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SECTION 1. CHEMICAL IDENTIFICATION

CHEMINFO Record Number: 349
CCOHS Chemical Name: Morpholine

Synonyms:
Diethylenimide oxide
Diethylene imidoxide
Diethylene oximide
1-Oxa-4-azacyclohexane
Tetrahydro-1,4-isoxazine
Tetrahydro-1,4-oxazine
Tetrahydro-2H-1,4-oxazine
Tetrahydro-4H-1,4-oxazine
Tetrahydro-p-oxazine

Chemical Name French: Morpholine
Chemical Name Spanish: Morfolina
CAS Registry Number: 110-91-8
UN/NA Number(s): 2054
RTECS Number(s): QD6475000
EU EINECS/ELINCS Number: 203-815-1
Chemical Family: Nitrogen oxygen heterocyclic compound / six membered oxygen nitrogen heterocyclic compound / tetrahydro oxazine / cyclic secondary amine / cyclic amino ether
Molecular Formula: C4-H9-N-O
Structural Formula: -O-CH2-CH2-NH-CH2-CH2- (cyclic structure)

SECTION 2. DESCRIPTION

Appearance and Odour:
Colourless, mobile, oily liquid with a characteristic, unpleasant, fishy amine-like odour; hygroscopic (absorbs moisture from the air).(6,19)

Odour Threshold:
0.011 ppm (detection); 0.07 ppm (recognition) (19)

Warning Properties:
GOOD - threshold limit value (TLV) is more than 250 times the odour threshold.

Composition/Purity:
Morpholine is available commercially as an anhydrous liquid of purity 98% and greater, and as 40%, 50%, 60%, 80% and 88% solutions with water. The impurities present depend on the production process used to make morpholine and may include 2-(2-aminoethoxy)ethanol, N-ethylmorpholine, ethylenediamine and 2- methoxyethanol (if produced from ethylene glycol), or N-hydroxyethylmorpholine (if produced from diethanolamine). Very small amounts of arsenic (up to 3 mg/kg) and lead (up to 20 mg/kg) have been reported to be present in cosmetic grade morpholine. N-nitrosomorpholine has been found in morpholine not stored under nitrogen.(6)

Uses and Occurrences:
Morpholine is used as a chemical intermediate in the rubber industry (for example, as an intermediate for rubber accelerators); as a corrosion inhibitor in steam boiler systems, for metals (such as silver), metal aerosol containers and valves, in aqueous hydraulic liquid system fluids, and in mineral lubricating and turbine oils; as an antioxidant for lubrication oils; as an intermediate for the manufacture of optical brighteners in detergent formulations, and emulsifying, dispersing and wetting agents; and for the synthesis of alkyl morpholines. It is also used as a solvent for a large variety of organic materials, including resins, dyes, waxes and casein; as a catalyst for the emulsion polymerization of butadiene and isoprene and for the production of polyurethane foams; as an intermediate in the synthesis of a large number of pharmaceuticals, crop protection agents, dyes, bactericides, fungicides and herbicides; in the production of waxes and polishes; as a separating agent in various purification procedures; in the extraction of aromatics from hydrocarbon mixtures; in food additive applications; as a defoaming agent used in the manufacture of paper and paperboard, and in animal glues, used for food packaging materials; as a component of adhesives; in cosmetic products; and in the textile industry.(6,20,21,22) An aqueous solution of morpholine can be used for removing carbon dioxide, hydrogen sulfide, and hydrogen cyanide from gases.(20)
Morpholine does not occur naturally. It may be present in the atmosphere in many industrial emissions and by volatilization through its use in waxes and polishes.(6)


SECTION 3. HAZARDS IDENTIFICATION

EMERGENCY OVERVIEW:
Colourless, mobile, oily liquid with a characteristic, unpleasant, fishy amine-like odour. Hygroscopic. FLAMMABLE LIQUID AND VAPOUR. Vapour is heavier than air and can accumulate in low-lying areas or tanks, and may spread long distances. Distant ignition and flash back are possible. Can decompose at high temperatures forming irritating/toxic gases, such as nitrogen oxides and ammonia. TOXIC. May be harmful if inhaled or absorbed through the skin. Vapour is extremely irritating to eyes and respiratory tract. May cause lung injury--effects may be delayed. Vapour may produce temporary blurring of vision with a general bluish or greyish haze and the appearance of halos around lights. CORROSIVE to the eyes and skin. May cause permanent eye injury, including blindness, and permanent scarring of the skin.



POTENTIAL HEALTH EFFECTS

Effects of Short-Term (Acute) Exposure

Inhalation:
Morpholine is a severe irritant to corrosive, but is detectable by smell at extremely low concentrations (0.011 ppm). Therefore, there is very good warning of exposure at concentrations well below those expected to produce health effects. Inhalation is expected to produce irritation of the nose, throat and upper airways. High concentrations can cause corrosive effects such as a burning sensation, sore throat, runny nose, coughing, wheezing, shortness of breath and difficulty breathing. In severe cases, potentially fatal lung injury (pulmonary edema) may result. The symptoms of pulmonary edema, such as chest pain and shortness of breath, may be delayed up to 24 hours after exposure. There is very little human information available, but these effects have been observed in animals exposed to high concentrations.
A human exposure to 12000 ppm (essentially saturated vapour concentration) resulted in nose irritation at 1 minute and coughing at 1.5 minutes. Repeated short-term inhalation caused sore throat.(1)

Skin Contact:
Morpholine and its concentrated solutions can cause corrosive skin injury, with severe burns, blistering and permanent scarring, based on animal and human information. Application of undiluted morpholine to the finger tips has caused an intense stinging sensation that is intolerable. The tissue became very dry after exposure with cracking of the cuticle around the nails. Even a 1/40 dilution caused discomfort.(1)
Concentrated morpholine can be absorbed through the skin and is expected to be toxic by this route of exposure, possibly due to its corrosive effects.

Eye Contact:
Morpholine and its concentrated solutions are corrosive and can cause permanent eye damage, including blindness, based on animal information. Vapour concentrations that are not irritating may produce temporary blurring of vision with a general bluish or greyish haze and the appearance of halos around lights. High vapour concentrations are irritating.
Employees have reported experiencing a temporary distortion of vision, which has been called "halo", "blue haze" or "foggy" vision. Distorted vision has typically developed toward the end of the shift and cleared up within hours of leaving work. In other cases, it has been described as occurring between 30 and 90 minutes after exposure and lasting 4-6 hours. Although no exposure data is available, it is experienced at concentrations below those which would produce eye or respiratory irritation. Examination of employees showed no corneal swelling, no alteration in clearness of vision and no permanent effects.(2,3)

Ingestion:
Morpholine can cause severe irritation or corrosive injury to the lips, mouth, throat, gastrointestinal tract and stomach. Symptoms may include a burning sensation, nausea, vomiting, diarrhea, and abdominal pain. In severe cases, death could result. Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

There are no reports of effects from long-term human exposure to morpholine.

Lungs/Respiratory System:
Animal evidence indicates that irritation of the nose, throat, upper respiratory tract and lungs could occur at high concentrations (100 ppm and above).

Skin:
Repeated or prolonged skin contact could result in dermatitis (dry, red, cracked skin).

Skin Sensitization:
Negative results for skin sensitization were obtained in one animal study.

Carcinogenicity:

There is no human information available. There is inadequate evidence for the carcinogenicity of morpholine to experimental animals.

The International Agency for Research on Cancer (IARC) has concluded that this chemical is not classifiable as to its carcinogenicity to humans (Group 3).

The American Conference of Governmental Industrial Hygienists (ACGIH) has designated this chemical as not classifiable as a human carcinogen (A4).

The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.

Teratogenicity and Embryotoxicity:
There is no human or animal information available.

Reproductive Toxicity:
There is no human information available. Very limited animal information suggests that morpholine would not cause reproductive effects.

Mutagenicity:
A study of peripheral lymphocytes in 24 people occupationally exposed to morpholine concluded that there was no significant increase in the number of cells with chromosome aberrations. However, there were design limitations with this study. Therefore, firm conclusions cannot be drawn.(5,6-unconfirmed) The limited information available from animal and short-term mutagenicity tests does not indicate that morpholine is mutagenic.

Toxicologically Synergistic Materials:
Exposure to morpholine and nitrites at the same time can lead to the production of N-nitrosomorpholine, a potent mutagen and carcinogen in a variety of test systems.(4)

Potential for Accumulation:
Morpholine is absorbed following oral, dermal or inhalation exposure and rapidly distributed in the body. In rabbits, mice, rats and hamsters, morpholine is quickly excreted almost completely unchanged in the urine. One day after administration, 70-90% morpholine was found in the urine. A small percentage is excreted in the expired air and feces. Up to 20% morpholine can be metabolized in the guinea pig, while much smaller amount is metabolized in the rat and hamster. The urinary metabolite identified in the rat and hamster was N-methylmorpholine.(4,6) In humans, morpholine is only metabolized to a limited extent and appears unchanged in the urine.(4)


SECTION 4. FIRST AID MEASURES

Inhalation:
Take precautions to ensure your own safety before attempting rescue (e.g. wear appropriate protective equipment, use the buddy system). Remove source of contamination or move victim to fresh air. If breathing is difficult, trained personnel should administer emergency oxygen. DO NOT allow victim to move about unnecessarily. Symptoms of pulmonary edema can be delayed up to 48 hours after exposure. Quickly transport victim to an emergency care facility.

Skin Contact:
Avoid direct contact. Wear chemical protective clothing, if necessary. As quickly as possible, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). Immediately flush with lukewarm, gently flowing water for at least 30 minutes. DO NOT INTERRUPT FLUSHING. If necessary, and it can be done safely, continue flushing during transport to emergency care facility. Quickly transport victim to an emergency care facility. Double bag, seal, label and leave contaminated clothing, shoes and leather goods at the scene for safe disposal.

Eye Contact:
Avoid direct contact. Wear chemical resistant gloves, if necessary. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for at least 30 minutes, while holding the eyelid(s) open. If a contact lens is present, DO NOT delay irrigation or attempt to remove the lens. Neutral saline solution may be used as soon as it is available. DO NOT INTERRUPT FLUSHING. If necessary, continue flushing during transport to emergency care facility. Take care not to rinse contaminated water into the unaffected eye or onto the face. Quickly transport victim to an emergency care facility.

Ingestion:
NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or is convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. Have victim drink 60 to 240 mL (2 to 8 oz) of water. If vomiting occurs naturally, have victim rinse mouth with water again. Quickly transport victim to an emergency care facility.

First Aid Comments:
Provide general supportive measures (comfort, warmth, rest).
Consult a doctor and/or the nearest Poison Control Centre for all exposures except minor instances of inhalation or skin contact.
Some first aid procedures recommended above require advanced first aid training. Protocols for undertaking advanced procedures must be developed in consultation with a doctor and routinely reviewed.
All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.



SECTION 5. FIRE FIGHTING MEASURES

Flash Point:
35 deg C (95 deg F) (closed cup) (6,23)

Lower Flammable (Explosive) Limit (LFL/LEL):
1.4% (6,23); 1.8% (20,23)

Upper Flammable (Explosive) Limit (UFL/UEL):
11.0% (6,23); 15.2% (20)

Autoignition (Ignition) Temperature:
290 deg C (555 deg F) (23,27); 310 deg C (590 deg F) (6,23)

Sensitivity to Mechanical Impact:
Probably not sensitive. Stable material.

Sensitivity to Static Charge:
Morpholine will not accumulate static charge, since it has a moderately high dielectric constant. Mixtures of warmed morpholine vapour and air at concentrations in the flammable range may be ignited by a static discharge of sufficient energy.

Electrical Conductivity:
Not available

Minimum Ignition Energy:
Not available

Combustion and Thermal Decomposition Products:
Nitrogen oxides, ammonia, carbon monoxide, carbon dioxide, and other irritant and toxic gases.(23) Under oxygen-poor conditions, hydrogen cyanide, nitriles, cyanic acid, isocyanates, nitrosamines, amides, carbamates and carbon monoxide can be produced.(6)

Fire Hazard Summary:
Flammable liquid. Can release vapours that form explosive mixtures with air at, or above, 35 deg C. Vapour is heavier than air and can accumulate in low-lying areas or tanks, and may travel a considerable distance to a source of ignition and flash back to a leak or open container. During a fire, irritating/toxic nitrogen oxides and ammonia may be generated. Vapour can accumulate in confined spaces resulting in a toxicity and flammability hazard. Closed containers may rupture violently and suddenly release large amounts of product when exposed to fire or excessive heat for a sufficient period of time. Water solutions of morpholine may be flammable or combustible.

Extinguishing Media:
Carbon dioxide, dry chemical powder, "alcohol resistant" foam, water spray or fog. Special multipurpose alcohol resistant fire-fighting foams are recommended for use on nearly all flammable liquids. Morpholine is water-soluble and will break down the common foams.(23) Foam manufacturers should be consulted for recommendations regarding types of foams and application rates.

Fire Fighting Instructions:
Evacuate area and fight fire from a safe distance or protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products. Wear full protective gear if exposure is possible. See Protection of Firefighters.
Stop leak before attempting to stop the fire. If the leak cannot be stopped, and if there is no risk to the surrounding area, let the fire burn itself out. If the flames are extinguished without stopping the leak, vapours could form explosive mixtures with air and reignite.
Water can extinguish the fire if used under favourable conditions and when hose streams are applied by experienced firefighters trained in fighting all types of flammable liquid fires.(23)
Closed containers may rupture violently when exposed to the heat of fire and suddenly release large amounts of products. Always stay away from ends of tanks, but be aware that flying material (shrapnel) from ruptured tanks may travel in any direction. If possible, isolate materials not yet involved in the fire, and move containers from fire area if this can be one without risk. Protect personnel. Otherwise, cool fire-exposed containers, tanks or equipment by applying hose streams. Cooling should begin as soon as possible (within several minutes) and should concentrate on any unwetted portions of the container. Apply water from the side and a safe distance. Cooling should continue until well after the fire is out. If this is not possible, use unmanned monitor nozzles and immediately evacuate the area.
If a leak or spill has not ignited, use water spray in large quantities to disperse the vapours and to protect personnel attempting to stop a leak. The resulting water solutions of morpholine may be flammable. Water spray can be used to dilute spills to non-flammable mixtures and flush spills away from ignition sources. Dike fire control water for appropriate disposal. Solid streams of water may be ineffective and spread material.
For an advanced or massive fire in a large area, use unmanned hose holder or monitor nozzles; if this is not possible withdraw from fire area and allow fire to burn. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank due to fire.
After the fire has been extinguished, toxic atmospheres may remain. Before entering such an area especially confined areas, check the atmosphere with an appropriate monitoring device while wearing full protective gear.

Protection of Fire Fighters:
Morpholine is corrosive and it and its decomposition products are very hazardous to health. Do not enter fire area without wearing specialized protective equipment suitable for the situation. Firefighter's normal protective clothing (Bunker Gear) will not provide adequate protection. A full-body encapsulating chemical protective suit with positive pressure self-contained breathing apparatus (NIOSH approved or equivalent) may be necessary.



NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

NFPA - Health: 3 - Short exposure could cause serious temporary or residual injury.
NFPA - Flammability: 3 - Liquids and solids that can be ignited under almost all ambient temperature conditions.
NFPA - Instability: 0 - Normally stable, even under fire conditions, and not reactive with water.

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

Molecular Weight: 87.12

Conversion Factor:
1 ppm = 3.56 mg/m3; 1 mg/m3 = 0.28 ppm at 25 deg C (calculated)

Physical State: Liquid
Melting Point: -3.1 deg C (26.4 deg F) (20); -4.9 deg C (23.2 deg F) (27,28)
Boiling Point: 128.2-128.9 deg C (262.8-264 deg F) (6,28)
Relative Density (Specific Gravity): 1.01 at 20 deg C (pure) (20,27) (water = 1)
Solubility in Water: Soluble in all proportions with the evolution of some heat.(21,28)
Solubility in Other Liquids: Soluble in all proportions in ethanol, methanol, acetone, diethyl ether, ethylene glycol, 2-hexanone, benzene, toluene, xylene and turpentine.(6,21)
Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = -0.86 (29)
pH Value: 10.77 (1%); 11.27 (10%); 11.47 (25%); 11.77 (pure) (calculated)
Basicity: Moderately strong base.
Dissociation Constant: pKa = 8.492 at 25 deg C (protonated species) (27,28)
Viscosity-Dynamic: 2.23 mPa.s (2.23 centipoises) at 20 deg C (22)
Viscosity-Kinematic: 2.21 mm2/s (2.21 centistokes) at 20 deg C (calculated)
Saybolt Universal Viscosity: 33.3 Saybolt Universal Seconds at 37.8 deg C (100 deg F) (calculated)
Surface Tension: 37.63 mN/m (37.63 dynes/cm) (24,27)
Vapour Density: 3.00 (air = 1) (calculated)
Vapour Pressure: 1.1 kPa (8.25 mm Hg) at 20 deg C (20); 1.34 kPa (10.08 mm Hg) at 25 deg C (28)
Saturation Vapour Concentration: 10900 ppm (1.09%) at 20 deg C; 13300 ppm (1.33%) at 25 deg C (calculated)
Evaporation Rate: Less than 1 (butyl acetate = 1)
Henry's Law Constant: 1.43 x 10(-2) Pa.m3/mol (cited as 1.41 x 10(-7) atm.m3/mol) at 25 deg C (estimated) (28); log H = -5.24 (dimensionless constant; calculated)

Other Physical Properties:
DIELECTRIC CONSTANT: 7.42 at 25 deg C (24,27)


SECTION 10. STABILITY AND REACTIVITY

Stability:
Normally stable. It is reported to decompose at high temperatures used in boiler steam cycles (greater than 250 deg C).(6)

Hazardous Polymerization:
Does not occur.

Incompatibility - Materials to Avoid:

NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.


STRONG OXIDIZING AGENTS (e.g. nitric acid, nitrates, peroxides, perchloric acid or perchlorates) - increased risk of fire and explosion. Evolution of toxic fumes of nitrogen oxides.(30,31)
STRONG ACIDS (e.g. hydrochloric acid, sulfuric acid, acetic acid), ACID ANHYDRIDES (e.g. acetic anhydride), ACID CHLORIDES (e.g. acetyl chloride) - can react violently (violent spattering).(30,31)
CELLULOSE NITRATE - cellulose nitrate may ignite spontaneously on contact with amines such as morpholine.(23,32)
NITROMETHANE - mixtures may be susceptible to initiation by a detonator.(32)
NITRITES, NITROUS ACID, NITROGEN OXIDES - reacts to form the mutagen and carcinogen, N-nitrosomorpholine.(6)
Morpholine is also incompatible with vinyl acetate, acrylates, alkalene oxides or epoxides, substituted allyls, epichlorohydrin, isocyanates, ketones, aldehydes, phenols, cresols and caprolactam solutions.(31)

Hazardous Decomposition Products:
None reported

Conditions to Avoid:
Temperatures above 35 deg C, heat, open flames, other ignition sources.

Corrosivity to Metals:
Morpholine attacks copper and zinc and their alloys, and lead at 20 deg C.(20,30) Morpholine is not corrosive to stainless steel (types 304, 316, 317), aluminum (types 3003 and Cast B-356), carbon steel (types 1010 and 1020), and nickel-base alloy, Hastelloy at 20 deg C.(33,34)

Corrosivity to Non-Metals:
Morpholine will attack some plastics, such as acrylonitrile-butadiene-styrene (ABS), styrene-acrylonitrile (SAN), Noryl, Bisphenol-A-fumarate and isophthalate polyesters, nylon 11, polysulfone and vinyl ester; and elastomers, such as Nitrile Buna-N (NBR), ethylene propylene, chloroprene, natural rubber, neoprene, and Viton A.(34,35,38,39) Morpholine does not attack plastics, such as Teflon, other fluorocarbons, polyvinyl chloride (PVC) and nylon 6 and 66; and elastomers, such as the fluorocarbons, Chemraz and Kalraz, and butyl rubber.(34,35,38,39)


SECTION 11. TOXICOLOGICAL INFORMATION

LC50 (male mouse): 1450 ppm (4-hour exposure)* (7)
LC50 (female mouse): 1900 ppm (4-hour exposure)* (7)
LC50 (female rat): 2150 ppm (4-hour exposure)* (7)
LC50 (male rat): 2250 ppm (4-hour exposure)* (7)
*Note: These values are reported in an abstract and the methods cannot be evaluated.
LC50 (mouse): 370 ppm (4-hour exposure); cited as 1320 mg/m3 (4-hour exposure) (8, unconfirmed)

LD50 (oral, rat): 1050 mg/kg (9)
LD50 (oral, mouse): 525 mg/kg (4,8-unconfirmed)
LD50 (oral, guinea pig): 900 mg/kg (1)

LD50 (dermal, rabbit): 500 mg/kg; cited as 0.5 mL/kg (9)

Eye Irritation:

Morpholine has produced severe irritation and corrosive injury.

Application of 0.005 mL of in excess of a 40% solution caused severe injury in rabbits (scored over 5 where 5 is severe injury; graded 7/10).(9) One drop of undiluted morpholine, repeated once after 5 minutes, caused fluid accumulation, clouding of the cornea and corrosive injury in rabbits within 24 hours.(6-citing unpublished information)

Skin Irritation:

Morpholine has produced corrosive injury. Even 2% solutions caused irritation after 72 hours.

Application of 0.01 mL of undiluted morpholine has produced tissue death (necrosis) in rabbits (graded 6/10).(9) A single application of 900 gm/kg to rabbits, under cover, caused the tissue to become black and die. Repeated application with dilution of the same total dose caused swelling and thickening of the skin with tissue death.(1) Application of 40% and 60% solutions produced irritation in rabbits immediately. A 2% solution produced irritation after 72 hours.(6-unconfirmed) Using standardized methodologies (unspecified), skin irritation scores of 6.6-8.0 (maximum possible) have been reported.(4, unconfirmed)

Effects of Short-Term (Acute) Exposure:

Morpholine is a severe irritant to corrosive. Inhalation produces irritation of the nose and respiratory tract. High concentrations can cause severe lung injury with bleeding. Skin contact causes tissue death. Oral exposure causes stomach and intestinal irritation and bleeding. Systemic effects from all routes of exposure are damage to the liver (fatty degeneration) and kidneys (severe damage to tubules).

Inhalation:
Inhalation exposure of rats and guinea pigs to 12000 or 18000 ppm (essentially saturated vapour concentrations) for up to 7 days was intensely irritating to the eyes, nose and respiratory tract and caused deaths. Bleeding in the lungs, severe kidney damage and fatty degeneration of the liver were noted. After 10 days recovery, lung damage persisted in animals exposed to 18000 ppm.(1) Rats exposed to 2000 ppm for 4 days or 450 ppm for 30 days developed reduced body weight, increased lung weight and signs of lung injury.(10-unconfirmed) Rats exposed to lower concentrations (73 ppm for 4 hours) still showed an increase in respiratory rate and lung irritation. This irritation was minimal at 11 ppm and not seen at 1 ppm.(4-unconfirmed)

Skin Contact:
A single skin exposure to 900 gm/kg, under cover, caused death in 2/7 rabbits, with corrosive skin damage and severe burns of underlying organs. Repeated daily exposure of rabbits and guinea pigs to 900 mg/kg, under cover, caused death of all animals within 2 weeks. Severe corrosive injury was observed and there was damage to liver and kidneys.(1)

Ingestion:
Oral toxicity studies with rats and mice caused gastrointestinal bleeding and diarrhea. Dosing of rats (160, 320 or 800 mg/kg) and guinea pigs (90, 180 or 450 mg/kg) for 30 days produced dose-related changes in the stomach (tissue death); liver (fatty degeneration); kidneys (severe damage to tubules), spleen and lungs. There were deaths with all exposures.(1) Rats fed 323 mg/kg for 4 weeks showed lowered weight gains. No effects were noted at 27.6 or 93 mg/kg, but detailed examination of the animals was not conducted.(4, unconfirmed)

Effects of Long-Term (Chronic) Exposure:

Inhalation studies for 13 weeks or 2 years showed normal growth, survival, hematology and chemistry. Eye damage and irritant changes to the mucous membranes of the nasal cavities were observed. One study reported dose-related incidence and severity of chronic pneumonia in rats exposed to 250 ppm.

Inhalation:
Rats exposed for 2 years to 0, 10, 50, or 150 ppm showed normal growth, survival, hematology and chemistry. Dose-related irritation of the eyes and nose was observed. At 150 ppm, there was eye damage (keratitis) and irritant changes to the mucous membranes of the nasal cavities, including tissue death.(11) Rats were exposed for 7 or 13 weeks to 0, 25, 100 or 250 ppm. At 250 ppm, there was irritant damage to the nasal cavity (focal erosion and metaplasia) and chronic pneumonia. Salivation and a reddish discharge was observed around the nose and mouth. Shallow, rapid breathing occurred at all exposures. At 100 ppm, less severe nasal cavity changes and pneumonia were noted. There were no effects at 25 ppm. No treatment-related effects in any blood, chemical or urinalysis studies were observed at any exposure.(12) Rats inhaling 450 ppm for 8 weeks showed decreased food consumption, increased relative lung and kidney weights and irritation to the eyes and nose.(7) This study is reported by abstract and the methods cannot be evaluated.

Skin Sensitization:
Negative results were obtained in sensitization tests (modified Buehler's method) using guinea pigs exposed to concentrations up to 2%.(13)

Carcinogenicity:
The International Agency for Research on Cancer (IARC) has concluded that there is inadequate evidence for the carcinogenicity of morpholine to experimental animals.(5)
Most oral exposure studies are either considered inadequate for evaluation or have not shown a significant increase in the incidence of tumours. In one oral rat study, a few tumours of the liver and lung occurred in treated animals. The author's noted that these tumours might be the result of the interaction of morpholine with a nitrite of unknown origin.(14) Negative results were obtained in an inhalation study using rats.(5,12,15) The ability of morpholine to form nitrosated compounds that have greater carcinogenic potential has been investigated in several studies. These studies are not reviewed here since they do not reflect the results of exposure to morpholine alone.

Reproductive Toxicity:
Very limited information suggests that morpholine is not a reproductive toxin.
Male rats exposed to 2 or 20 ppm for 4 months (cited as 8 or 70 mg/m3) showed no changes in sperm or testicular function.(16) Reproductive outcome was not assessed.

Mutagenicity:
It is not possible to conclude that morpholine is mutagenic, based on the available information. Morpholine can form nitrosated compounds that would have greater mutagenic potential. Several studies have investigated this effect. However, these studies are not reported here as they do not reflect the results of exposure to morpholine alone.
One positive in vivo study has been reported. However, deficiencies in the study were noted. Rats and guinea pigs exposed for 4 months to 2 or 20 ppm (cited as 8 or 70 mg/m3) showed an increase in the number of chromosomal aberrations in bone marrow cells.(6-unconfirmed) Other tests using live animals have either produced negative results or used routes of exposure that are not relevant to occupational exposures.(4,5,6,15)
Positive and negative results have been obtained in tests using cultured mammalian cells.(4,5,6,17) Mostly negative results have been obtained in tests using bacteria and yeast.(4,5,6,15)


SECTION 16. OTHER INFORMATION

Selected Bibliography:
(1) Shea, T.E., Jr. The acute and sub-acute toxicity of morpholine. Journal of Industrial Hygiene and Toxicology. Vol. 21, no. 7 (Sept. 1939). p. 236-245
(2) Jones, W.T., et al. Glaucopsia-blue-grey vision. British Journal of Industrial Medicine. Vol. 29, no. 4 (1972). p. 460-461
(3) Mastromatteo, E. Heterocyclic amine exposure with urethane forms. Journal of Occupational Medicine. Vol. 7, no. 10 (Oct. 1965). p. 507
(4) Trochimowicz, H.J., et al. Aliphatic and aromatic nitrogen compounds: morpholine. In: Patty's Toxicology. 5th ed. Edited by E. Bingham, et al. Vol. 4. John Wiley and Sons, Inc., 2001
(5) International Agency for Research on Cancer (IARC). Morpholine. In: IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 71, parts 1, 2 and 3. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. World Health Organization, 1999. p. 1511-1514
(6) International Programme on Chemical Safety (IPCS). Morpholine. Environmental Health Criteria; 179. World Health Organization, 1996
(7) Lam, H.F., et al. A re-evaluation of the toxicity of morpholine. [Abstract]. Federation Proceedings. Vol. 37 (1978). p. 679
(8) National Institute for Occupational Safety and Health (NIOSH). Morpholine. Last updated: 2002-10. In: Registry of Toxic Effects of Chemical Substances (RTECS(R)). [CD-ROM]. Canadian Centre for Occupational Health and Safety (CCOHS). Also available at: <ccinfoweb.ccohs.ca/rtecs/search.html>
(9) Smyth, H.F., Jr., et al. Range-finding toxicity data list V. AMA Archives of Industrial Hygiene and Occupational Medicine. Vol. 10 (1954). p. 61-68
(10) Takezawa, J., et al. Toxic effect of morpholine on rat lungs. Abstract. Federation Proceedings. Vol. 37, no. 3 (1978). p. 247
(11) Harbison, R.D., et al. Chronic morpholine exposure of rats. Fundamental and Applied Toxicology. Vol. 12, no. 3 (1989). p. 491-507
(12) Conaway, C.C., et al. Subchronic inhalation of morpholine in rats. Fundamental and Applied Toxicology. Vol. 4, no. 3 (1984). p. 465-472
(13) Wang, X., et al. Comparative studies of the sensitization potential of morpholine, 2-mercaptobenzothiazole and 2 of their derivatives in guinea pigs. Contact Dermatitis. Vol. 19, no. 1 (1988). p. 11-15
(14) Shank, R.C., et al. Dose-response study of the carcinogenicity of dietary sodium nitrile and morpholine in rats and hamsters. Food and Cosmetics Toxicology. Vol. 14 (1976). p. 1-8
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Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.


Review/Preparation Date: 2005-10-03



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