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EC number: 229-194-7 | CAS number: 6425-39-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1981-05-11 to 1983-05-13
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Deviations include: some details on test substance characterization, test animals and environmental conditions were missing; no information on testing of the diet for contamination; some examinations done at longer intervals than indicated in the test method
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 983
- Report date:
- 1986
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Deviations:
- yes
- Remarks:
- Some details on test substance characterization, test animals and environmental conditions were missing; no information on testing of the diet for contamination; some examinations done at longer intervals than indicated in the test method
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Morpholine
- EC Number:
- 203-815-1
- EC Name:
- Morpholine
- Cas Number:
- 110-91-8
- Molecular formula:
- C4H9NO
- IUPAC Name:
- morpholine
- Details on test material:
- - Name of test material: Morpholine
- Physical state: clear liquid of light viscosity
- Analytical purity: stated to be 99 % pure by the Sponsor.
- Stability under test conditions: on file with the Sponsor
- Storage condition of test material: The test material was stored in a walk-in refrigerator until 1 or 2 days before use, at which time an aliquot was removed and stored under a nitrogen blanket in a fume hood. The remainder of material from which aliquots were removed continued to be stored in the original container under a nitrogen blanket in a walk-in refrigerator.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, New York
- Housing: Individually housed in stainless-steel wire-mesh cages suspended in the same inhalation chambers in which their respective exposures occurred.
- Diet: Purina Certified Rodent Chow #5002 was available ad libitum except during exposures
- Water: Tap water via an automatic watering system was available ad libitum except during exposures
- Acclimation period: 19 days
ENVIRONMENTAL CONDITIONS
- Photoperiod: a 12-hour light/dark cycle was maintained
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: Filtered air
- Remarks on MMAD:
- MMAD / GSD: Not specified
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 6 m³ glass and stainless-steel inhalation chambers (one per group) ventilated with charcoal- and HEPA-filtered air from the same source under negative pressures
- Source and rate of air: 1.2 m³/min
- System of generating vapor: Morpholine was generated into each exposure chamber as a vapor by sweeping the head space of a glass generation flask containing liquid Morpholine. The Morpholine was replaced daily. The filtered air flow into the generation flasks was passed through Teflon tubing and Collins Carbon Dioxide Absorbant and was monitored using Manostat flowmeters. Each generation flask was placed in a water bath and enclosed in a ventilated Plexiglas safety chamber under negative air pressure. A Teflon-coated magnetic stirr bar was continuously activated in the high level generation flask to increase the available liquid surface area. Airflow into each exposure chamber was monitored.
- Air flow rate: 1.2m³/min - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations of morpholine in each exposure chamber atmosphere were analyzed approximately every 30 minutes using a Wilks-Miran 1a Infrared Analyzer and secondarily (at least once a week) using a Hewlett-Packard 5880A Gas Chromatograph with a Supelco 60/80 Tenax column with nitrogen as the carrier gas.
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 104 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm (nominal)
- Dose / conc.:
- 10 ppm (nominal)
- Dose / conc.:
- 50 ppm (nominal)
- Dose / conc.:
- 150 ppm (nominal)
- No. of animals per sex per dose:
- 70 animals per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The exposure levels were selected based on a subchronic inhalation study and were expected to include the maximum tolerated concentration.
- Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during exposures and at least twice daily during weekends
BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 13 weeks and biweekly throughout the remainder of the study
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to study initiation and on all surviving animals prior to the interim sacrifice (53 weeks), and prior to terminal sacrifice
- Dose groups that were examined: All
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to initiation of the sudy (from tail vein), at the interim sacrifice (from tail vein), and during the terminal sacrifice (abdominal aorta)
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10 animals/sex/group at the interim and terminal sacrifice. 10 animals/sex prior to study initiation (these animals were not subsequently used in the study)
- Parameters examined: hematocrit, hemoglobin, erythrocyte count, total leukocyte count, platelets a, prothrombin time, and differential leukocyte count.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to initiation of the sudy, at the interim sacrifice, and during the terminal sacrifice (all from the abdominal aorta)
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10 animals/sex/group at the interim and terminal sacrifice. 10 animals/sex prior to study initiation (these animals were not subsequently used in the study)
- Parameters examined: total protein, albumin, albumin/globulin ratio, calcium, sodium, potassium, alkaline phosphatase, total bilirubin, blood urea nitrogen, glucose, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, direct bilirubin, inroganic phosphorus, total cholesterol, total lipids, and triglycerides.
URINALYSIS: Yes
- Time schedule for collection of urine: Overnight urine samples were collected during fasting from the animals scheduled for blood sampling at each sacrifice.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: pH, specific gravity, glucose, ketones, bilirubin, albumin, occult blood, volume, microscopic examination of sediment, and gross appearance.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: the brain, adrenals, lungs, heart, liver, spleen, kidneys, and testes/ovaries from each rat sacrificed at week 53 and 105 were weighed and organ/body weight ratios were determined.
HISTOPATHOLOGY: Yes- Sections from the nasal turbinates, heart, lungs, bronchi, trachea, pharynx, thyroid/parathyroids, thoracic lymph nodes, salivary gland, esophagus, aorta, thymus, spleen, liver, pancreas, kidneys, adrenals, ovaries/testes, prostate/uterus, mesenteric lymph nodes, cervical lymph nodes, urinary bladder, stomach, small intestine (duodenum, ileum, jejunum), large intestine (colon, rectum), Zymbal's gland, gross lesions, tissue masses, skeletal muscle, mammary gland, brain, pituitary, spinal cord, sciatic nerve, bone with marrow, eyes and Harderian gland from all control and high-level animals (except those sacrificed at Week 53) were examined. In addition, the eyes and nasal turbinates of 60 rats/sex from the low- and mid-dose levels were examined microscopically. - Statistics:
- Statistical analyses included one-way ANCOVA, one-way ANOVA, Bartlett's test, Scheffe's multiple-pariwise comparison procedure, modified Tukey-Kramer hsd test, and the Gehan-Breslow technique.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- In males, there was a marginally significant trend toward decreased survival with no departure; however, there was no significant overall heterogeneity and control versus treated group comparisons did not reveal any significantly lower survival. In females, there was no trend or heterogeneity in the mortality with the high dose group actually showing better survival. Therefore, it was concluded that there was no treatment related effect on survival in either sex.
- Mortality:
- no mortality observed
- Description (incidence):
- In males, there was a marginally significant trend toward decreased survival with no departure; however, there was no significant overall heterogeneity and control versus treated group comparisons did not reveal any significantly lower survival. In females, there was no trend or heterogeneity in the mortality with the high dose group actually showing better survival. Therefore, it was concluded that there was no treatment related effect on survival in either sex.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- During the early weeks of the study there was an indication of a decrease in the rate of body weight gains among the mid- and high-dose groups, and in some weeks the differences reached statistical significance; however, subsequent to Week 5 (males) and Week 11 (females), no statistically significant differences were noted and body weight trends among treated groups were comparable to the controls.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The results of the ophthalmology reports indicate a treatment-related effect with respect to corneal changes. Keratoconjunctivitis was present at a high incidence in the high-dose group. The incidence at the low- and mid-dose groups was also increased over that noted in the control group, but the incidence was comparable between the low- and mid-dose groups. Lenticular changes were observed but were not dose dependent and a clear, conclusive association of lenticular changes with exposure to morpholine could not be made.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related trends or findings were apparent in either sex.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related trends or findings were apparent in either sex.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related trends or findings were apparent in either sex. Decreased urine volumes in the high-dose animals at Weeks 53 and 105 were not considered biologically meaningful.
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- The mean organ weight data of the treated groups of both sexes were comparable to those of the controls at weeks 53 and 105.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No consistent treatment-related trends were apparent in the gross findings in the male and female animals of either sex that died or were sacrificed in extremis during the study or were sacrificed during Weeks 53 and 105.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histomorphologic alterations in the eyes and anterior nasal cavity are attributed to exposure to morpholine. Eye lesions consisted primarily of keratitis, hypopyon and iritis, and were most prominent at the high dose level. The predominant finding in the nasal turbinates consisted of necrosis and neutrophil infiltration, and was most prevalent among the high-level group. Under the conditions of this bioassay, morpholine was not regarded as systematically toxic. Effects noted with respect to ocular and nasal changes were attributed to direct exposure on these tissues.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- Histopathological evaluation of tissues revealed no differences in the incidence of types of histological-proven neoplasms that could be attributed to treatment, and therefore, morpholine was not considered to be carcinogenic in this bioassay.
Effect levels
- Dose descriptor:
- NOEC
- Remarks:
- systemic
- Effect level:
- 50 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Highest concentration tested in the study, no chronic systemic toxicity was observed.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Under conditions of this bioassay, morpholine was not regarded as systemically toxic. Effects noted with respect to ocular and nasal changes are attributed to direct exposure to these tissues. Morpholine was not considered to be carcinogenic.
- Executive summary:
In this chronic repeated dose inhalation toxicity study (Huntsman, 1983), male and female rats that inhaled Morpholine at concentrations of 0, 10, 50, or 150 ppm (0, 36, 181 or 543 mg/m³), 6 hours/day, 5 days/week for 104 weeks showed normal growth, survival, haematology, and clinical chemistries. The incidence of neoplasia in Morpholine-exposed rats was not altered significantly compared to the concurrent controls. Rats exposed at the 150 ppm concentration developed focal erosion and focal squamous metaplasia of the epithelium of the anterior nasal cavity. Obvious evidence of chronic nasal irritation and inflammation with neutrophilic infiltration was documented in these same tissues. Ocular injury, including retinal degeneration, corneal irritation, uveitis, and corneal damage, was demonstrated only in rats exposed at 150 ppm. The distribution of ocular changes recorded in the groups exposed at 10 or 50 ppm Morpholine was similar to that seen in the controls. Chronic exposure of rats to Morpholine for 2 years at concentrations of 150 ppm or less revealed no carcinogenic potential or chronic systemic toxicity. Consistent with its known irritating properties, Morpholine produced only local irritation, which was limited almost exclusively to high-dose animals.
This chronic study is acceptable and satisfies in general the guideline requirement for a chronic oral study OECD 452 in rat.
Based on this study, a systemic NOEC of 181 mg/m³ (50 ppm) for repeated dose toxicity is derived.
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