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EC number: 632-619-2 | CAS number: 881685-58-1
- 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:
- 29 Oct 2007 to 22 Nov 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2008
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Jan 2001
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Aug 1998
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Apr 2004
- Qualifier:
- according to guideline
- Guideline:
- other: JMAFF, 12 - Nousan 8147, Teratology (2-1-18)
- Version / remarks:
- Nov 2000
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 632-619-2
- EC Number:
- 632-619-2
- Cas Number:
- 881685-58-1
- Molecular formula:
- C20 H23 F2 N3 O
- IUPAC Name:
- 632-619-2
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- HanRcc: WIST(SPF Quality)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 11 weeks (day 0 post coitum):
- Weight at study initiation: 192 - 231 g (day 0 post coitum):
- Housing: Animals were housed individually in Makrolon cages (type-3) with wire mesh tops and standardised granulated softwood bedding.
- Diet: Pelleted standard rat/mouse maintenance diet, ad libitum
- Water: Community tap water in water bottles, ad libitum.
- Acclimation period: Minimum 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
Humidity (%): 30 - 70
Air changes (per hr): 10 - 15
Photoperiod: 12 hours light/12 hours dark
Music: background music played at a centrally defined low volume for at
least 8 hours during the light period
IN-LIFE DATES: From: 17 Oct 2007 To: 22 Nov 2007
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% w/v aqueous CMC high viscosity
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet: once a week.
- Mixing appropriate amounts with vehicle: The test item was weighed into a plastic tray on a tared precision balance. The test item was then transferred into a mortar and ground with a pestle. Then the vehicle was added (w/v) in portions to suspend the test item and clean the mortar. The preparation was transferred into a glass beaker and homogenised using an ultra-turrax before subdividing. The test item formulation was prepared once a week. The preparation was subdivided into separate aliquots for dosing each day. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
- Storage temperature of food: Dose formulations were stored refrigerated (2 - 8 °C)
VEHICLE
- Concentration in vehicle: 2, 7.5 and 20 mg/mL
- Amount of vehicle: 10 mL/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- STABILITY OF TEST SUBSTANCE FORMULATIONS
Samples for determination of concentration, homogeneity and stability (7 days) of the dose formulations were taken during the first week of the administration period. Additionally, samples for determination of concentration were taken during the last week of the administration period. For homogeneity, three samples of approximately 2 g were taken from the top, middle and bottom of each formulation and transferred into amber glass vials. For content and stability, samples were taken from the middle only. The samples were frozen (-25 °C to -15 °C) pending analysis. Analysis was performed using a method provided by the Sponsor (capillary GC). - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused: yes, in special automatic mating cages i.e. with synchronised timing to initiate the nightly mating period.
- M/F ratio per cage: 1/1
- Length of cohabitation: nightly mating period until evidence of copulation was observed
- Proof of pregnancy: A copulation plug was observed, and/or the daily vaginal smear was sperm positive, referred to as day 0 of gestation. - Duration of treatment / exposure:
- Day 4 to 20 p.c.
- Frequency of treatment:
- Daily
- Duration of test:
- Untill Day 21 p.c.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Remarks:
- Low dose. Group 2
- Dose / conc.:
- 75 mg/kg bw/day (actual dose received)
- Remarks:
- Mid dose. Group 3
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Remarks:
- High dose. Group 4
- No. of animals per sex per dose:
- 24
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on results of a previous dose range finding toxicity study in Han Wistar rats, using dose levels of 0, 60, 125, and 250 mg/kg/day.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: Once daily, during acclimatisation and up to day of necropsy
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: Twice daily for viability / mortality
BODY WEIGHT:
- Time schedule for examinations: daily from day 0 until day 21 post coitum.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Food consumption was recorded at following intervals: Days 0 - 4, 4 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18 and 18 - 21 post coitum.
POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day: on day 21 post coitum, the scheduled necropsy, females were sacrificed by CO2 asphyxiation and the foetuses removed by Caesarean section. The necropsy was carried out in random manner.
- Organs examined: Post mortem examination, including gross macroscopic examination of all internal organs with emphasis on the uterus, uterine contents, position of foetuses in the uterus and the number of corpora lutea was performed and the data recorded. The uteri (and contents) of all females with live foetuses were weighed during necropsy on day 21 post coitum to enable the calculation of the corrected body weight gain. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Foetuses were removed from the uterus, sexed, weighed individually, examined for gross external abnormalities, sacrificed by a subcutaneous injection of sodium pentobarbital and allocated to one of the following procedures:
- Microdissection technique (sectioning/dissection technique). At least one half of the foetuses from each litter were fixed in Bouin's fixative (one foetus per container). They were examined by a combination of serial sections of the head and microdissection of the thorax and abdomen. This included detailed examination of the major blood vessels and sectioning of the heart and kidneys. After examination, the tissue was preserved in a solution of glycerine/ethanol (one foetus per container). Descriptions of any abnormalities and variations were recorded.
- The remaining foetuses were eviscerated and with the exception of over the paws, the skin was removed and discarded. Carcasses were processed through solutions of ethanol, glacial acetic acid with Alcian blue (for cartilage staining), potassium hydroxide with Alizarin red S (for clearing and staining ossified bone) and aqueous glycerine for preservation and storage. The skeletons were examined and all abnormalities and variations were recorded. The specimens were preserved individually in plastic bags. If no implantation sites were evident, the uterus was placed in an aqueous solution of ammonium sulphide to accentuate possible haemorrhagic areas of implantation sites.
Foetuses with abnormalities were photographed - Statistics:
- The following statistical methods were used to analyse maternal, reproduction and skeletal examination data:
- Means and standard deviations of various data were calculated and included in the report.
- All statistical tests were two-sided.
- Statistical significance between groups was evaluated by Analysis of Variance (ANOVA). In the case where variances were non-homogeneous, appropriate transformations were applied (e.g. log, square root, or double arcsine) to stabilise the variances before the ANOVA. The Dunnett many-one t-test was then used to compare each group to control based on the error mean square in the
ANOVA.
- Fisher's exact test was applied if the variables could be dichotomisd without loss of information.
- For statistical tests on foetal data, comparisons were made between groups for number of foetuses affected and number of litters affected, for completeness. The litter was considered the proper unit of measurement for overall study evaluation. - Indices:
- - From the on-line recorded reproduction data, the following parameters were calculated: Pre- and post-implantation losses, embryonic and foetal deaths, live and dead foetuses, foetuses with abnormalities and/or variations, foetal sex ratios and foetal body weights.
- For reproduction data, group mean values were calculated both on a litter basis and on a percentage per group basis.
- Mean foetal weights were calculated from the individual weights on a per litter basis. - Historical control data:
- Historic Control Data are provided for all reproductive and foetal findings observed in the current study. These historic control data were taken from 6 studies in the same strain of rat, evaluated by similar foetal examination criteria, in this laboratory between 2006 and 2007.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At 200 mg/kg/day, ventral recumbency and sedation were noted in all 24 dams between day 4 to day 9 p.c. Starting again on day 13 p.c., ventral recumbency was noted in a small number of females in this group up to day 18 p.c. Sedation and ruffled fur were noted in a few dams up day 21 p.c., the end of treatment
There were no clinical signs or symptoms noted at 20 and 75 mg/kg/day. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All female animals survived until scheduled necropsy.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 75 and 200 mg/kg/day, mean body weight was statistically significantly reduced compared to controls from day 7 and day 5, respectively, through the end of study. Mean body weight gain in these groups was also statistically significantly reduced starting on day 6 and 5, respectively, again until the end of study. When corrected for gravid uterine weights, females at 200 mg/kg/day lost an average of 6 g of body weight during treatment compared to a body weight gain in controls of approximately 34 g. At 75 mg/kg/day, body weight gain corrected for gravid uterine weight was decreased approximately 41% when compared with controls.
At 20 mg/kg/day, mean body weight and mean body weight gain were not influenced by treatment with the test item. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Mean food consumption at 75 and 200 mg/kg/day was statistically significantly reduced for the total treatment period (days 4 to 21 p.c.).
Mean food consumption at 20 mg/kg/day was considered to be unaffected by treatment - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related findings were noted in any dam at scheduled necropsy.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on pre-implantation loss and post-implantation loss
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on the number of living foetuses.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on implantation rate.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- General systemic toxicity
- Effect level:
- 20 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal developmental toxicity
- Effect level:
- > 200 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Calculated on litter basis, the mean body weight of foetuses was statistically significantly lower at 75 and 200 mg/kg/day.
There were no effects on mean foetal body weight at 20 mg/kg/day. - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratios were considered to be not influenced by treatment with the test substance.
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Variations were noted in all groups. These variations were known to be common in this strain of rat, and/or were within the range of the historical reference data. Thus, they were considered as not related to the treatment with the test substance.
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- - Skeletal examination: There were no treatment-related differences in the incidence of bone and cartilage abnormalities. The sporadic incidences noted (vertebra absent, cervical vertebral arch short, misshapen and / or reduced thoracolumbar vertebrae [thoracolumbar scoliosis]) were without dose-relationship and therefore considered to be of incidental nature. There were no treatment-related statistical differences in the incidence of bone and cartilage variations. The incidences of the variation “costal cartilages asymmetrically aligned at sternum” were slightly higher in the dosed groups compared to the control group, but were within the range of the historical reference data (based on litter) and thus considered to be of incidental nature. The other incidences of bone and cartilage variations were noted mostly without dose relationship, and were therefore considered to be of incidental nature.
- Bone examinations - ossification stage / supernumerary ribs: Skeletal examination (ossification stage) of foetuses did not reveal any direct test substance-related findings. Due to the statistically significantly reduced body weight of the foetuses at 75 and 200 mg/kg/day, the increased incidence of non-ossified or incompletely ossified bones were considered to be delayed development, and related to the maternal toxicity observed. At 200 mg/kg/day, statistically significantly higher incidences of a number of variations such as non-ossified vertebral bodies, incompletely ossified proximal phalanges, talus, and metatarsalia were observed. At 75 mg/kg/day, only the incidence of non-ossified cervical vertebral body 3 was statistically increased on a litter basis. All other incidences were similar in the test item treated groups and the control group and / or were within the range of historical reference data.
- Cartilage examinations: The noted incidence in common cartilage variations was dose-independent, not statistically significant in all but one finding on a litter basis, and therefore considered to be of incidental nature. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- During the visceral examination of foetuses, abnormalities were noted in 5 foetuses. Abnormalities observed included thoracic and abdominal situs inversus, heart interventricular septal defect, and diaphragmatic hernia. As they were noted without dose-relationship, they were considered to be of incidental nature.
Variations were noted in all groups. These variations were known to be common in this strain of rat, and/or were within the range of the historical reference data. Thus, they were considered as not related to the treatment with the test item.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Developmental toxicity
- Effect level:
- 20 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- skeletal malformations
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: skeletal defects
- Description (incidence and severity):
- Poor ossification
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 75 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Dose verification
The identity of the test substance was confirmed by the retention times of syn-isomer and anti-isomer which were similar to those measured in the working standards. The test item concentration in all samples was found to be within 86.4% and 102.9% of the nominal content. In addition, the homogenous distribution of the test item in 0.5% aqueous carboxymethylcellulose solution was demonstrated. The dosing formulations were considered to be stable for at least 7 days in the refrigerator
Table 1 Mortality and clinical signs or observations
|
Test substance (mg/kg/day) |
|||
Observation |
0 (control) |
20 |
75 |
200 |
Number of females |
24 |
24 |
24 |
24 |
Ventral recumbency |
0 |
0 |
0 |
24 |
Sedation |
0 |
0 |
0 |
24 |
Ruffled fur |
0 |
0 |
0 |
6 |
Number of animals with signs |
0 |
0 |
0 |
24 |
No clinical signs or observations |
24 |
24 |
24 |
0 |
Table 2 Intergroup comparison of maternal body weight (g)
|
Dose level test substance (mg/kg/day) |
|||
Maternal body weight |
0 (control) |
20 |
75 |
200 |
Day 0 (Pre-dosing) |
212 |
211 |
211 |
208 |
Day 4 (Pre-dosing) |
226 |
224 |
225 |
223 |
Day 5 |
229 |
226 |
227 |
218** |
Day 7 |
236 |
231 |
226** |
212** |
Day 10 |
249 |
243 |
239** |
221** |
Day 12 |
257 |
252 |
247* |
228** |
Day 15 |
272 |
267 |
261** |
240** |
Day 20 |
330 |
323 |
315* |
275** |
Day 21 |
341 |
333 |
325* |
282** |
Maternal body weight gain on day 21 |
114.6 |
108.6 |
99.8* |
59.5** |
Weight gain on day 21 corrected for gravid uterus weight (g) |
34.2 |
26.0 |
20.2** |
-5.7** |
*/**: Dunnett-Test based on pooled variance significant at 5 % (*) or 1 % (**) level
Table 3 Intergroup comparison of food consumption(g/rat/day)
|
|
Dose level test substance (mg/kg/day) |
|||
Food consumption |
0 (control) |
20 |
75 |
200 |
|
Pre-dosing: |
Days 0 - 4 |
21.9 |
21.7 |
21.9 |
22.1 |
During dosing |
Days 4 - 6 |
22.9 |
23.4 |
19.4** |
13.7** |
|
Days 6 - 9 |
22.9 |
21.5 |
19.4** |
13.5** |
|
Days 9 - 12 |
24.7 |
23.8 |
22.2** |
17.1** |
|
Days 12 - 15 |
24.6 |
23.5 |
22.3** |
17.7** |
|
Days 15 - 18 |
26.3 |
25.3 |
24.0** |
17.6** |
|
Days 18 - 21 |
25.2 |
24.6 |
22.3** |
16.7** |
*/**: Dunnett-Test based on pooled variance significant at 5 % (*) or 1 % (**) level
Table 4 Caesarean section observations for all pregnant females
Observation |
Test substance (mg/kg/day) |
|||
|
0 (control) |
60 |
125 |
250 |
Animals Assigned (Mated) |
24 |
24 |
24 |
24 |
Animals Pregnant |
23 |
23 |
24 |
24 |
Nonpregnant |
1 |
1 |
0 |
0 |
Corpora Lutea/Dam |
14.4 |
14.8 |
14.4 |
14.2 |
Implantations/Dam |
13.7 |
13.9 |
13.9 |
13.2 |
Gravid Uterus Weight (g) |
80.4 |
82.6 |
79.6 |
65.2 |
Total Litters (viable) |
23 |
23 |
24 |
24 |
Foetuses/Dam |
12.4 |
13.1 |
13.1 |
12.2 |
Number of Intra-uterine deaths (litters affected) |
29 (15) |
18 (12) |
18 (13) |
25 (14) |
Early deaths (Number of litters affected) |
26 (13) |
16 (11) |
16 (11) |
25 (14) |
Late deaths (Number of litters affected) |
3 (3) |
2 (2) |
2 (2) |
0 |
Mean Foetal Weight (g) |
4.8 |
4.7 |
4.5* |
4.0** |
Males (g) |
5.0 |
4.8 |
4.7* |
4.1** |
Females (g) |
4.7 |
4.6 |
4.4* |
3.9** |
Sex Ratio (% Males per litter) |
47.9 |
51.8 |
46.3 |
47.9 |
Pre-implantation Loss (%) |
4.8 |
6.2 |
3.5 |
7.0 |
Post-implantation Loss (%) |
9.2 |
5.9 |
5.4 |
7.9 |
* / ** : Dunnett-Test based on pooled variance significant at level 5% (*) or 1% (**)
Table 5 External/visceral examinations
|
test substance (mg/kg/day) |
|||
|
0 (control) |
20 |
75 |
200 |
Number of foetuses (litters) |
150 (23) |
156 (23) |
163 (24) |
151 (24) |
Number of abnormal foetuses (litters) |
0 |
1 (1) |
3 (3) |
1 (1) |
Number of foetuses with variations (litters) |
52 (21) |
55 (22) |
63 (23) |
76 (23) |
Table 6 Skeletal examinations - bone and cartilage abnormalities and variations
|
test substance (mg/kg/day) |
|||
|
0 (control) |
20 |
75 |
200 |
Number of foetuses (litters) |
136 (23) |
145* (23) |
152* (24) |
141 (24) |
Number of abnormal foetuses (litters) |
1 (1) |
0 |
2 (2) |
0 |
Number of foetuses with variations (litters) |
23 (12) |
31 (18) |
38 (17) |
34 (18) |
Costal cartilages asymmetrically aligned at sternum foetuses (litters) |
1 (1) |
3 (3) |
6 (5) |
7 (5) |
* One less fetus at cartilage examination.
Table 7 Bone examinations - ossification stage / supernumerary ribs
|
test substance (mg/kg/day) |
|||
Selected findings |
0 (control) |
60 |
125 |
250 |
Number of litters examined |
23 |
23 |
24 |
24 |
Non ossified: |
|
|
|
|
Non ossified: |
|
|
|
|
# / ##: Fisher's Exact Test significant at level 5% (#) or 1% (##)
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for maternal toxicity was 20 mg/kg/day beased on reduced body weight food consumptions and clinical signs. The NOAEL for developmental toxicity was considered to be 20 mg/kg/day as a result of reduced body weight and ossification.
- Executive summary:
The purpose of this OECD TG 414 study in compliance with GLP was to assess the effects of test substance on the pregnant rat and the embryonic and foetal development when administered orally, by gavage, once daily to mated female rats from day 4 through to day 20 post coitum. Each group consisted of 24 mated female rats. The test substance was administered at dose levels of: 0 (vehicle control, 20, 75 and 200 mg/kg/day, for respectively Group 1, 2, 3 and 4. A standard dose volume of 10 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (0.5 % w/v aqueous CMC high viscosity). All females were sacrificed on day 21 post coitum and the foetuses were removed by Caesarean section. Examination of dams and foetuses was performed in accordance with international recommendations.
All female animals survived until scheduled necropsy. Ventral recumbency and sedation were noted in 24/24 dams, and ruffled fur in 6/24 dams at 200 mg/kg/day. There were no findings in dams at 20 or 75 mg/kg/day. Mean food consumption at 75 and 200 mg/kg/day was statistically significantly reduced. Mean body weight and mean body weight gain was statistically significantly reduced starting on day 7and day 6 at 75 mg/kg/day and on day 5 post coitum at 200 mg/kg/day. There were no treatment-related effects on pre-implantation loss, implantation rate, post-implantation loss, or the number of living foetuses. No treatment related findings were noted in any dam at scheduled necropsy. At scheduled caesarean section, no abnormal live foetus was noted at external examination at 0, 20, 75, and 200 mg/kg/day, respectively.
Sex ratios were considered not to be influenced by treatment with the test item. Mean foetal body weight was statistically significantly reduced at 75 and 200 mg/kg/day.
As the abnormalities in foetuses of test item-treated dams were noted without dose-relationship, they were considered to be of incidental nature. There were no treatment-related visceral variations. There were no treatment related bone and cartilage abnormalities noted.
Skeletal examination (ossification stage) of foetuses did not reveal any direct test item-related findings. Due to the statistically significantly reduced foetal body weight at 75 and 200 mg/kg/day, the increased incidence of non-ossified or incompletely ossified bones were considered to be delayed development, and probably related to the maternal toxicity observed.
There were no treatment-related increases in the incidences of cartilage variations in any dose group when compared with controls. In this prenatal developmental toxicity study the doses of 20, 75, and 200 mg/kg/day were administered to pregnant Han Wistar rats.
Maternal toxicity was noted at 75 and 200 mg/kg/day with statistically significantly decreased food consumption and corresponding statistically significantly decreased body weight gain. Clinical signs were only noted at 200 mg/kg/day. At 75 and 200 mg/kg/day, the only treatment related foetal effects noted were decreased body weight and delayed ossification. These effects were considered to be secondary to the maternal toxicity observed at these dose levels.
In conclusion, there was no evidence of maternal and foetal toxicity at 20 mg/kg/day, which was established as a no observed adverse effect level (NOAEL).
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