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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://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1976-11-03 to 1976-11-24
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was performed in a manner similar to OECD TG 412 and was scientifically sound and is well documented. However, compared to today's standards, it shows shortcomings in the number of organs and parameters examined.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 977
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- yes
- Remarks:
- , shortcomings in the number of organs and parameters examined
- GLP compliance:
- no
- Remarks:
- pre-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)
- Exactly identification: SPF-Albino rats, Wistar II
- Age at study initiation: 8-9 weeks
- Weight at study initiation: Males: 162-164 g, females: 164-166 g
- Fasting period before study: No data
- Housing: Macrolon cage Type III (5 animals per cage)
- Diet: Altromin-R-standard feed, ad libitum
- Water: Ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Humidity (%): No data
- Air changes (per h): Artifical air circulation
- Photoperiod (h dark / h light): 12/12
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: Ehtanol/polyethylene glycol 400 (1:1)
- Remarks on MMAD:
- MMAD / GSD: 97% of the particles: 1.0 +/- 0.5 µm
3% of the particles: < 5.0 µm - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Dynamic inhalation apparatuses (Kimmerle & Eben (1973, Arch Toxicol 30:115)
- Method of particle size determination: Measurement with cascade impactor
VEHICLE
- Composition of vehicle: Ethanol/polyethylene glycol 400
- Concentration of test material in vehicle: 50%
- Purity of vehicle: No data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The atomized spray from the inhalation air was adsorbed on cotton wool and then eluted with benzene. The active substance was determined by gas chromatography with the help of a thermo-ionical nitrogen detector.
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week, 3 weeks
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
17.2 (13.5-21.0) mg/m3
Basis:
analytical conc.
- Remarks:
- Doses / Concentrations:
44.3 (39.5-48.0) mg/m3
Basis:
analytical conc.
- Remarks:
- Doses / Concentrations:
104.7 (92.7-133.5) mg/m3
Basis:
analytical conc.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Animal assignment: randomly
- Negative control: ethanol/polyethylene glycol (20mL/m3) - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 24 h after the last exposure (directly after section)
- Groups that were examined: All dose groups + negative control group, 5 males and 5 females per group
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: No
FOOD EFFICIENCY: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 24 h after the last exposure (directly after section)
- Groups that were examined: All groups, 5 males and 5 females per group
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- Parameters examined: Haematocrit; haemoglobin; No. of erythrocytes, leukocytes, and thrombocytes; differential haemogram
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 24 h after the last exposure (directly after section)
- Groups that were examined: all groups, 5 males and 5 females per group
- Animals fasted: No
- Parameters examined: GPT (Glutamate-Pyruvate-Transaminase), GOT (Glutamate-Oxalacetate-Transaminase), alkaline phosphatase, urea, creatinine, and glucose
URINALYSIS: Yes
- Time schedule for collection of urine: After the last exposure the urin was collected over 6 h during daytime
- Groups that were examined: All groups, 5 males and 5 females per group
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters examined: pH; content of glucose, protein, blood, bilirubin, and urobilinogen
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Weekly
- Dose groups that were examined: All groups
- Battery of functions tested: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
- Examined material: Liver, kidney, adrenal glands, heart, lung, thyroid glands, lymph nodes, spleen, testes, ovaries, trachea, larynx, oesophagus, stomach, and smears of bone marrow - Statistics:
- The statistical evaluation of the results was performed according to the Wilcoxon rank-sum test (Wilcoxon (1947) Biometrics 3:119).
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 Details on results
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see Details on results
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see Details on results
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- see Details on results
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- see Details on results
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- BODY WEIGHT AND WEIGHT GAIN
The body weight increase of the males, treated with the highest dose of crinipan (MEB 6401) was significantly decreased after 1 week of exposure until the end of the test (see Tables 1 and 4a). The body weights of the female rats were all in accordance with the physiological norm.
HAEMATOLOGY
The Nos. of leukocytes were significantly increased in males treated with 17.2 and 44.3 mg/m3. The evaluation of the differential haemograms did not show any sign of a percental shift in males of the 17.2 mg/m3 dose group; however, in the 44.3 mg/m3 group, a slight increase in the No. of segmented cells and a decrease in the No. of lymphocytes was observed. In female rats a significant increase in the No. in erythrocytes and haemoglobin in the group treated with 44.3 mg/m3 and a significant decrease in the No. of thrombocytes in the highest dose group was observed. Furthermore, an increase in the No. of lymphocytes and a decrease in the No. of segmented neutrophils were determined in the lowest dose group (17.2 mg/m3) (see Table 2).
CLINICAL CHEMISTRY
The values of GOT, GPT, and urea were all in the range of the physiological norm. However, a significant decrease of the creatinine values were observed in all treated male rats. In female rats, the values of alkaline phosphatase were decreased (compared to the controls) in the 44.3 mg/m3-dose group and the glucose values were significantly decreased in the two highest dose groups (see Table 3).
ORGAN WEIGHTS
Significant, but concentration-independent and randomly occurring differences in organ weights of the treated animals compared to that of the control group were observed in several organs. Males, treated with the lowest dose of crinipan showed increased absolute kidney weights and males treated with the highest dose showed decreased absolute weights of the hearts and decreased relative weights of lungs, livers, and testes (see Table 4a). In case of the female rats, animals of the highest dose group showed significantly increased absolute and relative weights of livers and adrenal glands. Concentration-dependently increased relative weights of thyroid glands were observed in male rats, treated with >/= 44.3 mg/m3 (see Table 4b).
HISTOPATHOLOGY: NON-NEOPLASTIC
Light-microscopically no pathological findings indicating for an organ-harming effect of crinipan (MEB 6401) were observed. The above-mentioned clinical findings (significant different weights of livers and adrenal glands) observed in the animals treated with the highest dose of crinipan were not microscopically verified. Some minor random findings was observed, as can be seen in Table 5.
In the smears of bone marrow, the following findings were observed in the treated animals compared to the control: In the highest dose group a slight increase in segmented leukocytes and a slight decrease of basophile cells. The fraction of eosinophil cells varied. Alltogether, there were hardly any differences observable.
Effect levels
- Dose descriptor:
- NOAEC
- Effect level:
- 44.3 mg/m³ air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: slightly decreased body weight in males and slight changes in organ weights in males and females, without any histopathological alterations.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1 Summarized body weight (bw) data of male rats
test week |
0 |
1 |
2 |
3 |
||
Dose [mg/m3] |
0 |
mean bw |
164 |
179 |
196 |
208 |
17.2 |
mean bw |
163 |
180 |
201 |
213 |
|
p<0.05 |
- |
- |
- |
- |
||
p<0.01 |
- |
- |
- |
- |
||
44.3 |
mean bw |
164 |
175 |
191 |
202 |
|
p<0.05 |
- |
- |
- |
- |
||
p<0.01 |
- |
- |
- |
- |
||
104.7 |
mean bw |
162 |
169 |
183 |
194 |
|
p<0.05 |
- |
+ |
- |
+ |
||
p<0.01 |
- |
+ |
+ |
+ |
Table 2 Summarized results of the examination of the haematological examinations (only parameters included with significantly
different values in any of the treated groups compared to the control)
Parameter (unit) |
No. of leukocytes (mio/µL) |
Haemoglobin (G/100 mL) |
Segmented cells |
Lymphocytes (% of all blood cells) |
||||
Sex (male (m); female (f) |
m |
w |
m |
f |
m |
f |
||
Dose (mg/m3)
|
0 |
mean w |
8.5 |
14.8 |
8.6 |
13.8 |
90.6 |
85.6 |
17.2 |
mean w |
10.0 |
14.3 |
14.8 |
6.2 |
84.8 |
93.6 |
|
p<0.05 |
- |
- |
- |
- |
- |
- |
||
p<0.01 |
+ |
- |
- |
+ |
- |
+ |
||
44.3 |
mean w |
11.6 |
15.4 |
19.2 |
14.4 |
80.4 |
84.8 |
|
p<0.05 |
- |
- |
+ |
- |
+ |
- |
||
p<0.01 |
+ |
+ |
+ |
- |
+ |
- |
||
104.7 |
mean w |
9.7 |
15.3 |
12.8 |
15.2 |
86.2 |
83.6 |
|
p<0.05 |
- |
- |
- |
- |
- |
- |
||
p<0.01 |
- |
- |
- |
- |
- |
- |
Table 3 Summarized results of the clinico-chemical examinations (only parameters included the values of which were
significantlydifferentin any treated group compared to the control group)
Parameter (unit) |
Creatinine (mg/100 mL) |
ALP* (mU/mL) |
Glucose (mg/100 mL) |
||
Sex (male (m); female (f) |
m |
f |
f |
||
Dose [mg/m3]
|
0 |
mean w |
0.77 |
257 |
97.4 |
17.2 |
mean w |
0.66 |
249 |
91.2 |
|
p<0.05 |
+ |
- |
- |
||
p<0.01 |
+ |
- |
- |
||
44.3 |
mean w |
0.67 |
225 |
90.7 |
|
p<0.05 |
+ |
- |
+ |
||
p<0.01 |
+ |
+ |
+ |
||
104.7 |
mean w |
0.60 |
267 |
89.8 |
|
p<0.05 |
+ |
- |
- |
||
p<0.01 |
+ |
- |
+ |
* ALP: alkaline phosphatase
Table 4a Summarized data of organ weights (w) for male rats (only organs included with significantly different weights in any of
the treated groups compared to the control)
Organ |
Body weight gain |
Thyroid glands |
Heart |
Lung |
Liver |
Kidney |
||||||||
Relative(r) / absolute (a) organ weight |
a |
r |
a |
r |
a |
r |
a |
r |
a |
r |
a |
r |
||
Dose [mg/m3]
|
0 |
mean w (g) |
208 |
208 |
* |
5 |
647 |
* |
* |
411 |
* |
3735 |
1271 |
* |
17.2 |
mean w (g) |
213 |
213 |
* |
5 |
683 |
* |
* |
424 |
* |
3886 |
1358 |
* |
|
p<0.05 |
- |
- |
* |
- |
- |
* |
* |
- |
* |
- |
- |
* |
||
p<0.01 |
- |
- |
* |
- |
- |
* |
* |
- |
* |
- |
+ |
* |
||
44.3 |
mean w (g) |
202 |
292 |
* |
6 |
609 |
* |
* |
427 |
* |
3906 |
1268 |
* |
|
p<0.05 |
- |
- |
* |
- |
- |
* |
* |
- |
* |
- |
- |
* |
||
p<0.01 |
- |
- |
* |
+ |
- |
* |
* |
- |
* |
- |
- |
* |
||
104.7 |
mean w (g) |
194 |
194 |
* |
6 |
592 |
* |
* |
445 |
* |
4186 |
1228 |
* |
|
p<0.05 |
+ |
+ |
* |
- |
- |
* |
* |
- |
* |
+ |
- |
* |
||
p<0.01 |
+ |
+ |
* |
+ |
+ |
* |
* |
+ |
* |
+ |
- |
* |
Table 4a Summarized data of organ weights (w) for female rats (only organs included with
significantly different weights in any of the treated groups compares to the control)
Organ |
Liver |
Adrenal glands |
||||
Relative(r) / absolute (a) organ weight |
a |
r |
a |
r |
||
Dose [mg/m3]
|
0 |
mean w (g) |
6250 |
3529 |
50 |
28 |
17.2 |
mean w (g) |
6279 |
3557 |
54 |
31 |
|
p<0.05 |
- |
- |
- |
- |
||
p<0.01 |
- |
- |
- |
- |
||
44.3 |
mean w (g) |
6145 |
3582 |
53 |
31 |
|
p<0.05 |
- |
- |
- |
- |
||
p<0.01 |
- |
- |
- |
- |
||
104.7 |
mean w (g) |
6962 |
4058 |
60 |
35 |
|
p<0.05 |
- |
+ |
- |
+ |
||
p<0.01 |
+ |
+ |
+ |
+ |
Table 5 Summarized results from the histopathological examinations (only organs included with findings
different from the control in any of the treated groups)
Dose (mg/m3) |
Animal No. |
Organ, taken from male (m) or female (f) animals |
|||||||
Larynx |
Trachea |
Heart |
Lung |
||||||
m |
f |
m |
f |
m |
f |
m |
f |
||
Control |
1 |
Oe+ |
o |
o |
Ez + |
o |
o |
o |
Ez 1 |
2 |
o |
o |
Ez + |
o |
o |
o |
Sch + |
o |
|
3 |
o |
o |
o |
o |
o |
o |
Gran + |
o |
|
4 |
o |
o |
o |
o |
o |
N 1 |
o |
pbRu + |
|
5 |
o |
o |
o |
o |
o |
o |
pvRu 1 |
pbRu + |
|
17.2 |
1 |
o |
o |
o |
o |
o |
o |
o |
o |
2 |
o |
o |
o |
o |
o |
o |
o |
o |
|
3 |
o |
o |
o |
o |
o |
o |
Gran 1 |
o |
|
4 |
o |
o |
o |
o |
o |
o |
o |
E + |
|
5 |
o |
o |
o |
o |
o |
o |
Gran 1 |
o |
|
44.3 |
1 |
o |
o |
o |
o |
o |
o |
o |
o |
2 |
o |
o |
o |
o |
o |
o |
o |
o |
|
3 |
o |
o |
o |
o |
o |
o |
o |
pbRu + |
|
4 |
o |
o |
o |
o |
N + |
o |
o |
o |
|
5 |
o |
o |
o |
o |
o |
o |
o |
Gran 1 |
|
104.7 |
1 |
o |
o |
o |
o |
o |
o |
o |
o |
2 |
o |
o |
o |
o |
o |
o |
o |
pbRu 1 |
|
3 |
Ez + |
o |
o |
Ez 1 |
o |
o |
o |
pbRu 1 |
|
4 |
o |
o |
Ez + |
o |
N + |
o |
o |
E + |
|
5 |
Ez + |
o |
Ez + |
o |
o |
o |
o |
o |
Abbreviations:
Ez = inflammatory-cellular infiltration; Gran = histocyte granuloma; N = scarring; oe =oedema; pbRu = peribronchial rounded cell infiltrates
Applicant's summary and conclusion
- Conclusions:
- A 3-week subacute inhalation study in Wistar rats was carried out using exposure at 17.2, 44.3, and 104.7 mg/ m3 in dynamic inhalation chambers for 6 h/d, 5 d/wk. Slightly reduced body weights were noted in males of the high dose group and males and females of the high dose groups showed weight changes in some organs. No histopathological alterations were observed. A NOAEC of 44.3 mg/ m3 was derived.
- Executive summary:
The subacute inhalation toxicity of crinipan was tested in a 3-week study in rats using three different test concentrations (17.2, 44.3, and 104.7 mg/ m3 air) in dynamic inhalation chambers, in which animals were exposed for 6 h/d, 5 d/wk. During the treatment period the neurobehaviour and body weights of the animals were daily recorded. After the last exposure, haematological and clinico-chemical parameters of the animals were determined and urine analysis was performed. In addition, histopathological examinations were done after section of the animals. Finally, a statistical evaluation of the results was done.
Body weights of males were slightly reduced, reaching statistical significance in the high dose group, but the reduction was >10% compared to controls. No body weight effect was seen in females.
The examination of haematological parameters revealed a significant, but not dose-related increase in the number of leucocytes in males of the low and mid dose groups.
The histopathological evaluation of the bone marrow smears yielded almost no differences between the treated and the control animals.
The clinico-chemical examinations yielded significantly decreased values of creatinine for all male rats which were not considered toxicologically relevant and were within the normal range (0.53-1.05 mg/100 mL) for male Wistar-II rats of this age. Mid dose females showed slightly decreased values for alkaline phosphatase and blood glucose (also in high dose females). All glucose values were within the physiological range (lowest average value: 89.9 mg/100 mL). These findings were therefore not considered toxicologically relevant.
High dose males showed significantly decreased absolute (but not relative) heart weights, and relative weight increases of testes, lung, liver and thyroids, while females had increased absolute and relative liver and adrenal weights.
At the mid dose significant increase of relative thyroid weights occurred in female rats only. In the absence of absolute weight changes, similar effects in males and the absence of any histopathological alterations, this effect was not considered toxicologically relevant.
In conclusion, a NOAEC of 44.3 mg/ m3 was derived.
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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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