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EC number: 202-974-4 | CAS number: 101-77-9
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 982
- Report date:
- 1982
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- not specified
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- 4,4'-methylenedianiline
- EC Number:
- 202-974-4
- EC Name:
- 4,4'-methylenedianiline
- Cas Number:
- 101-77-9
- Molecular formula:
- C13H14N2
- IUPAC Name:
- 4,4'-methylenedianiline
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: 607212
- Physical state: solid
- Analytical purity: > 98 %
- Purity test date: July 24, 1980
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability under test conditions: stable
Test animals
- Species:
- rat
- Strain:
- other: RAIf (F3-hybrid of RII 1/Tif x RII 2/Tif) (Specified pathogen free)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Animal Production, Ciba-Geigy LTD., 4332 Stein, Switzerland
- Age at study initiation: 4 weeks
- Weight at study initiation: 88 - 91 g (males); 90 - 91g (females)
- Fasting period before study: not specified
- Housing: Animals housed in groups of 5 in Macrolon cages type 4.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 15 -17
- Photoperiod (hrs dark / hrs light): 14/10
IN-LIFE DATES: From: August 11, 1980 To: December 15, 1980
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Rate of preparation (frequency): daily
- Mixing appropriate amounts with: water
- Storage temperature of food: ambient - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Pretest samples were analysed for concentration and stability of the test material. Samples taken at random from the prepared dosing solutions were analysed for concentration in the Central Analytical Laboratories of Ciba-Geigy LTD., Basle, Switzerland.
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- continuous
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/L drinking water
- Dose / conc.:
- 80 mg/L drinking water
- Remarks:
- Due to the small variation between nominal and actual measured concentrations, nominal values were used in calculation of test material intake.
Basis: nominal in water
- Dose / conc.:
- 400 mg/L drinking water
- Remarks:
- Due to the small variation between nominal and actual measured concentrations, nominal values were used in calculation of test material intake.
Basis: nominal in water
- Dose / conc.:
- 800 mg/L drinking water
- Remarks:
- Due to the small variation between nominal and actual measured concentrations, nominal values were used in calculation of test material intake.
Basis: nominal in water
- No. of animals per sex per dose:
- 80 males and 80 females per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for animal assignment: random
- Rationale for selecting satellite groups: random
- Post-exposure recovery period in satellite groups: 4 weeks
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 15 (after 30 days exposure) and after 1 month recovery
- Anaesthetic used for blood collection: No
- Animals fasted: Yes (20 hours fasting)
- How many animals: 10 rats/sex/group
- Parameters checked: Erythrocytes, Leukocytes, Haemoglobin, Haematocrit, Reticulocytes, Thrombocytes, MCV, MCH, Differential, prothrombin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 15 (after 30 days exposure) and after 1 month recovery
- Animals fasted: Yes (20 hours fasting)
- How many animals: 10 rats/sex/group
- Parameters checked: Glucose, urea nitrogen, sodium, potassium, calcium, ASP aminotransferase (GOT), ALT aminotransferase (GPT), alkaline phosphatase, creatinine, bilirubin, cholesterol, total proteins, protein electrophoresis
URINALYSIS: Yes
- Time schedule for collection of urine: week 15 (after 30 days exposure) and after 1 month recovery
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked: Specific gravity, pH, chemical findings test
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: Hearing tests - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- For each time point and parameter, a uni-variate statistical analysis was conducted. Each treated group was compared to control group in respect of dispersion and displacement. In addition, a trend test was applied considering all groups.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No clinical symptoms and no signs of local and/or systemic toxicity were observed, except that the animals of groups 3 and 4 (400 and 800 ppm) failed to gain weight.
BODY WEIGHT AND WEIGHT GAIN
The mean body weight of male and female groups 3 and 4 (400 and 800 ppm) was markedly depressed, whereas the mean body weight of male and female group 2 (80 ppm) was similar to that of the respective controls. After replacement of the medicated water with ordinary drinking water male and female groups 3 and 4 (400 and 800 ppm) did not recover essentially from this weight depression during a 4 weeks recovery period.
WATER CONSUMPTION AND COMPOUND INTAKE
The mean water consumption of male and female groups 3 and 4 (400 and 800 ppm) was markedly depressed, whereas the mean water consumption of male and female group 2 (80 ppm) was similar to that of the respective control groups. After replacement of the medicated drinking water the water consumption of male and female groups 3 and 4 (400 and 800 ppm) increased slowly to the amount consumed by the respective control groups towards the end of the 4 weeks recovery period.
HAEMATOLOGY
The males and females of group 3 and 4 (400 and 800 ppm) showed reduced numbers of erythrocytes, a reduced haemoglobin concentration and a lower haematocrit still present at the end of the recovery period.
The mean cell haemoglobin was increased in males of group 3 and 4 (400 and 800 ppm) at the end of the recovery period.
The mean cell volume was increased in the males of group 3 and 4 (400 and 800 ppm) at the end of the recovery period.
The number of reticulocytes in females of group 3 and 4 (400 and 800 ppm) was increased. The number of reticulocytes was increased in the males of group 3 and 4 (400 and 800 ppm) and in females of group 4 (800 ppm) at the end of the recovery period.
The number of leucocytes was increased in the males and females of group 4 (800 ppm). A slight increase of the number of the segmented neutrophils (relative) was observed in the males and females of group 4 (800 ppm) and in the males of group 3 and 4 (400 and 800 ppm) at the end of the recovery period. A decrease in the number of lymphocytes (relative) was observed in the females of group 4 (800 ppm). The prothrombin time was prolonged in the males and females of group 4 (800 ppm).
CLINICAL CHEMISTRY
The activity of the alkaline phosphatase was increased in the males and females of group 3 and 4 (400 and 800 ppm) at the end of the treatment period as well as at the end of the recovery period.
The alanine aminotransferase (GPT) activity was slightly increased in males and females of group 3 and 4 (400 and 800 ppm). A similar increase of the alanine aminotransferase (GPT) activity was observed in the males of group 4 (800 ppm) at the end of the recovery period.
The aspartate aminotransferase (GOT) activity was increased in the males and females of group 3 and 4 (400 and 800 ppm) and in the males of group 3 and 4 (400 and 800 ppm) at the end of the recovery period.
The urea-nitrogen-concentration was increased in the males and females of group 3 and 4 (400 and 800 ppm) and in males of group 4 (800 ppm) at the end of the recovery period.
The bilirubin and cholesterin concentrations were increased in the males and females of group 3 and 4 (400 and 800 ppm).
The total protein concentration was slightly increased in the males of group 3 and 4 (400 and 800 ppm). The albumin fraction (relative) was increased in the females of group 2 and 4 (80 and 800 ppm). The A1 globulin fraction (relative) was decreased in the males of group 3 and 4 (400 and 800 ppm). The beta-globulin fraction (relative) was increased in the males of group 3 and 4 (400 and 800 ppm). The beta-globulin fraction (relative) was decreased in the females of group 2 and 4 (80 and 800 ppm). The gamma-globulin fraction (relative) was decreased in the females of group 4 (800 ppm).
URINALYSIS
The findings in the urine were generally unremarkable and comparable to those of the control animals.
ORGAN WEIGHTS
Corresponding to the lower body weight in male and female groups 3 and 4 (400 and 800 ppm) the absolute organ weights of the animals in these groups were lower than in the respective control groups at the end of the treatment period. This influences also the organ weight ratios in that in male and female groups 3 and 4 (400 and 800 ppm) the organ to brain weight ratio was lower and the organ to body weight ratio was higher than in the respective control groups. No marked improvement in absolute and relative organ weights of males and females of group 3 and 4 (400 and 800 ppm) was observed at the end of the recovery period.
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathological examination revealed the following findings in animals of group 4 (800 ppm):
In all animals marked biliary liver lesions and goitrogeneous effects on the thyroid were apparent. All histologically examined treated male and female rats showed moderate or marked hyperplasia of small biliary ducts with initial fibrosis in the peripheral parts of the liver lobules. These liver changes persisted also after the recovery period. Clear fluid in the abdominal cavity was found in one male and in 4 females. Slight or moderate oedema in the interstitium of the pancreas was seen microscopically in 5 males and 3 females. In nearly all males (18/20) and in all females slight, moderate or marked hypertrophy of the thyroid follicular epithelial cells and diffuse hyperplasia of the glandular structures with marked colloid depletion was noted. In one male rat also focal nodular hyperplasia with reaccumulation of the colloid in some distended follicles developed. After the recovery period the thyroid stimulation was much less pronounced. Only in 3/10 males and 2/10 females slight stimulation of the follicular epithelium was still evident.
Histopathological examination revealed the following findings in animals of group 3 (400 ppm):
All the males and the majority of females (16/20) showed slight or moderate hyperplasia of small biliary ducts. "The severity of these microscopical liver lesions was similar in rats sacrificed after the recovery period. In 4/20 males and in 17/20 females slight or moderate stimulation of the follicular epithelium in the thyroids was noted. In one male and one female also focal nodular hyperplasia of the thyroid parenchyma with colloid reaccumulation in some follicles developed. No compound related thyroid changes were noted after the recovery period, however.
Histopathological examination revealed the following findings in animals of group 2 (80 ppm):
No compound related liver lesions were noted. However in 2/20 males and in 2/20 females slight stimulation of the follicular epithelium in the thyroids was observed upon histopathological examination.
OTHER FINDINGS
Whereas nephrocalcinosis was evident in all females of treatment and control groups, mineralisation was seen in all males of the mid dose group and in 21 of 30 males of the high dose groups. One male of the 80 ppm group and none of the control males showed kidney mineralisation.
Simple hearing tests performed at the beginning of the treatment period and towards the end of the recovery period revealed no treatment related effects on the auditory perception.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 7.5 mg/kg bw/day (nominal)
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: slight stimulation of the thyroidal follicular epithelium
- Dose descriptor:
- LOAEL
- Effect level:
- 8 mg/kg bw/day (nominal)
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: slight stimulation of the thyroidal follicular epithelium
Target system / organ toxicity
open allclose all
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 22 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 22 mg/kg bw/day (nominal)
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 22 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- 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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