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EC number: 224-809-5 | CAS number: 4500-29-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 08 October 2020 to 17 February 2021
- 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:
- 2021
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 2,2'-(cyclohexylimino)bisethanol
- EC Number:
- 224-809-5
- EC Name:
- 2,2'-(cyclohexylimino)bisethanol
- Cas Number:
- 4500-29-2
- Molecular formula:
- C10H21NO2
- IUPAC Name:
- 2,2'-(cyclohexylimino)bisethanol
Constituent 1
- Specific details on test material used for the study:
- Manufactured By
Clariant Iberica Produccion, S.A.
Autovia Tarragona-Salou
3110 La Canonja, Spain
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- Source: Hylasco Biotechnology (India) Pvt. Ltd.
4B, MN Park, Shameerpet Mandal,
Turkapally Village,
Medchal District-500078, Telangana, India
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Milli-Q water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The dose formulation samples were analyzed for active ingredient concentrations. The results indicated that the analyzed concentrations were within ± 10.0 % of the nominal concentration, and the relative standard deviation (% RSD) was less than 10.0 %.
Dose Level (mg/kg/day) Nominal Con.(mg/mL) Average Calculated Con.(mg/mL) Average %Recoverya, b % Relative Standard Deviationa
0 0.0 0.0 NA NA
45 4.5 4.62 - 4.50 102.7 - 100.0 0.606 - 0.958
90 9 9.24 - 8.9 102.6 - 98.87 0.595 - 0.398
180 18 18.1 - 18.0 100.5 - 99.81 0.416 - 0.287
a Results are the range of values determined from two occasions.
b Average % recovery was calculated from the nominal concentration.
NA – Not Applicable - Details on mating procedure:
- The female rats were cohabited with males in a 1:1 ratio and vaginal smears and / or vaginal plug we re examined in the morning hours of the subsequent day to confirm mating.
- Duration of treatment / exposure:
- Gestation day 5 to gestation day 19
- Frequency of treatment:
- Daily from gestation day 5 to gestation day 19
- Duration of test:
- Upto gestation day 20
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Vehicle control
- Dose / conc.:
- 45 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 90 mg/kg bw/day (nominal)
- Remarks:
- Mid dose
- Dose / conc.:
- 180 mg/kg bw/day (nominal)
- Remarks:
- High dose
- No. of animals per sex per dose:
- 24 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
A preliminary dose range finding study (DRF) in pregnant rats was carried out using 7 rats per group with Genamin CH 020 dosed at 45, 67.5, 100 and
150 mg/kg/day along with the concurrent vehicle control group (Study number N4888). The rats were treated with the dose formulations by oral gavage at a dose volume of 10 mL/kg body weight from GD 5 to 19 and observed for clinical signs and mortality.
In the DRF study, dose levels up to 150 mg/kg/day were tolerated. No test item related clinical signs were noted at any dose. The body weight gains, and food consumption were unaffected up to the highest dose of 150 mg/kg/day. There was no fetal developmental toxicity up to the highest tested dose of 150 mg/kg/day.
Based on the results of the dose range finding study and considering results from additional repeated dose toxicity studies, the following dose levels have been selected for this definitive study in consultation with the Sponsor:
G1 - Vehicle control - 0 mg/kg/day
G2 - Low dose - 45 mg/kg/day
G3 - Mid dose - 90 mg/kg/day
G4 - High dose - 180 mg/kg/day
- Rationale for animal assignment (if not random):
During the mating period, the female rats were cohabited with males in a 1:1 ratio and vaginal smears and / or vaginal plug were examined in the morning hours of the subsequent day. If sperm was detected in a vaginal smear and or if a vaginal plug was observed in the morning, the female was considered to be mated. This day was considered as Day 0 of gestation.
The females were cohabited in batches of required numbers. This procedure was continued until there were sufficient numbers of Day 0 pregnant rats for the study.
Day 0 pregnant rats obtained on each day were randomly distributed to different groups by body weight stratification method using ProvantisTM software.
After grouping and ascertaining the group mean body weight, the rats were given accession number as applicable to the group on each day of assignment.
Note: After confirming the day 0 of gestation, females were housed individually, and the unselected females and males were disposed after mating procedure.
The selected female rats were assigned to vehicle control, and three test item treatment groups.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATION: Yes
- Time schedule: Twice a day (pre dose and post dose) during treatment period
- Cage side observation checked in table 2 were included - Ovaries and uterine content:
- The ovaries and uterine contents were examined after termination GD 20.
• Pregnancy status
• Gravid uterine weight (from all rats subjected to caesarean section)
• Number of corpora lutea
• Number of implantation sites
• Number of early resorptions
• Number of late resorptions
• Gross evaluation of placenta - Blood sampling:
- At caesarean section, from each rat, blood was collected under isoflurane anaesthesia, with a fine capillary tube, by retro-orbital sinus puncture for the determination of total Triiodothyronine (T3), Thyroxine (T4) and Thyroid Stimulating Hormone (TSH) hormones.
Blood samples (about 1 mL from each rat) were collected in plain labelled tubes and kept on bench top for approximately 90 minutes before centrifugation. Serum was separated by centrifuging the whole blood samples at 5000 rpm for 5 minutes at 4°C. The serum samples were placed in labeled plastic tubes and stored at approximately -70 °C until they were analysed. - Fetal examinations:
- • Total number of fetuses
• Total number of live fetuses
• Total number of dead fetuses
• Individual fetal body weight
• Fetus sex (during visceral examination)
• External examination of fetus
• Soft tissue evaluation
• Skeletal examination
• Head examination (half the number of fetuses per litter) - Statistics:
- Data captured using the ProvantisTM laboratory information management system (LIMS), parameters such as maternal body weight, body weight change, food consumption, gravid uterine weight, body weight change corrected to gravid uterine weight, maternal food consumption, Pre/post implantation loss , no. of implantations, sex ratio, Number of corpora lutea, early and late resorptions, hormone analyses (T4, T3, TSH) and the weight of thyroid gland data were evaluated using the Levene test for homogeneity of variances and the Shapiro-Wilks test for normality of distributions. Data found to be homogeneous and of normal distribution, was analysed by analysis of variance (ANOVA). Data found to be nonhomogeneous or of nonnormal data was subjected for transformation and ANOVA was done on transformed data. When ANOVA was significant, pairwise comparisons of treated groups to the control group was made using a parametric test, Dunnett, to identify statistical differences.
Fetal weight for male and female was analyzed using Analysis of Covariance (ANCOVA) taking litter size as covariate for group. Anogenital distance for male and female was analyzed using Analysis of Covariance (ANCOVA) taking weight as covariate for group.
The incidence of dams with resorptions were tested for using Chi-square test followed by Fisher’s exact test for group association.
The incidence of fetus and litter (incidence and percent) observations for skeletal observations were tested using Cochran Armitage trend test and pair wise comparison were tested by Fisher’s exact test for group association.
All hypothesis testing was carried out at the 5% (2-sided) significance level. Significant differences are designated throughout the report as below:
*: Statistically significant difference from the control group at p < 0.05 - Historical control data:
- Refer Annexure 8
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- There was no morbidity or mortality and the treated rats were normal throughout the experimental period at all the doses tested.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The maternal absolute mean body weights, body weight gains and adjusted/corrected body weight gain were unaffected by treatment up to the highest dose of 180 mg/kg/day. The adjusted body weight gain was significantly lower (- 12%) at 90 mg/kg/day which is considered incidental as a similar trend was not observed at the highest dose of 180 mg/kg/day.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The maternal mean food consumption was unaffected by treatment up to the highest dose of 180 mg/kg/day. At 90mg/kg/day, the food consumption during GD 17-20 was significantly lower (- 9%) which is considered incidental as a similar trend was not observed at the highest dose of 180 mg/kg/day.
- Endocrine findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in total Triiodothyronine (T3), Thyroxine (T4) or Thyroid Stimulating Hormone (TSH) hormones at any dose level.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Thyroid gland weight was unaffected by treatment. No treatment-related histopathological effects were observed in the thyroid gland.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no test item related findings in any of the organs on gross examination.
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no test item related changes in organ weights and histopathology of thyroid glands from all treated groups.
The incidences of ectopic thymus and ultimobranchial cysts were randomly distributed across the groups and hence considered as incidental background findings and not related to test item administration. - Other effects:
- no effects observed
- Description (incidence and severity):
- Thyroid hormone levels (T3, T4 and TSH), thyroid weights, and thyroid histology were unaffected by treatment.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- No abortions in the study
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The post implantation loss rate at 45 mg/kg/day was significantly lower which could account for the observed higher total number of fetuses in this dose group. Gross evaluation of placenta revealed no remarkable findings.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 180 mg/kg bw/day
- Basis for effect level:
- other: maternal body weight and weight gain, corrected body weight gain and food consumption was unaffected up to 180 mg/kg/day.
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The litter parameters (mean fetal weight and number of live fetuses) were comparable between the vehicle control group and rats treated up to the highest dose of 180 mg/kg/day, except at 45 mg/kg/day, the total number of fetuses and thus the mean litter size was significantly higher. This was considered incidental and toxicological not relevant as a similar trend was not observed at the higher doses.
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- The mean anogenital distance in male and female fetuses were comparable to the concurrent vehicle control, except at 90 mg/kg/day the mean anogenital distance of male fetuses was significantly higher and this finding was considered incidental as a similar trend was not observed at the highest dose of 180 mg/kg/day.
- External malformations:
- no effects observed
- Description (incidence and severity):
- No test item-related changes were observed during external observations of fetuses of rats treated up to 180 mg/kg/day.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- There were no skeletal malformations observed in any litter at any of the tested dose leve.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No test item-related changes were observed during fresh visceral examination of fetuses of rats treated up to 180 mg/kg/day.
Fetal heads in all dose groups were normal when subjected to Wilsons Razor blade sectioning. - Other effects:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 180 mg/kg bw/day
- Sex:
- not specified
- Basis for effect level:
- other: fetal resorptions or post implantation loss were comparable to the control, no effects on fetal body weights and further the fetal external, visceral and skeletal examinations revealed no signs of teratogenicity or developmental toxicity up to 180 mg/kg/d
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Treatment related:
- no
Any other information on results incl. tables
Detailed results see attached background materials in "Overall remarks, attachements".
Summary of Maternal Survival, Pregnancy Status and Fetus Disposition
Parameters | Group No. | G1 | G2 | G3 | G4 |
Dose (mg/kg/day) | 0 | 45 | 90 | 180 | |
Total No. of rats found sperm positive / group | 24 | 24 | 24 | 24 | |
Duration of treatment | GD 5 to 19 (total 15 days) | ||||
Caesarean section (day of presumed gestation) | GD 20 | ||||
Number of rats sacrificed at caesarean section | 24 | 24 | 24 | 24 | |
Number. of rats non-pregnant at caesarean section | 2 | 1 | 1 | 5 | |
Number of rats pregnant at caesarean section | 22 | 23 | 23 | 19 | |
Number of litters examined | 22 | 23 | 23 | 19 | |
Total number of fetuses | 320 | 360 | 323 | 280 | |
Total number of dead fetuses | 0 | 0 | 0 | 0 | |
|
|
|
|
| |
Number of fetuses evaluated |
|
|
|
| |
a. External examination | 320 | 360 | 323 | 280 | |
b. Visceral examination | 157 | 172 | 158 | 135 | |
c. Skeletal examination | 163 | 188 | 165 | 145 |
Summary of Clinical Signs and Mortality
Observation Type: All Types | Female | |||
From Day 0 (Mating) to 20 | G1 0 mg/kg/day | G2 G3 45 90 mg/kg/day mg/kg/day | G4 180 mg/kg/day | |
Normal | 24 | 24 | 24 | 24 |
Killed - terminal kill | 24 | 24 | 24 | 24 |
Summary of Maternal Body Weight of Pregnant Rats
Sex: Female Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Body | 0 [a] | Mean | 271.90 | 271.08 | 273.68 | 266.23 |
Weight (g) | SD N | 21.61 22 | 21.10 23 | 21.55 23 | 22.09 19 | |
%Diff | - | -0.30 | 0.66 | -2.08 | ||
3 [a1] | Mean | 289.51 | 288.27 | 291.64 | 284.12 | |
SD | 19.20 | 22.19 | 21.92 | 22.74 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | -0.43 | 0.74 | -1.86 | ||
5 [a1] | Mean | 298.20 | 297.58 | 299.18 | 291.99 | |
SD | 18.67 | 22.94 | 23.53 | 22.98 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | -0.21 | 0.33 | -2.08 | ||
8 [a1] | Mean | 309.26 | 308.05 | 309.07 | 300.71 | |
SD | 19.11 | 24.47 | 25.32 | 22.66 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | -0.39 | -0.06 | -2.76 | ||
11 [a1] | Mean | 327.25 | 325.27 | 326.06 | 318.19 | |
SD | 20.58 | 24.66 | 26.88 | 22.94 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | -0.60 | -0.36 | -2.77 | ||
14 [a1] | Mean | 343.17 | 341.58 | 342.62 | 336.86 | |
SD | 22.09 | 26.01 | 28.16 | 25.64 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | -0.46 | -0.16 | -1.84 | ||
17 [a1] | Mean | 377.16 | 376.82 | 374.26 | 371.34 | |
SD | 25.80 | 26.65 | 28.71 | 25.66 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | -0.09 | -0.77 | -1.54 | ||
20 [a1] | Mean | 425.27 | 428.12 | 418.19 | 421.92 | |
SD | 33.79 | 30.87 | 35.93 | 31.82 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | - | 0.67 | -1.66 | -0.79 |
[a] - Anova & Dunnett(Log)
[a1] - Anova & Dunnett
Summary of Maternal Body Weight Gain of Pregnant Rats
Sex: Female Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Absolute | 0 → 3 [a] | Mean | 17.62 | 17.19 | 17.96 | 17.88 |
Weight Gain (g) | SD N | 5.55 22 | 3.60 23 | 3.75 23 | 3.07 19 | |
%Diff | . | -2.41 | 1.95 | 1.50 | ||
3 → 5 [a] | Mean | 8.69 | 9.31 | 7.53 | 7.87 | |
SD | 9.60 | 3.51 | 4.50 | 2.60 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 7.09 | -13.30 | -9.39 | ||
5 → 8 [a] | Mean | 11.06 | 10.47 | 9.89 | 8.72 | |
SD | 5.97 | 4.77 | 3.86 | 4.69 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -5.35 | -10.56 | -21.12 | ||
8 → 11 [a] | Mean | 17.98 | 17.23 | 16.99 | 17.48 | |
SD | 7.12 | 3.09 | 3.93 | 4.34 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -4.21 | -5.50 | -2.81 | ||
11 → 14 [a1] | Mean | 15.93 | 16.31 | 16.56 | 18.67 | |
SD | 5.04 | 4.61 | 3.50 | 4.85 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 2.39 | 3.98 | 17.23 | ||
14 → 17 [a] | Mean | 33.99 | 35.24 | 31.63 | 34.48 | |
SD | 9.34 | 7.38 | 5.32 | 6.74 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 3.67 | -6.93 | 1.44 | ||
17 → 20 [a] | Mean | 48.10 | 51.31 | 43.94 | 50.58 | |
SD | 13.62 | 7.30 | 14.54 | 9.53 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 6.66 | -8.66 | 5.15 |
Sex: Female Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Absolute | 0 → 5 [a] | Mean | 26.31 | 26.50 | 25.50 | 25.76 |
Weight Gain (g) | SD N | 11.57 22 | 5.67 23 | 4.70 23 | 4.15 19 | |
%Diff | . | 0.73 | -3.09 | -2.10 | ||
5 → 20 [a] | Mean | 127.06 | 130.55 | 119.02 | 129.93 | |
SD | 31.86 | 15.04 | 18.78 | 16.31 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 2.74 | -6.33 | 2.26 | ||
0 → 20 [a] | Mean | 153.37 | 157.05 | 144.51 | 155.69 | |
SD | 31.39 | 16.04 | 19.75 | 17.45 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 2.40 | -5.78 | 1.51 | ||
Adjusted | GD20 - GU WT | Mean | 339.32 | 337.46 | 335.55 | 333.03 |
Body weight (g) | [a] | SD N | 28.02 22 | 24.20 23 | 28.54 23 | 22.92 19 |
%Diff | . | -0.55 | -1.11 | -1.86 | ||
Adjusted | ADJ BWT- | Mean | 41.12 | 39.88 | 36.38 * | 41.04 |
Body weight Gain (g) | GD5BWT [a] | SD N %Diff | 26.94 22 . | 7.64 23 -3.02 | 13.28 23 -11.54 | 9.96 19 -0.20 |
[a] - Anova & Dunnett(Rank)
[a1] - Anova & Dunnett
Summary of Food Consumption of Pregnant Rats
Sex: Female Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Food Mean | 0 → 3 [a] | Mean | 23.66 | 23.56 | 23.38 | 22.37 |
Consumption (g/day) | SD N | 2.08 22 | 2.45 23 | 2.46 23 | 2.15 19 | |
%Diff | . | -0.44 | -1.22 | -5.45 | ||
3 → 5 [a] | Mean | 25.02 | 25.50 | 24.16 | 24.22 | |
SD | 2.76 | 2.63 | 2.87 | 2.14 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 1.88 | -3.47 | -3.22 | ||
5 → 8 [a] | Mean | 26.02 | 25.47 | 24.65 | 23.78 | |
SD | 2.57 | 3.16 | 3.07 | 2.02 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -2.14 | -5.28 | -8.63 | ||
8 → 11 [a] | Mean | 26.72 | 26.33 | 25.55 | 24.84 | |
SD | 2.55 | 2.60 | 3.25 | 2.40 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -1.45 | -4.37 | -7.04 | ||
11 → 14 [a] | Mean | 27.87 | 27.89 | 27.03 | 27.43 | |
SD | 3.06 | 2.66 | 3.41 | 2.57 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | 0.08 | -3.01 | -1.57 | ||
14 → 17 [a] | Mean | 28.45 | 28.43 | 27.50 | 27.39 | |
SD | 3.52 | 2.44 | 2.76 | 2.17 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -0.08 | -3.34 | -3.73 | ||
17 → 20 [a1] | Mean | 30.00 | 29.16 | 27.27 * | 29.30 | |
SD | 3.66 | 1.85 | 3.80 | 3.09 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -2.78 | -9.08 | -2.32 |
Sex: Female Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Food Mean | 0 → 5 [a] | Mean | 24.21 | 24.33 | 23.69 | 23.11 |
Consumption (g/day) | SD N | 1.99 22 | 2.30 23 | 2.44 23 | 1.99 19 | |
%Diff | . | 0.52 | -2.15 | -4.53 | ||
5 → 20 [a] | Mean | 27.81 | 27.46 | 26.40 | 26.55 | |
SD | 2.62 | 2.09 | 2.74 | 1.88 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -1.28 | -5.07 | -4.55 | ||
0 → 20 [a] | Mean | 26.91 | 26.68 | 25.72 | 25.69 | |
SD | 2.27 | 2.08 | 2.61 | 1.76 | ||
N | 22 | 23 | 23 | 19 | ||
%Diff | . | -0.87 | -4.41 | -4.54 |
[a] - Anova & Dunnett
[a1] - Anova & Dunnett(Rank): *: Statistically significant different from vehicle control at p < 0.05
Summary of Maternal Data
Sex: Female
Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Group size |
| N | 24 | 24 | 24 | 24 |
Pregnant at C/S |
| N | 22 | 23 | 23 | 19 |
Gravid Uterus Weight | [a] | Mean SD | 85.942 11.480 | 90.667 13.931 | 82.640 17.631 | 88.896 15.576 |
Number of CorporaLutea | [a1] | Mean SD Sum | 17.3 2.1 381 | 18.0 1.9 413 | 16.7 2.0 384 | 17.7 1.9 336 |
No. of Implantation | [a] | Mean SD Sum | 16.0 1.9 353 | 16.3 2.4 374 | 15.0 2.8 346 | 15.7 2.5 298 |
Dams with Early Resorption |
| N | 13 | 8 | 11 | 12 |
Number of Early Resorptions | [a] | Mean SD Sum | 1.1 1.2 24 | 0.5 0.7 11 | 0.7 0.9 16 | 0.8 0.7 15 |
% Early Resorption /Animal | [a] | Mean SD | 6.74 7.19 | 2.98 4.67 | 5.13 6.69 | 5.49 4.97 |
Dams with Late Resorption |
| N | 6 | 3 | 6 | 2 |
Number of Late Resorptions | [a] | Mean SD Sum | 0.4 0.8 9 | 0.1 0.3 3 | 0.3 0.6 7 | 0.2 0.5 3 |
% Late Resorption /Animal | [a] | Mean SD | 2.46 5.00 | 0.71 1.89 | 1.86 3.46 | 0.90 2.79 |
Dams with Resorptions | [f] | N | 17 | 9 | 14 | 12 |
Total Number of Resorption (Early + Late) | [f] | Mean SD Sum Trend | 1.5 1.2 33
| 0.6 0.9 14
| 1.0 1.0 23 | 0.9 1.0 18 0.7664 |
Pre-implantation Loss/Anima | [a] | Mean SD Sum | 1.27 0.98 28 | 1.70 1.79 39 | 1.65 1.61 38 | 2.00 2.45 38 |
% Pre-implantation Loss | [a] | Mean SD | 7.1 5.3 | 9.5 11.1 | 10.4 11.5 | 10.9 12.8 |
Post-implantation Loss/Animal | [a] | Mean SD Sum | 1.50 1.22 33 | 0.61 0.89 14 | 1.00 1.00 23 | 0.95 0.97 18 |
% Post-implantation Loss (%) | [a] | Mean SD | 9.2 7.5 | 3.7* 5.5 | 7.0 6.8 | 6.4 6.2 |
Note: Gross evaluation of placenta revealed no findings
[a] - Anova & Dunnett (Rank): *: Statistically significant different from vehicle control at p < 0.05
[a1] - Anova & Dunnett
[f] - Cochran Armitage, Chi-Squared & Fisher's Exact
Sex: Female Day(s) Relative to Mating | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | ||
Total Number of fetuses | [a] | Sum | 320 | 360* | 323 | 280 |
Total Number of Dead Fetuses |
| Sum | 0 | 0 | 0 | 0 |
Total Number of Live fetuses | [a] | Sum | 320 | 360* | 323 | 280 |
Mean Litter size | [a] | Mean SD N | 14.5 1.9 22 | 15.7* 2.5 23 | 14.0 3.0 23 | 14.7 2.8 19 |
Live Male fetus |
| Sum | 179 | 185 | 169 | 141 |
% Male Fetus |
|
| 55.9 | 51.4 | 52.3 | 50.4 |
Mean Fetal Weight- Male (g) | [c] | Mean SD | 3.873 0.212 | 3.873 0.245 | 3.902 0.300 | 4.044 0.468 |
Mean AGD- Male (mm) | [c1] | Mean SD | 2.60 0.11 | 2.62 0.08 | 2.68* 0.12 | 2.64 0.10 |
Live Female fetus |
| Sum | 141 | 175 | 154 | 139 |
% Female Fetus |
|
| 44.1 | 48.6 | 47.7 | 49.6 |
Mean Fetal Weight- Female (g) | [c2] | Mean SD | 3.663 0.193 | 3.684 0.202 | 3.730 0.277 | 3.825 0.460 |
Mean AGD- Female (mm) | [c3] | Mean SD | 0.92 0.06 | 0.94 0.06 | 0.95 0.06 | 0.94 0.06 |
Mean Fetal Weight -Male+Female (g) | [c4] | Mean SD | 3.785 0.189 | 3.777 0.217 | 3.809 0.267 | 3.940 0.446 |
Mean AGD Male + Female (mm) | [c5] | Mean SD | 1.86 0.26 | 1.80 0.21 | 1.84 0.30 | 1.79 0.21 |
[a] - Anova & Dunnett(Rank):
[c] - Ancova/Anova & Dunnett (Rank); {Covariate(s): Number of Live Male Fetuses}
[c1] - Ancova/Anova & Dunnett; Covariate(s): Number of Live Male Fetuses}
[c2] - Ancova/Anova & Dunnett (Rank); {Covariate(s): Number of Live Female Fetuses}
[c3] - Ancova/Anova & Dunnett; Covariate(s): Number of Live Female Fetuses}
[c4] - Ancova/Anova & Dunnett (Rank); {Covariate(s): Number of Live Fetuses}
[c5] - Ancova/Anova & Dunnett; Covariate(s): Number of Live Fetuses}
*: Statistically significant different from vehicle control at p < 0.05
Summary of Fetal External Observations
Exam Type: External | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day |
Number of Live Fetuses Examined | 320 | 360 | 323 | 280 |
Number of Litters Evaluated | 22 | 23 | 23 | 19 |
|
| |||
Variants | None | |||
|
|
|
|
|
Anamolies | None | |||
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|
Malformations | None |
Refer Appendix 9
Exam Type: Visceral | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day |
Number of Live Fetuses Examined | 157 | 172 | 158 | 135 |
Number of Litters Evaluated | 22 | 23 | 23 | 19 |
|
| |||
Variants | None | |||
|
|
|
|
|
Anamolies | None | |||
|
|
|
|
|
Malformations | None |
Summary of Fetal Skeletal Observations
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
Lumbar vertebrae | |||||
1st lumbar centrum, Split - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
1st lumbar centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 2(8.7) | 0(0.0) | |
8th lumbar centrum and arch, Extra - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 0(0.0) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 0(0.0) | |
thoracic vertebrae | |||||
13th thoracic centrum, Split - Anomaly | Fetuses N(%) | 1(0.6) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 1(4.5) | 1(4.3) | 0(0.0) | 1(5.3) | |
13th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 2(1.2) | 5(2.7) | 5(3.0) | 0(0.0) |
Litters N(%) | 2(9.1) | 5(21.7) | 5(21.7) | 0(0.0) | |
13th thoracic centrum, Assymetrical dumbbell shaped - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
13th thoracic centrum, Hypoplastic unilateral ossific - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
12th thoracic centrum, Split - Anomaly | Fetuses N(%) | 2(1.2) | 3(1.6) | 0(0.0) | 0(0.0) |
Litters N(%) | 2(9.1) | 3(13.0) | 0(0.0) | 0(0.0) | |
12th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 11(6.7) | 24(12.8) | 24(14.5)* | 6(4.1) |
Litters N(%) | 8(36.4) | 12(52.2) | 12(52.2) | 5(26.3) | |
12th thoracic centrum, Assymetrical dumbbell shaped - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
12th thoracic centrum, Asymmetrical split - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 1(0.6) | 0(0.0) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
thoracic vertebrae (Continued...) | |||||
12th thoracic centrum, Asymmetrical split - Anomaly | Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 0(0.0) |
11th thoracic centrum, Split - Anomaly | Fetuses N(%) | 2(1.2) | 4(2.1) | 0(0.0) | 0(0.0) |
Litters N(%) | 2(9.1) | 3(13.0) | 0(0.0) | 0(0.0) | |
11th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 15(9.2) | 31(16.5) | 29(17.6)* | 14(9.7) |
Litters N(%) | 11(50.0) | 15(65.2) | 17(73.9) | 10(52.6) | |
11th thoracic centrum, Assymetrical dumbbell shaped - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
10th thoracic centrum, Split - Anomaly | Fetuses N(%) | 1(0.6) | 2(1.1) | 3(1.8) | 0(0.0) |
Litters N(%) | 1(4.5) | 2(8.7) | 2(8.7) | 0(0.0) | |
10th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 23(14.1) | 35(18.6) | 34(20.6) | 14(9.7) |
Litters N(%) | 12(54.5) | 17(73.9) | 15(65.2) | 6(31.6) | |
9th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 13(8.0) | 16(8.5) | 10(6.1) | 6(4.1) |
Litters N(%) | 9(40.9) | 14(60.9) | 6(26.1) | 4(21.1) | |
8th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 3(1.8) | 6(3.2) | 4(2.4) | 3(2.1) |
Litters N(%) | 3(13.6) | 4(17.4) | 4(17.4) | 3(15.8) | |
7th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 3(1.8) | 1(0.7) |
Litters N(%) | 1(4.5) | 0(0.0) | 2(8.7) | 1(5.3) | |
6th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 3(1.8) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 2(8.7) | 0(0.0) | |
5th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 2(1.2) | 1(0.5) | 2(1.2) | 0(0.0) |
Litters N(%) | 2(9.1) | 1(4.3) | 2(8.7) | 0(0.0) | |
4th thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
thoracic vertebrae (Continued...) | |||||
4th thoracic centrum, Dumbbell-shaped - Anomaly | Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) |
3rd thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
2nd thoracic centrum, Dumbbell-shaped - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
2nd thoracic centrum, Incomplete ossification - Variation | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 1(5.3) | |
1st thoracic centrum, Delayed skeletal ossification - Variation | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
1st thoracic centrum, Incomplete ossification - Variation | Fetuses N(%) | 1(0.6) | 0(0.0) | 1(0.6) | 1(0.7) |
Litters N(%) | 1(4.5) | 0(0.0) | 1(4.3) | 1(5.3) | |
ribs | |||||
14th rib, Right, Rudimentary - Anomaly | Fetuses N(%) | 10(6.1) | 8(4.3) | 8(4.8) | 2(1.4) |
Litters N(%) | 7(31.8) | 7(30.4) | 6(26.1) | 2(10.5) | |
14th rib, Right, Accessory - Anomaly | Fetuses N(%) | 3(1.8) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 3(13.6) | 0(0.0) | 0(0.0) | 0(0.0) | |
14th rib, Right, Extra - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
14th rib, Left, Rudimentary - Anomaly | Fetuses N(%) | 16(9.8) | 16(8.5) | 13(7.9) | 5(3.4) |
Litters N(%) | 11(50.0) | 10(43.5) | 8(34.8) | 5(26.3) | |
14th rib, Left, Accessory - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 2(1.2) | 1(0.7) |
Litters N(%) | 1(4.5) | 0(0.0) | 2(8.7) | 1(5.3) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
ribs (Continued...) | |||||
14th rib, Left, Extra - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 0(0.0) | |
14th rib, Bilateral, Rudimentary - Anomaly | Fetuses N(%) | 18(11.0) | 11(5.9) | 11(6.7) | 15(10.3) |
Litters N(%) | 11(50.0) | 10(43.5) | 8(34.8) | 9(47.4) | |
14th rib, Bilateral, Accessory - Anomaly | Fetuses N(%) | 3(1.8) | 0(0.0) | 1(0.6) | 1(0.7) |
Litters N(%) | 3(13.6) | 0(0.0) | 1(4.3) | 1(5.3) | |
14th rib, Bilateral, Extra - Anomaly | Fetuses N(%) | 0(0.0) | 5(2.7) | 1(0.6) | 0(0.0) |
Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 0(0.0) | |
12th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
12th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
12th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 0(0.0) | |
11th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 2(1.2) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 2(8.7) | 1(5.3) | |
11th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
11th rib, Bilateral, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
11th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 0(0.0) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
ribs (Continued...) | |||||
10th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 4(2.4) | 2(1.4) |
Litters N(%) | 0(0.0) | 1(4.3) | 4(17.4) | 1(5.3) | |
10th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 1(5.3) | |
10th rib, Bilateral, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
10th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
9th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 2(1.2) | 2(1.4) |
Litters N(%) | 0(0.0) | 1(4.3) | 2(8.7) | 1(5.3) | |
9th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 1(5.3) | |
9th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
8th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 2(1.2) | 2(1.4) |
Litters N(%) | 0(0.0) | 1(4.3) | 2(8.7) | 1(5.3) | |
8th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 1(5.3) | |
8th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
7th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 1(0.6) | 3(2.1) |
Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 1(5.3) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
ribs (Continued...) | |||||
7th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 1(5.3) | |
7th rib, Left, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
7th rib, Bilateral, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
7th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
6th rib, Left, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 0(0.0) | 1(5.3) | |
6th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 1(0.6) | 3(2.1) |
Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 1(5.3) | |
6th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 1(5.3) | |
6th rib, Bilateral, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
6th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
5th rib, Right, Wavy Rib, Slight - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 2(1.2) | 2(1.4) |
Litters N(%) | 0(0.0) | 1(4.3) | 2(8.7) | 1(5.3) | |
5th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 1(0.7) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 1(5.3) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
ribs (Continued...) | |||||
5th rib, Bilateral, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 2(1.2) | 0(0.0) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 0(0.0) | |
4th rib, Right, Wavy Rib, Moderate - Anomaly | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 1(0.7) |
Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 1(5.3) | |
sternebrae | |||||
6th sternebra, Delayed skeletal ossification - Variation | Fetuses N(%) | 0(0.0) | 1(0.5) | 1(0.6) | 2(1.4) |
Litters N(%) | 0(0.0) | 1(4.3) | 1(4.3) | 2(10.5) | |
6th sternebra, Incomplete ossification - Variation | Fetuses N(%) | 54(33.1) | 51(27.1) | 45(27.3) | 42(29.0) |
Litters N(%) | 20(90.9) | 17(73.9) | 16(69.6) | 14(73.7) | |
5th sternebra, Hypoplastic - Anomaly | Fetuses N(%) | 25(15.3) | 23(12.2) | 14(8.5) | 17(11.7) |
Litters N(%) | 17(77.3) | 17(73.9) | 13(56.5) | 12(63.2) | |
5th sternebra, Asymmetrical ossification - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 2(1.4) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 2(10.5) | |
4th sternebra, Asymmetrical ossification - Anomaly | Fetuses N(%) | 3(1.8) | 3(1.6) | 1(0.6) | 4(2.8) |
Litters N(%) | 3(13.6) | 3(13.0) | 1(4.3) | 4(21.1) | |
4th sternebra, Incomplete ossification - Variation | Fetuses N(%) | 4(2.5) | 1(0.5) | 3(1.8) | 2(1.4) |
Litters N(%) | 3(13.6) | 1(4.3) | 2(8.7) | 2(10.5) | |
3rd sternebra, Hypoplastic - Anomaly | Fetuses N(%) | 0(0.0) | 1(0.5) | 0(0.0) | 0(0.0) |
Litters N(%) | 0(0.0) | 1(4.3) | 0(0.0) | 0(0.0) | |
3rd sternebra, Asymmetrical ossification - Anomaly | Fetuses N(%) | 1(0.6) | 2(1.1) | 0(0.0) | 1(0.7) |
Litters N(%) | 1(4.5) | 2(8.7) | 0(0.0) | 1(5.3) | |
3rd sternebra, Incomplete ossification - Variation | Fetuses N(%) | 0(0.0) | 0(0.0) | 1(0.6) | 1(0.7) |
Exam Type: Skeletal-Entire Number of Live Fetuses Examined: Number of Litters Evaluated: | G1 0 mg/kg/day | G2 45 mg/kg/day | G3 90 mg/kg/day | G4 180 mg/kg/day | |
163 22 | 188 23 | 165 23 | 145 19 | ||
sternebrae (Continued...) | |||||
3rd sternebra, Incomplete ossification - Variation | Litters N(%) | 0(0.0) | 0(0.0) | 1(4.3) | 1(5.3) |
2nd sternebra, Hypoplastic - Anomaly | Fetuses N(%) | 5(3.1) | 5(2.7) | 1(0.6) | 4(2.8) |
Litters N(%) | 3(13.6) | 4(17.4) | 1(4.3) | 4(21.1) | |
2nd sternebra, Asymmetrical ossification - Anomaly | Fetuses N(%) | 1(0.6) | 0(0.0) | 1(0.6) | 0(0.0) |
Litters N(%) | 1(4.5) | 0(0.0) | 1(4.3) | 0(0.0) | |
skull | |||||
Supraoccipital, Incomplete ossification - Variation | Fetuses N(%) | 14(8.6) | 10(5.3) | 5(3.0)* | 17(11.7) |
Litters N(%) | 6(27.3) | 5(21.7) | 4(17.4) | 9(47.4) | |
Squamosal, Incomplete ossification - Variation | Fetuses N(%) | 1(0.6) | 0(0.0) | 0(0.0) | 2(1.4) |
Litters N(%) | 1(4.5) | 0(0.0) | 0(0.0) | 2(10.5) | |
Parietal, Incomplete ossification - Variation | Fetuses N(%) | 21(12.9) | 19(10.1) | 12(7.3) | 25(17.2) |
Litters N(%) | 7(31.8) | 12(52.2) | 7(30.4) | 11(57.9) | |
Interparietal, Incomplete ossification - Variation | Fetuses N(%) | 17(10.4) | 18(9.6) | 8(4.8) | 19(13.1) |
Litters N(%) | 7(31.8) | 9(39.1) | 6(26.1) | 10(52.6) | |
Hyoid, Incomplete ossification - Variation | Fetuses N(%) | 10(6.1) | 21(11.2) | 14(8.5) | 16(11.0) |
Litters N(%) | 5(22.7) | 11(47.8) | 9(39.1) | 9(47.4) |
[Fetuses N] - Cochran Armitage, Chi-Squared & Fisher's Exact:
[Litters N] - Cochran Armitage, Chi-Squared & Fisher's Exact *: Statistically significant different from vehicle control at p < 0.05
Applicant's summary and conclusion
- Conclusions:
- Based on the above findings, it is concluded that, No Observed Adverse- Effect Level (NOAEL) for
• Maternal toxicity is 180 mg/kg/day as the maternal body weight and weight gain, corrected body weight gain and food consumption was unaffected up to 180 mg/kg/day.
• Fetal developmental toxicity and Teratogenicity is 180 mg/kg/day as fetal resorptions or post implantation loss were comparable to the control, no effects on fetal body weights and further the fetal external, visceral and skeletal examinations revealed no signs of teratogenicity or developmental toxicity up to 180 mg/kg/day. - Executive summary:
The objective of this study was to evaluate the developmental toxicity of Genamin CH 020 in pregnant female Wistar rats and developing embryos/fetuses consequent to treatment of Genamin CH 020 in pregnant rats by oral gavage from gestation day (GD) 5 to 19. This study was intended to provide a rational basis for risk assessment in humans and to establish a No Observed Adverse Effect Level (NOAEL) for maternal and developmental toxicity in rats.
A total of 96,Day 0 pregnant rats[1]were randomly divided into different groups according to the study design as follows:
Group Nos.
Groups
Dose
(mg/kg/day)
Dosage volume (mL/kg)
Concentration (mg/mL)
No. of Day 0 pregnant rats
G1
Vehicle control*
0
10
0
24
G2
Low dose
45
10
4.5
24
G3
Mid dose
90
10
9
24
G4
High dose
180
10
18
24
*Milli-Q®Water
The following parameters and endpoints were evaluated in this study: Clinical signs, body weights, body weight gains, food consumption, gross pathology, gravid uterine weights, intrauterine growth and survival,number of corpora lutea, and fetal parameters [sex, weight and anogenital distance, and external, visceral and skeletal observations].Approximately half the number of the fetuses from each litter were examined for visceral malformations and variations and the remaining half were evaluated for skeletal malformations and variations. In addition, from each dam, the thyroid was weighed and subjected to microscopic evaluation. Thyroid hormones levels were determined from the blood samples collected at terminal sacrifie (on GD 20).
Results of the study are summarized below:
· Clinical signs and gross necropsy changes: There were no clinical signs, or mortalities in treated rats at any of the doses tested.
Grossly, at necropsy no abnormalities were detected.
· Maternal Parameters: No treatment-related effects on maternal body weights and food consumption up to the highest tested dose of 180 mg/kg/day. The other maternal parameters comprising of uterine weight, implantations and early and late resorptions, post implantation loss were comparable to vehicle control group up to the high dose of 180 mg/kg/day. Gross evaluation of placenta revealed no remarkable findings.
· Litter Parameters: No treatment-related effects on litter parameters comprising of total number of fetuses, fetal weights, anogenital distance in male and female fetuses, were observed.
· Fetal examination: External, visceral and skeletal examinations revealed no teratogenic effects attributed to the test item.
· Thyroid hormone levels (T3, T4 and TSH), thyroid weights, and thyroid histology were unaffected by treatment.
Based on the above findings, it is concluded that, No Observed Adverse- Effect Level (NOAEL) for
• Maternal toxicity is 180 mg/kg/day as the maternal body weight and weight gain, corrected body weight gain and food consumption was unaffected up to 180 mg/kg/day.
• Fetal developmental toxicity and Teratogenicity is 180 mg/kg/day as fetal resorptions or post implantation loss were comparable to the control, no effects on fetal body weights and further the fetal external, visceral and skeletal examinations revealed no signs of teratogenicity or developmental toxicity up to 180 mg/kg/day.
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