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EC number: 212-298-1 | CAS number: 778-94-9
- 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
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- Nanomaterial aspect ratio / shape
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- Endpoint summary
- Stability
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- 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:
- 28 Feb - 27 Jun 2019
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 020
- Report date:
- 2020
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted 25 Jun 2018
- Deviations:
- yes
- Remarks:
- - no ED-relevant endpoints examined
- GLP compliance:
- yes
- Remarks:
- The test complied with the Principles of Good Laboratory Practices (GLP) of the Certification and Accreditation Administration of the People’s Republic of China (2013 revised edition).
- Limit test:
- no
Test material
- Reference substance name:
- 2-nitro-4-(trifluoromethyl)benzonitrile
- EC Number:
- 212-298-1
- EC Name:
- 2-nitro-4-(trifluoromethyl)benzonitrile
- Cas Number:
- 778-94-9
- Molecular formula:
- C8H3F3N2O2
- IUPAC Name:
- 2-nitro-4-(trifluoromethyl)benzonitrile
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- SPF grade
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Liaoning Changsheng Biotechnology Co., Ltd., Liaoning, China
- Age at study initiation: 12 weeks
- Weight at study initiation: range (males/females) 288.35 - 292.97 at Day 0
- Fasting period before study: no
- Housing: Animals were housed in pairs during acclimatization period, and at a ratio 2 : 1 (female : male) during the overnight mating period. After impregnation, the animals were caged individually in rat breeding boxes (L 46.0 cm x W 31.5 cm x H 20.0 cm). Animal litter was corn cob litter (Liaoning Changsheng Biotechnology Co., Ltd., Liaoning, China). The litter was replaced at least once weekly.
- Diet: SPF rat/mouse breeding feed (Liaoning Changsheng Biotechnology Co., Ltd., Liaoning, China); ad libitum
- Water: grade-one reverse osmosis water (Liaoning Qianyi Testing and Evaluation Technology Development Co., Ltd., Liaoning, China); ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.00 - 24.90 during acclimatization; 20.61 - 25.80 during test period
- Humidity (%): 41.80 - 67.80 during acclimatization; 40.00 - 70.00 during test period
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test solution preparation volume was determined based on the animal’s most recent body weight, and theoretical sample weight was calculated based on the designed dose. For each, the test sample was weighed, corn oil was added, mixed evenly to the mark (mixed with a homogeniser for 1 - 2 minutes, magnetically stirred for at least five minutes). All preparations were freshly prepared each time on the day of test chemical administration. Test chemical administration volume was 4 mL/kg.
VEHICLE
- Justification for use and choice of vehicle: Compared to water, the test sample can suspend better in oil.
- Concentration in vehicle: not reported
- Amount of vehicle: not reported
- Lot/batch no.: FN2018/12/19 and FN2019/01/25 - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M / F ratio per cage: 1 / 2
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: yes (When there were no findings of impregnated rats, the above-described method of co-caging and mating continued, until the number of pregnant animals required for the test was reached.)
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- Day 5 - 19 after animal impregnation
- Frequency of treatment:
- daily, 7 days/week
- Duration of test:
- until Day 20 of pregnancy
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day
- Dose / conc.:
- 60 mg/kg bw/day
- Dose / conc.:
- 240 mg/kg bw/day
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a pre-test with concentrations 50, 100, 200, 300, 500, 700 and 1000 mg/kg bw/day, administered via oral gavage for 14 days
- Fasting period before blood sampling for (rat) dam thyroid hormones: not performed
- Time of day for (rat) dam blood sampling: not performed
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS / DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
Cage side observations included changes in fur, eyes, mucous membranes, respiratory system, circulatory system, nervous system, as well as behavioural changes.
BODY WEIGHT: Yes
- Time schedule for examinations: weighed on days 0, 3, 5, 8, 11, 14, 17, and 20 of pregnancy
FOOD CONSUMPTION Yes
- Measured days 0 - 3, 3 - 5, 5 - 8, 8 - 11, 11 - 14, 14 - 17, and 17 - 20 of pregnancy
- Food consumption for each animal determined on days 0 - 3, 3 - 5, 5 - 8, 8 - 11, 11 - 14, 14 - 17, and 17 - 20 of pregnancy and mean diet consumption for the respective time intervals calculated as g food/test group
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: uterus and placenta - 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
- Other: number of live foetuses, number of dead foetuses, number of resorped foetuses - Blood sampling:
- Not performed
- 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 (visceral examinations) or all per litter (external examinations)
- Anogenital distance of all live rodent pups: no - Statistics:
- SPSS 24.0 was used for statistical analysis of data.
Statistical analysis of mean body weight, weight gain, mean food intake, weight of uterus and foetuses, number of corpora lutea, number of implantations, weight of placenta, body length of foetal rat, tail length of foetal rat, and body weight of foetal rat were performed. First, the one-sample Kolmogorov-Smirnov test method was used to perform the normal distribution test on the data, then Levene’s test method was used to perform the homogeneity of variance test on the data. If there were findings of significant difference (P ≤ 0.05) for any statistical result from the one-sample Kolmogorov-Smirnov test and Levene’s test, then the independent sample Kruskal-Wallis test was performed. If there were findings that the results of the independent sample Kruskal-Wallis test were significantly differenent (P ≤ 0.05), then further pairwise comparison was performed. If there were no findings that the results of the independent sample Kruskal-Wallis test were significantly different (P > 0.05), then calculations ceased. If, in the statistical results of the one-sample Kolmogorov-Smirnov test and Levene’s test, there were no findings of significant difference (P > 0.05), then single-factor analysis of variance (ANOVA) was used. If the statistical results of single-factor analysis of variance (ANOVA) showed significant difference (P ≤ 0.05), the Dunnett test was used to perform testing on the control group and all dose groups. If the statistical results of the single-factor analysis of variance (ANOVA) showed no significant difference (P > 0.05), then calculations ceased. For dead foetus incidence rate, resorbed foetus incidence rate, male and female gender ratio, foetal rat appearance, visceral malformation incidence rate, and skeletal malformation incidence rate, the chi-square test was used to carry out statistical analysis. - Indices:
- not performed
- Historical control data:
- not provided
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- After exposure to the test sample, four animals in the high dose group exhibited spontaneous declines in movement, and compared to the vehicle control group, there was a statistical significance (P ≤ 0.05); there were no anomalous symptoms in the low and medium dose groups. For details, see table 1.
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the test period, body weight in all dose groups was compared to the vehicle control group, and there was no statistical significance (P > 0.05). In the high dose group, on days 5 - 8, weight gain was lower than in the vehicle control group, and it was statistically significant (P ≤ 0.001).
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the medium dose group, mean animal food intake quantity on days 8 - 11 was lower than in the vehicle control group, and it was statistically significant (P ≤ 0.05). However, there was no dose-response relationship and, in consideration of changes in body weight and weight gain, it can be concluded that these changes were not toxicologically significant. For details, see table 2.
- 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):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Weight of uterus and placenta were not affected compared to the vehicle control group.
- Gross pathological findings:
- not examined
- 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:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal general toxicity
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: No effects observed at this dose level.
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- maternal general toxicity
- Effect level:
- 240 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal developmental toxicity
- Effect level:
- 240 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: No effects observed up to the highest dose tested.
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight in foetal rats in the low and medium dose groups was compared to the vehicle control group and there was no statistical significance (P > 0.05). Foetal rat body weight in the high dose group was lower than in the vehicle control group, and there was statistical significance (P ≤ 0.001). For details, see table 3.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- not specified
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- There were findings of one foetal rat with rib 14 accessory rib in the vehicle control group, five foetal rats in the low dose group, three foetal rats in the medium dose group, and 12 foetal rats in the high dose group. Incidence rates for rib 14 accessory rib in foetal rats in the low and medium dose groups were compared to the vehicle control group and they were not statistically significant (P > 0.05). The incidence rate for rib 14 accessory rib in the high dose group was higher than the vehicle control group and it was statistically significant (P ≤ 0.01). For details, see table 5.
There were findings of one foetal rat with 3rd sternebrae dumbbell-shaped ossification in the vehicle control group, five foetal rats in the low dose group, five foetal rats in the medium dose group, and 15 foetal rats in the high dose group. Incidence rates for 3rd sternebrae dumbbell-shaped ossification in the high dose group were higher than in the vehicle control group, and they were statistically significant (P ≤ 0.001). For details, see table 6.
There were findings of 22 foetal rats with 4th sternebrae dumbbell-shaped ossification in the vehicle control group, 43 foetal rats in the low dose group, 37 foetal rats in the medium dose group, and 69 foetal rats in the high dose group. Incidence rates for 4th sternebrae dumbbell-shaped ossification in foetal rats in the low and high dose groups compared to the vehicle control group were statistically significant (P ≤ 0.01, P ≤ 0.001). The medium dose group compared to the vehicle control group was not statistically significant (P > 0.05). For details, see table 7.
There were findings of zero foetal rats with 6th sternebrae deficiency in the vehicle control group, one foetal rat in the low dose group, one foetal rat in the medium dose group, and eight foetal rats in the high dose group. Incidence rates for 6th sternebrae deficiency in foetal rats in the high dose group were higher than in the vehicle control group and they were statistically significant (P ≤ 0.01). For details, see table 8.
There were findings of 26 foetal rats with 6th sternebrae incomplete ossification in the vehicle control group, 38 foetal rats in the low dose group, 42 foetal rats in the medium dose group, and 40 foetal rats in the high dose group. Incidence rates for 6th sternebrae incomplete ossification in foetal rats in all dose groups compared to the vehicle control group were statistically significant (P > 0.05). For details, see table 9.
In summary, foetal rat skeletons in the low dose group were compared to the vehicle control group and there was a statistically significant abnormal symptom, namely 4th sternebrae dumbbell-shaped ossification (P ≤ 0.01). Foetal rat skeletons in the medium dose group were compared to the vehicle control group and there were no statistically significant abnormal symptoms. Foetal rat skeletons in the high dose group were compared to the vehicle control group and there were statistically significant abnormal symptoms, namely 14th accessory rib (P ≤ 0.01), 3rd sternebrae dumbbell-shaped ossification (P ≤ 0.001), 4th sternebrae dumbbell-shaped ossification (P ≤ 0.001), and 6th sternebrae deficiency (P ≤ 0.01).
Of these, 4th sternebrae dumbbell-shaped ossification did not present a dose-response relationship in all dose groups, and no other skeletal abnormalities were exhibited in the low dose group, thus it did not possess toxicological significance. Based on the above results, the high dose had an impact on foetal rat skeletal development and increased the probability of skeletal abnormalities. - Visceral malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- There were findings of hydronephrosis in 17 foetal rats in the vehicle control group, 20 foetal rats in the low dose group, 24 foetal rats in the medium dose group, and 44 foetal rats in the high dose group. Incidence rates for hydronephrosis in foetal rats in the high dose group were higher than in the vehicle control group and there was statistical significance (P ≤ 0.001). For details, see table 4.
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- BODY LENGTH:
Foetal rat body length in the low dose group was compared to the vehicle control group and the difference was not statistically significant (P > 0.05). Foetal rat body length in the medium dose group was compared to the vehicle control group and it was statistically significant (P ≤ 0.001). Foetal rat body length in the high dose group was lower than in the vehicle control group, and it was statistically significant (P ≤ 0.001). As body length effects did not present a dose-response relationship and, in consideration of the fact that foetal rat body weight in the medium dose group did not present statistical significance, it was concluded that the effects observed in the medium-dose group were not toxicologically significant. For details, see table 3.
TAIL LENGTH:
Tail length in the low and medium dose groups was compared to the vehicle control group and there was no statistical significance (P > 0.05); foetal rat tail length in the high dose group was lower than in the vehicle control group, and there was statistical significance (P ≤ 0.001). For details, see table 3.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Effect level:
- 60 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects observed at this dose level.
- Key result
- Dose descriptor:
- LOAEL
- Remarks:
- developmental toxicity
- Effect level:
- 240 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- visceral malformations
Fetal abnormalities
open allclose all
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- external: tail
- Description (incidence and severity):
- Total tail length in the high dose group was statistically singnificantly lower than in the vehicle control group. In addition, foetal rat body length and foetel body weight in the high dose group were statistical singnificantly lower than in the vehicle control group.
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- visceral/soft tissue: urinary
- Description (incidence and severity):
- Incidence rates for hydronephrosis in foetal rats in the high dose group were higher than in the vehicle control group and there was statistical significance (P ≤ 0.001).
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: rib
- Description (incidence and severity):
- The incidence rate for rib 14 accessory rib in the high dose group was higher than the vehicle control group and it was statistically significant (P ≤ 0.01).
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: sternum
- Description (incidence and severity):
- There were findings of one foetal rat with 3rd sternebrae dumbbell-shaped ossification in the vehicle control group, five foetal rats in the low dose group, five foetal rats in the medium dose group, and 15 foetal rats in the high dose group. Incidence rates for 3rd sternebrae dumbbell-shaped ossification in the high dose group were higher than in the vehicle control group, and they were statistically significant (P ≤ 0.001).
Statistically abnormal symptoms in the foetal rat skeleton of the high dose group were: 14th accessory rib (P ≤ 0.01), 3rd sternebrae dumbbell-shaped ossification (P ≤ 0.001), and 6th sternebrae deficiency (P ≤ 0.01).
There were findings of zero foetal rats with 6th sternebrae deficiency in the vehicle control group, one foetal rat in the low dose group, one foetal rat in the medium dose group, and eight foetal rats in the high dose group. Incidence rates for 6th sternebrae deficiency in foetal rats in the high dose group were higher than in the vehicle control group and they were statistically significant (P ≤ 0.01).
There were findings of 26 foetal rats with 6th sternebrae incomplete ossification in the vehicle control group, 38 foetal rats in the low dose group, 42 foetal rats in the medium dose group, and 40 foetal rats in the high dose group. Incidence rates for 6th sternebrae incomplete ossification in foetal rats in all dose groups compared to the vehicle control group were statistically significant (P > 0.05).
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 240 mg/kg bw/day
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- presumably yes
Any other information on results incl. tables
Table 1: Maternal effects - Clinical Signs
Observation |
Vehicle control group |
Dose groups |
||
0 mg/kg |
15 mg/kg |
60 mg/kg |
240 mg/kg |
|
Appearance, fur |
0/20 |
0/20 |
0/20 |
0/20 |
Posture |
0/20 |
0/20 |
0/20 |
0/20 |
Urine, faeces |
0/20 |
0/20 |
0/20 |
0/20 |
Noise reflex |
0/20 |
0/20 |
0/20 |
0/20 |
Reaction sensitivity |
0/20 |
0/20 |
0/20 |
0/20 |
Eyes, nose, mouth |
0/20 |
0/20 |
0/20 |
0/20 |
Skin |
0/20 |
0/20 |
0/20 |
0/20 |
Chest and abdomen |
0/20 |
0/20 |
0/20 |
0/20 |
Lower abdominal area |
0/20 |
0/20 |
0/20 |
0/20 |
Muscle tension |
0/20 |
0/20 |
0/20 |
0/20 |
Respiration |
0/20 |
0/20 |
0/20 |
0/20 |
Movement |
0/20 |
0/20 |
0/20 |
4*/20 |
Neurology |
0/20 |
0/20 |
0/20 |
0/20 |
Head |
0/20 |
0/20 |
0/20 |
0/20 |
Notes: Movement abnormality was spontaneous reduction in movement; compared to the vehicle control group: *P ≤ 0.05.
Table 2: Maternal effects - Body weight gain changes
Date |
Vehicle control group |
Dose group |
||
0 mg/kg |
15 mg/kg |
60 mg/kg |
240 mg/kg |
|
d0-d3 |
16.50 ± 8.88 |
19.20 ± 6.53 |
20.59 ± 9.14 |
15.65 ± 8.96 |
d3-d5 |
10.43 ± 7.46 |
10.57 ± 7.36 |
8.83 ± 6.51 |
10.93 ± 5.65 |
d5-d8 |
14.54 ± 8.88 |
8.48 ± 5.86 |
11.43 ± 27.89 |
-4.82 ± 12.63*** |
d8-d11 |
11.84 ± 12.45 |
16.47 ± 5.24 |
11.71 ± 23.90 |
20.20 ± 9.66 |
d11-d14 |
15.80 ± 12.27 |
21.14 ± 12.28 |
17.84 ± 18.14 |
16.21 ± 7.20 |
d14-d17 |
33.57 ± 6.19 |
41.38 ± 9.70 |
35.64 ± 10.45 |
29.42 ± 8.56 |
d17-d20 |
54.71 ± 9.81 |
50.05 ± 13.27 |
50.28 ± 7.62 |
48.13 ± 7.70 |
Compared to the vehicle control group: ***P ≤ 0.001; unit: g
Table 3: Foetal effects - Body length, tail length and body weight
Group |
Dose (mg/kg) |
Mean body length (cm) |
Mean tail length (cm) |
Mean body weight (g) |
Vehicle control group |
0 |
3.841 ± 0.142 |
1.395 ± 0.055 |
4.005 ± 0.368 |
Low dose group |
15 |
3.840 ± 0.138 |
1.406 ± 0.053 |
4.093 ± 0.358 |
Medium dose group |
60 |
3.786 ± 0.148*** |
1.396 ± 0.064 |
3.957 ± 0.370 |
High dose group |
240 |
3.742 ± 0.164*** |
1.371 ± 0.058*** |
3.768 ± 0.459*** |
Compared to the vehicle control group: ***P ≤ 0.001
Table 4: Foetal effects - Visceral examination (Hydronephrosis)
Group |
Dose (mg/kg) |
Incidence number (n) |
Number of foetal rats examined (n) |
Incidence rate (%) |
Vehicle control group |
0 |
17 |
137 |
12.41% |
Low dose group |
15 |
20 |
150 |
13.33% |
Medium dose group |
60 |
24 |
148 |
16.22% |
High dose group |
240 |
44*** |
144 |
29.17% |
Compared to the vehicle control group: ***P ≤ 0.001
Table 5: Foetal effects - Skeletal examination (Rib 14 Accessory Rib)
Group |
Dose (mg/kg) |
Incidence number (n) |
Number of foetal rats examined (n) |
Incidence rate (%) |
Vehicle control group |
0 |
1 |
129 |
0.78% |
Low dose group |
15 |
5 |
139 |
3.60% |
Medium dose group |
60 |
3 |
142 |
2.11% |
High dose group |
240 |
12** |
136 |
8.82% |
Compared to the vehicle control group: **P ≤ 0.01.
Table 6: Foetal effects - Skeletal examination (3rd Sternebrae Dumbbell-Shaped Ossification)
Group |
Dose (mg/kg) |
Incidence number (n) |
Number of foetal rats examined (n) |
Incidence rate (%) |
Vehicle control group |
0 |
1 |
129 |
1.55% |
Low dose group |
15 |
5 |
139 |
3.60% |
Medium dose group |
60 |
5 |
142 |
3.52% |
High dose group |
240 |
15*** |
136 |
11.03% |
Compared to the vehicle control group: ***P ≤ 0.001
Table 7: Foetal effects - Skeletal examination (4th Sternebrae Dumbbell-Shaped Ossification)
Group |
Dose (mg/kg) |
Incidence number (n) |
Number of foetal rats examined (n) |
Incidence rate (%) |
Vehicle control group |
0 |
22 |
129 |
16.28% |
Low dose group |
15 |
43** |
139 |
30.94% |
Medium dose group |
60 |
37 |
142 |
26.06% |
High dose group |
240 |
69*** |
136 |
50.74% |
Compared to the vehicle control group: **P ≤ 0.01; ***P ≤ 0.001
Table 8: Foetal effects - Skeletal examination (6th Sternebrae Deficiency)
Group |
Dose (mg/kg) |
Incidence number (n) |
Number of foetal rats examined (n) |
Incidence rate (%) |
Vehicle control group |
0 |
0 |
129 |
0.00% |
Low dose group |
15 |
1 |
139 |
0.72% |
Medium dose group |
60 |
1 |
142 |
0.70% |
High dose group |
240 |
8** |
136 |
5.88% |
Compared to the vehicle control group: **P ≤ 0.01
Table 9: Foetal effects - Skeletal examination (6th Sternebrae Incomplete Ossification)
Group |
Dose (mg/kg) |
Incidence number (n) |
Number of foetal rats examined (n) |
Incidence rate (%) |
Vehicle control group |
0 |
26 |
129 |
20.16% |
Low dose group |
15 |
38 |
139 |
27.34% |
Medium dose group |
60 |
42 |
142 |
29.58% |
High dose group |
240 |
40 |
136 |
29.41% |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this test, based on the described effects, the minimum effects dose (LOAEL) of 2-nitro-4-(trifluoromethyl)benzonitrile in the prenatal developmental toxicity test in rats for foetal development was 240 mg/kg bw/day, and the maximum no effects dose (NOAEL) was 60 mg/kg bw/day. For maternal toxicity, the NOAEL for general toxicity was 60 mg/kg bw/day and the respective LOAEL was at 240 mg/kg bw day. As no maternal developmental toxicity was observed at any of the doses tested, the NOAEL for maternal developmental toxicity was 240 mg/kg bw/day.
Based on the findings of hydronephrosis in the offspring, a classification of Repr. 2 is warranted.
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