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EC number: 208-704-1 | CAS number: 538-75-0
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- October 2, 1991 - November, 1991.
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 991
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dicyclohexylcarbodiimide
- EC Number:
- 208-704-1
- EC Name:
- Dicyclohexylcarbodiimide
- Cas Number:
- 538-75-0
- Molecular formula:
- C13H22N2
- IUPAC Name:
- N,N'-dicyclohexylcarbodiimide
Constituent 1
- Specific details on test material used for the study:
- - Source: Tama Chemical Industry Co., Ltd.
- Lot: 10705
- Purity of 99.7 %
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan Co., Ltd.
- Age at study initiation: 5 weeks
- Weight at study initiation: 170-197 (males), 137-158 (females)
- Housing: 2 per cage (same sex), in polycarbonate cages (265 W x 426 D x 200 H mm: Tokiwa Scientific Instruments Co., Ltd.) .) laid with animal bedding (Beta chip: Nippon Charles River Co., Ltd.). The cage, feeder and water bottle were sterilised once per week.
- Diet: MF: Oriental Yeast Co., Ltd. ad libitum.
- Water: tap water, irradiated with ultraviolet light and filtered with a 5 µm filter, ad libitum.
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25ºC
- Humidity (%): 40-70%
- Air changes (per hr): 12 times/per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark
IN-LIFE DATES: Obtained on October 2, 1991.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Remarks:
- (Japanese Pharmacopoeia)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Olive oil (Japanese Pharmacopoeia) was added to the test substance, and the mixture was warmed at around 40 ºC and dissolved to a predetermined concentration;
the solution was prepared every 9 days, and it was kept in a cool dark place until immediately before administration.
VEHICLE
- Amount of vehicle (if gavage): the dosing volume was 5 ml/kg, based on the weight at the nearest measurement day.
- Purity: compliant with Japanese Pharmacopoeia standards. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stabilty of the solution (test item in olive oil) was analyzed, and it was confirmed that it was stable for 11 days after preparation, when stored in a cool dark place. No further details provided on the method. Accordingly, the test item solution was prepared every 9 days, and it was kept in a cool dark place until immediately before administration.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily (once in the morning)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 6 males / 6 females per group in 15 mg/kg and 100 mg/kg groups.
12 males / 12 females per group in control and 500 mg/kg group. - Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Dose levels were selected based on a preliminary oral toxicity study. Repeated oral administration of the test substance to SD rats at doses of 125, 250 and 500 mg/kg for 7 days resulted in toxic signs such as salivation, loss of locomotor activity, weight gain suppression, liver weight gain at 500 mg/kg; at 125 and 250 mg/kg, toxic signs such as spontaneous motor activity decrease were also observed. Based on this study, the high dose of this study was 500 mg/kg, the middle dose was 100 mg/kg, and the low dose was 15 mg/kg. In addition to this, a control group (only vehicle) was provided.
- Administration period: 28-days in the three doses-group and control group
- Post-exposure recovery period: 14 days in 6 males / 6 females for control and high dose groups (satellite groups).
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS:
- Time schedule: daily for morbidity, mortality, behaviour (4 weeks for all groups, up to 42 days for both recovery groups).
DETAILED CLINICAL OBSERVATIONS
- Time schedule: detalied observations including palpation once a week (4 weeks for all groups, up to 42 days for both recovery groups).
BODY WEIGHT:
- Time schedule for examinations: at the beginning of treatment and once a week thereafter (4 weeks for all groups, up to 42 days for both recovery groups).
FOOD CONSUMPTION: Food consumption was measured, although it is not a feeding study.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. Food was weighed at the beginning of the treatment and once a week thereafter, and the mean food intake per mouse per period was calculated (4 weeks for all groups, up to 40 days for both recovery groups).
FOOD EFFICIENCY: No.
WATER CONSUMPTION AND COMPOUND INTAKE: Water consumption was measured, although it is not a drinking water study.
- Time schedule for examinations: the tare was measured once a week and compared (4 weeks for all groups, up to 42 days for both recovery groups).
OPHTHALMOSCOPIC EXAMINATION: No.
HAEMATOLOGY:
- Time schedule for collection of blood: suvirval animals at the time of each planned killing (28 or 42 days) were bled from posterior vena cava after anesthesia by pentobarbital sodium (Nembutal injection solution: Dynabot Corporation) intraperitoneally and examined on the following items: red blood and white blood cell count, platelet count, hemoglobin concentration, hematocrit value, leukocyte percentage, reticulocyte count, prothrombin time, activated partial thromboxane plastin time, mean red blood cell volume, mean red blood cell hemoglobin content and mean red blood cell hemoglobin concentration.
CLINICAL CHEMISTRY:
- Time schedule for collection of blood: in the remaining blood used for hematalogical examination the following parameters were examined: total protein, albumin, A/G ratio, glucose, triglyceride, total cholesterol, urea nitrogen, creatinine, calcium, inorganic phosphorus, GOT (AST), GPT (ALT), γ-GTP, ALP, sodium, potassium, chloride.
URINALYSIS:
- Time schedule for collection of urine: fresh urine of the survival animals was collected before the end of the administration period (3 weeks) and on the end of th recovery period. The following parameters were determined: pH, protein, glucose, ketones, bilirubin, urobilinogen, ocult blood, specific gravity, sediment, urine volume, sodium, potassium and chlorine.
NEUROBEHAVIOURAL EXAMINATION: No.
IMMUNOLOGY: No. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes.
Surviving animals, at the time of each planned killing, were exsanguined, sacrificied and necropsied. Dead animals were necropsied as soon as they were found. Brain, liver, kidney, adrenal gland, testis and ovary were weighed.
HISTOPATHOLOGY: Yes.
The following organs were collected, fixed and stored: Harder's glands, brain, pituitary, eyeball (including accessory gland), lung, stomach, thyroid (including parathyroid), heart, liver, spleen, kidney, adrenal gland, bladder, testis or ovary, bone marrow (femur). The testes suspected of being altered, heart, liver, kidney, spleen, adrenal glands and those duodena that had shown changes in the autopsy, were microscopical examined. All the organs that were found abnormal at necropsy were examined too. Examinations were made in all dosing groups. - Statistics:
- The equidistance test by the Bartlett method was performed, one-way ANOVA was performed when the variance was uniform and Kruskal-Wallis test was performed when the variance was not uniform. Where the were significant differences between the groups, the method of Dunnett was applied. For uirne qualtitative test and urine sediments, Armitage's test was used.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced lococmotor activity and salivation were observed in the 500 mg/kg group.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female of the 500 mg/kg group died on day 13 of the administration period and another died on day 4 of the recovery period. Animals showed crouching, prone position, ataxic gait, tiptoe gait, clonic convulsions and gasping before death.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain was reduced in the 500mg/kg males and females group. A recovery tendency was observed in both sexs during the recovery period.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food consumption decreased in 500 mg/kg group (males and females) in the first week of administration, but no signifcant differences were observed after that.
- Water consumption and compound intake (if drinking water study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Water intake was increased in the 500 mg/kg (males and females).
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduction of mean red blood cell hemoglobin level and reduction of prothrombin time was detected in males of the highest dose group. Shortening of activated partial thromboplastin time and increase of platelet count were observed in females (highest dose group).
No change was observed at the end of the recovery period. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A decrease in alkaline phospatase was observed in the 500 mg/kg males group and an increase in potassium in the 500 mg/kg males and females group.
At the end of the recovery period, an increase in alkaline phosphatase was observed in males (500 mg/kg). An increase in inorganic phosphorus in males was observed too, but it was within the physiological variation range. - Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Urine volume tended to increase in both sexes although no significant differences was observed. Urinary pH was increased in the 500 mg/kg females group.
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Males showed an increase in the liver/body weight ratio while females showed an increase in both actual weight and liver/body weight ratio in the 500 mg/kg group. Females in the 500 mg/kg recovery group showed an increase in liver weight but the difference with the control group was reduced. The weight of adrenal glands in females was decreased but there were no differences in the adrenal weight/ body weight ratios.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There was an elargement of the duodenum with thickening of the mucosa in both sexes in the 500 mg/kg group. This change was not observed in the recovery group.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In the surviving animals, changes in the liver and duodenum of the 500 mg / kg group due to the administration of the test substance were observed in both sexes: enlarged hepatocytes around the Glissons capsules, eosinophilic hepatocyte cytoplasm and thickening of the duodenal mucosa.
In addition, fading foci in the kidney cortex, cyst formation, localized yellowing in the liver and brown / dark red spots in the lung were observed in a few cases, but it was considered to be a contingent lesion. - Details on results:
- After the recovery period, histological changes of the liver and duodenum dissapeared and other charged parameters tended to show values almost within the normal range.
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- histopathology: non-neoplastic
Target system / organ toxicity
open allclose all
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 500 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- duodenum
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 500 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- not specified
Any other information on results incl. tables
Table 3. Body weight (group mean values)
|
Days after commencement/cessation of treatment |
|||||||
Dose level (mg/kg) |
|
0 |
7 |
14 |
21 |
28/0 |
35/7 |
42/14 |
MALE |
|
|||||||
0 |
Mean SD N |
185 8.5 12 |
255 14.2 12 |
322 19.4 12 |
382 26.8 12 |
423 34.5 12 |
457 47.3 6 |
484 48.5 6 |
15 |
Mean SD N |
187 6.7 6 |
255 11.3 6 |
319 19.1 6 |
377 27.0 6 |
415 37.8 6 |
- |
- |
100 |
Mean SD N |
186 5.2 6 |
253 6.7 6 |
325 8.7 6 |
383 12.6 6 |
424 13.6 6 |
- |
- |
500 |
Mean SD N |
187 8.4 12 |
239 15.9 12 |
300 22.5 12 |
351 23.9 12 |
368 24.3 12 |
427 23.5 6 |
468 28.1 6 |
FEMALES |
|
|||||||
0 |
Mean SD N |
146 5.4 12 |
176 9.5 12 |
205 13.2 12 |
231 15.4 12 |
249 17.3 12 |
259 21.5 6 |
271 23.6 6 |
15 |
Mean SD N |
145 6.6 6 |
181 8.7 6 |
207 10.8 6 |
233 16.0 6 |
245 13.5 6 |
- |
- |
100 |
Mean SD N |
146 6.1 6 |
182 5.0 6 |
211 5.0 6 |
234 5.4 6 |
251 3.6 6 |
- |
- |
500 |
Mean SD N |
147 4.9 12 |
170 8.5 12 |
196 10.3 11 |
216 13.2 11 |
225 26.6 11 |
250 21.5 4 |
268 15.1 4 |
Table 4. Organ weight and ratio organ weight/body weight (6 animals per group per dose, treatment groups)
Dose level (mg/kg) |
|
Final body weight (g) |
Brain |
Brain/ body weight |
Liver |
Liver/ body weight |
Kidneys |
Kidneys/ body weight |
Adrenals(x10-3) |
Adrenals / body weight |
Testes /Ovaries (x10-3) |
Test-ovar/body weight |
|
|
|
(g) |
% |
(g) |
% |
(g) |
% |
(g) |
% |
(g)/ (mg) |
|
MALE |
|
|
|
|
|
|
|
|
|
|
|
|
0 |
Mean SD |
430 31.3 |
2.00 31.3 |
0.47 0.029 |
18.06 2.234 |
4.19 0.249 |
3.06 0.297 |
0.71 0.054 |
58.3 0.276 |
13.7 1.58 |
3.03 0.276 |
0.71 0.055 |
15 |
Mean SD |
415 37.6 |
1.97 0.089 |
0.48 0.051 |
17.61 2.925 |
4.22 0.316 |
3.01 0.210 |
0.73 0.021 |
61.3 7.57 |
14.8 1.69 |
3.24 0.464 |
0.79 0.178 |
100 |
Mean SD |
424 13.8 |
2.04 0.037 |
0.48 0.024 |
18.20 1.611 |
4.29 0.272 |
3.08 0.225 |
0.73 0.055 |
57.4 7.75 |
13.5 1.49 |
3.10 0.092 |
0.73 0.044 |
500 |
Mean SD |
4386 28.3 |
1.99 0.029 |
0.52 0.043 |
19.58 1.886 |
5.07 * 0.166 |
3.01 0.229 |
0.79 0.068 |
57.2 9.92 |
14.8 1.83 |
3.06 0.178 |
0.80 0.064 |
FEMALE |
|
|
|
|
|
|
|
|
|
|
|
|
0 |
Mean SD |
251 18.0 |
1.92 0.065 |
0.77 0.058 |
9.54 1.031 |
3.60 .0236 |
1.89 0.059 |
0.76 0.056 |
64.9 7.60 |
26.0 3.42 |
95.5 9.64 |
38.1 3.36 |
15 |
Mean SD |
246 13.5 |
1.88 0.053 |
0.77 0.051 |
9.13 0.811 |
3.70 0.194 |
1.85 0.126 |
0.75 0.046 |
68.5 6.76 |
28.0 3.88 |
95.7 13.69 |
38.9 4.75 |
100 |
Mean SD |
251 2.6 |
1.90 0.052 |
0.76 0.024 |
9.62 0.539 |
3.84 0.244 |
1.89 0.258 |
0.76 0.106 |
67.0 6.61 |
26.8 2.78 |
83.3 14.11 |
33.2 5.48 |
500 |
Mean SD |
231 17.3 |
1.84 0.054 |
0.80 0.062 |
12.61* 0.796 |
5.43 * 0.328 |
1.87 0.109 |
0.81 0.039 |
63.9 7.25 |
27.9 4.95 |
86.0 13.53 |
37.2 4.67 |
* Significantly different from control value p < 0.01
Table 5. Organ weight and ratio organ weight/body weight (6 animals per group per dose, recovery groups)
Dose level (mg/kg) |
|
Final body weight |
Brain |
Brain/ body weight |
Liver |
Liver/ body weight |
Kidneys |
Kidneys/ body weight |
Adrenals(x10-3) |
Adrenals / body weight |
Testes /Ovaries (x10-3) |
Test-ovar /body weight |
|
|
(g) |
(g) |
% |
(g) |
% |
(g) |
% |
(g) |
% |
(g)/ (mg) |
|
MALE |
|
|
|
|
|
|
|
|
|
|
|
|
0 |
Mean SD |
485 47.8 |
2.10 0.049 |
0.44 0.039 |
20.80 4.627 |
4.27 0.524 |
3.57 0.314 |
0.74 0.023 |
63.4 9.21 |
13.2 2.29 |
3.36 0.272 |
0.70 0.081 |
500 |
Mean SD |
467 27.8 |
2.11 0.077 |
0.45 0.020 |
20.39 2.464 |
4.35 0.260 |
3.33 0.280 |
0.71 0.028 |
57.1 9.62 |
12.3 2.64 |
3.22 0.245 |
0.69 0.036 |
FEMALE |
|
|
|
|
|
|
|
|
|
|
|
|
0 |
Mean SD |
271 23.7 |
1.9 0.061 |
0.73 0.059 |
10.20 1.640 |
3.75 0.284 |
19.99 0.166 |
0.74 0.056 |
76.7 5.68 |
28.6 4.34 |
110.2 15.88 |
40.7 5.62 |
500 |
Mean SD |
268 15.0 |
1.91 0.043 |
0.71 0.038 |
12.58 0.638* |
4.69 * 0.080 |
1.97 0.137 |
0.74 0.045 |
66.4 * 6.44 |
24.9 3.65 |
113.1 11.99 |
42.2 3.15 |
* Significantly different from control value p < 0.01
Table 6. Total incidence macroscopic and microscopic findings
MACROSCOPIC FINDINGS |
|||||||||||||
|
28 DAYS |
RECOVERY |
|||||||||||
|
SEX |
MALE |
FEMALE |
MALE |
FEMALE |
||||||||
|
DOSE LEVEL (MG/KG) |
0 |
15 |
100 |
500 |
0 |
15 |
100 |
500 |
0 |
500 |
0 |
500 |
ORGAN FINDINGS |
NUMBER OF ANIMALS |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
4 |
Duodenum enlargement |
0 |
0 |
0 |
5 |
0 |
0 |
0 |
4 |
0 |
0 |
0 |
0 |
|
Kidneys Focal discoloration Cyst |
0 0 |
1 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 1 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
|
Liver Focal yellowish change |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
|
Lungs Brownish/dark patch |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
1 |
0 |
0 |
|
MICROSCOPIC FINDINGS |
|||||||||||||
|
28 DAYS |
RECOVERY |
|||||||||||
|
SEX |
MALE |
FEMALE |
MALE |
FEMALE |
||||||||
|
DOSE LEVEL (MG/KG) |
0 |
15 |
100 |
500 |
0 |
15 |
100 |
500 |
0 |
500 |
0 |
500 |
ORGAN FINDINGS |
NUMBER OF ANIMALS |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
6 |
4 |
Liver Enlarged/eosinophilic hepatocytes Neutrophilic infiltration Focal fatty change |
0
0
0 |
0
0
0 |
0
0
0 |
5
0
0 |
0
0
0 |
0
0
0 |
0
0
0 |
6
1
0 |
0
0
1 |
0
0
0 |
0
0
0 |
0
0
0 |
|
Duodenum thickening of mucosa |
0 |
0 |
0 |
5 |
0 |
0 |
0 |
4 |
0 |
0 |
1/5 |
0 |
|
Heart Focal myocardial degeneration |
0 |
- |
- |
1 |
0 |
- |
- |
0 |
- |
- |
- |
- |
|
Kidneys Basophilic change of tubular epithelium Focal linphocytic in interstitium Hyaline droplets in tubular epithelium Cyst |
3
1 0
0
|
0/1
0/1 1/1
0/1
|
-
|
2
0 0
0
|
1
1 0
0
|
-
|
0/1
0/1 0/1
1/1 |
2
2 0
0
|
- |
- |
- |
- |
|
Lungs Focal hemorrhage into alveoli |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
1 |
0 |
0 |
- not examined
Applicant's summary and conclusion
- Conclusions:
- The NOEL was determined to be 100 mg/kg bw/day in male and female rats.
- Executive summary:
A 28-day repeated dose toxicity test was performed according toaccording to the Guidelines on Chemical Substitution Law (1986) (Guideline 28-Day Repeat Dose Toxicity Test of Chemical, Japan), similar to OECD 407 (GLP study). SD (Crj: CD) rats were treated with 0, 15, 100 and 500 mg/kg of the test substance by oral gavage for 28 days. 6 males and 6 females were selected for the groups of 15 and 100 mg/kg and 12 males/12 females for the control and 500 mg/kg groups. After the 28-days treatment, 6 males and 6 females for the control and 500 mg/kg groups were left to study their recovery over a period of 14 days. Animals of both sexes in the 500 mg/kg group showed reduced locomotor activity, salivation, inhibition of body weight gain, decreased food consumption and increased water intake. Two females in the 500 mg/kg dose group died, one during treatment and one during the recovery period. A decrease in alkaline phosphatase was also observed in males in the 500 mg / kg group. Pathological examination revealed increased relative liver weight, enlargement of the duodenum due to mucosal thickening and hepatocellular swelling in both sexes of the higher dose group. Histological changes in the liver and duodenum disappeared due to discontinuation of administration, and other changes also disappeared or showed a recovery tendency after the 14 days post-exposure. No effects were observed in the 100 and 15 mg/kg group in both males and females. Based on the above results, the NOEL under the test conditions was considered to be 100 mg/kg/day in both sexes.
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