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EC number: 253-775-4 | CAS number: 38083-17-9
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1977-02 to 1977-05
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was conducted according to a method comparable to the former OECD guideline 408 and was performed prior to the implementation of GLP.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 978
- Report date:
- 1978
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:
- not specified
- Principles of method if other than guideline:
- Male and female Wistar rats (each 15 males and females) received daily oral doses of the test item at dose levels of 5, 15, and 45 mg/kg in 0.5% aqueous Tylose via gavage for 3 months (90 d). Animals were observed for general symptoms and food and water consumption as well as body weight gains were recorded. Additionally, blood and urine samples were analyzed after 6 weeks and at the end of the study, and the animals were subjected to gross pathology and histopathology after termination of the study.
- GLP compliance:
- no
- Remarks:
- the study was conducted prior to the implementation of GLP
- Limit test:
- no
Test material
- Reference substance name:
- Climbazole
- EC Number:
- 253-775-4
- EC Name:
- Climbazole
- Cas Number:
- 38083-17-9
- Molecular formula:
- C15H17ClN2O2
- IUPAC Name:
- 1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethylbutan-2-one
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Breeder Winkelmann (Borchen, Germany)
- Age at study initiation: 42-49 d
- Weight at study initiation: Males: 119-122 g, females: 115-118 g
- Housing: Animals were housed in Makrolon cages (type II) on dust-free wood granulate.
- Diet: Altromin R powder (Altromin GmbH, Lage, Germany), ad libitum
- Water: Tap water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature: 23±2°C
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% aqueous Tylose
- Details on oral exposure:
- VEHICLE
- Amount of vehicle: 10 mL/kg - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- not applicable
- Duration of treatment / exposure:
- Animals were treated for 3 months (90 d).
- Frequency of treatment:
- Animals were treated daily (7 d per week) for 3 months (90 d).
Doses / concentrations
- Remarks:
- Doses / Concentrations:
5, 15, and 45 mg/kg
Basis:
actual ingested
- No. of animals per sex per dose:
- 15 males and 15 females were used per dose level.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Male and female animals were seperately assigned to 3 body weight groups (light, intermediate, and heavy) and were then randomised.
- Positive control:
- No positive control was used.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD ANd WATER CONSUMPTION:
- Food and water comsumption was weekly recorded by back-weighting.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 6 weeks and 3 months
- Anaesthetic used for blood collection: Yes (diethyl ether)
- How many animals: 5 males and 5 females from each of the groups
- Parameters examined: Numbers of erythrocytes, leukozytes, thrombocytes, and reticulocytes, haemoglobin content, heamatocrit, differential haemogram, MCH, and MCV
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 6 weeks and 3 months
- Anaesthetic used for blood collection: Yes (diethyl ether)
- How many animals: 5 males and 5 females from each the control an the high-dose group
- Parameters examined: Alkaline phosphatase (ALP), glutamate-oxaloactetate-transaminase (GOT), glutamate-oxaloactetate-transaminase (GPT), creatinine, urea, glucose, cholesterol, bilirubin, total protein content, triglycerides in the blood, triglycerides in the liver
URINALYSIS: Yes
- Time schedule for collection of urine: At 6 weeks and 3 months
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: semiquantitative: Glucose, blood, protein, pH, ketone bodies, bilirubin and urobilinogen; quantitative: protein; microscopic examination of the urine sediment after centrifugation
NEUROBEHAVIOURAL EXAMINATION: No
ORGAN WEIGHTS:
The following organs of animals that died during the study or were sacrificied at study termination were weighed: Thyroid gland, thymus, heart, lung, liver, spleen, kidneys, adrenal glands, and testes or ovaries. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- All animals that died were subjected to necropsy. At termination of the study, all other animals were sacrificed and examined by necropsy.
HISTOPATHOLOGY: Yes
- Histopathological examinations were performed on 10 animals each of the control and the high-dose group. The following organs were examined: Aorta, eyes, small intestine (doudenum, jejunum, ileum, and colon), femur, brain, bladder, heart, testes, pituitary gland, liver, lung, lymph nodes, stomach, spleen, epididymes, adrenal glands, kidneys, oesophagus, skeletal muscles, sternum, thymus, trachea, ovaries, pancreas, prostate, seminal vesicles, thyroid gland, and uterus as well as all tissues that showed macroscopic changes. - Other examinations:
- not applicable
- Statistics:
- Arithmetic group mean values, standard deviations as well as upper and lower confidence limits for p = 0.05 and p = 0.01 were calculated. Values for the treated groups were compared to those of the control group and differences were tested for significance using the U-test of Mann, Whitney, and Willcoxon for p = 0.05 and p = 0.01. These calculations were performed on an IBM-370/145 computer.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- see section "Details on results"
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- see section "Details on results"
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see section "Details on results"
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see section "Details on results"
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see section "Details on results"
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- see section "Details on results"
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- BODY WEIGHT AND WEIGHT GAIN
Males of the high-dose group showed a slight reduction in body weight gain, which became significant (p<0.05) from the 10th week onwards (see the image attached below).
WATER CONSUMPTION
Water consumption was slightly increased in males of the high-dose group (see table 1 in section "Any other information on results including tables").
HAEMATOLOGY
The haematologic examinations did not reveal any significant differences from the untreated control except for a statistically significant (p<0.01) reduction in the number of erythrocytes observed in males of the high-dose group at the end of the study (see table 2 in section "Any other information on results including tables"). This reduction in erythrocyte counts was not considered treatment-related, as the observed values still fell wthin the naturally occurring variation (i.e. 6.50 to 8.82 mill. erythrocytes/mL, as determined in 89 rats of the same age as the test animals).
CLINICAL CHEMISTRY
When evaluated at 6 weeks after inititation of the study, no significant differences in the parameters examined were noted, apart from a significant (p<0.01) reduction in creatinine levels observed in males of the high-dose group (see table 3 in section "Any other information on results including tables"). The reduction in creatinine levels were not regarded as a sign of kidney damage, as renal failure should result in an increase rather than in a decrease in creatinine levels, and the creatinine levels obseved in this study still fell wthin the naturally occurring variation (i.e. 0.52 to 0.88 mg/100 mL for males and 0.49 to 0.97 mg/100 mL for females, as determined in 135 untreated rats of the same age as the test animals).
When evaluated at the end of the study, the activity of alkaline phosphatase was significantly reduced in males and females of all treated groups (with p<0.05 for the low-dose and mid-dose groups and p<0.01 for the high-dose groups) (see table 4 in section "Any other information on results including tables"). This effect was found to be dose-related but was not considered an adverse effect, as the observed values still fell wthin the naturally occurring variation (i.e. 91 to 479 mU/mL, as determined in 135 untreated female rats of the same age as the test animals).
Furthermore, the activity of N-demethylase was significantly (p<0.01) increased in livers of males of the high-dose group, and the content of CYP-450 isoenzymes was significantly (p<0.05) increased in the livers of females of the high-dose group (see table 5 in section "Any other information on results including tables"). These changes were not considered adverse effects but the result of physiological adaptation processes or a result of the stimulation of the microsomal enzyme system.
URINALYSIS
When evaluated after 6 weeks after inititation of the study, urinary protein contents were significantly (p<0.05) elevated in males of the high-dose group (see table 6 in section "Any other information on results including tables"). However, no such observations were made during the evaluation at the end of the study. The elevation in urinary protein content was not considered indicative of kidney damage, as no other adverse renal effects were observed in this study and urinary protein content values generally show a wide variation.
ORGAN WEIGHTS
A significant (p<0.01) increase in liver weights was observed in females of the mid-dose and the high-dose group (see table 7 in section "Any other information on results including tables").
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 45 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Water intake of male rats
Dose (mg/kg/d) |
Average water intake |
|
L/animal |
mL/animal/d |
|
0 |
2.32 |
25.48 |
5 |
2.45 |
26.89 |
15 |
2.39 |
26.21 |
45 |
2.51 |
27.56 |
Table 2: Numbers of erythrocytes in blood of male rats at the end of the study
Dose (mg/kg/d) |
Number of erythrocytes |
0 |
8.62 |
5 |
8.41 |
15 |
8.54 |
45 |
7.94* |
* = p<0.01
Table 3: Creatinine levels in blood of male rats at 6 weeks
Dose (mg/kg/d) |
Creatinine levels |
0 |
0.73 |
5 |
0.67 |
15 |
0.63 |
45 |
0.58* |
* = p<0.01
Table 4: Alkaline phosphatase activity and creatinine levels and in blood of male and female rats at the end of the study
Dose (mg/kg/d) |
Alkaline phosphatase activity |
Creatinine levels |
||
males |
females |
males |
females |
|
0 |
199 |
198 |
0.75 |
0.64 |
5 |
221 |
174* |
0.71* |
0.67 |
15 |
276** |
171* |
0.69 |
0.60* |
45 |
233 |
147** |
0.64** |
0.58** |
* = p<0.05; ** = p<0.01
Table 5: Content of N-demethylase in the livers of male rats and content of CYP-450 isoenzymes in the livers of female rats at the end of the study
Dose (mg/kg/d) |
N-Demethylase |
CYP-450 isoenzymes |
males |
females |
|
0 |
88 |
31 |
5 |
92 |
31 |
15 |
108 |
29 |
45 |
150** |
37* |
* = p<0.05; ** = p<0.01
Table 6: Content of protein in the livers of male rats after 6 weeks
Dose (mg/kg/d) |
Protein |
0 |
68.5 |
5 |
71.1 |
15 |
74.9 |
45 |
105.9* |
* = p<0.05
Table 7: Liver weigths of female rats
Dose (mg/kg/d) |
Average liver weights |
0 |
6925 |
5 |
7298 |
15 |
7720* |
45 |
8232* |
* = p<0.01
Applicant's summary and conclusion
- Conclusions:
- In a 90-day study, male and female Wistar rats received daily oral doses of the test item at dose levels of 5, 15, and 45 mg/kg in 0.5% aqueous Tylose. A NOAEL of 45 mg/kg bw/day was derived. At this dose only a slight decrease of body weights in males was observed. Females showed an increase in liver weight of less than 20% compared to controls at 45 and 15 mg/kg bw/day that - in the absence of any histopathological or relevant clinical chemistry alterations - was considered an adaptive response.
- Executive summary:
Male and female Wistar rats (each 15 males and females) received daily oral doses of the test item at dose levels of 5, 15, and 45 mg/kg in 0.5% aqueous Tylose via gavage for 3 months (90 d). There was no effect on survival and no treatment-related clinical symptoms were observed. In males treated with the test item at a dose level of 45 mg/kg, a reduction in body weight compared to controls was observed which became statistically significant from the 10th week of treatment onwards. However, the body weight decrease was less than 0% compared to controls. No effects on body weight was found in females. At all doses there was a tendency for a reduced alkaline phosphatase activity in serum in females, while there was a slight increase in males. GOT and GPT transaminases were slightly lower in females of the low and mid dose groups. Creatinine tended to be lower (sometimes statistically significant) at all doses in males and females. In both sexes a slight increase in activity and protein content of Cytochrom P450 monooxygenases was found. Erythrocyte numbers were slightly, but statistically significantly reduced. In the absence of any corresponding histological findings, these effects on hematological and clinical chemistry parameters were not considered toxicologically relevant. The liver weights were significantly increased in females at the mid and high dose levels. However, increases were less than 20% compared to controls and in the absence of any histopathological alterations were considered to be an adaptive response. The results of the gross pathological and histopathological examinations did not reveal any indication of treatment-induced alterations. Based on these findings, a NOAEL of 45 mg/kg bw/day was derived.
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