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EC number: 202-728-6 | CAS number: 99-08-1
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Study period:
- 1992
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 992
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- (no post exposure period, max humidity > 70%, max Temp > 25°C, limited chemical chemistry, not all recommended organs were weighed, no post exposure group)
- GLP compliance:
- yes
- Remarks:
- FDA Good Laboratory Practices regulation (21 CFR 58)
- Limit test:
- no
Test material
- Reference substance name:
- 3-nitrotoluene
- EC Number:
- 202-728-6
- EC Name:
- 3-nitrotoluene
- Cas Number:
- 99-08-1
- Molecular formula:
- C7H7NO2
- IUPAC Name:
- 3-nitrotoluene
- Details on test material:
- - Name of test material (as cited in study report): m-nitrotoluene
- Analytical purity: >96%
- Impurities: < 1% (mostly o- and p-nitrotoluene)
- Storage: room temperature, protected from light
- Stability: reanalysis performed at approx. 4 months intervals indicated that the test substance was stable under the storage conditions chosen
- Other:-source: Eastman Kodak Co. (Rochester, NY, USA)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: F344/N
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY, USA)
- Age at study initiation: 6-8 weeks of age
- Mean weight range at study initiation: 119-125 (male), 95-98 (female)
- Housing: 5/cage (polycarbonate cages)
- Diet: Control groups received NIH-07 Open formula feed (Zeigler Brothers, Inc., Gardners, PA, USA) ad libitum; treated groups received NIH-07 Open formula feed mixed with the appropriate concentration of m-nitrotoluene, ad libitum.
- Water: ad libitum
- Acclimation period: 10-15 days
- Other: 5 viral screens performed at the study start and termination indicated no positive antibody titer
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.9 - 26.1
- Humidity (%): 32-90%
- Air changes (per hr): 16-29
- Photoperiod (hrs dark / hrs light): 12 hrs dark /12 light
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 625, 1250, 2500, 5000, or 10000 ppm
Basis:
nominal in diet
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Based on the results of a 14-day preliminary study
- Rationale for animal assignment: Animals were weighed and randomized using a computer program
- Post-exposure period: no
Examinations
- Observations and examinations performed and frequency:
- MORTALITY: Yes
Time schedule for check: twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a week
BODY WEIGHT: Yes
- Time schedule for examinations: recorded at study start and weekly thereafter.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for determination: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood and serum samples were collected from the retroorbital sinus using heparinezed microcapillary tube, after 1 week, 3 weeks, and at the end of the 13-week studies
- Anaesthetic used for blood collection: Yes (70% CO2/30% O2)
- Animals fasted: No
- Parameters checked: For hematologic analyses, samples were collected in plastic tubes containing potassium EDTA. Automated analyses were performed using a Coulter S-Plus IV (Hialeah, FL) and included erythrocyte, leukocyte, and platelet counts, hematocrit (HCT), hemoglobin (HGB) concentration, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Leukocyte differentials and morphologic evaluations of blood cells were determined from blood smears stained with Wright´s stain. Reticulocytes were stained by mixing equal amounts of blood and new methylene blue and incubating the preparation for 20 minutes. Smears made from these preparations were examined microscopically for determination of reticulocyte counts.
Methemoglobin concentrations were measured using a Co-Oximeter 482 (Instrumentation
Laboratories, Lexington MA).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 1 week, 3 weeks, and at the end of the 13-week studies.
- Parameters checked: alanine aminotransferase (ALT), alkaline phosphatase (AP), creatine kinase (CK), and concentrations of total protein, albumin, urea nitrogen (UN), and creatinine, SDH and concentrations of total bile acids
REPRODUCTIVE SYSTEM EVALUATIONS: Yes
- Time schedule for examinations: For the 12 days prior to sacrifice, females were subject to vaginal lavage with saline. The relative preponderance of leukocytes, nucleated epithelial cells, and large squamous epithelial cells were used to identify the stages of the estrual cycle. Sperm motility was evaluated at necropsy
- Test groups examined: 0, 2500, 5000, and 10000 ppm dose groups
- Parameters examined: Sperm morphology and vaginal cytology (SMVC), sperm motility, spermatid head count
- Methods: as described by Morrissey et al. (1988) Fundam. Appl. Toxicol. 11, 343-358 - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Time schedule: at conclusion of the feeding phase
- Number of animals: complete necropsies were performed on all (surviving) animals. Organs and tissues were examined for gross lesions
- Organs weighed: heart, right kidney, liver, lung, right testis, and thymus
HISTOPATHOLOGY: Yes
- Complete necropsy performed on all animals. Protocol-required tissues examined in all control animals, all early death animals, and all animals in the highest dose group with 60% survivors.
- Tissues examined: gross lesions, tissue masses or suspect tumors and regional lymph nodes, skin, mandibular and mesenteric lymph nodes, mammary glands with adjacent skin, salivary glands, thigh muscle, ileum, colon, cecum, rectum, liver, femur (to include diaphysis with marrow cavity and epiphysis), thymus, trachea, lungs and bronchi, heart, thyroid, parathyroids, esophagus, stomach, duodenum, jejunum, pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal vesicles, prostate, testes, epididymides, ovaries, uterus, nasal cavity and nasal turbinates, brain with stem, pituitary, preputial or clitoral glands. - Statistics:
- See (any other informations on materials and methods incl. tables)
Results and discussion
Results of examinations
- Details on results:
- All animals survived to the end of the studies after exposure to m-nitrotoluene.
Body weight gains of rats receiving m-nitrotoluene were reduced in groups given diet containing 5000 or 10000 ppm. Feed consumption was less in the groups receiving the 10000 ppm of the m-nitrotoluene compared to controls. There were no other clinical signs of toxicity attributed to m-nitrotoluene.
One week of treatment with m-nitrotoluene produced mild increases in erythrocyte count, HGB concentration (males only), and HCT in male and female rats in the highest dose group.
Other relevant findings were mild decreases in reticulocyte and platelet counts and activity of AP and mild increases in concentrations of UN, creatinine, and albumin.
After 3 weeks of treatment with m-nitrotoluene, erythrocyte count, HGB concentration, and HCT were decreased in male rats in most dose groups and in female rats in the highest dose group.
Increases in reticulocyte, nucleated erythrocyte, and platelet (males only) counts and methemoglobin concentrations also were present in the highest dose groups of both sexes. Mild increases in lymphocyte counts were seen in high dose male and female rats; high dose females had increases in leukocyte counts. Serum biochemical effects in male rats consisted of minimal decreases in concentrations of UN; increases in concentrations of creatinine were noted in male and female rats. Additionally, a mild increase in activity of ALT occurred in female rats in the 3 highest dose groups.
At the end of 13 weeks, erythrocyte counts, HGB concentration, and HCT were decreased in female rats in the highest 1 or 2 dose groups; in male rats, only erythrocyte counts were decreased in the highest treatment group. Increases occurred in MCV, MCH, reticulocyte and platelet counts, and methemoglobin concentrations in rats of both sexes in high dose groups (5000 and 10000 ppm). Biochemical changes in serum were limited to mild to moderate increases in bile acid concentrations in male and female rats in the 5000 and/or 10000 ppm groups.
At necropsy, the only treatment-related gross lesions were seen in the 10000 ppm group of male rats. In 4/10 rats, the testes and epididymes were smaller than in controls. Relative liver weights were moderately increased in males and females in the highest dose group, and relative kidney weights were increased in the top 2 dose groups in both sexes. The relative testis weight was substantially less than controls in the 10000 ppm group.
There was a treatment-related hyaline droplet nephropathy in the kidney of male rats. This was characterized by the presence of eosinophilic protein droplets in the renal tubular epithelium and tubule lumen. The droplets were irregular-shaped and increased in size and number as compared to the protein "resorption droplets" typically present in the kidney of control male rats.
Hyaline droplet nephropathy was graded a minimal severity in all dosed groups, but the number of protein droplets increased with dose. Necrosis and increased regeneration of the renal tubular epithelium, granular casts, and focal mineralization were not associated with the hyaline droplet nephropathy in this study. A no-effect-level for the hyaline droplet nephropathy was not achieved.
An increase in hemosiderin pigment and congestion of the spleen was observed in treated male and female rats when compared to controls; both were of minimal to mild severity.
Congestion was diagnosed when the vascular spaces of the red pulp were distended with erythrocytes; increased hemosiderin pigment was diagnosed when the brown (iron-positive) pigment in macrophages of the red pulp exceeded the amount normally seen in the spleen of control rats.
All male rats from the 10000 ppm group displayed mild to moderate degeneration of the testis, characterized by a reduction of germ cells and mature spermatids in the seminiferous tubules; cellular debris was present in the ducts of the epididymis. This testicular lesion was accompanied by a reduction in epididymal sperm count and concentration. Among females there was a dose-related decrease in the length of estrous and an increase in the period of diestrus. The length of the estrous cycle increased while the number of cycling animals diminished. There were no gross or histopathologic effects on the uterus or ovaries in this 13-week study.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Weight gain, Feed and Compound Consumption of Male and Female F344/N Rats in the 13 Week Dosed Feed Studies on m-Nitrotoluene
|
| Mean BodyWeights(grams) |
|
|
| ||
Nominal dose in feed (ppm) | Survival | Initial | Final | Change | Final weight relative to control (%) | Feedconsumption(g/day) | Estimated chemical consumed (mg/kgbw/d) |
Female | |||||||
0 | 10/10 | 98 | 194 | 96 |
| 10.8 | 0 |
625 | 10/10 | 95 | 199 | 104 | 103 | 10.7 | 48 |
1250 | 10/10 | 96 | 194 | 98 | 100 | 10.3 | 87 |
2500 | 10/10 | 94 | 195 | 101 | 101 | 10.2 | 172 |
5000 | 10/10 | 95 | 177 | 82 | 91 | 9.4 | 336 |
10000 | 10/10 | 97 | 166 | 69 | 86 | 8.4 | 638 |
Male | |||||||
0 | 10/10 | 119 | 346 | 227 |
| 16.3 | 0 |
625 | 10/10 | 123 | 354 | 231 | 103 | 16.5 | 46 |
1250 | 10/10 | 119 | 342 | 223 | 99 | 16.1 | 86 |
2500 | 10/10 | 123 | 353 | 230 | 102 | 16.3 | 171 |
5000 | 10/10 | 125 | 338 | 213 | 98 | 15.8 | 342 |
10000 | 10/10 | 123 | 281 | 158 | 81 | 13.4 | 661 |
Table 2: Lesions in F344/N Rats Receiving m-Nitrotoluene for 13 Weeks
Male F344 rats | |||||||
Dose (ppm) | 0 | 625 | 1250 | 2500 | 5000 | 1000 | |
No. of animals / dose group | 10 | 10 | 10 | 10 | 10 | 10 | |
Organ | Finding | Incidence | |||||
Kidney | neuropathy,hyalinedroplets | 0 | 9 (1.0) | 10 (1.0) | 10 (1.0) | 10 (1.0) | 10 (1.0) |
Spleen | hemosiderin pigment | 0 | 1 (1.0) | 0 | 2 (1.0) | 5 (1.0) | 10 (1.4) |
congestion | 1 (1.0) | 0 | 0 | 1 (1.0) | 0 | 9 (1.0) | |
| Female F344 rats | ||||||
Spleen | Hemosiderin pigment | 1 (1.0) | 9 (1.1) | 10 (1.1) | 10 (1.2)
| 8 (1.5)
| 10 (1.2)
|
| Congestion | 0 | 0 | 0 | 0 | 2 (1.0)
| 9 (1.0)
|
Incidence and severity score ( ) based on a scale of 1 to 4; 1 = minimal, 2 = mild, 3 = moderate, 4 = marked. Severity scores are averages based on the number of animals with lesions from groups of 10
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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