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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: dermal
Administrative data
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 07. Nov - 20. Dec 2000
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- GLP compliant
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)
- Version / remarks:
- 1998
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.9 (Repeated Dose (28 Days) Toxicity (Dermal))
- Version / remarks:
- 1992
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
- Version / remarks:
- 1981
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Landesanstalt für Pflanzenbau und Pflanzenschutz Rheinland-Pfalz, 02 Jul 1997
- Limit test:
- no
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:
- Wistar
- Remarks:
- CRL:WI (GLX/BRL/HAN) IGS BR
- Details on species / strain selection:
- Rats were selected since this rodent species is recommended in the respective test guidelines. Wistar rats were selected since there is extensive experience available in the laboratory with this strain of rats.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at study initiation: 9 weeks
- Weight at study initiation: males: 197.5 —238.3 9 (group mean: 219.7 g); females: 143.5 —171.0 9 (group mean: 155.3 g)
- Housing: The rats were housed singly in type DK llI stainless steel wire mesh cages supplied by Becker & Co., Castrop-Rauxel, Germany (floor area about 800 cm2) in a fully air-conditioned room
- Diet (e.g. ad libitum): ad libitum, basic maintenance diet rat/mouse/ hamster, meal. supplied by Provimi Kliba SA, Kaiseraugst, Switzerland.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Yes
DETAILS OF FOOD AND WATER QUALITY:
The food used in the study was assayed for chemical and microbiological contaminants. On the basis of the analytical findings the drinking water was found to be suitable. German Drinking Water Regulation (Trinkwasserverordnung, Bundesgesetzblatt, December 5, 1990) served as a guideline for maximum tolerable contaminants.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12
IN-LIFE DATES: From: 07. Nov 2000 (arrival) To: 20. Dec 2000
Administration / exposure
- Type of coverage:
- semiocclusive
- Vehicle:
- other: 0.05% Cremophor EL solution in doubly distilled water
- Details on exposure:
- TEST SITE
- Area of exposure:
- % coverage: 10 % of the body surface
- Type of wrap if used: 4 layers of porous gauze dressing ("Verbandmull Ph. Eur"., Lohmann GmbH &Co. KG) and an elastic dressing (Fixomull Stretch, Beiersdorf AG)
- Time intervals for shavings or clipplings: 5 days (males) and 6 days (females) before the first administration of the test substance, thereafter when necessary
but at least once a week.
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, with lukewarm water
- Time after start of exposure: 6 h
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL/kg bw
- Constant volume or concentration used: yes
VEHICLE
- Concentration (if solution): 0.05 %
USE OF RESTRAINERS FOR PREVENTING INGESTION: no - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The mean values which were analytically analyzed were 101.3 —108.7 % of the target concentrations
- Duration of treatment / exposure:
- 6 h
- Frequency of treatment:
- 5/week for 4 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.2 mg/kg bw/day (nominal)
- Remarks:
- 0.005 %
- Dose / conc.:
- 0.6 mg/kg bw/day (nominal)
- Remarks:
- 0.015 %
- Dose / conc.:
- 2 mg/kg bw/day (nominal)
- Remarks:
- 0.05 %
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Fasting period before blood sampling for clinical biochemistry: Before sacrifice the animals were fasted for 16 - 20 h
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
The animals were examined for evident signs of toxicity or mortality twice a day (in the morning and in the late afternoon) from Mondays to Fridays and once a day (in the morning) on Saturdays, Sundays and public holidays.
DETAILED CLINICAL EXAMINATIONS: Yes
conducted prior to the start of the administration period (day 0) and weekly thereafter (usually in the morning prior to test substance administration).
Parameters checked: behavior during handling, fur, skin (treated skin was not examined additionally during open field observation, as this was done daily prior to treatment), posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, impairment of gait, lacrimation, palpebralclosure, exophthalmus, feces (appearance/consistency), urine (volume/color), pupil size
DERMAL IRRITATION (if dermal study): Yes
BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the administration period in order to randomize the animals. During the administration period the body weight was determined on day 0 (start of administration) and thereafter at weekly intervals.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior the start of administration and at the end of the experiment
- Dose groups that were examined: all animals at the start of administration; at the end, the animals of high dose and control group were examined.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: before necropsy
- Anesthesia: No
- Animals fasted: Yes
- How many animals: 10 animals per test group and sex
- Parameters checked: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular, hemoglobin concentration, platelets, differential blood count, prothrombin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before necropsy
- Animals fasted: Yes
- How many animals: 10 animals per test group and sex
- Parameters checked: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-y-glutamyltransferase, serum-cholinesterase, erythrocyte-cholinesterase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
the following weights were assessed: anesthetized animals, liver, kidneys, adrenal glands, testes, epididymides, ovaries, uterus, spleen, brain, heart, thymus
HISTOPATHOLOGY: Yes
all gross lesions, salivary glands (mandibular and sublingual glands)
esophagus, stomach (glandular and non-glandular), duodenum, jejunum, ileum
cecum, colon, rectum, liver, pancreas, brain, pituitary gland, sciatic nerve, spinal cord (cervical, thoracic and lumbar cord), eyes, adrena| glands, thyroid glands, parathyroid glands, trachea, lungs, pharynx, larynx, nose, aorta, heart, bone marrow (femur), Iymph nodes (mandibular and mesenteric), spleen, thymus, kidneys, urinary bladder, testes, ovaries, oviducts, uterus/vagina, epididymides, prostate gland, seminal vesicles, fema|e mammary gland, skin (treated and untreated), skeletal muscle, sternum with marrow, femur with knee joint, extraorbita| lacrimal gland - Statistics:
- Food consumption, body weight, body, weight change, food efficiency:
Parametric one-way analysis using the F-test (ANOVA) (two-sided). If the resulting
p-value was equal or less 0.05, a comparison of each group with the control group using the DUNNETT‘s test (two-sided) was performed for the hypothesis of equal means
Clinical pathology parameters, except differential blood count:
Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided).lf the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using MANN-WHITNEY U-test (two-sided) for the equal medians
Weight parameters:
Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the
resulting p-value was equal or less 0.05, a pairwise comparison of each dose group with the control group was performed using the WILCOXON test for the hypothesis of equal medians.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Incidental findings were alopecia and shearing lesions.
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food consumption was statistically significantly increased in males of group 3 (2 mg/kg bw/d) on day 28, and statistically significantly decreased in females of group 2 (0.6 mg/kg bw/d) on day 14.
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- absolute weight changes:
In males of the high and low dose groups, the mean weight of the heart was slightly although significantly increased (+12.3% or + 9.9%, respectively), with no indication of a dose response relationship.
In female rats of the high dose group, the mean weight of the thymus was significantly increased (+ 26.3%).
relative weight changes:
In males of all treatment groups, the mean weight of the liver was significantly increased (+9.0%, + 5.5% or + 6.7% for low, mid or high dose groups, respectively), however, with no indication of a dose response relationship.
In female rats of the high dose group, the mean weight of the thymus was significantly increased (+ 22.0%). - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Gross lesions were noted in the glandular stomach (erosion/ulcer), liver (focus),
kidneys (retraction), epididymides (focus), ovaries (cyst), and skin (area with sparse hair). They were all noted at a low incidence, and they were all regarded to have developed unrelated to treatment.
No gross lesions were seen in the area of the treated skin. In the area of the nontreated skin, focal areas with sparse hair were noted in a few female animals (1/2/-/1 for dose groups 0 to 3). They were regarded to have developed spontaneously and unrelated to treatment. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Discussion of organ weight effects:
A toxicological relevance of significant liver weight effects is denied for the following reasons:
- no signicant weight change in the absolute weights
- no dose response relationship
- no such observation in female rats
- absence of a morphologic finding that may explain the weight change
- comparison with the historical control data of the same strain clearly indicates that the mean relative liver weight of the control rats (2.563 g) was the lowest in 15 other studies of the same rat strain and study duration (maximum: 4.109 g, minimum: 2.563 g, mean: 3.075 g)
The significantly increased mean absolute weight of the heart of male rats of the high dose group was also discredited as being treatment-related because
- the more reliable relative weight was not affected
- females did not show this effect
- histopathology did not indicate a finding that may have contributed to the weight
change.
The significantly increased mean absolute and relative weights of the thymus of
female rats of the high dose group were also considered incidental, as
- male rats were not so affected
- histopathology failed to show a morphologic alteration not only in the thymus but also in all other organs of the immune system.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 2 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: no substance-realted toxicity was observed up to and including the highest tested dose. However, significant dermal effects can be expected for doses exceeding 0.1 % (previous study finding)
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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