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Diss Factsheets
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EC number: 202-453-1 | CAS number: 95-80-7
- 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:
- repeated dose toxicity: oral
- Remarks:
- other: carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Meets generally accepted scientific standards, well documented and acceptable for assessment.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 979
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- yes
- Remarks:
- - only 2 doses tested
- GLP compliance:
- no
Test material
- Reference substance name:
- 4-methyl-m-phenylenediamine
- EC Number:
- 202-453-1
- EC Name:
- 4-methyl-m-phenylenediamine
- Cas Number:
- 95-80-7
- Molecular formula:
- C7H10N2
- IUPAC Name:
- 4-methylbenzene-1,3-diamine
- Details on test material:
- 2,4-Diaminotoluene (2,4-TDA); purity 99.9 % (gas-liquid chromatography, and with up to 6 minor
components)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Treatment of animals: the doses 125 and 250 ppm were given for 40 weeks; due to excessive depression in body weight gain low and high doses were then reduced to 50 and 100 ppm, respectively; administration of 50 ppm was continued for 63 weeks; surviving animals administered 100 ppm were killed at the end of 39 (males) or 44 (females) weeks due to morbidity. In another report, apparently of the same study, it was said that the 2,4-TDA doses were reduced at week 20, rather than week 40 (Cardy, 1979).
The time-weighted average dose was 79 ppm for the low-dose males and females for 103 weeks, 176 ppm for the high-dose males for 79 weeks, and 171 ppm for the high-dose females for 84 weeks. The calculated average intake of 2,4-TDA was approx. 5.9 mg/kg bw/day (low dose) and approx. 13 mg/kg bw/day (high dose). - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- up to 103 weeks
- Frequency of treatment:
- continuous
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 125/50 ppm (low dose), 250/100 ppm (high dose)
Basis:
nominal in diet
- No. of animals per sex per dose:
- 50 (dose groups); 20 (control groups)
- Control animals:
- yes, plain diet
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- effects observed, treatment-related
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Sex:
- male/female
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 5.9 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: The time-weighted average dose over a period of 103 weeks was 79 ppm for low dose males and females; from this an average 2,4-TDA intake of approx. 5.9 mg/kg bw/day was calculated.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Mortality was dose related in male and female rats. At both dose levels, male and female rats showed a decrease in survival time compared to controls as demonstrated in table 1 after 78 treatment weeks:
Table 1: Number of rats which were still alive at week 78 on study
Control | Low Dose | High Dose | |
Males |
18/20 (90 %) | 42/50 (84 %) | 32/50 (64 %) |
Females |
20/20 (100 %) | 46/50 (92 %) | 46/50 (92 %) |
All males given 250/100 ppm 2,4-TDA (high dose) were dead by 79 weeks, and females given high doses were dead or were terminated due to morbidity by 84 weeks. Mean body weights of dosed male and female rats were lower than those of the corresponding controls and were dose related. Non-neoplastic findings of this carcinogenesis bioassay in F344 rats revealed that 2,4-TDA was hepatotoxic. In the liver dosed animals exhibited various treatment induced non-neoplastic morphologic alterations which ranged from mild, scattered foci of lipidosis and focal necrosis of hepatocytes to severe, diffuse, toxic degenerative lesions. The incidence of primary hepatic lesions in rats is given in the following table 2:
Table 2: Number of rats with primary non-neoplastic lesions in the liver
Control | Low Dose | High Dose | |
Males |
2/20 (10 %) | 25/49 (51 %) | 36/50 (72 %) |
Females |
1/20 (5 %) | 23/50 (46 %) | 42/49 (86 %) |
In addition, kidney lesions were seen in both sexes (most marked in males). Microscopy of the kidneys revealed non-neoplastic lesions of different severity scored in the 1-5 grading system. The average numerical values are listed by dose and sex in the following table 3:
Table 3: Scoring of chronic renal disease in rats (mean average of severity grades/number of animals tested)
Control | Low Dose | High Dose | |
Males |
2.1 / 20 | 3.7 / 49 | 3.9 / 50 |
Females |
1.3 / 19 | 2.0 / 50 | 2.8 / 49 |
1-5 grading system mean: 1=minimal changes detectable as slight basement membrane thickening seen most in Bowman's capsule. 2=the stage of mild glomerular change and scattered, atrophic, dilated tubules with intratubular proteinaceous casts. 3 and 4=subjective divisions of degree of the above changes along with glomerular atrophy and sclerosis, lymphoid aggregates, and a variable degree of interstitial fibrosis and architectural derangement. A score of 4 indicated severe involvement. 5=reserved for end-stage kidneys.
Corresponding to the renal disease was a high incidence of associated secondary hyperparathyroidism in low- and high-dose males. The affected parathyroid glands were spherical and bulged from the surface of the cut thyroid gland. Associated lesions included metastatic calcification in numerous locations and absorption in bone with proliferation of osteoclasts and myelofibrosis.
In F344 rats an average dose of approx. 5.9 mg/kg bw/day 2,4-TDA showed hepatotoxic effects, induced the development of chronic renal disease, and an increased incidence of tumors. An overall NOAEL for rats was not demonstrated.
Applicant's summary and conclusion
- Executive summary:
In a carcinogenicity study F344 rats were administered with feeding concentrations of 0, 125/50 and 250/100 ppm 2,4 -TDA over a period of up to 103 weeks. The time-weighted average dose was 79 ppm for the low-dose males and females for 103 weeks, 176 ppm for the high-dose males for 79 weeks, and 171 ppm for the high-dose females for 84 weeks. The calculated average intake of 2,4-TDA was approx. 5.9 mg/kg bw/day (low dose) and approx. 13 mg/kg bw/day (high dose). In this study survival time and mean body weights were dose related decreased in males and females. In both sexes an average dose of approx. 5.9 mg/kg bw/day 2,4-TDA showed hepatotoxic effects, induced the development of chronic renal disease, and an increased incidence of tumors. An overall NOAEL for rats was not demonstrated.
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