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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2001-05-08 to 2001-07-02
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD guideline 414 with GLP regulations.
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:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Principles of method if other than guideline:
- no data
- GLP compliance:
- yes
- 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:
- rabbit
- Strain:
- Chinchilla
- Details on test animals or test system and environmental conditions:
- Acclimatization: 7 days minimum (prior to pairing) under test conditions with an evaluation of the health status;
Number of animals: 96 mated females, 24 per group;
Age at pairing: 17 to 23 weeks;
Body weights (day 0 post coitum): 2510-4297 g;
Conditions: Animals were housed under standard laboratory conditions: air-conditioned with 10-15 air changes per hour; temperature range 20 ± 3°C and relative humidity range 30-70%), 12 h artificial fluorescent light / 12 h dark with background music played at a centrally defined low volume for at least 8 h during the light period. Accommodation individually in stainless steel cages
Diet: Pelleted standard Kliba 3418 rabbit maintenance diet was available ad libitum
Water: Tap water, provided in water bowls, was available ad libitum.
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- other: not applicable
- Vehicle:
- water
- Remarks:
- Bi-distilled water with 4% CMC.
- Details on exposure:
- Mated female were assigned to the four groups containing each 24 rabbits. The dose levels selected are 0, 15, 30, and 60 mg/kg body weight/ day (based from dose range-finding study in rabbit) during the gestation from day 6 through 27 post coitum.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Concentration, homogeneity and stability of the test item/vehicle mixtures were determined from samples drawn during the first and last week of the treatment period using HPLC technique.
- Details on mating procedure:
- After acclimatization, females were placed in cages with sexually mature males (1:1) until copulation had been observed. After mating, the females were removed and caged individually. The day of mating was designated day 0 post coitum. Mated females were assigned to the four groups using a randomization procedure based on body weight adjusted so that a similar number of rabbits was allocated to each group on each day of mating and ensuring an acceptable distribution of males to which the females were mated.
- Duration of treatment / exposure:
- day 6 to 27 of pregnancy
- Frequency of treatment:
- once daily
- Duration of test:
- not applicable
- No. of animals per sex per dose:
- 24 female pregnant rabbits per dose level
- Control animals:
- yes
- Details on study design:
- not applicable
Examinations
- Maternal examinations:
- Bahaviour and appearance; mortality; food consumption; body weight-increase were recorded
- Ovaries and uterine content:
- no data
- Fetal examinations:
- Caesarean and investigation of the foetuses:
The caesarean was carried out on the female rabbits after injecting sodium pentobarbital (1 mL/kg body weight) anaesthetic on the 28th day of pregnancy.
Post mortem examination, including grass macroscopic examination of all internal organs, with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea in each ovary, were performed and the data recorded. When considered appropriate, samples of macroscopic changes in the dams were fixed in neutral phosphate-buffered 4% formaldehyde solution for possible macroscopic examination. The uteri (and contents) of all females with live fetuses were weighed at necropsy to enable the calculation of the corrected body weight gain. Additionally, placental weights were determined.
If no implantation sites were evident, the uterus was placed in an aqueous solution of ammonium sulfide to accentuate possible hemorrhagic areas of implantation sites. The number and distribution of implantations in uterine horns, classified as empty implantation sites, embryonic resorptions, fetal resorptions, dead fetuses or live fetuses were recorded. Fetuses were removed from the uterus, killed by subcutaneous injection of sodium pentobarbital (0.1 mL per fetus), and weighed individually, examined for grass external abnormalities and prepared for examination as follows:
1) The fetuses were dissected; the organs examined and any abnormal findings were recorded. The sex of each fetus was noted.
2) The thoracic organs were fixed in neutral phosphate buffered 4% formaldehyde solution (without separation) and examined for malformations of the heart (septum defects) and major blood vessels. The lungs were also examined for abnormal findings.
3) After the skin had been removed, the cranium was examined for the degree of ossification.
4) From half of the fetuses the heads were separated from the trunks and fixed in a solution of trichloroacetic acid and formaldehyde. They were serially sectioned and examined (evaluation of the internal structures of the heads, including the eyes, brain, nasal passages and tongue). Descriptions of any abnormal findings were recorded.
5) From all fetuses the skin with the exception of over the paws and the dorsal cervical fat pads was removed and discarded. The trunks of the fetuses without the heads and the fetuses with heads were then processed through solutions of ethanol, glacial acetic with Alcian blue (for cartilage staining), potassium hydroxide with Alizarin red S (for clearing and staining ossified bone) and aqueous glycerin for preservation and storage. The skeletons were examined and all abnormal findings and variations were recorded. Fetuses with external abnormalities were photographed. - Statistics:
- Mean body weight gain (%), mean corrected body weight gain (corrected for uterus weight) and mean daily food consumption were calculated by a computer program based on online recorded data.
Calculations for evaluation of the reproduction data were performed by a computer program based on online recorded data. The following data were calculated: Pre- and post-implantation losses, embryonic and fetal deaths, live and dead fetuses, abnormal fetuses, sex ratios of fetuses and fetal body weights.
For reproduction data, group mean values were calculated both on a litter basis and on a percentage per group basis. Mean fetal weights were calculated from the individual weights both on a per group and on a per litter basis.
To test the statistical significance, the following procedures were used:
1) Means and standard deviations of various data were calculated and included in the report.
2) If the variables could be assumed to follow a normal distribution, the Dunnett many-one test, based on a pooled variance estimate, was used for intergroup comparisons (i.e. single treatment groups against the control group).
3) The Steel test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
4) Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information. - Indices:
- no data
- Historical control data:
- no data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: 30 mg/kg body weight
Details on maternal toxic effects:
General tolerability:
At 60 mg/kg/day, one female was found dead on day 27 post coitum and one female was killed in extremis on day 25 post coitum. At 30 mg/kg/day, one female was found dead on day 28 post coitum. No mortalities were noted at 15 mg/kg/day or in vehicle control. One female was killed after abortion at 30 and 15 mg/kg/day and in vehicle control, each. These abortions were noted on post coital days 26, 28 and 26, respectively. At 60 mg/kg/day, four females were noted with local alopecia (affecting cervical regions, abdomen or legs), which was in one case combined with bitten-off claws at the left hind leg. Alopecia was noted from post coital days 13, 12, 23 and 10, respectively, until necropsy. From one female, which was killed in extremis on that day, bloody vaginal discharge was noted on day 25 post coitum. At 30 mg/kg/day, local alopecia on the left foreleg and the cervical region was noted for one female from post coital day 21 until necropsy.
Food consumption and body weights:
At 60 mg/kg/day, food consumption of dams with live fetuses at caesarean section was markedly reduced during the first four recording intervals after the start of treatment (i.e. post coital days 6-18). From post coital day 18 until caesarean section food consumption was similar to vehicle controls. At 30 mg/kg/day, food consumption was clearly reduced following start of treatment until day 18 post coitum although to a lesser extent than at 60 mg/kg/day. Food consumption from day 18 post coitum until caesarean section was similar to vehicle control. Food consumption of at 15 mg/kg/day was unaffected by treatment with the test item. Body weight gain of dams with live fetuses at Caesarean section was statistically significantly decreased from post coital days 7 to 23 at 60 mg/kg/day and from days 7 to 22 at 30 mg/kg/day when compared to vehicle controls. As for food consumption body weight gain was similar to that of vehicle controls towards the end of the treatment period. Body weight gain at 15 mg/kg/day was similar to vehicle controls during the entire study.
Reproduction data:
At 60 mg/kg/day, a test item-related increase in the incidence of total post-implantation loss (i.e. implantation sites only at caesarean section) was noted (7 dams versus 1 dam in vehicle control). When calculated for all females surviving until scheduled necropsy (including females with total post-implantations loss), the mean number of fetuses per dam was statistically significantly decreased at 60 mg/kg/day (5.6 versus 8.6 in vehicle control). Also at 30 mg/kg/day the number of fetuses per dam was decreased (7.5) but to a lesser extent. When calculated only for dams with live fetuses at caesarean section (excluding females with total post-implantation loss), there was a slight increase in post-implantation loss at 60 and 30 mg/kg/day (9.9 and 9.7% of implantation sites versus 6.9% in vehicle control).
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 15 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: clinical signs, reduced food consumption, reduced body weight gain, mortality
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Body weights and sex ratios
No test item-related effects on mean fetal body weights or sex ratios were noted.
External and fresh visceral examination
No fetal abnormalities that were considered to be test item-related were noted.
Examination of fixed fetal heads (including brains) and fixed fetal thoracic organs
No fetal abnormalities that were considered to be test item-related were noted.
Skeletal and cartilage examination
No fetal abnormalities that were considered to be test item-related were noted.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 60 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Summary of performance of mated females
Group Dose (mg/kg) |
1 (0) |
2 (15) |
3 (30) |
4 (60) |
Number of mated females |
24 |
24 |
24 |
24 |
Number of pregnant females |
23 |
23 |
23 |
23 |
Non pregnant |
1 |
1 |
1 |
1 |
Implantation sites only |
1 |
0 |
1 |
7 |
Killed after abortion |
1 |
1 |
1 |
0 |
Killed in extremis or died spontaneously |
0 |
0 |
1 |
2 |
Number of females with live fetuses at termination |
21 |
22 |
20 |
14 |
Applicant's summary and conclusion
- Conclusions:
- In a GLP, OECD 414 prenatal toxicity study in rabbits treatment with the test item caused mortalities and clinical symptoms, reduced food consumption and decreased body weight gain from 30 mg/kg body weight/day onwards. Based on these results, the NOEL (no observed effect level) for maternal organisms was considered to be 15 mg/kg body weight/day.
Treatment with the test item up to and including 60 mg/kg body weight/day caused no effects on any fetal data recorded. Based on these results, the NOEL for fetal organisms was considered to be 60 mg/kg body weight/day. - Executive summary:
In order to detect effects on embryonic and fetal development in pregnant rabbits, test item (HR 00/600306) was administered orally (gavage) once daily, from day 6 through to day 27 post coitum at dose levels of 15, 30 or 60 mg/kg body weight/day. The dose levels were selected based from previous dose range-finding study in rabbits. There were 24 mated female rabbits in each treatment group.
Treatment with the test item caused mortalities and clinical symptoms, reduced food consumption, decreased body weight gain, and altered reproductive data e.g. pre- and post-implantation loss, etc from 30 mg/kg body weight/day onwards. Based on these results, the NOEL (no observed effect level) for maternal organisms was considered to be 15 mg/kg body weight/day.
Treatment with the test item up to and including 60 mg/kg body weight/day caused no effects on any fetal data recorded e.g. body weight, sex ratio, external, skeletal or visceral abnormalities, etc. Based on these results, the NOEL for fetal organisms was considered to be 60 mg/kg body weight/day.
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