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EC number: 406-370-3 | CAS number: 58890-25-8 MDI/CHA
- 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:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 14 June 1990 - 12 July 1990
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
- Report date:
- 1991
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 12 May 1981
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- September 1984
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea
- EC Number:
- 406-370-3
- EC Name:
- 3,3'-dicyclohexyl-1,1'-methylenebis(4,1-phenylene)diurea
- Cas Number:
- 58890-25-8
- Molecular formula:
- C27 H36 N4 O2
- IUPAC Name:
- 1-cyclohexyl-3-[4-({4-[(cyclohexylcarbamoyl)amino]phenyl}methyl)phenyl]urea
- Test material form:
- solid
- Details on test material:
- - Name of test material (as cited in study report): MDI/CHA
- Physical state: white yellowish solid
- Storage condition of test material: at room temperature in the dark
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: BRL Ltd., Basel, Switzerland
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: males: 179 to 198 g; females: 120 to 156 g
- Fasting period before study: Overnight
- Housing: Animals were housed 5 to a cage (same sex) in stainless steel suspended cages with wire mesh floors.
- Diet: Free access to standard pelleted laboratory animal diet (Kliba, Klingentalmuehle AG, 4303, Kaiseraugst, Switzerland).
- Water: Free access to tap water.
- Acclimation period: Sixteen days (7 days pre- and 10 days post randomisation).
DETAILS OF FOOD AND WATER QUALITY:
Diet: Each batch was analysed for contaminants and results were examined and archived.
Water: Results of chemical and contaminants analyses were examined and archived quarterly.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 25
- Humidity (%): 50 - 74
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 14 June 1990 To: 12 July 1990
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Frequency: Once daily, approximately the same time each day, 7 days per week.
Dose volume: 5 mL/kg body weight - Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test article was weighed into a glass flask on an analytical balance and the vehicle (w/w) added.
The test article formulation was daily prepared immediately prior to dosing. Homogeneity during
treatment was maintained using a magnetic stirrer. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Due to analytical limitations, only samples of the high dose concentrations prepared after completion of the treatment period were analysed to check accuracy of preparations. Formulation procedures used were identical to those used during the study.
- Duration of treatment / exposure:
- 28 days.
- Frequency of treatment:
- Once daily, approximately the same time each day, 7 days per week.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Five
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale: Based on data from previous studies in rats.
- Positive control:
- No.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily. Severity of observations were graded.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and on the day preceding termination, prior to overnight fasting.
FOOD CONSUMPTION:
- Weekly
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Both eyes were examined following instillation of atropine sulphate solution before commencement of treatment and during the last week of treatment.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Immediately prior to post mortem examination, between 8.00 and 10.00 a.m.
- Anaesthetic used for blood collection: Yes (ether) / No / Not specified
- Animals fasted: Yes, Yes, overnight before blood sampling, but water was provided.
- How many animals: all rats/sex/group
- Parameters checked: According to test guidelines.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Immediately prior to post mortem examination, between 8.00 and 10.00 a.m.
- Animals fasted: Yes, overnight before blood sampling, but water was provided.
- How many animals: all rats/sex/group
- Parameters checked: According to test guidelines.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- NECROPSY:
All animals surviving to the end of the observation period (day 29) were deeply anaesthetised by in traperitoneal injection of sodium pentobarbital and subsequently exsanguinated. All necropsies were performed by experienced prosectors and descriptions of all macroscopic abnormalities recorded.
ORGAN WEIGHTS:
The following organ weights (and terminal body weight) were recorded at termination: Adrenal glands, Heart, Kidneys, Liver, Spleen and Testes.
HISTOTECHNOLOGY:
All organ and tissue samples, as defined under Histopathology (following), were processed, embedded and cut at a thickness of 2-4 micrometers and stained with haematoxylin and eosin. All slides for histopathological examination were dispatched to RCC (UK) Ltd., Hereford, England.
HISTOPATHOLOGY:
Slides of adrenals, heart, kidneys, liver and spleen, collected at termination from all animals of the
control and high dose group as well as from all gross lesions of all animals were examined by a
pathologist. - Statistics:
- The following statistical methods were used to analyse the body weight, organ weights and clinical laboratory data:
Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnett-test (many to one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups.
The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a
normal distribution. All tests were two-sided and in all cases p<0.05 was accepted as the lowest level of significance.
The exact Fisher-test was applied to the ophthalmoscopic examination data.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One male receiving 200 mg/kg/day showed chromodacryorrhoea over the study period and rales on one occosion during week 3. In the absence of corroborative findings in the opposite sex and in the absence of a treatment related distribution these findings were considered not to represent a sign of toxicity. Alopecia was noted over 10 days or more among 3/5 females receiving 1000 mg/kg/day. However, as alopecia is commonly noted among rats of this age and strain, it was considered not to have arisen as an effect of treatment.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Minor statistically significant changes noted between control and treated animals in inorganic phosphate and calcium values, were considered to have occurred fortuitously and not to be of toxicological significance.
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Organ weights and relative organ weights of treated animals were indistinguishable from those of control animals. Statistically significantly decreased relative spleen weights in comparison with control weights among females receiving 1000 mg/kg/day were within normal biological variation and considered not to be of toxicological significance.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Details on results:
- Analysis of dose preparations: The accuracy of preparation testing revealed that the highest nominal
concentration analyzed was in agreement with the concentrations prepared.
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: No treatment-related changes observed.
Target system / organ toxicity
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In conclusion, treatment with the substance, dosed via oral gavage at dose levels 50, 200 or 1000 mg /kg bw/day resulted in a NOEL for males and females of 1000 mg/kg bw/day based on absence of adverse effects at 1000 mg/kg bw/day, the highest dose tested.
- Executive summary:
In this subacute 28-day toxicity study performed according to OECD 407 guideline and GLP principles, MDI/CHA was administered daily by gavage to SPF-bred Wistar rats to 0, 50, 200 and 1000 mg/kg bw/day.
There were no changes in clinical appearance, body weights, food consumption, ophthalmoscopic examination, clinical laboratory investigations, macroscopic examination, organ weights and microscopic examination that were considered to be an effect of treatment. Based on the absence of
adverse effects at 1000 mg/kg bw/day, the NOEL for males and females in this study is at least 1000 mg/kg bw/day, the highest dose tested.
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