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Diss Factsheets
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EC number: 212-658-8 | CAS number: 838-88-0
- 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:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Meets generally accepted scientific standards, well documented and acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Liver and lung tumors in dogs from 4,4'-methylene-bis(2-methylaniline).
- Author:
- Stula EF, Barnes JR, Sherman H, Reinhardt CF, Zapp Jr JA
- Year:
- 1 970
- Bibliographic source:
- J. Environ Pathol Toxicol 1: 339-356.
Materials and methods
- Principles of method if other than guideline:
- Determination of target organ toxicty including carcinogenicty in dogs following chronc and repeated exposure to 4,4'-methylenedi-o-toluidine.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- 4,4'-methylenedi-o-toluidine
- EC Number:
- 212-658-8
- EC Name:
- 4,4'-methylenedi-o-toluidine
- Cas Number:
- 838-88-0
- Molecular formula:
- C15H18N2
- IUPAC Name:
- 4-[(4-amino-3-methylphenyl)methyl]-2-methylaniline
- Details on test material:
- - Name of test material (as cited in study report): 4,4'-methylene-bis(2-methylaniline)
The sample was >99 percent active ingredient. It was crystalline, beige in color, and slightly soluble in water. The melting point was 157-159 °C, and the molecular weight was 226.16.
Constituent 1
Test animals
- Species:
- dog
- Strain:
- Beagle
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- The dogs were fed a commercial dog chow ad libitum. They were housed in separate cages in a climate-controlled room and were put into an outside concrete exercise yard daily. Separate exercise yards were used for control and test dogs.
Administration / exposure
- Route of administration:
- oral: capsule
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- up to 7.0 years
- Frequency of treatment:
- The dogs were dosed 100 mg per day, 3 times per week for the first 6 weeks, then 5 times per week for 5 weeks, at which time the dose was reduced to 50 mg per day 5 times per week continuously for up to 7.0 years.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100 mg/day (11 weeks) then 50 mg/kg until end of the study
Basis:
actual ingested
- No. of animals per sex per dose:
- 6 female dogs
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Each of six purebred female beagle dogs, approximately one year old, was dosed orally with MeMDA in a gelatin capsule. They were dosed 100 mg per day, 3 times per week for the first 6 weeks, then 5 times per week for 5 weeks, at which time the dose was reduced to 50 mg per day 5 times per week continuously for up to 7.0 years. When a dog exhibited anorexia, MeMDA was not administered until the dog was eating again. Six purebred female beagle dogs were kept as untreated controls and were sacrificed after 8.3 to 9.0 years on test, as they served as controls for several other tests.
Examinations
- Observations and examinations performed and frequency:
- Specimens of blood and 24-hour urine samples were collected from each dog, once before the test began, and then after 7, 14, 18, 24, 30, 33, 39, 43, 47, 55, 63, 69, 77, 83, 89, 92, and 102 months on test. The following tests were performed:
HEMATOLOGY: erythrocyte count; hemoglobin concentration; hematocrit; total leucocyte count; differential leucocyte count.
BIOCHEMISTRY (on blood): glucose; urea nitrogen; cholesterol; alkaline phosphatase; glutamic-pyruvic transaminase; total protein; albumin-globulin ratio.
URINALYSIS: volume, pH, appearance, osmolality; protein; sugar; blood; acetone; urobilinogen; bilirubin; microscopic examination of sediment.
URINE SEDIMENT CYTOLOGY: Once each year a 12-hour urine specimen was collected in 250 ml 95 percent ethyl alcohol. Fifty ml of the above mixture was centrifuged at 1500 rpm for 20 minutes. The sediment was fixed and stained and examined microscopically. - Sacrifice and pathology:
- NECROPSY: dogs were sacrificed by electrocution and a complete necropsy was performed. Color photographs were taken of various gross lesions. Tissues were fixed in Bouin's fluid and in 10 percent buffered formalin. Tissues were embedded in paraffin and stained with hematoxylin-eosin.
- Statistics:
- Fisher's Exact Test
Results and discussion
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Mortality: One substance treated dog died after 2.8 years. Four dogs treated with the test substance were sacrificed in extremis after the following time periods: 2.7, 4.0, 5.2, and 6.0 years.
Hematology and clinical chemistry:
The erythrocyte count, hemoglobin concentration, and hematocrit of substance treated dogs were generally lower than those of the untreated controls. Four of six substance treated dogs had elevated blood urea nitrogen during an approximate six-month time period prior to death or being sacrificed in extremis. One dog of the control group had elevated plasma glutamic-pyruvic transaminase and and alkaline phosphatase during the entire test period. All substance treated dogs showed elevated plasma glutamic-pyruvic transaminase and all but one had an elevated plasma alkaline phosphatase.
Microscopic examination of the urine sediment did not reveal neoplastic changes in the genitourinary tract of test or control dogs.
Histopathology:
Four of the six substance treated dogs had a thin, pale, irregular renal cortex. Microscopically, there was a severe proximal tubular atrophy with fibrosis. Three of six treated dogs had subintimal fibrosis of inedium sized renal arteries with a reduction in the size of the lumen. These effects on the kidneys were not seen in the control dogs.
Multiple pale focal areas and/or pale nodules in the liver measuring up to 5.0 cm in diameter were found in all substance treated dogs at necropsy. Histologically, these focal areas were classified as focal cell alteration, cholangiofibrosis, nodular hyperplasia, or hepatocellular carcinoma. In focal cell alteration there was no disruption of the liver architecture; the affected
hepatocytes were usually enlarged with a centrally positioned nucleus and a vacuolated cytoplasm. Usually the vacuolation was not spherical to suggest a fatty change, although fatty change was at times a minor component of the lesion designated as focal cell alteration. Cholangiofibrosis was seen in 2/6 dogs of the control group.
Carcinogenicity:
The three dogs that survived treatment with the test substance for 5.2 to 7.0 years developed hepatocellular carcinomas. In addition, two them developed lung carcinomas. The tumors contained glandular and epidermoid characteristics and were classified as combined epidermoid and adenocarcinomas, with a possible origin from the bronchus and/or bronchial glands.
No liver or lung tumor were observed in the six dogs of the control group. Thus, the increase in the tumor rate was considered to be statistically relevant (liver tumors: p <0.05; lung tumors: p <0.10).
Four dogs of the control group, treated for 8.3 to 9.0 years, had mammary tumors, whereas no mammary tumors were observed in dogs treated with the test substance for for 2.7 to 7.0 years.
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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