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EC number: 237-163-4 | CAS number: 13676-54-5
- 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:
- From 22 May to 05 October 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- The study was run according to OECD test guidelines and in compliance with GLP; on thia basis it is considered reliable without restrictions.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1,1'-(methylenedi-p-phenylene)bismaleimide
- EC Number:
- 237-163-4
- EC Name:
- 1,1'-(methylenedi-p-phenylene)bismaleimide
- Cas Number:
- 13676-54-5
- Molecular formula:
- C21H14N2O4
- IUPAC Name:
- 1-(4-{[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl]methyl}phenyl)-2,5-dihydro-1H-pyrrole-2,5-dione
- Reference substance name:
- N,N'-Diphenylmethane bismaleimide
- IUPAC Name:
- N,N'-Diphenylmethane bismaleimide
- Reference substance name:
- BMI
- IUPAC Name:
- BMI
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- Batch number: 1K72J
Purity: 94.2%
Constituent 1
Constituent 2
Constituent 3
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: (P) 70 days
- Weight at study initiation: (P) Males: 339-399 g; Females: 225-277 g
- Housing: Animals were housed inside a barriered rodent facility.
- Diet (e.g. ad libitum): The animals were allowed free access to a standard rodent diet except overnight before routine blood sampling.
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate or polypropylene bottles fitted with sipper tubes.
- Acclimation period: five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C.
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): a cycle of 12 hours continuous light and 12 hours continuous dark per 24 hours
IN-LIFE DATES: From: 2 July 2012 To: Males 7 August 2012, Females 18 August 2012
No additional data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1% Methylcellulose
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance was prepared for administration as a series of graded concentrations in the vehicle. Starting with the lowest concentration, the required amount of the test substance was weighed, transferred to a suitably sized mortar and ground to a fine powder using a pestle. Small amounts of the vehicle were added and mixed with the test substance to form a smooth paste. The suspension was poured into a measuring cylinder which had been wetted with the vehicle. The mortar was rinsed thoroughly with the vehicle and the rinsed residue was added to the measuring cylinder. The required volume was achieved by addition of the remaining vehicle and the suspension was transferred to a beaker and mixed using a high shear homogeniser until homogenous. During magnetic stirring, the suspension was transferred to the final containers, via syringe. Remaining concentrations were prepared in ascending group order using the same method.
VEHICLE
- Concentration in vehicle: 10, 30, 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
No additional data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Apparatus and instrumentation
High performance liquid chromatograph (HPLC)
Sample process
A representative sample of test formulation (nominally 1 mL, accurately weighed) was dissolved using ultrasonic vibration in a suitable volume of diluent. The extract was diluted using mobile phase to provide a solution containing test substance at an expected concentration within the range 1.0 μg/mL to 2.0 μg/mL.
The concentration of the test substance in the final solution was quantified by high performance liquid chromatography using UV detection as detailed in the chromatographic section.
Typical chromatographic conditions
Analytical column: Agilent Poroshell 120EC C18, 2.7 μm, 100 × 4.6 mm
Column temperature: 40°C
Mobile phase: Acetonitrile/water/acetic acid 45/55/0.3 v/v/v
Flow rate: 1.00 mL/minute
Detector wavelength: UV, 235 nm
Injection volume: 5 μL
Run time: 5 minutes
Approximate retention time: 3.8 minutes
The mean concentrations of the test substance in test formulations analysed for the study were within +10/-15% of nominal concentrations, confirming accurate formulation. - Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- Males were treated daily, two weeks before pairing up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing and gestation, until Day 6 of lactation.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100, 300 or 1000 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10 males and 10 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- None stated
- Positive control:
- None stated
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment.
BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each male was recorded before dose administration, on the day that treatment commenced (Week 0), weekly throughout the treatment period and before necropsy. Females were weighed before dose administration, on the day that treatment commenced (Week 0), weekly until mating was detected, on Days 0, 6, 13 and 20 after mating and on Days 1, 4 and 7 of lactation.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
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: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During Week 2 (prior to pairing)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: the first five surviving males and females in each group
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During Week 2 (prior to pairing)
- Animals fasted: Yes
- How many animals: the first five surviving males and females in each group
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data
No additional data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, All external features and orifices were examined visually. After ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and pelvic cavities and their viscera were exposed and examined in situ. Any abnormal position, morphology or interaction was recorded.
HISTOPATHOLOGY: Yes - Other examinations:
- None stated
- Statistics:
- None stated
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- 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 specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
One male receiving 100 mg/kg/day was found dead on Day 28 of treatment. There were no in-life findings prior to this animals death. Post mortem examination revealed a perforated oesophagus; the thorax contained clear fluid with pale adhesions, dark lungs and bronchi and reduced contents of the colon, ileum and caecum. This death was not considered related to treatment.
There were no signs recorded at routine observations or in association with dosing.
BODY WEIGHT AND WEIGHT GAIN
There were no dosage related effects of treatment upon male or female bodyweight.
Mean bodyweight and bodyweight gain was slightly higher for males receiving 300 mg/kg/day when compared with Controls. Overall bodyweight gain was slightly, but not statistically significantly higher for males receiving the test substance when compared with Controls, but no dose response was apparent.
During the pre-pairing phase mean bodyweight gain for females receiving the test substance up to 1000 mg/kg/day was slightly lower than that of the Control values, however, there was no dose response. Mean bodyweight and bodyweight gain was slightly higher during the gestation phase, but slightly lower than Controls during the lactation phase for females receiving the test substance.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption was considered not to be affected by treatment with the test substance up to 1000 mg/kg/day by males and females prior to pairing, during gestation and lactation when compared with Controls.
Group mean food intake was statistically significantly higher during Days 0-5 of gestation for females receiving 300 or 1000 mg/kg/day; however, this slight increase was of no biological importance.
HAEMATOLOGY
There were no consistent findings at haematological investigations to suggest any adverse dose response to treatment with the test substance. Haematological investigation in Week 2 of treatment revealed, occasional parameters which were statistically significantly different from Control but there was no clear biological significance of dosage relationship.
CLINICAL CHEMISTRY
The biochemical examination of the blood plasma in Week 2 of treatment detected no consistent changes suggestive of treatment related effect. Sporadic intergroup differences which appeared statistically significant included increased urea, creatinine and potassium levels in males and increased glucose levels in animals receiving 100 mg/kg/day when compared with Controls; in the absence of similar findings at higher doses a relationship to treatment is uncertain. Cholesterol and bile acids were lower in males receiving 1000 mg/kg/day when compared with Controls; there was no dose response for the cholesterol data and the bile acid data was highly variable.
ORGAN WEIGHTS
Organ weights were not obviously affected by treatment with the test substance, when compared with Controls.
Mean adjusted spleen weights were statistically significantly higher in males receiving 1000 mg/kg/day, when compared with Controls; this was not evident in the females
GROSS PATHOLOGY
The macroscopic examination of males after five weeks of treatment or on Day 7 of lactation revealed no intergroup differences.
The nature and incidence of all findings were consistent with the commonly seen background of macroscopic changes.
HISTOPATHOLOGY: NON-NEOPLASTIC
The following examined tissues had no findings microscopically:
Adrenals, Brain, Caecum, Colon, Duodenum, Epididymides, Eyes, Ileum, Jejunum, LN Mesenteric, Liver, Lt. LN Axillary, Mammary, Peyer's Patch, Prostate, Sciatic Nerve, Seminal Vesicles, Skeletal Muscle, Skin, Spinal C. Cerv., Spleen, Sternum + Marrow, Stomach, Thymus, Thyroids, Trachea, Urinary Bladder
No additional data
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no test substance related adverse effects observed up to and including 1000 mg/kg bw/day, the highest dose tested
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- It is concluded that oral administration of the test substance to Crl: CD (SD) rats for at least 5 weeks at doses of 100, 300 and 1000 mg/kg/day was well tolerated with no toxicologically significant systemic effects and there was no effect of treatment on reproductive performance, including mating performance, fertility and offspring survival and development up to Day 7 of age.
For general toxicity the no-observed-adverse-effect level (NOAEL) was considered to be 1000 mg/kg/day and for reproductive /developmental toxicity the no-observed-adverse-effect-level (NOAEL) was also considered to be 1000 mg/kg/day.
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