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EC number: 202-928-3 | CAS number: 101-25-7
- 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
Carcinogenicity
Administrative data
Description of key information
REACH_not carcinogenic up to 9 mg/animal/d | rat (male/female) | 1y study | Hadidian et al.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Principles of method if other than guideline:
- 1-year chronic toxicity / carcinogenicity study
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- other: Fischer
- Details on species / strain selection:
- Fischer rats are reasonably small; the average weight of the males was no more than 436 g, that of the females 326 g. Another advantage is that they are sensitive to toxic materials but do not respond excessively to carcinogenic stresses, thus avoiding the problem of false positives.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The animals were Fischer strain weanling rats, obtained from the Charles River Breeding Laboratories, Wilmington, Mass. After 1 week in a holding facility, they were placed on
experiment. Groups of 2 or 3 rats of the same sex were housed in galvanized cages with screen bottoms, in quarters with controlled temperature and humidity. They had free access to Purina Laboratory Chow and water. - Route of administration:
- oral: gavage
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Part 1 (toxicity): 8 w
Part 2 (MTD): 8 w
Part 3 (Main Study): 52 w - Frequency of treatment:
- 5 times per week
- Post exposure period:
- 6 m
- Dose / conc.:
- 300 other: mg/animal/d
- Remarks:
- PART 1 (toxicity test)
- Dose / conc.:
- 100 other: mg/animal/d
- Remarks:
- PART 1 (toxicity test)
- Dose / conc.:
- 30 other: mg/animal/d
- Remarks:
- PART 1 (toxicity test)
- Dose / conc.:
- 10 other: mg/animal/d
- Remarks:
- PART 1 (toxicity test)
- Dose / conc.:
- 9 other: mg/animal/d
- Remarks:
- MAIN STUDY
ca. 22 mg/kg/d males and 31 mg/kg/d females based on final body weight - Dose / conc.:
- 3 other: mg/animal/d
- Remarks:
- MAIN STUDY (1/3 MTD)
ca. 7 mg/kg/d males and 10 mg/kg/d females based on final body weight - Dose / conc.:
- 0.03 other: mg/animal/d
- Remarks:
- MAIN STUDY
ca. 0.07 mg/kg/d males and 0.1 mg/kg/d females based on final body weight - No. of animals per sex per dose:
- MAIN STUDY
- 3 in the dose group of 9 mg/animal/d
- 15 in the 1/3 MTD dose of 3 mg/animal/d
- 12 in the dose group of 0.03 mg/animal/d - Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
- Positive control:
- 2 mg per day of the versatile carcinogen N-2-fluorenylacetamide (12 males/females)
- Observations and examinations performed and frequency:
- Animals were examined 5 times per week during the gavaging process, and any abnormality was carefully recorded.
Body weight was measured every other week. - Sacrifice and pathology:
- Where the condition of an animal was such that survival seemed unlikely, the rat was killed and dissected. All other animals were killed at the end of the planned period.
A sample of 3 males and 3 females was killed after 1 year, the end of compound administration. The main group was necropsied 6 months later. The terminal body weight and the weights of the liver, kidneys, spleen, adrenal glands, and the pituitary were obtained. These tissues and in addition lungs, gastrointestinal tract (esophagus, stomach, and intestines), bladder, gonads, thyroids, mammary glands, and tissues with lesions were fixed in 10% formalin. Grossly abnormal tissues were examined microscopically. In addition, histologic sections of a random sample of 25% of grossly normal tissues were read. If any additional abnormalities turned up in this survey, the remaining tissues of the appropriate groups were also studied. Sections were prepared and routinely stained with hematoxylin and eosin. - Clinical signs:
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- PART 1 (toxicity test):
300 mg/animal/d 3/3; 100 mg/animal/d 3/3; 30 mg/animal/d 3/3; 10 mg/animal/d 0/3
MAIN STUDY:
Average survival period for the complete study was 550 days. Mean survival period [d] in detail for all dose groups was:
- 9 mg/animal/d: males 556, females 553
- 3 mg/animal/d: males 524, females 509
- 0.03 mg/animal/d: males 556, females 557
One female on the 0.03 mg level, dead after 492 days, showed a squamous cell carcinoma of the tongue obstructing the oral cavity. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- - 9 mg/animal/d: Initial mean bw males 55g, females 53g; final mean bw males 405g, females 289g
- 3 mg/animal/d: Initial mean bw males 60g, females 53g; final mean bw males 422g, females 309g
- 0.03 mg/animal/d: Initial mean bw males 65g, females 52g; final mean bw males 412g, females 300g - Food efficiency:
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- 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:
- no effects observed
- Description (incidence and severity):
- Mean liver weights [g]:
- 9 mg/animal/d: males 14 (12-17), females 12 (9-15)
- 3 mg/animal/d: males 17 (14-20), females 12 (7-14)
- 0.03 mg/animal/d: males 17 (14-20), females 11 (9-13) - Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - 9 mg/animal/d (3 animals per sex): no findings
- 3 mg/animal/d (15 animals per sex): Males no findings; Females 5 polyp uterus, (spontaneous occurring tumors), 1 hepatotoxic
- 0.03 mg/animal/d (12 animals per sex): Males no findings; Females: 2 polyp uterus, (spontaneous occurring tumors) - Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - 9 mg/animal/d (3 animals per sex): Males: 1 interstitial cell tumor testes, 1 cyst adenoma lung; Females no findings
- 3 mg/animal/d (15 animals per sex): Males: 6 interstitial cell tumor testes (typical aged male Fischer rats); Females: 1 mammary fibrodadenoma, 1 mammary adenomasarcoma, 1 sarcoma
- 0.03 mg/animal/d (12 animals per sex): Males: 2 interstitial cell tumor testes, 1 cystadenoma lung; Females: 1 squamous cell carcinoma tongue - Other effects:
- not specified
- Relevance of carcinogenic effects / potential:
- No significant increase of carcinogenic effects compared to controls.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 9 other: mg/animal/d
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: neoplastic
- histopathology: non-neoplastic
- Remarks on result:
- other: no significant increase of carcinogenic effects
- Key result
- Critical effects observed:
- no
- Conclusions:
- The test material showed no significant increase of carcinogenic effects compared to controls up to a daily dose of 9 mg/animal (ca. 22 mg/kg bw/d for males and 31 mg/kg bw/d for females based on final body weight).
Reference
Negative and Solvent Controls
Relatively few lesions were seen in younger animals. None of the relatively large number of male and female Fischer strain rats in these control groups bore hepatomas or other liver lesions in a period of over 600 days. Mammary adenocarcinomas were comparatively infrequent, affecting only 6 of a total of 160 rats autopsied between 531 and 600 days. Fibroadenoma likewise was found mostly in old females. There were a number of other tumors in a variety of sites,
chiefly in the endocrine glands or in the respiratory system, and some lymphomas.
Both vehicle and untreated control male rats exhibited a progressively increasing proportion of interstitial cell tumors of the testis. This lesion was diagnosed in almost all the males autopsied at 600 days. Within the designated experimental period of approximately 600 days, the Fischer strain rats had a fairly low spontaneous tumor rate, except for the interstitial cell tumor, which is typical for aged male Fischer rats.
Mean Bodyweight (survival period 531 - 599 d):
Males initial bw 62 +/- 4.9; final bw 419 +/- 33.4
Females inital bw 54 +/- 4.2; final bw 323 +/- 25.5
Liver weights (survival period 531 - 599 d):
Males 16.0 +/- 1.3
Females 12.3 +/- 0.97
Noncancerous Lesions
Among the noncancerous lesions in female rats of the Fischer strain, there was a fair incidence of uterine polyps, hyperplastic mammary glands, and endometrial hyperplasia. Small numbers of males had testicular atrophy and some showed interstitial tissue hyperplasia. In this extensive study involving almost 6,000 rats, a relatively low incidence (about 4%) of pulmonary disease was seen over the 18-month experimental period, testifying to the value of the newer cesarianderived,
barrier-bred rats used in the tests and also to the careful management of the animal facilities.
Positive Control (N-2 -Fluorenylacetamide)
In the positive control series encompassing 6 groups of 12 male and 12 female Fischer rats, quite reproducible tumor patterns were obtained.
With the 2 mg level of N-2 -fluorenylacetamide, the survival time of the males ranged from 209-365 days (average of the 6 groups, minimum 238 and maximum 343 days). 70 of 71 males exhibited hepatoma, and 54 of these lesions metastasized, generally to the lung and in a few cases to the adrenals. Relatively few other primary tumor sites were affected. Six rats bore tumors of the external ear duct, 1 had a mammary adenocarcinoma, and 10 developed a variety of neoplasms at several sites. Of interest are tumors of the lips which are not generally seen with this compound. They may have been specifically caused by a combination of carcinogenicity from the compound and repeated friction trauma from the intubations.
Although females were somewhat less responsive to this agent, the survival time was not much longer than with males, from 229-384 days or an average minimum of 240 and maximum of 353 days. The liver was less involved; 46 of 71 females had hepatoma and only 4 of these metastasized. On the other hand, 21 of the rats had ear duct tumors, 28 had mammary adenocarcinoma, and 3 additional females had fibroadenomas. A wide variety of lesions at various sites were observed in 20 additional rats, including 4 tumors of the skin, not usually seen with this compound, and 2 of the tongue or lip.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
DNPT has been tested in the rats after oral and intraperitioneal application. No carcinogenicity has been observed.
However, studies suffer from short duration. In the key study the maximally tolerated chronic dosage was determinedin dose range finding studies. Fischer rats were treated 5 times a week for 52 weeks, for a total of 260 individual doses, unless mortality occured.
No increases in the incidence of tumors in groups of 12 males and 12 females, 15 males and 15 females as well as 3 males and 3 females receiving 0.03 mg, 3 mg and 9 mg/animal were observed. A squamous cell carcinoma of the tongue was seen in one female receiving the lowest dose.
Based on the existing studies DNPT does not exert carcinogenic effects.
Additional information
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