Hazardous substance assessment – Morpholine

Identification

Chemical name:

Morpholine

CAS #:

110-91-8

Chemical composition:

C₄H₉NO

Synonyms:

Tetrahydro-1,4-oxazine; 1-Oxa-4-azacyclohexane; Diethylene imidoxide; Diethyleneimide oxide; p-Isoxazine, tetrahydro-.

UN #:

2054

Pictogram(s):

Figure 1 - Text description

The symbol within the pictogram is a human skull with two crossed bones behind it. The symbol indicates that hazardous products with this pictogram can cause death or poisoning.

Figure 2- Text description

The symbol within the pictogram shows a container dripping liquid onto a piece of metal and another container dripping liquid onto a hand. This symbol indicates that hazardous products with this pictogram can:

• damage or destroy metal
• cause irreversible damage to the skin (for example, burns, blisters, scarring)
• produce tissue damage in the eye or vision loss that is irreversible or not fully reversible within 21 days

Figure 3 - Text description

The symbol within the pictogram is a flame with a line underneath it. This symbol indicates that hazardous products with this pictogram can ignite easily and burn rapidly if they are not stored and handled properly.

WHMIS classification

Health hazards:

Acute Toxicity (Oral) – Category 4

Acute Toxicity (Dermal) – Category 3

Skin Corrosion – Category 1A

Serious Eye Damage – Category 1

Physical hazards:

Flammable Liquids – Category 3

Health hazards

Acute Toxicity (Oral):

Category 4

Median lethal dose (LD₅₀) (rat, female): 1,050 mg/kg ^{Footnote 1}.

In a pre-guideline study, morpholine was administered by gavage to unfasted groups of 5 female rats. Rats were observed for a period of 14 days ^{Footnote 1}.

The available data meet the classification criteria for Acute Toxicity (Oral) – Category 4; HPR 8.1.1(1).

Acute Toxicity (Dermal):

Category 3

LD₅₀ (rabbit, male): 505 mg/kg ^{Footnote 1}.

In a pre-good laboratory practice (pre-GLP) and pre-guideline study, the LD₅₀ was determined in groups of 4 male New Zealand albino rabbits ^{Footnote 1}. The LD₅₀ value was cited as 0.50 mL/kg; using a specific gravity of 1.01 ^{Footnote 2}, this value is equivalent to 505 mg/kg.

The available data meet the classification criteria for Acute Toxicity (Dermal) – Category 3; HPR 8.1.1(1).

Acute Toxicity (Inhalation – Gases):

Not applicable

Morpholine is not a gas.

Acute Toxicity (Inhalation – Vapours):

Does not meet criteria

In an acute inhalation toxicity test (no guideline specified), 5 Sprague-Dawley rats per sex were exposed to morpholine by whole body vapour inhalation for 6 hours at a target concentration of 18.1 mg/L ^{Footnote 3}. When measured using gas chromatography (GC) or infrared spectroscopy (IR), the chamber concentration of morpholine was 4.6 or 5.4 mg/L, respectively. Within 24 hours, 9 of the 10 rats had died. The information available for this study indicates that the chamber temperature was high at 28°C.

In a supporting study conducted similarly to the Organisation for Economic Co-operation and Development Test Guideline (OECD TG) 403, rats were exposed to morpholine vapour (99.2% purity) at concentrations of 35.1 mg/L (nominal) for 1 hour (6 rats per sex), 28.8 mg/L (nominal) for 3 hours (3 per sex) or 21.14 mg/L (nominal) for 5.5 hours (3 per sex) ^{Footnote 4}. Chamber vapour concentrations were not measured. There were 0, 2 and 6 deaths at 35.1 mg/L (1 hour), 28.8 mg/L (3 hours) and 21.14 mg/L (5.5 hours), respectively. The median lethal concentration (LC₅₀) value (4-hour) was <24.8 mg/L (nominal).

In another study conducted similarly to the OECD TG 403, 6 rats were exposed to morpholine (purity not reported) for 4 hours at a concentration of 23.6 mg/L ^{Footnote 4}. Actual chamber concentrations were not measured. There were no mortalities. The LC₅₀ (4-hour) was determined to be >23.6 mg/L.

The available data do not meet the classification criteria for Acute Toxicity (Inhalation – Vapours).

Acute Toxicity (Inhalation – Dusts and Mists):

No data available

Skin Corrosion / Irritation:

Category 1A

In a study conducted equivalently to OECD TG 404, 0.5 mL of undiluted morpholine was applied to 1 site on the clipped dorsal trunk of 6 New Zealand White rabbits (3 males and 3 females) for an exposure period of 3 minutes (based on study summary ^{Footnote 5}). Observations for responses were recorded immediately after patch removal and at 55 minutes. Grading of irritation was performed according to the method of Draize. Following an exposure period of 3 minutes, severe erythema, severe edema and necrosis were observed in 6 out of 6 animals tested.

In another OECD TG 404 study, dermal exposure for 4 hours to dilutions of 20, 40, and 60% morpholine was also tested ^{Footnote 4Footnote 5}. Only mean 0.5-, 24-, 48- and 72-hour scores were reported. The 40% dilution of morpholine caused mean 0.5-, 24-, 48- and 72-hour scores of 4/4 for erythema and 2.5/4 for edema; the 60% dilution caused mean 0.5-, 24-, 48- and 72-hour scores of 4/4 for erythema and 2.6/4 for edema. Necrosis was not described at these concentrations. Mean 0.5-, 24-, 48- and 72-hour scores for the 20% dilution of morpholine were 2.08/4 for erythema and 0.67/4 for edema, not meeting criteria for classification as a skin irritant (based on study summary ^{Footnote 5}). The available data suggest that morpholine is an irritant at more diluted concentrations (Category 2 [HPR 8.2.2(3)]) and corrosive at less diluted concentrations, meeting the criteria for Category 1A for skin corrosion [HPR 8.2.2(2)].

The available data meet the classification criteria for Skin Corrosion– Category 1A [HPR 8.2.2(2)].

Serious Eye Damage / Eye Irritation:

Category 1

In an OECD TG 405 study, 100 µL of undiluted morpholine was instilled into the conjunctival sac of the left eye of rabbits (based on study summary ^{Footnote 5}). The eyes were washed after 4 seconds, 30 seconds or after 24 hours. Per exposure time, 3 rabbits were used in the study. All 3 exposures caused irritation and necrosis in and around the eyes. After an exposure time of 24 hours, burns were observed. At 30 seconds of exposure, 2 of the animals also experienced corrosion both inside and around the eyes. After the observation period of 21 days, eye injuries were still observed in 1 animal.

In another OECD TG 405-compliant study, a 24-hour exposure to undiluted morpholine caused necrosis in the eye, detachment of the outer layers of the cornea and loss of fur as well as sores and scarring on the front of the upper eyelids^{Footnote 5}. In a range-finding study, severe corneal necrosis was observed following application of 0.005 mL of a 40% solution of morpholine to the eyes of albino rabbits^{Footnote 6}.

The available data meet the classification criteria for Serious Eye Damage– Category 1 [HPR 8.3.2(1)].

Respiratory Sensitization:

No data available

Skin Sensitization:

Does not meet criteria

In a Buehler test, male Hartley guinea pigs (10 per dose) were induced with 5% morpholine in petrolatum and challenged with morpholine up to 2% in white petrolatum by occlusive, epicutaneous exposure ^{Footnote 7}. No reactions were reported following morpholine exposure or in the negative control group.

The available data do not meet the classification criteria for Skin Sensitization.

Germ Cell Mutagenicity:

Does not meet criteria

In vivo: In a mammalian germ cell study, morpholine (500 mg/kg) was administered by oral gavage to pregnant Syrian golden hamsters on day 11 or 12 of pregnancy ^{Footnote 8}. The hamster embryos were excised 24 hours later and examined for chromosomal aberrations, micronucleus formation, morphological or malignant transformation and drug resistance mutation. Treatment with morpholine did not cause an increase in chromosomal aberrations or in the frequency of micronuclei in primary embryonic cell cultures.

In vitro: Negative or weakly positive results were obtained in a bacterial reverse mutation assay with Salmonella typhimurium strains TA 1535, TA 1537, TA 98 and TA 100 and Escherichia coli WP2 uvr A when tested with and without metabolic activation ^{Footnote 4Footnote 9Footnote 10}. In a study conducted similarly to OECD TG 476, morpholine was weakly positive in a mouse lymphoma forward mutation assay without activation and negative with activation ^{Footnote 4}. In a study conducted similarly to OECD TG 479, morpholine did not cause a meaningful increase in sister chromatid exchange in Chinese hamster ovary (CHO) cells, either with or without metabolic activation ^{Footnote 4}. Without metabolic activation, morpholine was negative in a chromosomal aberration assay in Chinese hamster lung cells and in an unscheduled DNA synthesis assay in rat hepatocytes ^{Footnote 4}. Negative or false positive results were also reported in Balb/3T3 cells in an in vitro transformation assay ^{Footnote 11Footnote 12}.

The available data do not meet the classification criteria for Germ Cell Mutagenicity.

Carcinogenicity:

Does not meet criteria

Morpholine has been classified as Group 3 (Not classifiable as to its carcinogenicity to humans) after review by the International Agency for Research on Cancer (IARC)^{Footnote 13}. Morpholine has been classified as A4 (Not classifiable as a human carcinogen) after review by the American Conference of Governmental Industrial Hygienists (ACGIH) ^{Footnote 14}. Morpholine has not been reviewed by the National Toxicology Program (NTP).

In a combined chronic/carcinogenicity study, morpholine was administered by whole body inhalation exposure to Sprague-Dawley rats at concentrations up to 543 mg/m³ for 6 hours per day, 5 days per week for 52 weeks (10 animals per sex per group) or for 104 weeks (60 animals per sex per group) ^{Footnote 15}. There was no evidence of an increased incidence of carcinogenesis due to chronic morpholine inhalation. Other studies conducted via inhalation and oral exposure reported that morpholine was not carcinogenic ^{Footnote 16}.

The available data do not meet the classification criteria for Carcinogenicity.

Reproductive Toxicity:

Does not meet criteria

In a repeat-dose vapour inhalation study in rats, conducted similarly to the OECD TG 453, no effects were reported on the reproductive organs after 104 weeks of exposures up to 0.543 mg/L of morpholine for 6 hours per day, 5 days per week ^{Footnote 4}. In a study conducted similarly to OECD 413, male and female rats were exposed to morpholine vapour at concentrations up to 0.89 mg/L for either 7 or 13 weeks ^{Footnote 4}. No effects on the testes or ovaries were reported.

The available data do not meet the classification criteria for Reproductive Toxicity.

Specific Target Organ Toxicity – Single Exposure:

Does not meet criteria

Oral Route of Exposure: No human data are available. In an acute toxicity study in animals performed according to OECD TG 401, clinical signs such as breathing abnormalities, effects on gait, postural abnormalities and eye closure were observed in rats at doses of 2,500 and 3,200 mg/kg (based on study summary ^{Footnote 5}). The LD₅₀ value was determined to be 1,900 mg/kg. These doses are too high to meet classification criteria. In another study, animals administered 1.6 g/kg had no gross pathological changes ^{Footnote 17}. Gastrointestinal bleeding and haemorrhage of the stomach were noted in rats given large doses up to 10 g/kg. The available data do not meet classification criteria for this hazard class.

Dermal Route of Exposure: In an acute dermal toxicity study, 0.9 g/kg was applied to the clipped skin of the midsection of 7 rabbits. Clinical symptoms consistent with the corrosive nature of the substance were observed ^{Footnote 17}.

Inhalation Route of Exposure: No human data are available. In a rat study, animals were exposed by inhalation for 4 hours to morpholine at 260, 40, or 3 mg/m^{3 Footnote 17}. At 260 mg/m³, an increase in respiratory rate but no effect on the weight of the lungs was noted. The exposed rats also retained a greater amount of stain, an indicator of cell damage, than did control animals. Rats exposed to morpholine at 40 mg/m³ showed more cell damage than controls. There were no changes in respiratory rate or lung weight observed at concentrations of 3 or 40 mg/m³. In another rat study, inhalation of a highly saturated vapour of morpholine caused mortality after 3 hours of exposure and local irritation to exposed tissues, including respiratory tract, was reported ^{Footnote 3}. Respiratory distress and lung damage were also noted, likely due to the corrosive nature of morpholine.

The available data do not meet the classification criteria for Specific Target Organ Toxicity – Single Exposure.

Specific Target Organ Toxicity – Repeated Exposure:

Does not meet criteria

Oral Route of Exposure: Male rats were administered morpholine in the diet at dosages up to 323 mg/kg/day for 4 weeks ^{Footnote 17}. An increase in weight of adrenal glands and a lower mean body weight gain were observed in animals treated with 323 mg/kg/day. Lower doses had no observed effects. In rats administered morpholine by gavage (0, 160, 320 or 800 mg/kg/day) for 30 days, swelling, congestion and necrosis and/or desquamation of the liver, kidneys, lungs and stomach were observed in the 800 and 320 mg/kg/day groups. Of the 20 rats exposed to 0.16 g/kg morpholine, 12 survived and no gross lesions were noted. In a 56-day study, female rats were fed 500 mg/kg morpholine per day^{Footnote 5}. No animals in either test or control groups died within the study period. After 270 days had elapsed, all animals of the test group were sacrificed; the only symptom was moderate adiposis of the liver.

Dermal Route of Exposure: In a repeat-dose dermal toxicity study, morpholine was applied daily at a dose of 900 mg/kg to the clipped skin of rabbits ^{Footnote 18}. All rabbits (7/7) died before the eleventh dose. Necrosis of the treated skin, and inflammation and congestion of the underlying organs were evident upon gross examination. Microscopic lesions of the liver and effects on kidneys and spleen were observed. The dose used was too high to use for classification.

Inhalation Route of Exposure: Focal erosion of the nasal turbinates was observed in rats following inhalation of 0.89 mg/L morpholine vapour for 13 weeks ^{Footnote 3}. Necrosis of the nasal turbinates was observed in rats following inhalation of 0.186 mg/L morpholine vapour for 104 weeks ^{Footnote 3}. In another study, rats were exposed to 0, 25, 100 or 250 mg/L morpholine vapour, 6 hours/day, 5 days per week for 13 weeks (based on the study's summary ^{Footnote 5}). No animals died during the 13-week exposure. The mean weight of the males exposed to 250 mg/L was consistently lower than the mean weight of male controls during weeks 6-13 and lesions in the lungs were possibly treatment related. Damage to the nasal passages was also noted in the high dose animals and to a lesser extent in 2 female animals of the 100 mg/L exposure group. Doses in these studies are too high to use for classification.

A non-guideline study in male rats (n=6-8/group) exposed to 0.08 mg/L morpholine for 4 hours per day for 8 days via whole-body inhalation reported increased thyroid gland activity after 4 days. The toxicological significance of the finding was not clear ^{Footnote 5}. No treatment-related changes in mortality, body weights, organ weights or clinical pathology parameters were observed in a 2-year study in rats with exposures up to 150 ppm morpholine vapour ^{Footnote 5}.

The available data do not meet the classification criteria for Specific Target Organ Toxicity – Repeated Exposure.

Aspiration Hazard:

No data available

No human data are available for morpholine. This substance is not a liquid hydrocarbon.

Biohazardous Infectious Materials:

Not applicable

Morpholine is not a microorganism, protein or nucleic acid.

Physical hazards

Explosives:

Not evaluated*

* Explosives are excluded from the HPAand its regulations. Explosives are regulated under the Explosives Act. For more information, visit Natural Resources Canada.

Flammable Gases:

Not applicable

Morpholine is not a gas. The classification criteria for Flammable Gases do not apply to this substance.

(Flammable) Aerosols:

Not evaluated

Classification of a hazardous product in the Flammable Aerosols or Aerosols hazard class is product dependent.

Oxidizing Gases:

Not applicable

Morpholine is not a gas. The classification criteria for Oxidizing Gases do not apply to this substance.

Gases Under Pressure:

Not applicable

Morpholine is not a gas. The classification criteria for Gases Under Pressure do not apply to this substance.

Flammable Liquids:

Category 3

Morpholine has a flash point of 35 °C (closed cup), which meets the criteria for Category 3^{Footnote 17}.

The available data meet the classification criteria for Flammable Liquids – Category 3 [HPR 7.6.1(2)].

Flammable Solids:

Not applicable

Morpholine is not a solid. The classification criteria for Flammable Solids do not apply to this substance.

Self-reactive Substances and Mixtures:

Does not meet criteria

Morpholine begins to degrade at a temperature of 135 °C ^{Footnote 5}. Self-reactive substances and mixtures must have a self-accelerating decomposition temperature (SADT) of ≤75°C to meet the minimum classification in this hazard class.

The available data do not meet the classification criteria for Self-reactive Substances and Mixtures.

Pyrophoric Liquids:

Does not meet criteria

Morpholine has an auto-ignition temperature of 255 °C ^{Footnote 5}. Pyrophoric liquids react at room temperature.

The available data do not meet the classification criteria for Pyrophoric Liquids.

Pyrophoric Solids:

Not applicable

Morpholine is not a solid. The classification criteria for Pyrophoric Solids do not apply to this substance.

Self-heating Substances and Mixtures:

Does not meet criteria

Morpholine has an auto-ignition temperature of 255 °C ^{Footnote 5}, which is well above the temperature of at which spontaneous combustion would need to occur to meet classification criteria (140°C).

The available data do not meet the classification criteria for Self-heating Substances and Mixtures.

Substances and Mixtures which, in Contact with Water, Emit Flammable Gases:

Not applicable

Morpholine has a chemical structure that does not contain metals or metalloids and is, therefore, excluded from classification [HPR 7.12.1(1)].

Oxidizing Liquids:

Not applicable

Paragraph 7.13.1(1)(b) of the HPR excludes from classification any organic liquid that contains oxygen, fluorine or chlorine if those elements are chemically bonded only to carbon or hydrogen. The oxygen atom in morpholine is chemically bonded only to carbon ^{Footnote 5}.

Oxidizing Solids:

Not applicable

Morpholine is not a solid. The classification criteria for Oxidizing Solids do not apply to this substance.

Organic Peroxides:

Not applicable

Morpholine is not an organic peroxide. The classification criteria for Organic Peroxides do not apply to this substance.

Corrosive to Metals:

Does not meet criteria

Morpholine is not corrosive to stainless steel, aluminum or carbon steel at 20 °C ^{Footnote 2}.

The available data do not meet the classification criteria for Corrosive to Metals.

Combustible Dusts:

Not applicable

Morpholine is not a solid. The classification criteria for Combustible Dusts do not apply to this substance.

Simple Asphyxiants:

Not applicable

Morpholine is not a gas. The classification criteria for Simple Asphyxiants do not apply to this substance.

Pyrophoric Gases:

Not applicable

Morpholine is not a gas. The classification criteria for Pyrophoric Gases do not apply to this substance.

Chemicals Under Pressure:

Not evaluated

Classification of a hazardous product in the Chemicals Under Pressure hazard class is product dependent.

Regulatory and other information

Regulatory information:

Hazardous substance assessments are prepared by Health Canada as educational and information resources. Under the HPA, suppliers of hazardous products must, upon the sale or importation of a hazardous product, provide a safety data sheet and label that meet the requirements set out in the HPR.

Other information:

The information and classifications contained in these hazardous substance assessments are based on publicly available sources, such as peer-reviewed literature or reports by international bodies. New information, including proprietary information, could have an impact on the classification of substances or hazardous products containing them. It is the responsibility of the supplier to ensure the accuracy, sufficiency and reliability of their hazardous product classifications.

Last updated:

2022

Prepared by:

Workplace Hazardous Materials Bureau, Health Canada