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EC number: 240-357-1 | CAS number: 16245-77-5
- 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:
- repeated dose toxicity: oral, other
- Remarks:
- Combined repeated dose & carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from peer reviewed publication
Data source
Reference
- Reference Type:
- publication
- Title:
- Repeated dose oral toxicity study of the test chemical
- Author:
- Imaida et al
- Year:
- 1 983
- Bibliographic source:
- Toxicology Letters
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Refer below principle
- Principles of method if other than guideline:
- Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- p-phenylenediamine
- EC Number:
- 203-404-7
- EC Name:
- p-phenylenediamine
- Cas Number:
- 106-50-3
- Molecular formula:
- C6H8N2
- IUPAC Name:
- benzene-1,4-diamine
- Details on test material:
- - Name of test material: p-phenylenediamine- Molecular formula: C6H8N2- Molecular weight: 108.1432 g/mol- Substance type: Organic- Physical state: No data- Impurities (identity and concentrations): No data
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Details on species / strain selection:
- No data
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Japan, Inc., Kanagawa, Japan- Age at study initiation: 6 weeks- Weight at study initiation: No data- Fasting period before study: No data- Housing: Rats were housed in plastic cages- Diet (e.g. ad libitum): Oriental M powdered diet (Oriental Yeast Co., Tokyo, Japan)- Water (e.g. ad libitum): Tap water ad libitum- Acclimation period: No dataENVIRONMENTAL CONDITIONS- Temperature (°C): 24˚C- Humidity (%):No data- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): No dataIN-LIFE DATES: From: To: No data
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- No data
- Vehicle:
- other: Feed
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose levels of 0, 25 or 50 mg/Kg/dayDIET PREPARATION- Rate of preparation of diet (frequency): No data- Mixing appropriate amounts with (Type of food): No data- Storage temperature of food: No dataVEHICLE- Justification for use and choice of vehicle (if other than water): No data- Concentration in vehicle: 0, 25 or 50 mg/Kg/day- Amount of vehicle (if gavage): No data- Lot/batch no. (if required): No data- Purity: No data
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No data
- Duration of treatment / exposure:
- 80 weeks
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- 0, 25 or 50 mg/Kg/day
- No. of animals per sex per dose:
- 0 mg/Kg/day: 24-25 rats25 mg/Kg/day: 63-66 rats50 mg/Kg/day: 63-66 rats
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Details on study design- Dose selection rationale: The concentrations of p-phenylenediamine used were decided from the results of the subacute toxicity test. - Rationale for animal assignment (if not random): No data- Rationale for selecting satellite groups: No data- Post-exposure recovery period in satellite groups: No data- Section schedule rationale (if not random): No data
- Positive control:
- No data
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No data- Time schedule: No data- Cage side observations checked in table [No.?] were included. No dataDETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: Yes- Time schedule for examinations: weeklyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, weekly- 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 dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: Yes- Time schedule for collection of blood: All animals surviving in week 80 were subjected to hematological analysis.- Anaesthetic used for blood collection: No data - Animals fasted: No data - How many animals: All animals surviving in week 80- Parameters checked in table [No.?] were examined. No dataCLINICAL CHEMISTRY: No data - Time schedule for collection of blood: No data- Animals fasted: No data- How many animals: No data- Parameters checked in table [No.?] were examined. No dataURINALYSIS: No data - Time schedule for collection of urine: No data- Metabolism cages used for collection of urine: No data- Animals fasted: No data - Parameters checked in table [No.?] were examined. No dataNEUROBEHAVIOURAL EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No data- Battery of functions tested: sensory activity / grip strength / motor activity / other: No dataOTHER: No data
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, Animals were killed after 80 weeks or when they became moribund and were necropsied after death. All organs were examinedMacroscopically.HISTOPATHOLOGY: Yes, All organs were examined macroscopically, and then fixed in 10% buffered formalin and sections were prepared for histological examination.
- Other examinations:
- No data
- Statistics:
- No data
Results and discussion
Results of examinations
- Clinical signs:
- not specified
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was no relation between the average body weight and the concentration of p-phenylenediamine in male rats, but the body weight of female rats given 0.1% p-phenylenediamine was less than that of the controls.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- The food consumption of male and female rats in the experimental groups was not significantly different from those of the controls.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- The number of red and white blood cells and the hematocrit and hemoglobin values were not significantly different in different groups.
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In females in group 1, given 0.1% p-phenylenediamine, the mean weights of the body and spleen were less than those of the control, and in females in group 2, given 0.05%, the mean weight of the spleen was less than that of the control.
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The incidences of non-neoplastic lesions, including hemorrhage of the pituitary gland, fatty degeneration of the liver, fibrosis of the pancreas and pneumonia, were also not significantly different in different groups. No marked changes of the thyroid gland were observed in any rats.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The first tumor (a pheochromocytoma) was observed in a male rat that died of pneumonia in week 60. In both sexes the highest incidence of neoplastic lesions was that of pheochromocytomas of the adrenal gland. These lesions were observed in 10 (27.8%) of 36 male rats given 0.1% p-phenylenediamine, 8 (22.9%) of 35 male rats given 0.05% p-phenylenediamine and 6 (31.6%) of 19 males in the control group, but there was no significant difference in their incidences in different groups. In females, pheochromocytomas were also found in all experimental groups, although at lower incidences than in males. Other neoplastic lesions were as follows: hyperplasia of the forestomach in males, a fibroadenoma of the mammary gland in a female, a fibroma of the skin in a male, lymphomas in females and ductal hyperplasia of the pancreas in a female. The incidences of these neoplastic lesions were not significantly different in different groups.
- Other effects:
- not specified
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 25 mg/kg bw (total dose)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No significat effects were noted at the mentioned dose level
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw (total dose)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No significant alterations were noted at the mentioned dose level
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table: Hematological Data On Rats Treated For Up To 80 Weeks
Treatment (mg/Kg/day) | Sex | Number of rats | RBC (104/mm3) | WBC (/mm3) | Ht (%) | Hb (g/dl) |
50 | M | 16 | 823.6±167.1b | 42600±23900 | 43.6± 7.2 | 18.3± 2.1 |
25 | M | 11 | 1099.2± 82.0 | 59553± 22792 | 56.2± 6.4 | 21.9± 2.2 |
0 | M | 1 | 1016.0 | 12550 | 40.1 | 14.3 |
50 | F | 11 | 802.6±103.9 | 44570± 19271 | 44.5± 7.8 | 20.5±2.4 |
25 | F | 32 | 883.0± 158.0 | 46265 ±18398 | 47.0±9.3 | 19.0± 2.5 |
0 | F | 6 | 1077.9± 155.9 | 16550±1602 | 44.6±10.6 | 15.7± 3.5 |
Table: Weights of body, liver, kidney and spleen of rats treated for up to 80 weeks
Treatment (mg/Kg/day) | Sex | Number of rats | Terminal body weight (g) | Liver | Kidneys | Spleen | |||||
Left | Right | ||||||||||
g | %bw | g | %bw | g | %bw | g | %bw | ||||
50 | M | 16 | 243.8±46.6b | 5.74±0.91 | (2.3) | 1.07±0.10
| (0.4) | 1.08±0.11 | (0.4) | 0.50±0.11 | (0.2) |
25 | M | 11 | 207.8±29.5 | 5.29± 0.80 | (2.5) | 1.00±0.09 | (0.5) | 0.99±0.09 | (0.5) | 0.39±0.08 | (0.2) |
0 | M | 1 | 241.7 | 5.02 | (2.1) | 1.02 | (0.4) | 0.96 | (0.4) | 0.41 | (0.2) |
50 | F | 11 | 138.5±20.6 | 4.71±0.89 | (3.4) | 0.78±0.05 | (0.6) | 0.79±0.09 | (0.6) | 0.44±0.12e | (0.3) |
25 | F | 32 | 171.5±31.8 | 3.97±0.65 | (2.3) | 0.69±0.05 | (0.4) | 0.68±0.04 | (0.4) | 0.46±0.14
| (0.3) |
0 | F | 6 | 174.4±2.5 | 3.57±0.24 | (2.0) | 0.56±0.16 | (0.3) | 0.71±0.01 | (0.4) | 0.63±0.02 | (0.4) |
Table: Incidence Of Preneoplastic And Neoplastic Lesions In treated F344 Rats
Organ | Lesion | Number of rats affected/Number examined (%) | |||||
Female | Male | ||||||
Dose (mg/Kg/day) | 0 | 25 | 50 | 0 | 25 | 50 | |
Adrenal gland | Pheochromocytoma | 1/21 | 1/37 | 2/42 | 6/19 | 8/35 | 10/36 |
Forestomach | Hyperplasia | 0/21 | 0/37 | 0/42 | 0/19 | 6/35 | 1/36 |
Mammary gland | Fibroadenoma | 0/21 | 0/37 | 1/42 | 0/19 | 0/35 | 0/36 |
Skin | Fibroma | 0/21 | 0/37 | 0/42 | 1/19 | 0/35 | 0/36 |
Hematopoietic system | Lymphoma | 1/21 | 0/37 | 1/42 | 0/19 | 0/35 | 0/36 |
Pancreas Ductal | hyperplasia | 0/21 | 0/37 | 1/42 | 0/19 | 0/35 | 0/36 |
Applicant's summary and conclusion
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 25 mg/kg/day for female rats and 50 mg/Kg/day for male rats when F344 rats were exposed to the test chemical for 80 weeks.
- Executive summary:
Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using 6 week old male F344 rats in a 80 weeks study. The test chemical was mixed with feed and used at dose level of 0, 25 or 50 mg/Kg/day.The animals were observed for changes in body weight and food consumption, hematology, organ weight changed and were subjected to gross and histopathology. There was no relation between the average body weight and the concentration of p-phenylenediamine in male rats, but the body weight of female rats given 0.1% p-phenylenediamine was less than that of the controls. The food consumption of male and female rats in the experimental groups was not significantly different from those of the controls. The number of red and white blood cells and the hematocrit and hemoglobin values were not significantly different in different groups. In females in group 1, given 0.1% p-phenylenediamine, the mean weights of the body and spleen were less than those of the control, and in females in group 2, given 0.05%, the mean weight of the spleen was less than that of the control. The first tumor (a pheochromocytoma) was observed in a male rat that died of pneumonia in week 60. In both sexes the highest incidence of neoplastic lesions was that of pheochromocytomas of the adrenal gland. These lesions were observed in 10 (27.8%) of 36 male rats given 0.1% p-phenylenediamine, 8 (22.9%) of 35 male rats given 0.05% p-phenylenediamine and 6 (31.6%) of 19 males in the control group, but there was no significant difference in their incidences in different groups. In females, pheochromocytomas were also found in all experimental groups, although at lower incidences than in males. Other neoplastic lesions were as follows: hyperplasia of the forestomach in males, a fibroadenoma of the mammary gland in a female, a fibroma of the skin in a male, lymphomas in females and ductal hyperplasia of the pancreas in a female. The incidences of these neoplastic lesions were not significantly different in different groups. The incidences of non-neoplastic lesions, including hemorrhage of the pituitary gland, fatty degeneration of the liver, fibrosis of the pancreas and pneumonia, were also not significantly different in different groups. No marked changes of the thyroid gland were observed in any rats. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical for 80 weeks.
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