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EC number: 476-700-9 | CAS number: 15365-14-7
- 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
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- Additional physico-chemical information
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- Endpoint summary
- Stability
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- 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: dermal
Administrative data
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 August 2014 to 24 March 2016
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- GLP status of study not documented.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- not specified
- Remarks:
- The study was conducted in compliance with Metrology Accreditation of P.R.C.
- Limit test:
- no
Test material
- Test material form:
- solid
- Details on test material:
- - Appearance: black solid
- Storage conditions: at room temperature, kept in a dry place and sealed
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Zhejiang Center of Laboratory Animals, Hangzhou, Zhejiang
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 4 - 5 weeks old
- Weight at study initiation: 186 – 244 g (the intragroup weight variation did not exceed ±10 % of the mean weight between-groups; the intergroup weight variation did not exceed ± 5 % of the mean weight between-groups)
- Housing: animals were housed in pairs, by sex in suspended, wire bottom, stainless steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3 °C
- Humidity (%): 40 - 70 %
- Air changes (per hr): 12 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours darek / 12 hours light
Administration / exposure
- Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Remarks:
- the test material was mixed with distilled water (mass ratio of 1:1.1) to form a paste
- Details on exposure:
- TEST SITE
- Area of exposure: the dorsal surface of the trunk of each animal was clipped free of fur on the day prior to treatment
- % coverage: 10% (minimum)
- Type of wrap if used: the area of application was covered with a cellophane patch and secured with non-irritating adhesive tape. The rats were fixed with rat fixator to prevent possible ingestion of the test material.
- Time intervals for shavings or clipplings: at least once a week
REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was gently washed with tap water
- Time after start of exposure: 6 hours after application
TEST MATERIAL
- For solids, paste formed: yes - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 316 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 2 groups of 15 males and 15 females received applications of 0 (control) and 1000 mg/kg bw/day
2 groups of 10 males and 10 females received applications of 100 and 316 mg/kg bw/day test material - Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale:
Doses were based on the acute dermal LD50 values (> 20000 mg/kg bw/day in male and female rats)
- Post-exposure recovery period in satellite groups: Ten rats (five per sex per group) in the control and high groups (two additional satellite groups) were observed for at least 14 days post treatment, for observation of reversibility or persistence of any toxic effects
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were observed twice daily for signs of morbidity/mortality
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure and at least once a week thereafter
Signs noted included, but not be limited to, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling) or bizarre behaviour (e.g. self-mutilation, walking backwards) were recorded.
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Once before the first exposure and at least once a week thereafter
BODY WEIGHT: Yes
- Time schedule for examinations: prior to the initiation of the study, weekly thereafter, and at death/or sacrifice
FOOD CONSUMPTION: Yes
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule: Ophthalmological examination was made prior to the administration of the test material and at the termination of the study
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the study, blood samples were obtained from abdominal aorta of each rat
- Anaesthetic used for blood collection: Yes (10% chloral hydrate )
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked included: white blood cell (WBC), red blood cell (RBC), haemoglobin (HGB), haematocrit (HCT) , lymphocyte (LYM), granulocyte (GRA) , monocyte (MID), Eosinophil (EOS), basophil (BAS), red blood cell volume distribution width (RDW), platelet (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the study, blood samples were obtained from abdominal aorta of each rat
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked included: total bilirubin (BIL-T), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), globulin (GLB), alkaline phosphatase (ALP), urea nitrogen (BUN), creatinine (CREA), glucose(GLU), potassium (K), sodium (Na), chlorine (Cl), calcium (Ca)
URINALYSIS: Yes
At the end of the study, urinalyses were conducted from each rat and results were read using CF-U180 urine analyser. Parameters measured included appearance (colour and clarity), glucose (uGLU), bilirubin (uBIL), ketone (KET), occult blood (RBC), acidity (PH), protein (PRO), urobilinogen (uBG), nitrite (NIT), and leukocytes (LEU). - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
All animals in the study was subjected to a full, detailed gross necropsy which includes careful examination of the external surface of the body, all orifices, and the cranial, thoracic and abdominal cavities and their contents.
ORGAN WEIGHTS: Yes
The liver, kidneys, adrenals, testes, epididymis, uterus, ovaries, thymus, spleen, brain and heart of all animals were trimmed of any adherent tissue, as appropriate, and their wet weight taken as soon as possible. Organ coefficients were calculated by expressing organ weight as a percentage of body weights.
HISTOPATHOLOGY: Yes
Tissues and organs (all gross lesions, brain, spinal cord, stomach, thyroid, thymus, small and large intestines, pancreas, liver, kidneys, adrenals, spleen, heart, trachea and lungs, gonads, uterus, accessory sex organs, prostate, urinary bladder, lymph nodes, peripheral nerve, bone marrow, skin) samples from control and treated rats were cut into thin slices, and then fixed into 4% formaldehyde for more than one week. The tissues and organs were then processed through a graded series of ethanol and xylene, and embedded in paraffin. Organs and tissues sections were stained with hematoxylin and eosin (H&E) for histopathological examination under a microscope. - Statistics:
- A parametric or non-parametric test was selected based on the results of normality test and homogeneity of variance test. One-way analysis of variance and Dunnett’s t test were used in parameter test. Kruskal-Wallis rank sum test and Wilcoxon-Wilcox rank sum test were used in non-parametric test. Student’s t test was adopted by comparing data between additional high dose and additional control group, or nonparametric Wilcoxon test. Fisher's exact probability test was used for enumeration data. The BMDS2.50 (US EPA) software was used to calculate benchmark dose.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- no systemic clinic signs were observed throughout the study period.
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- During exposure period, erythema and scab were observed on the skin of rats in animals of the high dose group (15 males and 15 females), intermediate dose group (8 males and 8 females), and in the low dose group (2 males and 5 females). Compared with the control group, there were statistically significant differences in all groups of rats except for the low dose group of male rats. Skin irritation symptoms in the high dose group disappeared 7 days later after exposure ended.
No oedema was noted. - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- During exposure period, for male rats, body weight gains in the low and high dose group was lower than the control group, the differences both had statistical significance (p < 0.05), but with no obvious dose-effect relationship (Spearman rank correlation: correlation coefficient rs = 0.2283, p = 0.1920).
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No effects on food consumption were noted during the exposure period or during the recovery period.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- Ophthalmological examination was made prior to the administration of the test material and at the termination of the study. The results showed that no abnormal changes were found in each dose group for males and females.
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At the end of exposure period, for female rats, WBC, GRA, EOS, BAS of the high dose group animals were higher than for the animals in the control group, LYM, PT of high dose group were lower than the control group; for male rats, RDW, APTT of high dose group was higher than the control group, WBC was lower than the control group (p < 0.05).
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- For female rats, GLU of low dose group was increased, Cl-, Na+ of the intermediate dose group were increased and ALB, A/G were decreased; Cl-, Na+, Ca+ of high dose group were increased and ALB, A/G were decreased at the end of the exposure; ALB,Cl-, Na+, Ca+ of high dose group were increased and A/G was decreased at the end of additional observation. For male rats, AST, ALT of low dose group were increased and Ca+ was decreased, ALT, Cl-, Na+, BUN of high dose group were increased at the end of the exposure; A/G of high dose group were decreased and ALB was increased at the end of additional observation, the differences had statistical significance, but no obvious dose-effect relationship and/or biological significance were found.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- Compared the treatment groups with the control group, the differences had no significance (p > 0.05).
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At the end of exposure period, for female rats, the organ weight and the organ coefficient (liver, adrenal) of high dose group were higher than control group, the differences both had statistical significance (p < 0.05). In addition, the organ coefficient of the brain in the low dose group was higher than in the control group, the differences had statistical significance (p < 0.05), but no obvious dose-effect relationship was found.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities were observed at gross necropsy.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No abnormal changes were observed in any treated groups compared with the control group.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
open allclose all
- Dose descriptor:
- BMDL10
- Effect level:
- 11.35 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- dermal irritation
- Dose descriptor:
- BMDL10
- Effect level:
- 15.41 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- dermal irritation
- Dose descriptor:
- NOAEL
- Remarks:
- systemic effects
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical biochemistry
- Dose descriptor:
- NOAEL
- Remarks:
- systemic effects
- Effect level:
- 316 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical biochemistry
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 1: The statistics of local skin irritation signs
Sex |
Group |
Number |
erythema, scab |
||
Number |
|
average credit |
|||
Female |
Control |
15 |
0 |
|
0.00 ± 0.00 |
|
Low dose |
10 |
5# |
|
1.10 ± 1.16* |
|
Intermediate dose |
10 |
8# |
|
2.17 ± 1.15* |
|
High dose |
15 |
15# |
|
3.32 ± 0.15* |
Male |
Control |
15 |
0 |
|
0.00 ± 0.00 |
|
Low dose |
10 |
2 |
|
0.19 ± 0.52 |
|
Intermediate dose |
10 |
8# |
|
1.69 ± 1.17* |
|
High dose |
15 |
15# |
|
3.09 ± 0.35* |
Note:
# Fisher probabilities, compared with the control group, P < 0.0170
*Dunnett’s t test,compared with the control group, P < 0.05
Table 2: Skin irritation (erythema) gradings
Number |
Sex |
Group |
Observation time(week) |
|||||||||||||||||
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
17 |
|||
F1 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F2 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F3 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F4 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F5 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F6 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F7 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F8 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F9 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F12 |
Female |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F13 |
Female |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
F14 |
Female |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
F15 |
Female |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
F16 |
Female |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
F17 |
Female |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
F18 |
Female |
Low |
0 |
0 |
0 |
0 |
1 |
1 |
1 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F19 |
Female |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F23 |
Female |
Low |
0 |
0 |
0 |
1 |
1 |
1 |
2 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F24 |
Female |
Low |
0 |
0 |
0 |
0 |
1 |
1 |
2 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F25 |
Female |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F26 |
Female |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F27 |
Female |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F28 |
Female |
Low |
0 |
0 |
0 |
1 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F29 |
Female |
Low |
0 |
0 |
0 |
0 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F34 |
Female |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
Number |
Sex |
Group |
Observation time(week) |
|||||||||||||||||
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
17 |
|||
F35 |
Female |
Intermediate |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F36 |
Female |
Intermediate |
0 |
0 |
1 |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F37 |
Female |
Intermediate |
0 |
0 |
1 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F38 |
Female |
Intermediate |
0 |
0 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F39 |
Female |
Intermediate |
0 |
0 |
0 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F45 |
Female |
Intermediate |
0 |
0 |
1 |
1 |
0 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F46 |
Female |
Intermediate |
0 |
0 |
0 |
2 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F47 |
Female |
Intermediate |
0 |
0 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F48 |
Female |
Intermediate |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
F49 |
Female |
Intermediate |
0 |
0 |
1 |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F56 |
Female |
high |
0 |
2 |
1 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F57 |
Female |
high |
0 |
2 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F58 |
Female |
high |
0 |
2 |
1 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F59 |
Female |
high |
0 |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F67 |
Female |
high |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F68 |
Female |
high |
0 |
0 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F69 |
Female |
high |
0 |
1 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F78 |
Female |
high |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F79 |
Female |
high |
0 |
0 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F89 |
Female |
high |
0 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
F123 |
Female |
Additional high |
0 |
1 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
F124 |
Female |
Additional high |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
F125 |
Female |
Additional high |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
F126 |
Female |
Additional high |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
F127 |
Female |
Additional high |
0 |
0 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
Number |
Sex |
Group |
Observation time(week) |
|||||||||||||||||
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
17 |
|||
M1 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M2 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M3 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M4 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M5 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M6 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M7 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M8 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M9 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M12 |
Male |
Control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M13 |
Male |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
M14 |
Male |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
M15 |
Male |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
M16 |
Male |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
M17 |
Male |
Additional control |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
M18 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M19 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M23 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M24 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
1 |
3 |
3 |
3 |
4 |
4 |
4 |
- |
- |
- |
- |
M25 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M26 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M27 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M28 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M29 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M34 |
Male |
Low |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
Number |
Sex |
Group |
Observation time(week) |
|||||||||||||||||
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
16 |
17 |
|||
M35 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
0 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M36 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
0 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M37 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M38 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
1 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M39 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M45 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M46 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M47 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
2 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M48 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
0 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M49 |
Male |
Intermediate |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
- |
- |
- |
- |
M56 |
Male |
high |
0 |
0 |
0 |
1 |
1 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M57 |
Male |
high |
0 |
0 |
0 |
1 |
1 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M58 |
Male |
high |
0 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M59 |
Male |
high |
0 |
0 |
1 |
2 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M67 |
Male |
high |
0 |
1 |
2 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M68 |
Male |
high |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M69 |
Male |
high |
0 |
1 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M78 |
Male |
high |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M79 |
Male |
high |
0 |
0 |
1 |
3 |
3 |
3 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M89 |
Male |
high |
0 |
0 |
1 |
2 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
- |
- |
- |
- |
M123 |
Male |
Additional high |
0 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
M124 |
Male |
Additional high |
0 |
0 |
0 |
1 |
1 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
M125 |
Male |
Additional high |
0 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
M126 |
Male |
Additional high |
0 |
0 |
0 |
2 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
M127 |
Male |
Additional high |
0 |
0 |
0 |
3 |
1 |
2 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
0 |
0 |
0 |
0 |
Applicant's summary and conclusion
- Conclusions:
- The BMDS2.50 (US EPA) software was used to calculate the benchmark dose which was considered to be a suitable replacement to a NOAEL value. Under the conditions of the study the BMDL of the test material in female and male rats were 11.35 mg/kg bw/day and 15.41 mg/kg bw/day, respectively.
- Executive summary:
The repeated dose toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guideline OECD 411.
During the study 50 Sprague Dawley rats per sex were randomly assigned to four groups: one control group, one low dose group, one intermediate dose group and one high dose group representating test material concentrations of 0.0, 100.0, 316.0, 1000.0mg/kg, respectively. All test animals were exposed to test material and observed for 90 days. Ten rats (five per sex per group) in the control and high groups (two additional satellite groups) were observed for at least 14 days post treatment, for observation of reversibility or persistence of any toxic effects. Clinical signs, mortality, food consumption and body weight change were evaluated. When the study was terminated, urinalyses, gross necropsy, haematology, clinical biochemistry and histopathology were carried out.
Compared with the control group, for female rats the intermediate dose group, Cl- and Na+ were increased while ALB, A/G were decreased. In the high dose group, for female rats, WBC, GRA, EOS, BAS, Cl-, Na+, Ca+, organ weight and organ coefficient (liver, adrenal) were increased, LYM, PT, ALB, A/G were decreased at the end of the exposure period, Cl-, Na+, Ca+ were increased, total food efficiency, A/G were decreased at the end of additional observation period; for male rats, RDW,APTT, Cl-, Na+, BUN were increased, WBC was decreased at the end of exposure period, A/G was decreased at the end of additional observation day. During exposure period,erythema and scab were observed on the skin of rats in the high dose group(15 males and 15 females, the average score of male rats was 3.09 and female rats was 3.32), in intermediate dose group (8 males and 8 females, the average score of male rats was 1.69 and female rats was 2.17), and in the low dose group (2 males and 5 females, the average score of male rats was 0.19 and female rats was 1.10). Compared with the control group, there were statistically significant differences in all groups of rats except low dose group of male rats.Skin irritation symptoms in the high dose group disappeared 7 days later after exposure finished. During exposure and additional 28-day observation period, no systemic clinic signs were observed in rats. There were no abnormal changesin each dose group for males and females on ophthalmological examination prior to the administration of the test material and at the termination of the study. Compared with the control, there was no statistical significance in any treated groups on gross anatomy. At the end of exposure or additional 14-days, no significant histopathological changes were observed in any treated groups compared with control group.
The systemic NOEL was 100 mg/kg bw/day. For local skin irritation effects, the BMDS2.50 (US EPA) software was used to calculate the benchmark dose which was considered to be a suitable replacement to a NOAEL value. Under the conditions of the study the BMDL of the test material in female and male rats were 11.35 mg/kg bw/day and 15.41 mg/kg bw/day, respectively.
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

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