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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: dermal
Administrative data
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 4th November 1997 - 22nd May 1998
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 998
- Report date:
- 1998
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
- Version / remarks:
- 1981
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.28 (Sub-Chronic Dermal Toxicity Test: 90-Day Repeated Dermal Dose Study Using Rodent Species)
- Version / remarks:
- 1988
- Qualifier:
- according to guideline
- Guideline:
- other: TSCA guideline reference CFR 798.2250
- Version / remarks:
- draft June 1996
- GLP compliance:
- yes
- 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
- Source and lot/batch No. of test material: Ex Fluka, 352776-1796
- Purity: 97.4%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient temperature in the dark
Test animals
- Species:
- rat
- Strain:
- other: Alpk:APrSD
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Rodent Breeding Unit, Zeneca Pharmaceuticals, Alderley Park
- Weight at study initiation: 120 - 145 g (Males), 100 - 125 g (Females) upon arrival at CTL
- Fasting period before study: No
- Housing: The rats were individually housed in multiple rat racks suitable for animals of this strain and weight range expected during the course of the study.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 11 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): At least 15
- Photoperiod (hrs dark / hrs light): Artificial light 12/12
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- ethanol
- Details on exposure:
- TEST SITE
- Area of exposure: at least 7 cm x 7 cm of the dorso-Iumbar skin.
- % coverage: ca. 10 %
- Type of wrap if used: Each dressing consisted of a 4 ply gauze patch (approximately 7 cm x 7 cm) to cover the treated area. This patch was covered by a patch of plastic film held in position by an adhesive bandage (approximately 25 cm x 5 or 7.5 cm) around which were wrapped 2 pieces of PVC tape.
- Time intervals for shavings or clipplings: Sixteen to thirty-two hours before the first application of the test substance
REMOVAL OF TEST SUBSTANCE
- Washing: warm water
- Time after start of exposure: 6 hours
TEST MATERIAL
- Amount applied: 2 mL/kg bodyweight
- Constant volume or concentration used: no
- For solids, paste formed: no
VEHICLE
- Lot/batch No: Y00332/005
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The dose preparations were analysed to confIrm satisfactory achieved concentration at all dose levels. This analysis was performed twice during the study. The stability of the test substance in the vehicle at room temperature was evaluated for the low and high dose solutions.
- Duration of treatment / exposure:
- The animals were dosed dermally, for a total of 50 applications (4-6 applications per 7 day period), over a period of 70 days.
- Frequency of treatment:
- 4 - 6 applications per 7 day period
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Group 1
- Dose / conc.:
- 3 mg/kg bw/day
- Remarks:
- Group 2
- Dose / conc.:
- 30 mg/kg bw/day
- Remarks:
- Group 3
- Dose / conc.:
- 60 mg/kg bw/day
- Remarks:
- Group 4
- Dose / conc.:
- 90 mg/kg bw/day
- Remarks:
- Group 5
- No. of animals per sex per dose:
- 10 males and 10 females
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at the time of dosing and after decontamination on each application day
DERMAL IRRITATION: Yes
- Time schedule for examinations: at the time of dosing and after decontamination on each application day
BODY WEIGHT: Yes
- Time schedule for examinations: each day of dosing throughout the study
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 data
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The eyes of all animals were examined pre-experimentally and those of the control and high dose group animals during the week of termination.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all animals
- Parameters examined: haemoglobin, red cell count, mean cell volume, mean cell haemoglobin concentration, red cell distribution width, total and differential white blood cell count, platelet count, blood cell morphology, mean cell haemoglobin, haematocrit
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At study termination
- Animals fasted: No
- How many animals: all animals
- Parameters examined: urea, creatinine, glucose, total protein, triglycerides, potassium, calcium, total bilirubin, creatine kinase activity, alkaline phosphatase activity, alanine aminotransferase activity, albumin, albumin/globulin ratio, cholesterol, sodium, chloride, phosphorus (as phosphate), gamma-glutamyl transferase activity, aspartate aminotransferase activity
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
All animals were subjected to a full examination post mortem. This involved an external observation and a careful internal examination of all organs and structures.
HISTOPATHOLOGY: Yes
Abnormal tissues, liver, thyroid and skin (treated and untreated) were processed from all animals. The kidneys and lungs were processed from the control and high dose group animals only. - Statistics:
- All data were evaluated using the GLM procedure in SAS (1989).
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Dermal irritation:
- effects observed, treatment-related
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
It was noted that some animals on some days of dosing exhibited signs of distress whilst bandaged for 6 hours. Consequently, alternative types of dressings, bandages and methods to retain the test substance were evaluated to try and alleviate the distress of the animals. As the alternative methods did not significantly reduce the stress experienced by some of the animals, the study was terminated early on day 71.
There were four early terminations unrelated to treatment with the test item. In addition, one male rat (30 mg test item/kg body weight/day group) was killed for humane reasons on day 11 since necrotic skin was noted on the area of application. With regards to general clinical observations, there were no toxicologically relevant findings at any dose level in either males or females treated with the test item.
BODY WEIGHT AND WEIGHT GAIN
Treatment of male and female rats had no significant effects on bodyweights throughout the study.
FOOD CONSUMPTION
Food consumption was slightly lower in female rats in the 90 mg /kg bodyweight/day group, and the maximum effect was 7 % below control values. This small effect is considered to be of little toxicological relevance.
FOOD EFFICIENCY
There was no effect of treatment on food utilisation.
OPHTHALMOSCOPIC EXAMINATION
The administration of 90 mg /kg bodyweight/day to both male and female rats for 5 days per week for 70 days had no effect on the appearance of the eyes as evaluated by ophthalmoscopy
HAEMATOLOGY
Overall, there were no treatment related findings on any haematological parameters evaluated.
CLINICAL CHEMISTRY
In the high dose group, plasma cholesterol was increased in male rats, plasma albumin to globulin ratio was decreased in males, and plasma levels of glucose, albumin and total protein were significantly decreased in female rats which may reflect the lower food consumption in this group. All of these changes are minimal and are considered to be of no toxicological significance. Certain other parameters were also statistically significantly changed in either male or female rats, but as they only occurred in the 2 lowest groups, it is considered that they are unrelated to treatment.
ORGAN WEIGHTS
Kidney weights for the males in the high dose group were slightly lower than the control values. However, in the absence of pathological findings, this small decrease is considered to be of little toxicological significance. There were no other effects of treatment on organ weights in either male or female rats.
GROSS PATHOLOGY
There were treatment-related macroscopic findings in the treated skin. There was an increased incidence of scabs in males and females treated with 30, 60 or 90 mg/kg bodyweight/day dose groups, and discoloration of the skin in males from all treatment groups and in females treated with 30, 60 or 90 mg/kg bodyweight/day dose groups. In addition, a small number of animals from treated groups had scabs in the untreated skin. There were no other treatment-related macroscopic findings.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were treatment-related microscopic findings in the treated skin of rats killed intercurrently and at termination. There was an increased incidence of lesions which were considered to represent dermatitis in males and females treated with 30, 60 or 90 mg/kg bodyweight/day.
No treatment-related effects were seen in any of the other tissues examined.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Remarks:
- systemic toxicity
- Effect level:
- 90 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: highest test dose
- Dose descriptor:
- NOEL
- Remarks:
- skin lesions
- Effect level:
- 3 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: scabs and discoloration of the skin
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
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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