly due to its Henry's law constant and water-like volatility, yet the compound's high aqueous solubility (fully miscible) favors dissolution over partitioning to air or sediment.^[1] Experimental data and modeling from international assessments confirm negligible long-term accumulation in groundwater or sediments, as degradation kinetics outpace transport and sorption processes.^[27] The n-octanol/water partition coefficient (log Kow ≈ -0.86 to -2.55 at pH 7) further underscores minimal partitioning into biota or hydrophobic matrices, reinforcing that morpholine does not behave as a persistent, bioaccumulative substance in natural systems.^[1]^[27]

Ecological Effects and Bioaccumulation

Morpholine demonstrates moderate acute toxicity to fish, with LC₅₀ values ranging from 180 to 380 mg/L for rainbow trout (Oncorhynchus mykiss) over 96 hours, varying by water hardness.^[27] Comparable lethality is observed in other species, including 350 mg/L for bluegill sunfish (Lepomis macrochirus) and 400 mg/L for tidewater silversides (Menidia peninsulae).^[27] Invertebrates show similar sensitivity, as evidenced by EC₅₀ values of 100-120 mg/L for Daphnia magna immobilization at 24 hours.^[27] These effects primarily arise from gill irritation and osmotic disruption due to morpholine's basic and corrosive properties, rather than systemic poisoning.^[27] Algae exhibit greater acute sensitivity, with growth inhibition EC₅₀ of 28 mg/L for Selenastrum capricornutum over 96 hours and toxicity thresholds of 4.1 mg/L for Scenedesmus quadricauda.^[27] Protozoans display intermediate responses, with toxicity thresholds of 12-18 mg/L for species such as Entosiphon sulcatum and Chilomonas paramaecium.^[27] Microbial communities tolerate higher concentrations, with a toxicity threshold of 310 mg/L for aerobic Pseudomonas putida after 16 hours and NOEC up to 8700 mg/L for related Pseudomonas strains.^[27] Terrestrial and aquatic plants show low chronic sensitivity, as indicated by an EC₅₀ of 383 mg/L for lettuce (Lactuca sativa) seed germination inhibition over 3 days.^[27] These thresholds suggest minimal disruption to microbial degradation processes or plant growth under typical environmental exposures. Morpholine possesses negligible bioaccumulation potential, evidenced by a bioconcentration factor (BCF) below 2.8 in carp (Cyprinus carpio) over 42 days per OECD Guideline 305.^[69] Its highly negative log K_ow of -2.55 at pH 7 facilitates rapid excretion and dilution in food webs, precluding biomagnification.^[27] While industrial spills could cause localized acute impacts, morpholine's role in corrosion inhibition mitigates broader ecosystem metal leaching from pipes and boilers.^[3]

Regulations and Global Standards

International and National Regulations

In the European Union, morpholine is registered under the REACH Regulation (EC) No. 1907/2006 as a substance manufactured or imported in volumes exceeding 1,000 tonnes per year per registrant, necessitating comprehensive chemical safety assessments, exposure scenarios, and risk management measures for handlers to mitigate hazards during production, use, and disposal.^[70] Enforcement by the European Chemicals Agency includes mandatory communication of safe use instructions down the supply chain and periodic updates to registration dossiers based on new data, with rationale centered on protecting workers and the environment from its corrosive and irritant properties while enabling continued industrial applications.^[71] In the United States, morpholine is included on the Toxic Substances Control Act (TSCA) Chemical Substance Inventory as an active existing chemical, subjecting it to EPA reporting requirements under the Chemical Data Reporting rule for sites manufacturing or processing over 25,000 pounds annually, and requiring premanufacture notices for any significant new uses not previously reviewed.^[72] The EPA enforces these through inspections and penalties for non-compliance, with the underlying rationale emphasizing oversight of potential environmental releases and occupational exposures without prohibiting established uses supported by toxicity data indicating manageability under standard controls.^[73] Morpholine is not listed in Annex III of the Rotterdam Convention, thus exempt from its prior informed consent procedures for international trade in hazardous chemicals, reflecting assessments that its risks do not warrant such export/import notifications despite its flammability and reactivity.^[74] For agricultural applications, such as boiler water treatment in food processing, the U.S. Department of Agriculture has evaluated morpholine under the National Organic Program, granting allowances as a synthetic processing aid when residues are absent and use aligns with good manufacturing practices, without establishing specific residue tolerances due to its volatility and lack of bioaccumulation in final products.^[75] Empirical evidence from these evaluations supports deregulation in low-exposure contexts, countering precautionary approaches that might impose undue restrictions absent demonstrated harm.

Risk Assessments and Usage Restrictions

The 1995 evaluation by the International Programme on Chemical Safety (IPCS) under the World Health Organization assessed morpholine's health risks from industrial exposures, determining that typical workplace levels below 20 ppm (8-hour time-weighted average) provide sufficient margins of safety against respiratory irritation, skin effects, and potential systemic absorption, with no evidence of carcinogenicity or genotoxicity warranting broader prohibitions beyond standard controls like ventilation and personal protective equipment.^[3] This assessment informed occupational guidelines, such as the US Occupational Safety and Health Administration's permissible exposure limit of 20 ppm, without recommending usage bans for permitted applications in chemical manufacturing, rubber vulcanization, or boiler water treatment.^[76] Dietary risk assessments for morpholine residues, primarily from its use in edible fruit coatings as a fungistat and in boiler steam for food processing, have consistently affirmed negligible consumer health risks at observed levels below 10-50 ppm on treated produce. The US Food and Drug Administration's authorization under 21 CFR §172.235 permits morpholine salts of fatty acids as indirect food additives, with residue monitoring ensuring exposures remain far below no-observed-adverse-effect levels (e.g., oral NOAEL of 100 mg/kg/day in rodent studies), thereby avoiding the need for tolerance exemptions in most cases.^[77] Similarly, post-2010 evaluations of related morpholine derivatives in agricultural formulations, including residue trials on crops like apples, support maximum residue limits that protect against chronic intake risks, with estimated dietary exposures constituting less than 1% of acceptable daily intakes.^[78] Usage restrictions stem directly from these assessments' identification of irritation hazards, leading to targeted prohibitions: the European Union banned morpholine in cosmetics since 1986 due to dermal and ocular corrosivity at concentrations above 0.1%, while Germany limits it to 10 mg/kg in boiler feedwater for food industry steam generation to minimize condensate carryover.^[3] Although advocacy from organic agriculture groups has pushed for outright exclusion of synthetic morpholine-based preservatives in favor of natural alternatives, citing precautionary concerns over long-term low-dose effects, empirical toxicology data—showing rapid metabolism, low bioaccumulation (log Kow 0.86), and absence of reproductive or developmental toxicity at relevant doses—override such positions, upholding approvals where margins exceed exposures by factors of 100 or more.^[18] No global standards impose production quotas or phase-outs, reflecting consensus on manageable risks under regulated conditions.^[3]

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Recovery of morpholine from aqueous solutions thereof
The process is exemplied by the following examples of thc continuous production of morpholine from diethanolamine by dehydration with sulfuric acid.
[23]
US3038949A - Vulcanization of latex with 4, 4'-dithiodimorpholine
Patent 1,443,149, issued January 23, 1923) first showed it possible to vulcanize the individual rubber particles in latex by subjecting the latex containing ...
[24]
US2777846A - Process of producing morpholine from diethanolamine
Dehydration of diethanolamine employing. about 1.8 parts of 66 Baum sulfuric acid per part of diethanolamine by slowly adding the amine to the acid while ...Missing: routes | Show results with:routes
[25]
An excellent method to produce morpholine by bipolar membrane ...
The conventional route for Mp is through the dehydration of diethanolamine with sulfuric acid by the following cyclodehydration reactions (1), (2).
[26]
DE1918388A1 - Process for the production of morpholines
Diethanolamine consumed 1715 - 1050 = 665 g. Yield ar. Morpholine 91.6 %. Beispiel example kk.
[27]
Morpholine (EHC 179, 1996) - INCHEM
Brunnemann & Hoffmann (1991) reported that since 1981 they had routinely determined the concentrations of NMOR in a leading snuff brand in the USA with the aim ...Missing: history | Show results with:history
[28]
(PDF) Morpholines. Synthesis and Biological Activity - ResearchGate
Aug 9, 2025 · ... MORPHOLINE. SYNTHESIS. The simplest synthesis of morpholine is based on. the reaction of bis(2-chloroethyl) ether with excess. aqueous ammonia ...
[29]
Morpholine Production Cost Analysis Reports 2025
Production from Diethylene Glycol with Ammonia: The manufacturing process of Morpholine starts with the combination of Diethylene glycol and ammonia with ...
[30]
US4647663A - Synthesis of morpholine - Google Patents
This invention relates to an improved process for producing morpholine. The improvement resides in continuously charging the diethylene glycol and ammonia ...
[31]
Morpholine Market Size & Share Trends, 2034 - Industry Research
Balaji Amines: Holds nearly 20% of global morpholine market share, with production capacities exceeding 60,000 tons annually. Their facilities in India ...
[32]
US4739051A - Preparation of morpholine - Google Patents
Morpholine and other cyclic imines are obtained by reacting diethylene glycol and other appropriate diols with ammonia under hydrogenating conditions.
[33]
[PDF] Morpholine - IARC Publications
Morpholine is tyically used as follows: rubber chemicals, 40%; corrosion inhibitors,. 30%; waxes and polishes, 5%; optical brighteners, 5%; and miscellaneous, ...Missing: commercialization history
[34]
4,4-DITHIODIMORPHOLINE - Ataman Kimya
4,4-Dithiodimorpholine is primarily used as a vulcanization accelerator and sulfur donor in the production of natural and synthetic rubber materials. The ...<|separator|>
[35]
[PDF] Morpholine.pdf - Agricultural Marketing Service
Nov 29, 2000 · Melting point -4.9 °C, boiling point 128.9 °C. Density 0.995 g/ml. (See. Attachment M-7 from Chemfinder), also supplier MSDS files in ...
[36]
Applications of Morpholine in Chemical Industry - ChemicalBook
Nov 20, 2019 · Morpholine is used as a corrosion inhibitor for metals such as copper, iron, lead, zinc and other metals. It is widely used in areas such as ...
[37]
1-morpholino-1-cyclohexene - Organic Syntheses Procedure
1. An excess of morpholine is required because the water that separates during the reaction always contains a considerable amount of it in solution.Missing: applications | Show results with:applications
[38]
Morpholine - (Organic Chemistry) - Vocab, Definition, Explanations
Morpholine is a heterocyclic organic compound with the chemical formula C₄H₉NO. It is a colorless liquid with a characteristic amine-like odor and is widely ...
[39]
Morpholine as a Privileged Structure: A Review on the Medicinal ...
The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to ...
[40]
[PDF] Determination of Morpholine in Linezolid by Ion Chromatography
Morpholine is used as a building block in a multistep synthesis to produce linezolid (Figure 1), which is a synthetic antibiotic of the oxazolidinone class.Missing: moiety furosemide
[41]
The 4-morpholinoaniline derivate drugs: the antimicrobial Linezolid...
The 4-morpholinoaniline derivate drugs: the antimicrobial Linezolid (Zyvox), the anticoagulant blood thinner Rivaroxaban ...Missing: furosemide | Show results with:furosemide
[42]
Morpholine as ubiquitous pharmacophore in medicinal chemistry
Morpholine is an organic chemical compound having a six-membered ring containing two heteroatoms nitrogen and oxygen, considered as the important nucleus in ...
[43]
[PDF] Morpholine - Classic Chemicals
Morpholine itself is a solvent for a large variety of organic materials, including resins, dyes, and waxes. It can be used as a catalyst. Morpholine is still ...
[44]
MORPHOLINE | - atamankimya.com
Morpholine is commonly used as a solvent in organic synthesis, reactions and chemical industry research due to its low cost and polarity.
[45]
Morpholine: A Multi-Purpose Chemical for Industrial Applications ...
What is Morpholine? Morpholine is a colorless, hygroscopic liquid with a characteristic amine-like odor. Its chemical structure consists of a six-membered ...Missing: appearance | Show results with:appearance
[46]
Quantification of Morpholine in Peel and Pulp of Apples and ...
Jun 5, 2020 · Morpholine salts of fatty acids have been used in wax coatings on the surfaces of fruit and vegetable commodities in China and the United ...
[47]
edible coatings from morpholine-free wax microemulsions
Technical Abstract: Coatings were made by the drying of wax microemulsions composed of water, wax, fatty acid, ammonia and antifoam; with morpholine sometimes ...
[48]
[PDF] Health effects of morpholine based coating for fruits and vegetables
Morpholine itself is likely not a health risk, but can form a carcinogen during digestion. It is also an industrial pollutant and VOC.
[49]
Morpholine (Amine) [Group 5] resistance management strategy
Morpholines are useful for controlling powdery mildew diseases on a wide range of crops and for controlling a range of cereal foliar diseases (Table 1).
[50]
Determination of morpholine residue in fruit and fruit juices by gas ...
May 1, 2022 · Morpholine has been banned in the European Union, and no maximum residue limits have been established (European Union Food Additives Database, ...Missing: related | Show results with:related
[51]
https://www.sigmaaldrich.com/sds/sial/252360
[52]
Hazardous substance assessment – Morpholine - Canada.ca
Sep 28, 2023 · Morpholine has an auto-ignition temperature of 255 °C, which is well above the temperature of at which spontaneous combustion ...
[53]
[PDF] Material Safety Data Sheet (MSDS) - Morpholine
May 1, 2022 · Toxicological Data on Ingredients: Morpholine: ORAL (LD50): Acute: 1450 mg/kg [Rat]. 525 mg/kg [Mouse]. DERMAL (LD50): Acute: 500 mg/kg [Rabbit] ...
[54]
[PDF] SAFETY DATA SHEET - FUJIFILM Wako
310 mg/kg ( Rat ). 7.8 mg/L ( Rat ) 4h. Chemical Name. Acute toxicity -oral- source information. Acute toxicity -dermal- source information. Acute toxicity - ...
[55]
Morpholine (IARC Summary & Evaluation, Volume 47, 1989)
Apr 13, 1999 · Morpholine is not classifiable as to its carcinogenicity to humans (Group 3). For definition of the italicized terms, see Preamble ...
[56]
[PDF] Agents Classified by the IARC Monographs, Volumes 1–123
Nov 2, 2018 · 000110-91-8 Morpholine. 3. 47, 71. 1999. 003795-88-8 5 ... carcinogenic to humans (Group 1). There is sufficient evidence in.
[57]
https://www.cdc.gov/niosh/docs/2017-137/pdfs/FY17_SNP_Morpholine_2017-137.pdf
[58]
NIOSH Pocket Guide to Chemical Hazards - Morpholine - CDC
Morpholine · Exposure Limits. NIOSH REL. TWA 20 ppm (70 mg/m3) ST 30 ppm (105 mg/m3) [skin]. OSHA PEL. TWA 20 ppm (70 mg/m3) [skin] See Appendix G · Measurement ...
[59]
https://www.osha.gov/annotated-pels/table-z-1
[60]
[PDF] Morpholine - Santa Cruz Biotechnology
Inhalation of amine vapors may cause irritation of the mucous membrane of the nose and throat, and lung irritation with respiratory distress and cough. ...
[61]
1988 OSHA PEL Project - Morpholine | NIOSH - CDC
Exposure to morpholine produces nasal and bronchial irritation and liver and kidney impairment in animals (Shea 1939/Ex. 1-758); the substance readily ...Missing: applications | Show results with:applications
[62]
[PDF] T-PV2123-01-0305-CH Target concentration: OSHA PEL: ACGIH TLV
May 14, 2003 · The fully validated NIOSH Method S-150 for morpholine suggests that morpholine can be ... Occupational Exposure to Hazardous Chemicals in ...
[63]
https://inchem.org/documents/iarc/vol71/101-morphol.html
[64]
[PDF] Safety Data Sheet: Morpholine - Carl ROTH
1.1. Product identifier. Identification of the substance. Morpholine ≥99 %, for synthesis. Article number. 9691. Index No (GB CLP). 603-011-00-4. EC number.
[65]
A Summary of the Health Hazard Assessment of Morpholine in Wax ...
May 4, 2017 · It was concluded that morpholine, as currently used in the wax coating of fruits and vegetables, does not pose a risk to health.
[66]
https://inchem.org/documents/hsg/hsg/hsg092.htm
[67]
Screening assessment - Heterocycles Group - Canada.ca
Morpholine has been identified for use as an emulsifier in the preparation of wax coatings for fresh produce, such as apples (Health Canada 2002). Morpholine ...
[68]
Degradation of Morpholine by an Environmental Mycobacterium ...
Under these conditions, morpholine was degraded in 13 h at a rate of about 0.8 mM/h. The two intermediary compounds, 2-(2-aminoethoxy)acetate and glycolate, ...Missing: persistence half-
[69]
[PDF] Safety Data Sheet Morpholine Revision 5, Date 01 Oct 2022 - Redox
Sep 23, 2025 · Morpholine is flammable, corrosive to metals, toxic if swallowed, inhaled, or in contact with skin, and causes severe skin burns and eye damage.<|control11|><|separator|>
[70]
https://echa.europa.eu/registration-dossier/-/registered-dossier/13364
[71]
Morpholine - Registration Dossier - ECHA
Classification & Labelling & PBT assessment; Manufacture, use & exposure ... EC Name: Morpholine; CAS Number: 110-91-8; Molecular formula: C4H9NO; IUPAC ...Missing: CLP | Show results with:CLP
[72]
Morpholine - Substance Details - SRS | US EPA
Below are the EPA applications/systems, statutes/regulations, or other sources that track or regulate this substance. This table shows how each list refers to ...<|separator|>
[73]
TSCA Chemical Substance Inventory | US EPA
Sep 11, 2025 · The Toxic Substances Control Act (TSCA) Chemical Substance Inventory contains all existing chemical substances manufactured, processed, or imported in the ...How to Access the TSCA · Notification (Active-Inactive) Rule · UVCBsMissing: morpholine | Show results with:morpholine
[74]
Annex III Chemicals - Rotterdam Convention
The chemicals listed in Annex III include pesticides and industrial chemicals that have been banned or severely restricted for health or environmental reasons.Missing: morpholine | Show results with:morpholine
[75]
Morpholine | Agricultural Marketing Service - USDA
Oct 26, 2023 · December 2000 Petition (pdf) requesting addition to §205.605 for use as a processing aid (boiler chemical) (cyclohexylamine, diethylaminoethanol ...Missing: limits tolerances
[76]
https://www.osha.gov/chemicaldata/120
[77]
21 CFR § 172.235 - Morpholine. - Legal Information Institute
Morpholine may be safely used as a component of food, subject to the following restrictions. (a) It is used as the salt(s) of one or more of the fatty acids.
[78]
Validation of Analytical Method for Analysis of Morpholine on Apples
Summary: The objectives of this project were: 1. Validation of an analytical method developed by Dr. Michelangelo Anastassiades at the EU Reference Laboratory ...<|separator|>