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EC number: 203-640-0 | CAS number: 109-02-4
- 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: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- read-across from related substance
- Justification for type of information:
- Read-across from structural analogue (4-ethylmorpholine). Justification of the read-across approach is included in section 13.
Cross-reference
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 2003 - 2005
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- Read-across GLP study performed according to OECD Guideline 407. The original study report is in Japanese language, although the figures and tables are in English. An English summary is available from the Japanese authorities and an extensive summary is present in the OECD HPV program files. After assessing the tables with results, the derived NOAEL seems to be underestimated.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): N-ethylmorpholine
- Molecular formula (if other than submission substance): C6 H13 N O
- Molecular weight (if other than submission substance): 115.18
- Smiles notation (if other than submission substance): CCN1CCOCC1
- InChl (if other than submission substance): InChI=1/C6H13NO/c1-2-7-3-5-8-6-4-7/h2-6H2,1H3
- Analytical purity: equal or more than 99%
- Impurities (identity and concentrations): 0.05% as moisture
- Lot/batch No.: 2901P0
- Stability under test conditions: The test solution was prepared and diluted to dosing concentrations by injection solvent every week. The diluted solution was confirmed to be stable for 8 days.
- Storage condition of test material: The test solution was kept in a refrigerator - Species:
- rat
- Strain:
- other: Crj:CD(SD)IGS
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan, Inc.
- Age at study initiation: 4 weeks old
- Weight at study initiation: day 1 mean weight: males 148.3 g (142.8-156.5 g) and females 126.9 g (120.3-133.7 g)
- Fasting period before study: unknown
- Acclimation period: 8 days before use - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test solution was prepared and diluted to dosing concentrations by injection solvent every week. They were kept in a refrigerator. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- GC method. Further details unknown.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- actual ingested
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- actual ingested
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Remarks:
- actual ingested
- Dose / conc.:
- 800 mg/kg bw/day (nominal)
- Remarks:
- actual ingested
- No. of animals per sex per dose:
- 10 at 0 and 800 mg/kg bw/day)
5 at 50 and 200 mg/kg bw/day) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Recovery group: 0 (vehicle), 800 mg/kg bw/day
Recovery period: 14 days - Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, daily
DETAILED CLINICAL OBSERVATIONS: Yes, once a week
Functional observations (ambulation, rearing, auditory, visual, proprioceptive stimuli, grip strength) in 4th week of dosing period and 2nd week of recovery period.
BODY WEIGHT: Yes (incl. body weight changes and body weight gain)
On day 1, 2, 4, 8, 11, 15, 18, 22, 25, 28 of dosing period and on day 1, 4, 8, 11, 14 of recovery period
FOOD CONSUMPTION: Yes
On day 1, 8, 15, 22 of dosing period and on day 1 and 8 of recovery period.
HAEMATOLOGY: Yes, at end of dosing period and at the end of the recovery period.
Parameters examined: RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet, PT, APTT, WBC, % of neutrophils, eosinophils, basophils, monocytes, lymphocytes
CLINICAL CHEMISTRY: Yes, at the end of dosing period and at the end of the recovery period.
Parameters examined: total protein, albumin, A/G, BUN, creatinine, glucose, total cholesterol, triglyceride, total bilirubin, inorganic P, Ca, Na, K, Cl, ALP, GPT, GOT, gamma-GTP
URINALYSIS: Yes, on day 23 of dosing period .
Parameters examined: urinary volume, specific gravity, pH, color, turbidity, protein, glucose, ketone, bilirubine, occult blood, urobilinogen, sodium, potassium and chlorine.
Microscopic examination of urinary sediment: red blood cells, crystal, cast, white blood cells, epithelial cells.
ORGAN WEIGHT: Yes - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, at the end of dosing period and at the end of recovery period.
Absolute organ weights: brain, thymus, heart, liver, kidneys, spleen, adrenal glands, testes, epididymides, ovaries.
HISTOPATHOLOGY: Yes
Organs examined: liver, kidney, spleen, heart, prostate, ovary, lung & bronchus, adrenal gland, stomach, ileum, colon, mesenteric and submandibular lymphnodes, thymus, trachea, brain, spinal cord, sciatic nerve & gastrocnemial muscle, thyroid gland, testis, epididymis, uterus, urinary bladder, bone & marrow of femur, jejunum. - Statistics:
- Barlett's tests were initially performed for body weight, food consumption, hematological examination results, hemostasis examination results, blood chemical examination results, urinalysis results (urine volume and urinary osmolality), organ weight, and relative organ weight. When their values were equal variance on Barlett's tests, Dunnett's multiple comparison tests were performed and the significant difference between dose groups were examined. Fischer's exact tests were performed for pathological examination. Additionally, F-test, Student t-test, Aspin-Welch t-test, chi-square test, Wilcoxon test, and mann-Whitney U-test were also used.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- - Both sexes:
In 200 or 800 mg/kg bw/day group: cage-licking and chewing were observed.
In 800 mg/kg bw/day group: Action tremors, decrease in movement, a crouching position, eyelid closure and salivation were observed. In detailed clinical observation, increased incidences of slight irritability, of touch responses vocalization and action tremors were observed. A few females showed intermitted walking and prone position. In the functional test at the 4th week of administration, lower number of rearing was observed in females during the first 30 minuts after administration. Numbers of animals showing no ambulation trend to decrease in both sexes during each testing period. In the recovery period, a high number of rearing was observed in males during the first 30 minutes of observation. No other clinical signs were observed during the recovery period. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- - Both sexes: No deaths were observed in any of the treatment groups during dosing and recovery period.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- - Male: The body weight gains at 800 mg/kg bw/day decreased significantly from day 2 of the administration period to the end of the recovery period.
- Female: The body weight gains at 800 mg/kg bw/day were lower from day 4 of the administration period to the end of recovery period, and decreased significantly from day 4 to 11, on day 28 of the administration period, and from day 4 to day 14 of the recovery period. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - Male: The food consumption at 800 mg/kg bw/day decreased significantly from day 1 of the administration period to day 1 of the recovery period.
- Female: The food consumption at 800 mg/kg bw/day decreased significantly from day 1 to 8 of the administration period. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- after administration period:
- Male: Reduction of prothrombin time and activated partial thromboplastin time were found at 800 mg/kg bw/day. Although significant reductions for PT were found at 50 and 200 mg/kg bw/day, the author judged that these changes had no toxicological meaning.
- Female: Although reduction of prothrombin time was found at 50 mg/kg bw/day, the author judged that these changes were non-toxicological. Higher percentage of neutrophil and monocyte and lower percentage of eosinophil and lymphocyte in differential leukocyte ratio, and increase in platelet were found at 800 mg/kg bw/day.
after recovery period:
- Male: None
- Female: Increase in platelet was found at 800 mg/kg bw/day. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- after administration period:
- Male:
in 800 mg/kg bw/day group: Increase in inorganic phosphate, calcium and blood urea nitrogen; decreases in chloride and albumin
- Female:
in 800 mg/kg bw/day group: Increase in inorganic phosphate, glucose and triglyceride; decreases in chloride, GOT and total bilirubin. GOT was also decreased in 50 and 200 mg/kg bw/d females.
after recovery period:
- Male:
in 800 mg/kg bw/day group: increases in A/G ratio
- Female:
in 800 mg/kg bw/day group: decreases in total protein, albumin, glucose. - Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Male: Protein was decreased in 800 mg/kg bw group
- Female: Keton bodies and urobilinogen was increased and specific gravity was decreased in 800 mg/kg bw group
No effects during recovery period were observed. - Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- after administration period:
- Male:
in 800 mg/kg bw/day group: decrease in absolute weight of epididymides, increase in relative weight of brain, liver, kidneys, adrenal glands and testes.
- Female:
in 800 mg/kg bw/day group: decrease in absolute weight of brain, increase in absolute weight of liver, increase in relative weights of liver and kidneys
after recovery period:
- Male:
in 800 mg/kg bw/day group: decrease in absolute weight of heart and liver, increase in relative weight of brain
- Female:
in 800 mg/kg bw/day group: increase in relative weight of brain - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopically: No toxicological change was observed.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- after administration period:
- Male:
in 800 mg/kg bw/day group:
Very slight hypertrophy of centrilobular hepatocytes in liver (1/5)
Very slight vacuolation of epithelium in distal and Henle's loop in kidneys (3/5)
- Female:
in 800 mg/kg bw/day group:
Very slight or slight hypertrophy of centrilobular hepatocytes in liver (4/5)
Very slight microgranuloma in liver (1/5)
Very slight and slight vacuolation of epithelium in distal and Henle's loop in kidneys (2/5)
(No. of animal with change/No. of animal tested)
After recovery period:
- Male: None
- Female: None - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Remarks:
- disregarded
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: This NOAEL was derived by the authors of the study, based on clinical signs (cage licking and chewing) at 200 and 800 mg/kg bw/d. As these clinical signs do not constitute an adverse effect, this NOAEL is disregarded.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Based on toxicologically adverse effects at 800 mg/kg bw/d only.
- Critical effects observed:
- not specified
- Conclusions:
- The NOAEL for oral repeated dose toxicity in Cjr:CD(SD)IGS rats is considered to be 50 mg/kg bw/day for both sexes based on cage licking and chewing at 200 and 800 mg/kg bw/d. These clinical signs do not represent a toxicologically adverse effect and are furthermore not mentioned in an OECD 421 study, performed in the same lab with the same rat strain. As relevant adverse effects are observed at 800 mg/kg bw/d only, a NOAEL of 200 mg/kg bw/d is proposed.
Table
1 Hematology of rats treated orally with
N-ethylmorpholine in the twenty-eight-day repeat dose
toxicity test
------------------------------------------------------------
After
the After
the
administrationrecovery
period period
Dose 0 800 0 800
(mg/kg
b.w./day)
------------------------------------------------------------
Male
No. of animals5 5 5 5
------------------------------------------------------------
PT (sec) 22.6 13.6**16.6 17.4
+/-S.D. 3.1 1.3 2.3 2.6
APTT (sec) 24.3 19.8**24.4 25.0
+/-S.D. 2.1 1.0 1.9 1.1
------------------------------------------------------------
Female
No. of animals5 5 5 5
------------------------------------------------------------
Platelet (X10E4/uL)
100.4 115.3*97.0 112.8*
+/-S.D. 12.3 7.4 11.0 8.6
Neutrophil
(%) 6 12* 9 8
+/-S.D. 2 5 3 3
Eosinophil (%) 2 0** 2 2
+/-S.D. 1 0 1 0
Monocyte (%)2 5* 3 3
+/-S.D. 1 2 0 2
Lymphocyte (%)
90 83 86 87
+/-S.D. 3 6 3 4
------------------------------------------------------------
PT: prothrombin time, APTT; activated partial thromboplastin
time
Significant difference from control group; *p=<0.05,
**p=<0.01
Table 2 Blood chemical examination of rats treated orally
with N-ethylmorpholine in the twenty-eight-day repeat dose
toxicity test
------------------------------------------------------------
After
the After
the
administrationrecovery
period period
Dose 0 800 0 800
(mg/kg
b.w./day)
------------------------------------------------------------
Male
No. of animals5 5 5 5
------------------------------------------------------------
Albumin (g/dL) 2.9 2.6* 3.0 3.1
+/-S.D. 0.1 0.2 0.0 0.1
A/G 1.28 1.20 1.21 1.42*
+/-S.D. 0.13 0.08 0.08 0.16
BUN (mg/dL)14 19* 18 17
+/-S.D. 1 2 2 1
Inorganic phosphorus (mg/dL)
8.1 9.9* 7.9 7.8
+/-S.D. 0.2 0.9 0.3 0.3
Ca (mg/dL) 8.9 9.5* 9.2 9.1
+/-S.D. 0.2 0.4 0.2 0.2
Cl (mEq/dL) 107.5 104.5*105.9 107.7
+/-S.D. 1.0 1.9 0.6 1.6
------------------------------------------------------------
Female
No. of animals5 5 5 5
------------------------------------------------------------
Total protein (g/dL)
4.9 4.7 5.7 5.4*
+/-S.D. 0.2 0.2 01. 0.1
Albumin (g/dL) 2.9 2.7 3.5 3.3*
+/-S.D. 0.2 0.2 0.1 0.1
Glucose (mg/dL)
100 124** 131 104*
+/-S.D. 7 12 21 12
Triglyceride (mg/dL)
10 28* 14 14
+/-S.D. 3 19 4 6
Total bilirubin (mg/dL)
0.10 0.05**0.12 0.10
+/-S.D. 0.02 0.02 0.02 0.03
Inorganic phosphorus (mg/dL)
7.2 8.6** 6.4 6.4
+/-S.D. 0.5 0.6 0.7 0.8
Cl (mEq/dL) 110.4 106.4*107.5 109.0
+/-S.D. 1.2 0.5 0.9 1.8
------------------------------------------------------------
Significant difference from control group; *p=<0.05,
**p=<0.01
Table 3 Absolute and relative organ weights of rats treated
orally with N-ethylmorpholine in the twenty-eight day repeat
dose toxicity test
------------------------------------------------------------
After
the After
the
administrationrecovery
period period
Dose 0 800 0 800
(mg/kg
b.w./day)
------------------------------------------------------------
Male
No. of animals5 5 5 5
------------------------------------------------------------
Heart 1210.4992.0 1472.11164.1**
+/-S.D. 45.4 104.6 141.2 118.1
Liver 11721 10504 13403 11036*
+/-S.D. 573.8 1362.51205.81316.9
Epididymides 623.1 552.9*973.3 933.6
+/-S.D. 26.0 34.5 90.8 72.9
-Relative organ weight (mg/g)
Brain 5.585 6.754*4.792 5.504*
+/-S.D. 0.307 0.482 0.352 0.584
Liver 33.36 38.17** 31.05 30.54
+/-S.D. 1.22 3.56 2.32 1.57
Kidneys 7.91 9.90**7.32 7.88
+/-S.D. 0.52 0.90 0.60 0.51
Adrenal glands 0.15 0.22**0.15 0.17
+/-S.D. 0.01 0.04 0.03 0.02
------------------------------------------------------------
Female
No. of animals5 5 5 5
------------------------------------------------------------
-Absolute organ weight (g)
Brain 1794.31687.5* 1823.71819.1
+/-S.D. 98.8 47.3 65.2 17.4
Liver 6530 8353** 7974 7002
+/-S.D. 739 1026 1086 808
-Relative organ weight (mg/g)
Brain 9.024 8.677 7.121 8.126*
+/-S.D. 0.835 0.826 0.598 0.381
Liver 32.64 42.61** 30.88 31.26
+/-S.D. 1.65 2.69 1.68 3.74
Kidneys 9.16 10.79** 8.04 8.50
+/-S.D. 0.61 0.72 0.32 0.80
------------------------------------------------------------
Significant difference from control group; *p=<0.05,
**p=<0.01
Table 4 Summary of histopathological findings of rats
treated orally with N-ethylmorpholine in the
twenty-eight-day repeat dose toxicity test
------------------------------------------------------------
After
the After
the
administrationrecovery
period period
Dose 0 800 0 800
(mg/kg
b.w./day)
------------------------------------------------------------
Male
No. of animals5 5 5 5
------------------------------------------------------------
-Liver
Hypertrophy of centrilobular hepatocytes
0 1 0 0
-Kidneys
Vacuolation of epithelium in distal and Henle's loop
0 3 0 0
------------------------------------------------------------
Female
No. of animals5 5 5 5
------------------------------------------------------------
-Liver
Hypertrophy of centrilobular hepatocytes
0 4* 0 0
Microgranuloma
0 1 0 2
-Kidneys
Vacuolation of epithelium in distal and Henle's loop
0 2 0 0
------------------------------------------------------------
Significant difference from control group; *p=<0.05,
**p=<0.01
Data source
Materials and methods
Test material
- Reference substance name:
- 4-methylmorpholine
- EC Number:
- 203-640-0
- EC Name:
- 4-methylmorpholine
- Cas Number:
- 109-02-4
- Molecular formula:
- C5H11NO
- IUPAC Name:
- 4-methylmorpholine
- Test material form:
- liquid
Constituent 1
Results and discussion
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: Based on reliable read-across information of N-ethylmorpholine is available (Klimisch 2), no adverse effect is expected. NOAEL is based on toxicologically adverse effects at 800 mg/kg bw/d only.
Target system / organ toxicity
- Critical effects observed:
- no
- System:
- other: Based on reliable read-across information of N-ethylmorpholine is available (Klimisch 2), no adverse effect is expected.
Applicant's summary and conclusion
- Conclusions:
- No reliable repeated dose toxicity study is available with the test substance. Data generated with the related substance 4-ethylmorpholine is used for endpoint coverage. The NOAEL for oral repeated dose toxicity in Cjr:CD(SD)IGS rats is considered to be 50 mg/kg bw/day for both sexes based on cage licking and chewing at 200 and 800 mg/kg bw/d. These clinical signs do not represent a toxicologically adverse effect and are furthermore not mentioned in an OECD421 study, performed in the same lab with the same rat strain. As relevant adverse effects are observed at 800 mg/kg bw/d only, a NOAEL of 200 mg/kg bw/d is proposed.
The same is assumed to be correct for the target substance.
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