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EC number: 266-719-9 | CAS number: 67564-91-4
- 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:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 19. Sep to 23. Oct 1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 980
- Report date:
- 1980
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: The study was conducted on the basis of a 90-day study under the EPA Pesticide Program, Part II, Fed. Reg. Vol. No. 163
- Version / remarks:
- August 1978
- GLP compliance:
- no
- Remarks:
- predating GLP
Test material
- Reference substance name:
- cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine
- EC Number:
- 266-719-9
- EC Name:
- cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine
- Cas Number:
- 67564-91-4
- Molecular formula:
- C20H33NO
- IUPAC Name:
- (2R,6S)-4-[3-(4-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- MURA:SPRA (SPF 68 Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: MUS RATTUS, Brunnthal, FRG,
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: male rats: 210 +/- 15g, female rats: 180 +/- 15 g.
- Housing: singly in Makrolon wire cages (type MD III of Becker & Co., Castrop-Rauxel, FRG)
- Diet (e.g. ad libitum): HERILAN—MRH "Haltungsdiät" of H. EGGERSMANN KG, Rinteln, FRG, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 2 - 3 weeks before a 5-day preliminary flow and adaptation period was conducted
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 5
- Photoperiod (hrs dark / hrs light): 12
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- nose only
- Vehicle:
- other: fully demineralized water and ethanol
- Mass median aerodynamic diameter (MMAD):
- < 1.2 µm
- Remarks on MMAD:
- The value given refers to the MMAD 50; the aerodynamic diameter was below 1.2 µm in 50-53 % of the particles in all treated groups.
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The two-component atomizers are fitted to the upper part
of an aerodynamic exposure equipment (INA 20, head-nose exposure system) so that the aerosol is generated direct in the equipment.
- Method of holding animals in test chamber: rats used for the study were restrained in glass tubes their snouts projecting into the inhalation chamber
- Rate of air: 1500 + 300 L/h (exposure group), 1800 L/h (solvent control and air control)
- System of generating particulates/aerosols:
for technical reasons, the test substance was dissolved in analysis-grade ethanol and fully demineralized water, was supplied to two-component
atomizers (Rhema, Hofheim, FRG) by means of continuous infusion pumps (UNITA I, B. Braun, Melsungen, FRG) and atomized with compressed-air.
- Temperature, humidity, pressure in air chamber: a pressure slightly above the atmospheric pressure being set up in the equipment. Relative humidity in the equipment was adjusted to 40 - 60 % for the exposure groups by atomizing accurately metered amounts of water by means of ultrasonics or Pari nebulizers, through which a continuously measured bleed stream of the supply air was passed. Air control conditioned air (t = 21 °C, rel. humidity = 55 5 %) was used.
- Air flow rate: the flow of exhaust air was adjusted in such a way that it was 20 % less than the flow of supply air, 1440 L/h
- Method of particle size determination: The particle size analysis was carried out using a cascade impactor. Once a week a sample was taken for each group with the cascade impactor at a sampling velocity of 1.25 m/sec. The deposits in the probe and on the upper metal plate were analyzed as separate samples and evaluated together under "deposits". The glass-fiber collecting discs and the backup filter were eluted separately and analyzed by gas chromatography.
TEST ATMOSPHERE
- Brief description of analytical method used: A gas chromatographical determination of the test substance in ethanol was used. 5 mL of internal standard was added to the samples and filled with ethanol in 50-mL graduated flasks up to the calibration mark. Then 2-ml tubes were filled for the Automatic Sampler and analyzed. The volume injected was 2 µL
- Samples taken from breathing zone: yes
VEHICLE (if applicable)
- Justification for use and choice of vehicle: for technical reasons
- Composition of vehicle: 70 g analysis-grade ethanol, 2 g fully demineralized water
- Concentration of test material in vehicle: 8 g
- a solvent (aqueous ethanol) control group was included in the study in addition to a fresh-air control group. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- gas chromatographical determination
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 5 days/week - 6 hours/day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.01 mg/L air (nominal)
- Remarks:
- analytically verified
- Dose / conc.:
- 0.04 mg/L air (nominal)
- Remarks:
- analytical concentration: 0.042 mg/L
- Dose / conc.:
- 0.16 mg/L air (nominal)
- Remarks:
- analytical concentration: 0.165 mg/L
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The highest aerosol concentration of 0.16 mg/l was chosen taking the results of a feeding study into consideration; the amount consumed daily was used as
the basis for estimating the concentration for a 6-hour inhalation. Toxic effects were expected to occur at this concentration. The concentrations for the other
test groups Were obtained by reducing this concentration by the factor of 1/4 in each case to give the concentrations of 0.04 mg/l and 0.01 mg/l.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- The behavior and appearance of the animals was checked each day during and after exposure.
BODY WEIGHT: Yes
- Time schedule for examinations: once a week (Wednesdays) always at the same time of the day
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 7 days before administration and 28 days after the beginning of administration
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: all animals
- Parameters checked: hemoglobin, erythrocyte count, mean cell volume, platelet count, leukocyte count, hematocrit, mean hemoglobin content per erythrocyte, mean corpuscular hemoglobin concentration, differential blood count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see hematology
- Animals fasted: Not specified
- How many animals: all animals
- Parameters checked: total bilirubin, creatinine, urea, sodium, potassium, total protein, glucose, calcium, chloride, triglycerides, cholesterol, albumin, globulins, A/G ratio, lactate dehydrogenase, glutamic pyruvic transaminase, alkaline phosphatase, glutamic oxalacetic transaminase, plasma cholinesterase, erythrocyte cholinesterase, brain cholinesterase
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
BRONCHOALVEOLAR LAVAGE FLUID (BALF): No
LUNG BURDEN: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Organ weights: heart, liver, kidneys, brain
Organ fixation: head (including eyes, lacrymal glands, nasal cavity, nasal mucosa,
paranasal sinus, nasopharynx, oral cavity, tongue, teeth, tonsils, salivary glands, regional lymph nodes, outer, middle and inner ear, pituitary and Zymbal’s glands), heart, aorta thoracica, nasal mucosa, trachea (with larynx), lungs with mainstem bronchi (right and left), tongue, esophagus, stomach (forestomach and glandular stomach), small intestine (duodenum, jejunum and ileum), large intestine (cecum and colon), salivary glands, liver, pancreas, spleen, thymus, sternum with sternal marrow. kidneys, urinary bladder, testes, epididymides, prostate, ovaries, uterus in toto, pituitary, adrenals, thyroids (with parathyroids), brain, skeletal muscle, eye with optic nerve, skin
all changes were described macroscopically
HISTOPATHOLOGY: Yes
Microscopical examination of the above mentioned fixed organs was performed for all animals of the solvent control, air control group and animals of the highest dose group (0.16 mg/L); following organs of all animals of the dose group 0.01 and 0.04 mg/L were examined: aorta thoracica, nasal mucosa, trachea (with larynx), lungs with mainstem bronchi (right and left), tongue, esophagus, liver, kidneys, thyroids (with parathyroids), eye (with optic nerve), skin - Statistics:
- Clinical examinations and pathology: The statistical evaluation was carried out using a t test generalized by WILLIAMS (1 and 2) for a simultaneous comparison of several dose groups with a control group.
Blood and plasma examinations: the individual dose groups were compared with the control group and with each of their initial values (blood sampling 0) using the t test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In test group 2 (0.01 mg/L) 3 animals had crusts on the bridge of their noses which occurred for the first time after the 14th exposure but had subsided by the day of sacrifice.
In test group 3 (0.04 mg/L) these crusts also occurred on the nose, but in 13 animals and only after 10 exposures. One female animal also had encrusted eyes with subsequent alopecia on the day of sacrifice. One male animal had crusts on the front and back extremities.
All the animals in test group 4 (0.16 mg/L) exhibited similar symptoms, but they were more pronounced. The female animals reacted more strongly than the male
ones. They had slight piloerection.
The crusts observed, are probably due to the effect of contact with the test
substance, the causes of which are, however, partially
of a technical nature. Contamination of the tubes may lead to the contact effect on the extremities. Impaction of the aerosol on the noses projecting into the inhalation apparatus also leads to contamination by the test substance. The crusts observed thus probably are a conglutination and reaction resulting from the skin-irritating test substance which is not primarily specific to inhalation. - Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- 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:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A concentration-related reduction in plasma cholinesterase activity in both sexes was observed. The inhibitory effect was particularly noticeable in the female animals which in the highest test group (0.16 mg/L) exhibited only about half the enzyme activity of the control group. Whereas the statistical comparison between the lowest test group (0.01 mg/L) and the air control revealed a marked but not significant drop in activity, the evaluation in comparison with the solvent control showed a statistically significant difference in the female animals. However, it cannot be ruled out that the additional adverse effect that ethanol has on
the liver metabolism leads to a greater reduction in plasma chlolinesterase activity which is caused by metabolites of the substance.
At the end of the period of administration, there was a slight increase in alkaline phosphatase and glutamic pyruvic transaminase activity in both sexes in test
groups 3 and 4 (0.04 and 0.16 mg/L). In addition, there were signs of an increase in glutamic oxalacetic transaminase activity in the male animals of test group 4.
A reduction in the cholesterol level was detected in both sexes in test group 4 (0.16 mg/L) - Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Statistically significant increases in the absolute and relative liver weights which must be regarded as induced by the test substance occurred after 4-week inhalation in male and female rats in test group 3 (0.04 mg/L) and test group 4 (0.16 mg/L). Since this effect of the substance was more pronounced when statistically comparing test groups 2 — 4 with the solvent control (test group 1) than when comparing test groups 2 - 4 with the air control (test group 0), the latter method of calculation was preferred in assessing the changes in liver weight.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Focal changes to the skin around the opening of the nose which were prominent in the gross pathological findings in the rats of test groups 3 and 4 might have been induced by the test substance although most of them were only isolated findings.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Focal basal cell hyperplasia at the tip of the bifurcation or at the origin of the mainstem bronchi and the related focal basal cell hyperplasia in a mainstem bronchus of the lung specimens detected in the longitudinal sections of the trachea in test group 3 (0.04 mg/l) and test group 4 (0.16 mg/l) must be interpreted as substance-induced in the sense of an unspecific irritation response.
- Histopathological findings: neoplastic:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 0.01 other: mg/l
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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