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MORPHOLINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Morpholine is a corrosion inhibitor, emulsifier, solvent, optical bleacher, food additive, and chemical intermediate (IRPTC, 1984).

Specific Substances

    1) Diethyleneimide oxide
    2) Diethylene imidoxide
    3) Tetrahydro-1,4-isoxazine
    4) Molecular Formula: C4-H9-N-0
    5) CAS 110-91-8
    6) MORPHOLINE MIXTURE
    1.2.1) MOLECULAR FORMULA
    1) C4-H9-N-O

Available Forms Sources

    A) USES
    1) Morpholine is used in many industrial settings. Exposure may come from ingestion, inhalation, eye, or dermal exposure (Clayton & Clayton, 1994).
    2) Uses of morpholine include (ACGIH, 1986; Proctor et al, 1988):
    1) Boiler water additive
    2) Rubber accelerator
    3) Corrosion inhibitor
    4) Detergent brightener
    5) Wax and polish additive
    6) Book paper preservative
    7) Organic Synthesis
    8) Solvent for casein, dyes, resins, and waxes
    9) Insecticides
    10) Antiseptics
    11) Food additive

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Human exposures have been limited. Corneal, nasal, dermal, and lung irritation have been reported. Effects in animals are similar to symptoms seen with ammonium hydroxide. The clinical picture is one of pronounced mucous membrane irritation of the gastrointestinal and upper respiratory tract.
    0.2.4) HEENT
    A) Conjunctivitis, corneal damage, and the perception of halos have been reported after ocular exposure to morpholine. The amount of irritation and damage is dependent upon the concentration of morpholine.
    B) Nasal irritation and sore throat have been reported from morpholine exposure.
    0.2.6) RESPIRATORY
    A) Cough and nasal irritation have been seen in humans exposed to 1200 ppm for about 1.5 minutes.
    0.2.8) GASTROINTESTINAL
    A) Irritation of the gastrointestinal tract is likely after exposure to morpholine. The amount of irritation is dependent upon the concentration.
    0.2.9) HEPATIC
    A) Although hepatic damage has been reported in animals, it has not been seen in humans.
    0.2.10) GENITOURINARY
    A) Although kidney damage has been reported in fatal exposures in animals, it has not been seen in human exposures.
    0.2.14) DERMATOLOGIC
    A) Skin contact represents a moderate degree of hazard, which decreases as the concentration decreases to 25% or less in water.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the potential carcinogenic activity of morpholine in humans.

Laboratory Monitoring

    A) Although not reported in humans, liver and kidney damage might occur after exposure to morpholine. Monitor liver and kidney function.
    B) A chest x-ray may be required if a substantial respiratory exposure has occurred.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There is no specific antidote; treatment is symptomatic and supportive.
    B) Emesis should not be induced.
    C) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    D) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) Human exposures have been minimal; most reports come from animal experimentation. Probable oral lethal dose in human is 50 to 500 mg/kg.
    B) TLV - 20 ppm
    C) Irritation of the nose, throat, and lungs was seen in humans exposed to 1200 ppm for 1.5 minutes.

Clinical Effects

Summary Of Exposure

    A) Human exposures have been limited. Corneal, nasal, dermal, and lung irritation have been reported. Effects in animals are similar to symptoms seen with ammonium hydroxide. The clinical picture is one of pronounced mucous membrane irritation of the gastrointestinal and upper respiratory tract.

Heent

    3.4.1) SUMMARY
    A) Conjunctivitis, corneal damage, and the perception of halos have been reported after ocular exposure to morpholine. The amount of irritation and damage is dependent upon the concentration of morpholine.
    B) Nasal irritation and sore throat have been reported from morpholine exposure.
    3.4.3) EYES
    A) RABBITS - One drop in rabbit eyes produced purulent conjunctivitis with subsequent keratoleukoma and cicatrization of the eyelids (IRPTC, 1984).
    B) RABBITS - Morpholine as well as N-ethylmorpholine and N-methylmorpholine have caused transient corneal edema (Grant & Schuman, 1993). When dropped into rabbit eyes, it caused corneal clouding and ulceration of the conjunctiva (Carpenter & Smyth, 1946).
    C) Morpholine as well as the N-ethyl and N-methyl derivatives mentioned above have caused a foggy, blue-grey vision with halos surrounding lights. This occurred in workers exposed to vapors and lasted for several hours. Onset was generally after work and cleared by the next day (Grant & Schuman, 1993; Jones & Kipling, 1972; Mastromatteo, 1965).
    3.4.5) NOSE
    A) NASAL IRRITATION is seen in animals and was reported after a 1.5 minute exposure to 1200 ppm in humans (HSDB , 2001; Shea, 1939). Necrosis of the nasal surfaces was seen in rats who inhaled 250 ppm for 7 weeks (Conway et al, 1984).
    3.4.6) THROAT
    A) Transfer of morpholine by pipette produced a severe sore throat and reddened mucous membranes (ACGIH, 1986).

Respiratory

    3.6.1) SUMMARY
    A) Cough and nasal irritation have been seen in humans exposed to 1200 ppm for about 1.5 minutes.
    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) Cough and nasal irritation was seen in a human exposed to 1200 ppm for 1.5 minutes (Shea, 1939).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PNEUMONITIS
    a) Animals exposed to 250 ppm for 7 to 13 weeks showed chronic murine pneumonia including perivascular or peribronchial lymphoid hyperplasia and focal pneumonitis (Conway et al, 1984).

Gastrointestinal

    3.8.1) SUMMARY
    A) Irritation of the gastrointestinal tract is likely after exposure to morpholine. The amount of irritation is dependent upon the concentration.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GASTROENTERITIS
    a) Animal studies have shown that ingested morpholine is intensely irritating to the intestinal tract (Clayton & Clayton, 1994).

Hepatic

    3.9.1) SUMMARY
    A) Although hepatic damage has been reported in animals, it has not been seen in humans.
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) RATS - A rat exposed to 18,000 ppm for 8 hours died showing liver congestion and cloudy swelling. Cellular necrosis was seen in animals that died after longer exposures (Shea, 1939). Rats exposed to up to 250 ppm for 13 weeks did not show overt liver toxicity but did demonstrate foci of mononuclear inflammatory cells with some nonsuppurative pericholangitis (Conway et al, 1984).

Genitourinary

    3.10.1) SUMMARY
    A) Although kidney damage has been reported in fatal exposures in animals, it has not been seen in human exposures.
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) NEPHROPATHY TOXIC
    a) A RAT exposed to 18,000 ppm for 8 hours showing kidney congestion and cloudy swelling after death. Animals exposed for longer periods showed degeneration of the epithelial lining of the kidney tubule (Shea, 1939).
    b) RATS exposed to 250 ppm for up to 13 weeks showed only slight focal nephropathy. No gross abnormalities were seen (Conway et al, 1984).
    2) LACK OF EFFECT
    a) RATS - Spermatogenesis in rats chronically exposed to 70 and 8 mg/m(3) for months, for 4 hours, 5 times weekly was NOT affected (IRPTC, 1984).

Dermatologic

    3.14.1) SUMMARY
    A) Skin contact represents a moderate degree of hazard, which decreases as the concentration decreases to 25% or less in water.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Skin contact represents a moderate degree of hazard which decreases as the concentration decreases to 25% or less in water (ACGIH, 1986). Morpholine is a corrosive irritant to skin (Sax & Lewis, 1989).
    B) DISORDER OF SKIN
    1) Morpholine is a selective melanocyte growth inhibitor that is thought to interfere with melanin synthesis (Noga et al, 1986).
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SKIN NECROSIS
    a) Application of pure morpholine on murine tails led to a burning effect. Necrosis was not seen after a 10 minute exposure, but after 150 minutes, necrosis and rejection of tails was seen in all animals. Even animals that had lost their tails did not show systemic effects (IRPTC, 1984).
    b) RABBIT experiments have shown the threshold of an irritant effect to be 1/200 of the molar solution (IRPTC, 1984).

Reproductive

    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) Various lower animals (mollusks, frogs, and fish) which were exposed to morpholine or the reaction product nitroso-morpholine did not show development of neoplasms. The relevance to human exposures is unclear (IRPTC, 1984).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS110-91-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Morpholine
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the potential carcinogenic activity of morpholine in humans.
    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) RATS - Morpholine was shown to produce a 3% incidence of hepatocellular carcinomas in Sprague-Dawley rats given 1000 ppm in their diet for 125 weeks (Shank & Newberne, 1976). This may have been due to N-nitrosomorpholine products.
    B) SARCOMA
    1) RATS - Morpholine was shown to produce a 2% incidence of lung angiosarcomas in Sprague-Dawley rats given 1000 ppm in their diet for 125 weeks. This may have been due to N-nitrosomorpholine products (Shank & Newberne, 1976).
    C) NEOPLASM
    1) MICE - A significantly increased number of lung adenomas was seen in male CD-mice exposed to both 0.1% (v/v) morpholine in their drinking water as well as 1 to 2 ppm of nitrogen dioxide (Van Stee et al, 1980).
    2) There have been many experimental animal studies with morpholine, either alone or in combination with chemicals known to react to produce N-nitrosomorpholine. Morpholine alone produced lung and liver tumors when given orally to mice (RTECS), but was not carcinogenic by itself in other studies (Greenblatt, 1971; EW Vanstee , 1983).
    3) When given orally together with sodium nitrite, morpholine caused liver and kidney tumors in rats (Lijinsky & Taylor, 1977) and lung tumors in mice (Greenblatt, 1971). Nasal lesions were produced in a 13 week inhalation exposure study in rats (Conaway et al, 1984). Other studies of morpholine with sodium nitrite in the drinking water did not cause cancer in rats (Garcia & Lijinsky, 1973). Together with 20 ppm of nitrogen dioxide, it was not carcinogenic in mice (EW Vanstee , 1983).
    D) LACK OF EFFECT
    1) The IARC Working Group concluded there was inadequate evidence for carcinogenicity of morpholine in experimental animals (IARC, 1989). Harbison et al (1989) found no carcinogenic potential from chronic exposure of rats to morpholine for 2 years at concentrations of 150 ppm or less.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Although not reported in humans, liver and kidney damage might occur after exposure to morpholine. Monitor liver and kidney function.
    B) A chest x-ray may be required if a substantial respiratory exposure has occurred.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Although not reported in humans, liver and kidney damage were seen in animals exposed to significant amounts. If substantial exposure occurs in a human, monitor liver and kidney function.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) CHEST X-RAY may be required in symptomatic patients after substantial exposures.

Methods

    A) CHROMATOGRAPHY
    1) Gas and gas-liquid chromatography may be used to detect morpholine in urine, feces, blood, plasma, bile and biological tissues (HSDB , 2001; Clayton & Clayton, 1994).
    2) Other analytical methods for the separation and/or determination of morpholine include ion-exchange chromatography, mass spectrometry, thermogravimetric analysis, spectrophotometry and colorimetric analysis (Clayton & Clayton, 1994).
    B) OTHER
    1) One method for detecting morpholine is the reaction with 2,4-dinitrochlorobenzene or carbon disulfide and copper acetate. It forms a colored solution which is measured via colorimetry. Sensitivity is 5 mcg in the analyzed volume of solution (IRPTC, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Although not reported in humans, liver and kidney damage might occur after exposure to morpholine. Monitor liver and kidney function.
    B) A chest x-ray may be required if a substantial respiratory exposure has occurred.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) Emesis should not be induced due to the potential for alkaline irritation.
    B) DILUTION -
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    C) ACTIVATED CHARCOAL -
    1) Morpholine has not been specifically tested for adsorption onto activated charcoal. Until more data are available, use of activated charcoal is recommended.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Should not be induced due to the potential for alkaline irritation.
    B) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    C) ACTIVATED CHARCOAL
    1) Morpholine has not been specifically tested for adsorption onto activated charcoal. Until more data are available, use of activated charcoal is recommended.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific antidote; treatment is symptomatic and supportive.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) Human exposures have been minimal; most reports come from animal experimentation. Probable oral lethal dose in human is 50 to 500 mg/kg.
    B) TLV - 20 ppm
    C) Irritation of the nose, throat, and lungs was seen in humans exposed to 1200 ppm for 1.5 minutes.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) PROBABLE ORAL LETHAL DOSE (HUMAN): 50 to 500 milligrams/kilogram; between 1 teaspoonful & 1 ounce for 70 kg person (HSDB , 2001).
    B) ANIMAL DATA
    1) Repeated daily exposure of rats to 18,000 ppm for 8 hours was lethal to some animals; those dying had damage to lungs, liver, and kidneys (Proctor et al, 1988).

Maximum Tolerated Exposure

    A) ANIMAL DATA
    1) RAT -
    a) Exposure for 1 hour to a concentrated vapor produced no deaths (Smyth et al, 1954).
    b) Rats survived exposure to 8000 parts per million for 8 hours (Smyth et al, 1954).
    c) Harbison et al (1989) found no systemic toxicity from chronic exposure of rats to morpholine for 2 years at concentrations of 150 parts per million or less.
    2) RABBITS -
    a) THRESHOLD OF IRRITANT EFFECTS - (Rabbits skin) - 1/200 of a molar solution (IRPTC, 1984).
    b) OCULAR EXPOSURE - One drop of morpholine in rabbit eyes produced purulent conjunctivitis and subsequent keratoleukoma and cicatrixation of eyelids (IRPTC, 1984).

Workplace Standards

    A) ACGIH TLV Values for CAS110-91-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Morpholine
    a) TLV:
    1) TLV-TWA: 20 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: Skin
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Eye dam; URT irr
    d) Molecular Weight: 87.12
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS110-91-8 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Morpholine
    2) REL:
    a) TWA: 20 ppm (70 mg/m(3))
    b) STEL: 30 ppm (105 mg/m(3))
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: [skin]
    1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.
    f) Note(s):
    3) IDLH:
    a) IDLH: 1400 ppm
    b) Note(s): [10%LEL]
    1) [10%LEL]: The 10%LEL designation is provided where the IDLH was based on 10% of the lower explosive limit. This is used for safety purposes in some cases even though toxicity is not indicative of irreversible health effects or impairment of escape exists only at higher concentrations.

    C) Carcinogenicity Ratings for CAS110-91-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Morpholine
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Morpholine
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Morpholine
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS110-91-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Morpholine
    2) Table Z-1 for Morpholine:
    a) 8-hour TWA:
    1) ppm: 20
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 70
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: Yes
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 413 mg/kg (RTECS, 2001)
    B) LD50- (ORAL)MOUSE:
    1) 525 mg/kg (RTECS, 2001)
    C) LD50- (ORAL)RAT:
    1) 1450 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Morpholine is an alkaline irritant/caustic depending upon its concentration.

Toxicologic Mechanism

    A) Morpholine inhibits biochemical oxygen consumption at 100 and 10 mg/L concentrations (IRPTC, 1984).

Physicochemical

Physical Characteristics

    A) Morpholine is a colorless, oily, mobile, hydroscopic liquid with an amine-like odor (ACGIH, 1986; Budavari, 1989; Sax & Lewis, 1989).
    B) fish-like odor (AAR, 1987)
    C) ammoniacal odor (CHRIS , 1992)

Ph

    A) 11 ( for a 25% aqueous solution) (HSDB , 1992)

Molecular Weight

    A) 87.12 (Budavari, 1989)

Other

    A) ODOR THRESHOLD
    1) 0.01 ppm (CHRIS , 2002)

References

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