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EC number: 202-918-9 | CAS number: 101-14-4
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27 Augustus 2003 - 20 January 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: No deviations reported. The study fully meets the current guidelines.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
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
Test material
- Details on test material:
- - Name of test material (as cited in study report): 4, 4'-methylene bis (2-chlorobenzen amine)
- Substance type: white, needlelike crystalline powder
- Physical state: solid
- Analytical purity: 99.76%
- Impurities (identity and concentrations): not mentioned
- Purity test date: 2002-12-12
- Lot/batch No.: FG-3002
- Expiration date of the lot/batch: not mentioned
- Stability under test conditions: stable during study period; purity was 98.98% at 2004-01-01
- Storage condition of test material: protected from air and moisture at 3-5 °C
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: males; 335-435 g; females; 198-267 g
- Fasting period before study: not mentioned
- Housing: individually in wire-mesh steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 day
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 45 -65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: once weekly
VEHICLE
- Justification for use and choice of vehicle (if other than water): test substance is soluble in olive oil, not in water
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no. (if required): KH 21
- Purity: not mentioned - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The first lot of each dosing solution was analyzed by HPLC. The concentrations measured were as expected.
- Duration of treatment / exposure:
- males 42 days; females 42-55 days
- Frequency of treatment:
- once daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 0.4, 2, 10, 50 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on dose-range finding study of 14 days
- Rationale for animal assignment (if not random): at random
- Rationale for selecting satellite groups: not mentioned
- Post-exposure recovery period in satellite groups: not mentioned
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: first hour after dosing
BODY WEIGHT: Yes
- Time schedule for examinations: Males: day 1, 7, 14, 21, 28, 35, 42 during dosing period; day 7, 14 during recovery period
Females: day 1, 7, 14 during dosing; day 0, 7, 14, 20 on gestation days; day 0, 4 lactation days
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
HAEMATOLOGY: Yes
- Time schedule for collection of blood: day of last dosing and end of recovery period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all
- Parameters checked: erythrocytes (+ Heinz body containing), hemoglobin, hematocrit, reticulocytes, methemoglobin, platelets, leucocytes
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day of last dosing and end of recovery period
- Animals fasted: Yes
- How many animals: all
- Parameters checked: LDH, GPT, gamma-GTP, choline-esterase, total protein, albumin, A/G ratio, total cholesterol, triglyceride, Ca, inorganic phosphorus, Cl, K.
URINALYSIS: Yes
- Time schedule for collection of urine: males on day 40 and recovery day 8
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked: gross appearance, qualitative pH, occult blood, protein, glucose, ketone body, urobilinogen, bilirubin, sedimentation, volume, specific gravity, concentration sodium and potassium.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: last day of dosing and end of recovery period
- Battery of functions tested: sensory activity and reflex functions - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes - organ weight
HISTOPATHOLOGY: Yes - Other examinations:
- Observation of newborn pups: number of littermates, sex, malformations of pups, clinical signs, body weight, pathological examinations.
- Statistics:
- Where there was a significant difference (<5% level of significance) of mean values or frequencies between the control and treated groups were analyzed with the following statistical tests. (As for the data of pups born, the mean value per littermate was treated as one sample): If there was more than three treated groups, the following parametric data was first examined for uniformness of variance by the Bartlett's test: body weight, body weight gain, food consumption, landing foot splay width, grip strength, locomotor activity, quantitative data of urinalysis, hematological data, blood biochemical data, organ weight, number of corpora lutea, number of implantation sites, paring days until copulation, gestation length, number of pups born, number of live pups, number of dead pups . The parametric data with uniform variance were then examined by a one-way analysis of variance (ANOVA). Both parametric data with non-uniform variance and non-parametric data such as differential leukocyte count, qualitative data of urinalysis, implantation index, live birth index, delivery index, estrous cycle, viability index were analyzed with the Kruskal-Wallis rank test. Results with significant difference found in these analyses were examined using a multiple comparison procedure with the Dunnett or Dunnett-type test. When comparing data between two test groups, parametric data was firstly examined using the F test. The data with uniform variance was next examined by Student t-test and the data with non-uniform variance was examined by Aspin-Welch's t-test. Non-parametric data was examined by Mann-Whitney U test. The categorical data including clinical signs, detailed observations, sensory and reflex function test, incidence of abnormality in necropsy and histopathological test, copulation index, fertility index, delivery index, and sex ratio of pups was examined by Fisher's exact probability test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- salviation in 50 mg/kg group 8 days after dosing
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- salviation in 50 mg/kg group 8 days after dosing
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- females 50 mg/kg group showed decreased body weight
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- males 50 mg/kg group decreased at day 1
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- both sexes at 50 mg/kg group
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- in females of 10 mg/kg group and in both sexes of 50 mg/kg group
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- males 50 mg/kg group decreased at day 1
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- both sexes at 50 mg/kg group
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- both sexes at 50 mg/kg group
- Details on results:
- CLINICAL SIGNS AND MORTALITY
During the administration period, salviation was observed in 6 male and 3 female rats out of 12 in the 50 mg/kg group 8 days after dosing. Salviation was also observed in 3 of 5 rats in the 50 mg/kg female satellite group. Salviation was generally observed from 10 to 30 minutes after dosing or immediately after dosing in some cases. During the recovery period, there were no rats showing changes in clinical signs. No deaths occurred during administration and recovery periods.
BODY WEIGHT AND WEIGHT GAIN
During the administration period, the body weight of female rats of the 50 mg/kg group was significantly decreased on gestation days 14 and 20, and significant decreased body weight gain was also observed during the gestation period. Body weights of females of the same group on the lactation day 0 and 4 had a tendency to show values lower than those of the control group, but there was no difference observed in the body weight gain during the period. In the female satellite group, the body weight tended to be slightly lower than that in the control group, but the difference was not significant. In male rats, there were no changes in either body weight or body weight gain. During the recovery period, there were no significant changes in either body weight or body weight gain in both sexes.
FOOD EFFICIENCY
During the administration period, food consumption of male rats on dosing day 1 in the 50 mg/kg group was significantly decreased.
HAEMATOLOGY
In the hematological test performed at the end of the administration period, significant changes were observed in the 50 mg/kg group: decrease in erythrocyte count and methemoglobin in both sexes, decrease in hemoglobin concentration and hematocrit value and increase in reticulocyte count and platelet count in the males, and increase in Heinz bodies-containing erythrocytes in the females. Also observed in the 50 mg/kg group, there was a tendency for hemoglobin concentration and hematocrit value to be lower and for reticulocyte count to be higher. At the end of the recovery period, significant differences in the hemoglobin concentration and hematocrit value of male rats was found, but the differences became smaller. Except for these points, no changes were found. In female rats at the end of the recovery, methemoglobin was noted as having slightly increased. Despite this significant difference, the value was within the normal range.
CLINICAL CHEMISTRY
In the blood biochemical test performed at the end of the administration period, a significant decrease in total protein and albumin of female rats in the 10 mg/kg group was found. In the 50 mg/kg group, there was a significant decrease in total protein and albumin of both sexes, and A/G ratio showed significant decrease in female rats and showed the tendency of having a lower value in male rats. In the same group, there were significant increases in total cholesterol, triglyceride and inorganic phosphorus in male rats, and in LDH and gamma-GTP in female rats; LDH and gamma-GTP in male rats and potassium of both sexes had also tendency to show a higher value. At the end of the recovery period, no significant changes in any test items found.
URINALYSIS
During the administration and recovery period, there were no significant changes found in any items of urinalysis.
NEUROBEHAVIOUR
There were no significant changes at the measurement time points of dosing week 6 and recovery week 2.
ORGAN WEIGHTS
In animals sacrificed after the administration period, a significant increase in relative weight of the kidney was found in female rats in the 10 mg/kg group. In the 50 mg/kg group, a significant increase in relative weight of the kidney was found in female rats. Significant increases were also found in absolute and relative weight of the liver and relative weight of the spleen in male rats; and in relative weight of both the liver and thyroid, and absolute and relative weight of the spleen in female rats. In animals sacrificed after the recovery period, there were significant differences in relative weights of male spleen, female liver and female kidney but the differences tended to decrease. There weren't any changes in male liver, female spleen and female thyroid. There was a significant increase in relative weight of testis in rats sacrificed after recovery period.
HISTOPATHOLOGY: NON-NEOPLASTIC
Changes attributed to the test article were found in the liver, spleen and kidneys.
Liver:
In the 50 mg/kg group, those changes characterized by swelling (centrilobular zone) and fatty degeneration (in intermediate zone) of hepatocytes were found in all of 6 male rats and 6 out of 8 female rats, and 3 of these male rats showed single cell necrosis of hepatocytes in the centrilobular zone. In female rats in the same group, there was another rat showing prominent fatty degeneration only. There was significant difference in the incidences of swelling and fatty degeneration of hepatocytes in both sexes compared with those in the control group. These changes were not found in the recovery group.
Kidney:
Among 5 male rats in each group, mildly basophilic change of renal tubules was found in 1 control groups whereas there was an increase tendency of the incidence with 3 in the 10 mg/kg group and 4 in the 50 mg/kg group, and the degree of this change tended to be more severe. In female rats, there wasn't any increase tendency of basophilic change of renal tubules found. In the male recovery group, there was no difference in the incidence of basophilic change of renal tubules compared to that in the control group.
Spleen:
Mild hemosiderin deposits in splenic red pulp were found in all rats of both sexes in the control group and moderate in 4 male rats from the 10 mg/kg group and in 5 male rats and 4 female rats from the 50 mg/kg group, and there was a significant difference in the incidence of moderate hemosiderin deposits. As for extramedullary hematopoiesis in splenic red pulp in female rats, only mild cases were found except for one rat in the control group with a moderate degree, but 4 rats showed moderate extramedullar hematopoiesis in the 50 mg/kg group and tendency for the enhancement. In the recovery group, increased tendency for hemosiderin deposits remained in female rats, which was not significantly different, and there were no differences in both hemosiderin deposits and extramedullary hematopoiesis in male rats compared with those in the control group.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 2 mg/kg bw/day (actual dose received)
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
none
Applicant's summary and conclusion
- Conclusions:
- Sprague-Dawley rats were treated with 0, 0.4, 2, 10, and 50 mg/kg 4,4'-methylene bis (2-chloro-aniline) once daily during 42 days (males) or up to 4 days after delivery (females). 4,4'-methylene bis (2-chloro-aniline) had toxic effects on the spleen, liver and kidneys following repeated administration in rats. Overall, a NOEL of 2 mg/kg was reported for 4,4'-methylene bis (2-chloro-aniline).
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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