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EC number: 701-340-9 | CAS number: -
- 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://chesar.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:
- 28 July 2020 to 04 November 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
- Remarks:
- DRF study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 13 March 2020 to 08 May 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Reason / purpose for cross-reference:
- reference to other study
- Remarks:
- main study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- DRF study, only 10 pregnant females.
- GLP compliance:
- no
- Remarks:
- Following the OECD Principles of Good Laboratory Practices [C (97) 186/Final], however GLP status will not be claimed for the study.
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: In-house bred animals
- Age at study initiation: 9 to 10 weeks
- Weight at study initiation: Males: 259.90 to 289.32 g, Females: 202.35 to 263.47 g
- Fasting period before study: no
- Housing: Acclimatization - Maximum of three animals of same sex per cage were housed in sterilized standard polypropylene cage (Size: L 430 × B 285 × H 150 mm).
- Housing: Cohabitation Period - During cohabitation, three animals (one male and two females) were housed in standard polypropylene cage (Size: L 430 × B 285 × H 150 mm).
- Housing: Post-mating - After confirming presence of sperm in the vaginal smear and / or vaginal plugs (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually in polypropylene cage (Size: L 430 × B 285 × H 150 mm).
- Diet (e.g. ad libitum): not specified
- Water (e.g. ad libitum): not specified
- Acclimation period: minimum 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 to 23.2°C
- Humidity (%): 46 to 65%
- Air changes (per hr): 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light and 12 hours dark cycle
IN-LIFE DATES: From: 13 March 2020 To: 08 May 2020 - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item formulations were freshly prepared before dose administration on each treatment day. The required quantity of test item was weighed and triturated well in a mortar with a small quantity of vehicle until a homogenous suspension was formed and thereafter the entire quantity of the formulation was transferred into measuring cylinder. A small quantity of vehicle was added to rinse the mortar and this was transferred into the measuring cylinder. The rinsing procedure of mortar and pestle was repeated (many times) to ensure the transfer of the contents to the measuring cylinder. Finally, the volume was made up to required quantity with vehicle to get desired concentration of 10, 30 and 100 mg/mL of test item for low, mid and high dose groups respectively. The test formulations were maintained under stirring conditions using magnetic stirrer to maintain homogeneity of the test item formulations.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item was in-soluble in distilled water and uniformly suspended in 0.5% w/v Carboxy Methyl Cellulose at the concentration of 100 mg/mL (the highest dose concentration selected for the study considering the dose volume of 10 mL/kg body weight) as per in-house solubility/suspendibility test results. Hence, 0.5% w/v Carboxy Methyl Cellulose was used as vehicle for test item formulations and the details were recorded in the raw data and presented in the study report.
- Concentration in vehicle: 10 - 100mg/mL
- Amount of vehicle (if gavage): 10mL/kg bw
- Lot/batch no. (if required): BCBN1690V - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity of the test item in dose formulations was not established under this dose range finding study. However, freshly prepared test item formulations were administered to the animals.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: 2 weeks or until confirmation of mating
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: not detailed
- Verification of same strain and source of both sexes: yes, in-house bred line
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- Duration of treatment / exposure:
- Gestation Day 5 to Day 19
- Frequency of treatment:
- once daily
- Duration of test:
- 20 days
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 10 females in each group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: LD50 of similar test item Silicic acid, aluminum sodium salt, sulfurized, EC number 309-928-3 is >2000 mg/kg obtained from acute oral toxicity study in rats conducted as per OECD423 TG, The NOAEL of test item is 50 mg/kg when tested at 50, 500 and 5000 mg/kg obtained from a 90-day repeated oral toxicity study in rats conducted similar to ECD408 TG, The NOAEL for maternal toxicity is >=300 mg/kg, NOAEL for reproductive toxicity>=1000 mg/kg and NOAEL for offspring development >=1000 mg/kg when tested at 100, 300 and 1000 mg/kg body weight obtained from a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study in rats conducted as per OECD422 TG, The NOAEL for maternal toxicity is >100 mg/kg and the NOAEL for fetal toxicity (teratogenicity) is >10000 mg/kg when tested at 10, 100, 1000, 10000 mg/kg obtained from a Prenatal Developmental Toxicity Study in rats conducted in lines with OECD414 TG. Based on the above available information, the doses of 100, 300 and 1000 mg/kg body weight for vehicle control, low dose, mid dose and high dose groups, respectively were selected.
- Rationale for animal assignment (if not random): The body weight of mated females on its GD 0 was recorded and arranged in the ascending order of their body weight until required number of mated females acquired for each group. These mated females were distributed to all the groups based on their body weights so as to maintain comparable mean body weight for all groups
- Fasting period before blood sampling for (rat) dam thyroid hormones: n/a
- Time of day for (rat) dam blood sampling: n/a - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily for clinical signs of toxicity and twice daily
for mortality and morbidity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily for clinical signs of toxicity and twice daily
for mortality and morbidity
BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 3, 5, 8, 11, 14, 17, 19 and on 20
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): no feeding study
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): no drinking study
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Ovaries, Uterus with cervix, Thyroid with Parathyroid glands
- 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
- Blood sampling:
- - Plasma: No
- Serum: No - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: No
- Head examinations: No
- Anogenital distance of all live rodent pups: Yes - Statistics:
- Parametric: One-way ANOVA with Dunnett’s post test: Gestation body weight (g), Percent change in gestation body weight (%), Corrected body weight (g), Percent change in corrected body weight (%), Gravid uterus weight (g), Feed consumption (g), Mean Fetal weight (g) per dam, Mean Fetal crown rump length (mm) per dam, Mean Fetal ano-genital distance (mm) and ratio per dam, Organ weight. Non-Parametric: Kruskal-Wallis: No. of corpora lutea per dam, No. of implantations per dam, Litter size per dam, No. of live/dead fetuses per dam, No. of early/late resorptions per dam, Percent of live/dead fetuses per dam, Percent of early/late resorptions per dam, Sex ratio (m/f) per dam, Pre/Post-implantation losses (%) per dam, Fetal external anomalies per dam. Frequencies Comparison: Cross Tabs - Chi-square test: Pregnancy rate, No. of dams with/without live fetuses, No. of dams with/without dead fetuses, No. of litters with/without resorptions
- Indices:
- - Corrected Body weight (g) = (Gestation day 20 body weight - Gestation day 5 body weight) -
Gravid uterus weigh
- Percent of Live Fetuses per dam = (Number of Live Fetuses / Litter Size) x 100
- Percent of Dead Fetuses per dam = (Number of Dead Fetuses/ Litter Size) x 100
- Percent of Early Resorptions (%) per dam = (Number of Early Resorptions/Number of Implantation sites) x 100
- Percent of Late Resorptions (%) per dam = (Number of Late Resorptions / Number of Implantation sites)x 100
- Pre-implantation Loss (%) per dam = [(Number of Corpora lutea - Number of Implantation sites)/ Number of Corpora lutea]x 100
- Post-implantation Loss (%) per Dam = [(Number of Implantation sites - Number of Viable fetuses )/ Number of Implantation sites]x 100
- Sex Ratio (m/f) = Number of live male fetuses / Number of live female fetuses
- Male/Female Fetuses (%) = (Number of live male/female fetuses/ Total number of live fetuses)x 100
- Ano-genital Distance Ratio = Cube root of Fetal weight (g) /Ano-genital distance measurement (mm)
- Fetal incidence (%) = (Number of Fetuses with particular observation per group/Total number of Fetuses examined per group)x 100
- Litter incidence (%) = (Number of Litters/dams with particular observation per group/Total number of Litters per group) x 100 - Historical control data:
- not available
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A statistically significant reduction in the percent change in mean maternal body weight gain was noted during Gestation Day (GD) 8 to 11 at all the tested dose groups when compared with the vehicle control group. However, this noted change is considered as incidental and unrelated to treatment as there were no changes noted in feed consumption during this period and also no clinical signs were noted at any time point of treatment.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- A statistically significant reduction in mean maternal feed consumption was noted during GD 5 to 8 at all the tested dose groups when compared with the vehicle control group. However, this noted change is considered as incidental and unrelated to treatment as there were no effects noted in mean body weight and percent change in mean body weight gain during this period and also the change was inconsistent during treatment period.
- 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
- Description (incidence and severity):
- The absolute and relative thyroid along with the parathyroid weight did not reveal any changes when weighed post-fixation at all the tested dose groups.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in mean number of implantation sites at all the tested dose groups. The pre-and post-implantation losses per dam were unaffected at all the tested dose groups.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in mean number of resorptions.
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in mean live or dead fetuses at all the tested dose groups.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in pregnancy rate at all the tested dose groups.
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in mean gravid uterus weight at all the tested dose groups. There were no effects noted in mean number of corpora lutea at all the tested dose groups.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effects observed up to the highest dose tested
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes noted in mean fetal weight at all the tested dose groups.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in mean sex ratio at all the tested dose groups.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There were no effects noted in mean litter size at all the tested dose groups.
- Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- There were no changes noted in mean ano-genital distance measurement / ratio per dam at all the tested dose groups.
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A total of 103 (9), 104 (10), 90 (8) and 100 (9) fetuses (litters) were available for gross external examination from G1, G2, G3 and G4 respectively. There were no test itemrelated external bnormalities noted in fetuses of all the tested dose groups and the vehicle control group. However, subcutaneous haemorrhagic spots on skin were noted as 1 (1), 1(1) and 3(3) [fetal incidences (litter incidences)] from vehicle control group G1 and tested dose groups G2 and G3 respectively. This noted occurrence is considered as incidental and unrelated to treatment.
- Skeletal malformations:
- not examined
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There were no test item-related changes noted in any of the group fetuses subjected to visceral (soft tissue) examination on the day of caesarean section.
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no changes noted in mean crown rump length at all the tested dose groups.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed up to the highest dose tested
- Key result
- Abnormalities:
- no effects observed
- Key result
- Developmental effects observed:
- no
- Conclusions:
- The oral administration of test item by gavage to presumed pregnant female Sprague Dawley Rats from Gestation Day 5 to 19 did not produce any indication of maternal and developmental toxicity at the dose levels of 100, 300 and 1000 mg/kg body weight/day under experimental conditions employed.
- Executive summary:
To establish doses for a definitive pre-natal developmental toxicity study a dose range finding study was performed similar to OECD 414, non GLP using Sprague Dawley Rats. Doses of 100mg/kg, 300mg/kg and 1000mg/kg were chosen in this study based on available toxicological data in similar substance. 10 pregnant rats were allocated to each dose group and a concurrent vehicle control group of 10 animals was added. Carboxy methyl cellulose was chosen as vehicle and the test item was applied via oral (gavage) from gestation day 5 to 19 once daily. During the experiment, any clinical signs, mortality, body weight development, feed consumption was recorded. On GD20 the animals were euthanized and were subject to gross necropsy and relevant organs like ovaries, uterus with cervix and thyroid and parathyroid glands extracted. The sex, weight, crown-rump lengths, Ano-genital distance of the fetuses were determined and their soft tissue examined. Particular attention was paid to their reproductive tract and if external and internal sex matched. There were no signs of toxiticy in maternal animals for any endpoint. Similar, for pre-natal developmental toxicity no signs of toxicity could be noted besides some non test-item related alterations recorded during the external examination. The oral administration of test item by gavage to presumed pregnant female Sprague Dawley Rats from Gestation Day 5 to 19 did not produce any indication of maternal and developmental toxicity at the dose levels of 100, 300 and 1000 mg/kg body weight/day under experimental conditions employed and the same are then considered appropriate for the definitive test.
TABLE 1 SUMMARY OF PREGNANCY STATUS, CLINICAL SIGNS OF TOXICITY AND MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) | Pregnancy Status |
| Clinical Signs and Mortality Record | |||
No. of Presumed Pregnant Animals / Group | No. of Females confirmed with Pregnancy | Rate of Pregnancy (%) | Clinical Signs of Toxicity revealed (No. of Animals) | No. of Mortalities / Total No. of animals | ||
G1, F & 0 | 10 | 9 | 90.0 | N (10) | 0/10 | |
G2, F & 100 | 10 | 10 | 100.0 | N (10) | 0/10 | |
G3, F & 300 | 10 | 8 | 80.0 | N (10) | 0/10 | |
G4, F & 1000 | 10 | 9 | 90.0 | N (10) | 0/10 |
N: Normal
TABLE 2 SUMMARY OF GESTATION BODY WEIGHT (g) RECORD
(mg/kg body weight/day) | Body Weight (g) on Gestation Day (GD) | |||||||||
0 | 3 | 5 | 8 | 11 | 14 | 17 | 19 | 20 | ||
G1, F & 0 | Mean | 247.08 | 255.53 | 263.45 | 274.18 | 293.15 | 311.72 | 335.72 | 358.76 | 371.63 |
±SD | 24.92 | 25.58 | 25.13 | 26.33 | 32.82 | 33.92 | 32.85 | 39.43 | 40.92 | |
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 243.54 | 250.26 | 259.01 | 266.90 | 279.13 | 293.08 | 315.48 | 339.71 | 349.73 |
±SD | 16.73 | 16.60 | 18.19 | 19.08 | 21.37 | 20.17 | 23.26 | 29.33 | 31.50 | |
n | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 256.13 | 262.40 | 270.75 | 278.41 | 288.26 | 299.95 | 323.46 | 347.08 | 359.33 |
±SD | 17.14 | 17.20 | 18.86 | 18.56 | 20.59 | 20.02 | 22.82 | 22.87 | 25.41 | |
n | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 248.64 | 256.81 | 264.03 | 271.91 | 282.68 | 299.23 | 324.77 | 346.72 | 360.42 |
±SD | 19.65 | 18.66 | 18.02 | 18.86 | 20.44 | 27.61 | 30.08 | 35.63 | 34.04 | |
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: Number of Animals
TABLE 3 SUMMARY OF PERCENT CHANGE IN GESTATION BODY WEIGHT (%) GAIN RECORD
Group, Sex & Dose (mg/kg body weight/day) | Percent Change in Body Weight (%) during Gestation Day (GD) | ||||||||
0 to 3 | 3 to 5 | 5 to 8 | 8 to 11 | 11 to 14 | 14 to 17 | 17 to 19 | 19 to 20 | ||
G1, F & 0 | Mean | 3.43 | 3.15 | 4.08 | 6.80 | 6.38 | 7.86 | 6.76 | 3.59 |
±SD | 0.83 | 1.28 | 1.86 | 2.73 | 2.48 | 3.96 | 1.88 | 1.58 | |
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 2.78 | 3.48 | 3.04 | 4.56* | 5.06 | 7.64 | 7.61 | 2.94 |
±SD | 1.09 | 1.16 | 1.40 | 1.78 | 1.47 | 2.92 | 2.37 | 1.94 | |
n | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 2.46 | 3.16 | 2.85 | 3.52* | 4.09 | 7.83 | 7.34 | 3.51 |
±SD | 0.80 | 0.86 | 1.06 | 1.21 | 1.27 | 1.71 | 1.49 | 0.81 | |
n | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 3.33 | 2.84 | 2.98 | 3.95* | 5.75 | 8.55 | 6.69 | 4.03 |
±SD | 1.06 | 0.83 | 0.90 | 1.58 | 2.94 | 1.71 | 2.07 | 1.56 | |
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: Number of Animals
*: Statistically significant (P<0.05) change than the vehicle control group
TABLE 4 SUMMARY OF GRAVID UTERUS WEIGHT (g) AND MATERNAL BODY WEIGHT CHANGE CORRECTED FOR GRAVID UTERINE WEIGHT (g)
Group, Sex & Dose (mg/kg body weight/day) | Body Weight Change (g) GD 5 to 20 | Gravid Uterus Weight (g) | Corrected Body weight (Gram) | Corrected Body weight (Percentage) | |
G1, F & 0 | Mean | 108.18 | 74.97 | 33.21 | 12.45 |
±SD | 23.74 | 15.41 | 20.50 | 7.76 | |
n | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 90.71 | 61.14 | 29.57 | 11.49 |
±SD | 21.65 | 15.04 | 10.60 | 4.36 | |
n | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 88.59 | 63.58 | 25.00 | 9.19 |
±SD | 12.54 | 6.60 | 10.74 | 3.56 | |
n | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 96.39 | 65.18 | 31.21 | 11.65 |
±SD | 25.48 | 16.10 | 15.35 | 5.31 | |
n | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 5 SUMMARY OF AVERAGE GESTATION FEED CONSUMPTION (g/animal/day) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
| Average Feed Consumption (g/animal/day) during Gestation Day | |||||||
0 to 3 | 3 to 5 | 5 to 8 | 8 to 11 | 11 to 14 | 14 to 17 | 17 to 19 | 19 to 20 | ||
G1, F & 0 | Mean | 16.58 | 21.27 | 19.78 | 21.17 | 22.46 | 25.39 | 22.06 | 24.38 |
±SD | 1.82 | 1.72 | 1.46 | 2.86 | 1.52 | 1.90 | 3.33 | 4.92 | |
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 17.24 | 19.20 | 17.99* | 19.72 | 22.50 | 24.32 | 22.56 | 23.91 |
±SD | 1.83 | 2.69 | 1.15 | 1.32 | 1.80 | 3.39 | 3.62 | 5.17 | |
n | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 17.45 | 19.58 | 17.80* | 18.99 | 22.29 | 23.59 | 21.46 | 25.89 |
±SD | 1.08 | 1.58 | 2.18 | 2.82 | 2.16 | 1.83 | 2.34 | 6.53 | |
n | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 19.28 | 19.34 | 17.32* | 19.14 | 22.25 | 24.61 | 20.84 | 26.48 |
±SD | 4.09 | 0.74 | 1.00 | 1.68 | 1.30 | 1.78 | 2.10 | 5.34 | |
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: Number of Animals
*: Statistically significant (P<0.05) change than the vehicle control group
TABLE 6 SUMMARY OF UTERI OBSERVATIONS PER LITTER DURING CAESAREAN SECTION RECORD
Group, Sex & Dose (mg/kg body weight/day) | No. of Corpora lutea | No. of Implantations | Litter size | No. of Live Fetuses | No. of Male Live Fetuses | |
G1, F & 0 | Mean | 12.89 | 12.44 | 11.56 | 11.44 | 6.33 |
±SD | 1.36 | 1.59 | 2.19 | 2.35 | 3.00 | |
n | 9 | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 11.70 | 11.40 | 10.40 | 10.40 | 5.20 |
±SD | 2.50 | 2.46 | 3.13 | 3.13 | 2.62 | |
n | 10 | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 12.00 | 11.63 | 11.25 | 11.25 | 5.13 |
±SD | 1.77 | 1.51 | 1.67 | 1.67 | 0.64 | |
n | 8 | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 12.22 | 11.89 | 11.11 | 11.11 | 4.56 |
±SD | 1.99 | 2.26 | 2.76 | 2.76 | 1.51 | |
n | 9 | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 6 (Contd…). SUMMARY OF UTERI OBSERVATIONS PER LITTER DURING CAESAREAN SECTION RECORD
Group, Sex & Dose (mg/kg body weight/day) | No. of Female Live Fetuses | No. of Dead Fetuses | No. of Early Resorptions | No. of Late Resorptions | |
G1, F & 0 | Mean | 5.11 | 0.11 | 0.56 | 0.33 |
±SD | 1.17 | 0.33 | 1.01 | 0.71 | |
n | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 5.20 | 0.00 | 0.90 | 0.10 |
±SD | 1.87 | 0.00 | 1.29 | 0.32 | |
n | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 6.13 | 0.00 | 0.38 | 0.00 |
±SD | 1.73 | 0.00 | 0.74 | 0.00 | |
n | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 6.56 | 0.00 | 0.78 | 0.00 |
±SD | 2.35 | 0.00 | 1.39 | 0.00 | |
n | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 7 SUMMARY OF MATERNAL DATA PER LITTER RECORD
Group, Sex & Dose (mg/kg body weight/day) | Pre-Implantation Loss (%) | Post-Implantation Loss (%) | Percent of Dead Fetus | Percent of Early Resorptions | Percent of Late Resorptions | |
G1, F & 0 | Mean | 3.52 | 8.32 | 1.23 | 4.75 | 2.65 |
±SD | 5.53 | 12.91 | 3.70 | 9.09 | 5.76 | |
n | 9 | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 2.37 | 10.01 | 0.00 | 9.24 | 0.77 |
±SD | 5.27 | 12.25 | 0.00 | 12.64 | 2.43 | |
n | 10 | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 2.76 | 3.23 | 0.00 | 3.23 | 0.00 |
±SD | 5.61 | 6.61 | 0.00 | 6.61 | 0.00 | |
n | 8 | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 3.17 | 6.80 | 0.00 | 6.80 | 0.00 |
±SD | 4.93 | 12.65 | 0.00 | 12.65 | 0.00 | |
n | 9 | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 7 (Contd…). SUMMARY OF MATERNAL DATA PER LITTER RECORD
Group, Sex & Dose (mg/kg body weight/day) |
| Male/Female Sex ratio | Male Fetuses (%) | Female Fetuses (%) | Percent of Live Fetuses |
G1, F & 0 | Mean | 1.41 | 52.45 | 47.55 | 98.77 |
±SD | 0.91 | 18.79 | 18.79 | 3.70 | |
n | 9 | 9 | 9 | 9 | |
G2, F & 100 | Mean | 1.16 | 48.80 | 51.20 | 100.00 |
±SD | 0.78 | 15.06 | 15.06 | 0.00 | |
n | 10 | 10 | 10 | 10 | |
G3, F & 300 | Mean | 0.94 | 46.43 | 53.57 | 100.00 |
±SD | 0.46 | 9.53 | 9.53 | 0.00 | |
n | 8 | 8 | 8 | 8 | |
G4, F & 1000 | Mean | 0.79 | 41.93 | 58.07 | 100.00 |
±SD | 0.41 | 11.52 | 11.52 | 0.00 | |
n | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 8 SUMMARY OF ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose (mg/kg body weight/day) | Thyroid along with parathyroid # | |
G1, F & 0 | Mean | 0.0192 |
±SD | 0.0034 | |
n | 9 | |
G2, F & 100 | Mean | 0.0206 |
±SD | 0.0014 | |
n | 10 | |
G3, F & 300 | Mean | 0.0198 |
±SD | 0.0019 | |
n | 8 | |
G4, F & 1000 | Mean | 0.0211 |
±SD | 0.0020 | |
n | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals; #: Weighed Post fixation
TABLE 9 SUMMARY OF TERMINAL BODY WEIGHT (g) AND ORGAN WEIGHT (%) RELATIVE TO TERMINAL BODY WEIGHT RECORD
Group, Sex & Dose (mg/kg body weight/day) | Terminal Body Weight (g) | Thyroid along with parathyroid | |
G1, F & 0 | Mean | 371.63 | 0.0052 |
±SD | 40.92 | 0.0012 | |
n | 9 | 9 | |
G2, F & 100 | Mean | 349.73 | 0.0060 |
±SD | 31.50 | 0.0009 | |
n | 10 | 10 | |
G3, F & 300 | Mean | 359.33 | 0.0055 |
±SD | 25.41 | 0.0005 | |
n | 8 | 8 | |
G4, F & 1000 | Mean | 360.42 | 0.0059 |
±SD | 34.04 | 0.0008 | |
n | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 10 SUMMARY OF MEAN FETAL WEIGHT (g) PER LITTER, MEAN FETAL CROWN RUMP LENGTH (mm) PER LITTER AND MEAN ANOGENITAL DISTANCE (AGD) RATIO PER LITTER RECORD
Group, Sex & Dose (mg/kg body weight/day) | Mean Fetal Weight (g) | Mean Crown Rump Length (mm) | Mean Ano-genital Distance Measurement (mm) | Mean Ano-genital Distance Ratio | ||||||||
Male | Female | Male | Female | Male | Female | Male | Female | |||||
G1, F & 0 | Mean | 4.12 | 3.86 | 37.62 | 35.83 | 3.56 | 2.47 | 2.22 | 1.58 | |||
±SD | 0.18 | 0.17 | 1.18 | 1.06 | 0.32 | 0.14 | 0.21 | 0.08 | ||||
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 | ||||
G2, F & 100 | Mean | 4.16 | 3.87 | 37.81 | 36.19 | 3.49 | 2.50 | 2.17 | 1.60 | |||
±SD | 0.13 | 0.07 | 0.86 | 0.32 | 0.16 | 0.14 | 0.11 | 0.09 | ||||
n | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | ||||
G3, F & 300 | Mean | 4.12 | 3.85 | 37.72 | 36.33 | 3.54 | 2.44 | 2.21 | 1.55 | |||
±SD | 0.16 | 0.14 | 0.78 | 0.48 | 0.12 | 0.14 | 0.07 | 0.09 | ||||
n | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | ||||
G3, F & 1000 | Mean | 4.17 | 3.88 | 38.13 | 36.34 | 3.56 | 2.47 | 2.21 | 1.58 | |||
±SD | 0.21 | 0.19 | 0.34 | 0.54 | 0.07 | 0.14 | 0.07 | 0.08 | ||||
n | 9 | 9 | 9 | 9 | 9 | 9 | 9 | 9 |
F: Female; SD: Standard Deviation; n: No. of Animals
TABLE 11 SUMMARY RECORD OF FETAL EXTERNAL EXAMINATION PER LITTER
Parameters | Group | G1 | G2 | G3 | G4 | ||||||
Dose | 0 | 100 | 300 | 1000 | |||||||
Number of Dams | 9 | 10 | 8 | 9 | |||||||
Total Number of fetuses evaluated for | 103 | 104 | 90 | 100 | |||||||
|
|
|
|
| |||||||
No. of Fetuses (No. of Litters) noted with | 102 (8) | 103 (9) | 87 (5) | 100 (9) | |||||||
Percentage of Fetuses (Percentage of Dams) with No Abnormality Detected | 99.03 (88.89) | 99.04 (90.00) | 96.67 (62.50) | 100.00 (100.00) | |||||||
|
|
|
|
| |||||||
No. of Fetuses (No. of Dams) noted with Malformations | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |||||||
Percentage of Fetuses (Percentage of Dams) with Malformations | 0.0 (0.0) | 0.0 (0.0) | 0.0 (0.0) | 0.0 (0.0) | |||||||
|
|
|
|
| |||||||
No. of Fetuses (No. of Dams) with Variations | 1 (1) | 1 (1) | 3 (3) | 0 (0) | |||||||
Percentage of Fetuses (Percentage of Dams) with Variations | 0.97 (11.11) | 0.96 (10.00) | 3.33 (37.50) | 0.00 (0.00) | |||||||
VARIATIONS | |||||||||||
HAEMORRHAGIC SPOTS [EXTERNAL] | |||||||||||
Haemorrhagic spot | Fetal Incidences | 1 | 0.97 | 1 | 0.96 | 3 | 3.33 | 0 | 0.00 | ||
Litter Incidences | 1 | 11.11 | 1 | 10.00 | 3 | 37.50 | 0 | 0.00 | |||
|
| No. of fetuses with abnormality |
% of Abnormality | : | ------------------------------------------ X 100 |
|
| Total No. of fetuses examined |
TABLE 12 SUMMARY OF FETAL VISCERAL EXAMINATION PER LITTER RECORD
Parameters | Group | G1 | G2 | G3 | G4 |
Dose (mg/kg body weight/day) | 0 | 100 | 500 | 1000 | |
Number of Dams | 9 | 10 | 8 | 9 | |
Total Number of Fetuses evaluated for | 103 | 104 | 90 | 100 | |
|
|
|
|
| |
No. of Fetuses (No. of Litters) noted with | 103 (9) | 104 (10) | 90 (8) | 100 (9) | |
Percentage of Fetuses (Percentage of Dams) with | 100.00 (100.00) | 100.00 (100.00) | 100.00 (100.00) | 100.00 (100.00) | |
|
|
|
|
| |
No. of Fetuses (No. of Dams) with Malformations | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
Percent of Fetuses (Percent of Dams) with Malformations | 0.00 (0.00) | 0.00 (0.00) | 0.00 (0.00) | 0.00 (0.00) | |
|
|
|
|
| |
No. of Fetuses (No. of Dams) with Variations | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
Percentage of Fetuses (Percentage of Dams) with Variations | 0.00 (0.00) | 0.00 (0.00) | 0.00 (0.00) | 0.00 (0.00) |
|
| No. of fetuses with abnormality |
% of Abnormality | : | ------------------------------------------ X 100 |
|
|
TABLE 13 SUMMARY OF GROSS PATHOLOGY FINDINGS RECORD
Parameters ↓ | Sex | Female | |||
Group & Dose (mg/kg body weight/day) | G1 & 0 | G2 & 100 | G3 & 300 | G4 & 1000 | |
No. of Animals | 10 | 10 | 10 | 10 | |
No. of Animals found dead during treatment period | 0 | 0 | 0 | 0 | |
No. of Animals moribund sacrificed during treatment period | 0 | 0 | 0 | 0 | |
No. of Animals sacrificed terminally | 10 | 10 | 10 | 10 | |
Gross Pathology Findings | |||||
External | |||||
No. of animals with No Abnormality Detected | 10 | 10 | 10 | 10 | |
Internal | |||||
No. of animals with No Abnormality Detected | 10 | 10 | 10 | 10 |
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)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Sodium polysulfide aluminosilicate with a SOD-type framework structure
- EC Number:
- 701-340-9
- Molecular formula:
- |Na+6-x+y+z (S2•-)y(S3•-)z|[Al6-x Si6+x O24] - SOD Where: 6 ≤ 6-x+y+z ≤ 8 0 ≤ x ≤ 1.2 1 ≤ y+z ≤ 2
- IUPAC Name:
- Sodium polysulfide aluminosilicate with a SOD-type framework structure
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: In-house bred animals
- Age at study initiation: Minimum of 10 weeks
- Weight at study initiation: Males: 251.54 g to 289.11 g & Females: 204.23 g to 250.27 g
- Fasting period before study: No
- Housing: Pre-mating/Acclimatization - Maximum of three animals of same sex per cage were housed in sterilized standard polypropylene cage (Size: L 430 × B 285 × H 150 mm). Steam sterilized clean paddy husk was used as bedding material and was changed along with the cage at least twice a week
- Housing: Mating - During mating, three rats (one male and two females) were housed in standard polypropylene cages.
- Housing: Post mating - After confirming presence of sperm in the vaginal smear (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually in polypropylene cages.
- Diet (e.g. ad libitum): ad libitum - Altromin maintenance diet for rats and mice (manufactured by Altromin Spezialfutter GmbH & Co. KG)
- Water (e.g. ad libitum): ad libitum - Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period: for a minimum period of five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1ºC to 23.5 ºC
- Humidity (%): relative humidity 50 to 62%
- Air changes (per hr): 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light and 12 hours dark
IN-LIFE DATES: From: To: 28 July 2020 to 04 November 2020
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The required quantity of test item was weighed and triturated well in a mortar with a small quantity of vehicle until a homogenous suspension was formed and thereafter the entire quantity of the formulation was transferred into measuring cylinder. A small quantity of vehicle was added to rinse the mortar and this was transferred into the measuring cylinder. The rinsing procedure of mortar and pestle was repeated many times to ensure the transfer of the contents to the measuring cylinder. Finally, the volume was made up to required quantity with vehicle to get desired concentration of 10, 30 and 100 mg/mL of test item for low, mid and high dose groups respectively.
VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5% w/v Carboxy Methyl Cellulose, test item was insoluble in distilled water
- Concentration in vehicle: 100 mg/mL (maximum)
- Amount of vehicle (if gavage): 10mL/kg
- Lot/batch no. (if required): BCBN1690V
- Purity: n/a - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Verification of concentration and homogonetiy of the test item was conduced by BIONEEDS INDIA PRIVATE LIMITED DEVARAHOSAHALLY, SOMPURA HOBLI, NELAMANGALA TALUK, BANGALORE RURAL DISTRICT, PIN - 562 111, KARNATAKA, INDIA which hold the Good Laboratory Practice Certificate (GLP). 0.1 mL of sample was pipetted out into a digestion tube, a volume of 6 mL of concentrated nitric acid was added and placed in microwave sample preparation system and digested by the selected method. After digestion, the digestion tubes were cooled to room temperature and the contents were transferred to suitable volumetric flasks and diluted with Milli-Q water.
TECHNIQUE AND TEST METHOD: ICP-MS
TEST PARAMETERS: Timings Sweeps : 30 Seconds, Reading : 1, Replicates : 3, Analyte : Aluminium, Mass : 26.9815, Sample Flush : 35 seconds, Read Delay : 15 Seconds, Wash : 45 seconds, Mode : KED, Flow (Helium) : 4.0 mL, Vehicle: 0.5% Carboxymethyl Cellulose
ACCEPTANCE CRITERIA: Homogeneity and dose formulation analysis of prepared test formulations for the dose concentration verification were performed during first and last week of the treatment and the obtained mean results were within the range of 85 to 115% of the nominal concentration and the relative standard deviation (% RSD) is ≤10%. - Details on mating procedure:
- - Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1:2 ratio (one male and two females)
- Length of cohabitation: until evidence of copulation was observed or for two weeks.
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility. yes
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: In-house bred animals
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no - Duration of treatment / exposure:
- Gestation days 5 to 19
- Frequency of treatment:
- once daily
- Duration of test:
- Acclimatization: 28 July 2020 to 20 August 2020
Cohabitation: 04 August 2020 to 03 September 2020
Treatment: 10 August 2020 to 23 September 2020
Necropsy: 25 August 2020 to 24 September 2020
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose range finding study, conducted with the doses of 100, 300 and 1000 mg/kg body weight based on the available literature. Oral administration of test item to pregnant female Sprague Dawley Rats from Gestation Day 5 to 19 did not produce any indication of maternal and prenatal-developmental toxicity at all these tested dose levels in the dose range finding study.
- Rationale for animal assignment (if not random): evenly distributed to all the groups based on their body weights so as to maintain comparable mean body weight for all groups
- Fasting period before blood sampling for (rat) dam thyroid hormones: 0
- Time of day for (rat) dam blood sampling: within 2 hours before necropsy.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily for clinical signs of toxicity and twice daily for mortality and morbidity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on gestation days (GD) 0, 3, 5, 8, 11, 14, 17, 19 and on 20 (day of caesarean section).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not feeding study
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Recorded as g/animal/day during gestation days 0-3, 3-5, 5-8, 8-11, 11-14, 14-17, 17-19 and 19-20
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No applicable
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not drinking water study
POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day 20
- Organs examined: Ovaries, Uterus with cervix, Thyroid and Parathyroid glands
- 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
- Other: observation of uterine content. - Blood sampling:
- - Plasma: No
- Serum: Yes
- Volume collected - n/a
- Other: blood samples were collected as follows:
- From all dams at termination for mandatory assessment of thyroid hormones T4, T3 and thyroid stimulating hormone (TSH) within 2 hours before necropsy.
- Blood samples from non-pregnant females were also collected but were not pooled with the pregnant dams. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
- Anogenital distance of all live rodent pups: Individual fetus was measured for its anogenital distance on the day of caesarean section - Statistics:
- Parametric: One-way ANOVA with Dunnett’s post test: Maternal body weight, Percent change in maternal body weight , Corrected body weight for maternal increase, Gravid uterus weight, Maternal feed consumption, Mean fetal weight per dam, Mean fetal crown rump length per dam, Mean fetal anogenital distance per dam, Serum T3, T4 and TSH levels, Organ weight
Non-Parametric: Kruskal-Wallis: No. of corpora lutea per dam, No. of implantations per dam, Litter size per dam, No. of live/dead fetuses per dam, Percent of live/dead fetuses per dam, No. of early/late resorptions per dam, Percent of early/late resorptions per dam, Sex ratio (m/f) per dam, Pre/Post implantation losses (%) per dam, Fetal external / visceral / skeletal anomalies per dam
Frequencies Comparison: Cross Tabs -Chi-square test: No. of Pregnant / Non-pregnant females (Pregnancy status), No. of dams with / without live fetuses, No. of dams with / without dead fetuses, No. of dams with / without resorptions - Indices:
- - Corrected Body weight (g) = (Gestation day 20 body weight - Gestation day 5 body weight) -
Gravid uterus weigh
- Percent of Live Fetuses per dam = (Number of Live Fetuses / Litter Size) x 100
- Percent of Dead Fetuses per dam = (Number of Dead Fetuses/ Litter Size) x 100
- Percent of Early Resorptions (%) per dam = (Number of Early Resorptions/Number of Implantation sites) x 100
- Percent of Late Resorptions (%) per dam = (Number of Late Resorptions / Number of Implantation sites)x 100
- Pre-implantation Loss (%) per dam = [(Number of Corpora lutea - Number of Implantation sites)/ Number of Corpora lutea]x 100
- Post-implantation Loss (%) per Dam = [(Number of Implantation sites - Number of Viable fetuses )/ Number of Implantation sites]x 100
- Sex Ratio (m/f) = Number of live male fetuses / Number of live female fetuses
- Male/Female Fetuses (%) = (Number of live male/female fetuses/ Total number of live fetuses)x 100
- Ano-genital Distance Ratio = Ano-genital distance (mm) / Cube root of Fetal weight (g)
- Fetal incidence (%) = (Number of Fetuses with particular observation per group/Total number of Fetuses examined per group)x 100
- Litter incidence (%) = (Number of Litters/dams with particular observation per group/Total number of Litters per group) x 100 - Historical control data:
- Historical control data not included in report. Historical control data from in-house of the same species and strain.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of toxicity noted at all the tested dose groups and vehicle control group animals during the experimental period.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no morbidity/mortality noted at all the tested dose groups and vehicle control group animals during the experimental period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes noted in mean gestation (maternal) body weight and percent change in mean gestation (maternal) body weight gain at all the tested dose groups when compared with the vehicle control group.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no changes noted in mean gestation (maternal) feed consumption at all the tested dose groups when compared with the vehicle control group.
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Thyroid hormone T3: There were no changes noted for this parameter across the dose groups when compared to the vehicle control group. The statistically significant increase in serum T3 levels (ng/mL) at groups G3 and G4 is considered as incidental and un-related to treatment with test item due to lack of a dose-response relationship and also the obtained values were within the historical control range of same species and strain.
Thyroid hormone T4: There were no changes noted for this parameter across the dose groups when compared to the vehicle control group.
Thyroid stimulating hormone THS: There were no statistically significant differences noted for this parameter across the dose groups when compared to the vehicle control group due to noted larger standard deviations from groups G3 and G4. However, the noted differences in mean value from groups G3 and G4 when compared with vehicle control group are considered as incidental and also the obtained mean values from all the tested dose groups are within in-house historical control range. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- The thyroid along with parathyroid was collected, preserved and weighed post fixation from all the dams of each dose group. There were no changes and no significant differences noted for mean absolute and relative weight for this organ in all the tested dose groups when compared to the vehicle control group.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological changes noted in any of the animals from all the tested dose groups and vehicle control group during conduct of the necropsy.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no test item-related changes noted in thyroid along with the parathyroid subjected to histopathological examination at all the tested dose group animals. The noted ultimobranchial cyst/s in thyroid gland is considered as incidental finding as they occurred randomly across the dose groups including concurrent controls and/or were expected from laboratory rats of this age.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences noted for percentage of pre- or post-implantation loss per litter at all the tested dose groups when compared to the vehicle control group.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences in the number and percentage of early or late resorptions per dam across dose groups when compared to the vehicle control group.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences noted for number of dead fetuses at all the tested dose groups when compared to the vehicle control group.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- pregnancy with rates of 88%, 92%, 88% and 92% in groups G1, G2, G3 and G4 respectively
- Other effects:
- no effects observed
- Description (incidence and severity):
- The mean number of corpora lutea per litter was 13.00, 13.22, 13.50 and 13.48 for groups G1, G2, G3 and G4 respectively. There were no changes or no statistically significant differences noted at all the tested dose groups when compared with vehicle control group for number of corpora lutea.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: Highest concentration tested, no adverse effects observed
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes noted in mean fetal weight of either sex across the dose groups when compared with the vehicle control group.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences noted for number of live fetuses at all the tested dose groups when compared to the vehicle control group.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences noted for male/female sex ratio across the dose groups when compared to the control group.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- The mean litter sizes, assessed as the total number of fetuses in utero (live plus dead) per dam, was 11.64, 11.83, 11.86 and 12.13 for groups G1, G2, G3 and G4, respectively. There were no changes or no statistically significant differences noted at all the tested dose groups when compared with vehicle control group for litter size.
- Anogenital distance of all rodent fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean male fetal anogenital distance per litter was 4.25 mm, 4.30 mm, 4.20 mm and 4.28 mm and the mean female anogenital distance per litter was 2.47 mm, 2.51 mm, 2.57 mm and 2.59 mm for groups G1, G2, G3 and G4 respectively. The mean male fetal anogenital distance ratio per litter was 2.61, 2.67, 2.60 and 2.65 and the mean female anogenital distance ratio per litter was 1.55, 1.58, 1.62 and 1.64 for groups G1, G2, G3 and G4 respectively.
Statistically significant increase in mean female fetal anogenital distance and mean fetal anogenital distance ratio per litter was noted at groups G3 and G4 when compared with the vehicle control group. These changes are considered as incidental and un-related to treatment as the obtained range is within in-house historical control range. - Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The
noted general / developmental variations such as subcutaneous hemorrhagic spot/s beneath the skin on different regions of the body, pale skin colored fetuses, kinked tail and noted external malformations such as unilateral supernumerary digit of hindlimb, unilateral fused digits of hindlimb paw unilateral, hyperextension of forelimb unilateral, misshappened/flat head, short forelimb unilateral across the tested dose group litters are considered incidental as these incidences are comparable with the vehicle control group and also these developmental alterations are common for this species and strain. Also, no remarkable differences or statistically significant changes were noted for these alterations in any of the tested dose groups when compared with vehicle control group. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The below mentioned occasional incidences of skeletal developmental variations were
noted across the tested dose group litters.
- incomplete ossification of skull bones (parietal/interparietal/supraoccipital/ex-occipital/ mandibular/zygoma);
- incomplete or bipartite or unossification of sternabral bones (sternabra 2, 3, 4, 5 and 6);
- wavy ribs (both unilateral and bilateral);
- extra ossification site/s near to first lumbar vertebra i.e. immediately after 13th rib (both unilateral and bilateral);
- dumbbell or semi-bipartite ossification of thoracic verterbral centrum (centrum no. 8, 9, 10, 11, 12 and 13) and lumbar vertebral centrum (centrum no. 2);
- hemicentric ossification of thoracic verterbral centrum (centrum no. 11 and 12);
- incomplete or unossification of metacarpal no. 5 or proximal phalanges of forelimb;
- incomplete ossification of pubis bone unilateral.
The below mentioned occasional incidences of skeletal malformation were noted across
the tested dose group litters.
- fused skull bones (parietal) - single incidence for a fetus from vehicle control group;
- missing rib unilateral (rib no. 12) - single incidence for a fetus from vehicle control group;
- fused rib no. 11 and 12 - single incidence for a fetus from group G3;
- fused rib no. 12 and 13 - single incidence for a fetus from group G1;
- rudimentary rib (14th rib) - single incidences for a fetus from group G2, G3 and G4 each;
- split centrum no. 10 of thoracic vertebra - 1, 2, 0 and 1 fetal and litter incidences from group G1, G2, G3 and G4 respectively.
- split centrum no. 11 of thoracic vertebra - 0, 2, 2 and 3 fetal and litter incidences from group G1, G2, G3 and G4 respectively.
- split centrum no. 12 of thoracic vertebra - 1, 1, 1 and 2 fetal and litter incidences from group G1, G2, G3 and G4 respectively.
- split centrum no. 13 of thoracic vertebra - 0, 0, 1 and 0 fetal and litter incidences from group G1, G2, G3 and G4 respectively.
These skeletal developmental variations and skeletal malformations are considered as incidental and un-related to treatment as these findings occurred infrequently or at a frequency similar to the vehicle control group and did not occur in a dose-dependant manner. Also, the occurred mean litter/fetal proportions were within the in-house historical control range of this species and strain. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no test item-related fetal visceral/soft tissue malformations or developmental variations for any of the fetuses examined from all the tested dose group litters. The noted developmental variations such as pale or discolored adrenals/liver lobes/lung lobes, fused liver lobes, dilatation of renal pelvis and dilatation of ureters across the tested dose group litters are considered incidental as these incidences are comparable with the vehicle control group and also these developmental variations are common for this species and strain. There were no remarkable differences or statistically significant changes noted for these variations in any of the tested dose groups when compared with vehicle control group.
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean male fetal crown rump length per litter was 37.28 mm, 37.40 mm, 37.56 mm and 37.67 mm and the female mean crown rump length per litter was 36.61 mm, 36.96 mm, 36.79 mm and 36.92 mm for groups G1, G2, G3 and G4 respectively. Statistically significant increase in mean male fetal crown rump length per litter was noted at group G4 when compared with the vehicle control group. This change is considered as incidental and un-related to treatment as the obtained range is within in-house historical control range.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Highest dose tested, no adverse effects observed
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
TABLE 1. SUMMARY OF PREGNANCY STATUS, CLINICAL SIGNS OF TOXICITY AND MORTALITY RECORD
Group & Dose (mg/kg body weight/day) | Pregnancy Status | Clinical Signs and Mortality Record | |||
No. of Presumed Pregnant Animals / Group | No. of Presumed Pregnant Animals / Group | Rate of Pregnancy (%) | Clinical Signs of Toxicity revealed (No. of Animals) | No. of Mortalities / Total No. of animals | |
G1 & 0 | 25 | 22 | 88.0 | N (25) | 0/25 |
G2 & 100 | 25 | 23 | 92.0 | N (25) | 0/25 |
G3 & 300 | 25 | 22 | 88.0 | N (25) | 0/25 |
G4 & 1000 | 25 | 23 | 92.0 | N (25) | 0/25 |
TABLE 2. SUMMARY OF GESTATION BODY WEIGHT (g) RECORD
Group & Dose (mg/kg body weight/day) |
| Body Weight (g) on Gestation Day (GD) | ||||||||
0 | 3 | 5 | 8 | 11 | 14 | 17 | 19 | 20 | ||
G1 & 0 | Mean ±SD | 251.79 | 258.46 | 265.3 | 274.34 | 285.93 | 300.86 | 323.93 | 343.93 | 358.5 |
13.58 | 12.74 | 12.08 | 12.31 | 15.43 | 15.91 | 19.21 | 24.16 | 28.5 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G2 & 100 | Mean ±SD | 257.16 | 264.34 | 271.41 | 281.48 | 292.19 | 305.77 | 328.69 | 350.58 | 366.59 |
12.26 | 10.56 | 10.52 | 12.39 | 13.49 | 14.67 | 17.94 | 21.18 | 27.52 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
G3 & 300 | Mean ±SD | 252.48 | 259.66 | 266.37 | 275.52 | 287.86 | 301.9 | 326.49 | 349.47 | 365.92 |
16.2 | 16.12 | 16.59 | 16.32 | 16.93 | 19.56 | 21.46 | 24.03 | 27.12 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G4 & 1000 | Mean ±SD | 257.53 | 265.91 | 273.18 | 283.86 | 295.36 | 309.37 | 336.11 | 359.99 | 372.98 |
17.79 | 16.62 | 15.73 | 15.79 | 15.18 | 16.49 | 19.04 | 24.34 | 25.84 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
Table 3 SUMMARY OF PERCENT CHANGE IN GESTATION BODY WEIGHT (%) RECORD
Group & Dose (mg/kg body weight/day) |
| Percent Change in Body Weight (%) during Gestation Day (GD) | |||||||
0 to 3 | 3 to 5 | 5 to 8 | 8 to 11 | 11 to 14 | 14 to 17 | 17 to 19 | 19 to 20 | ||
G1 & 0 | Mean ±SD | 2.68 | 2.67 | 3.42 | 4.2 | 5.24 | 7.7 | 6.14 | 4.19 |
1.05 | 1.03 | 1.34 | 1.77 | 1.37 | 4.19 | 2.74 | 2.26 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G2 & 100 | Mean ±SD | 2.83 | 2.68 | 3.7 | 3.8 | 4.65 | 7.5 | 6.65 | 4.49 |
1.38 | 1.01 | 1.19 | 0.77 | 1.46 | 3.16 | 2.19 | 1.96 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
G3 & 300 | Mean ±SD | 2.86 | 2.59 | 3.46 | 4.49 | 4.85 | 8.18 | 7.04 | 4.68 |
1.1 | 0.78 | 1.03 | 1.45 | 1.32 | 2.85 | 2.33 | 1.62 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G4 & 1000 | Mean ±SD | 3.31 | 2.77 | 3.93 | 4.08 | 4.75 | 8.66 | 7.08 | 3.61 |
1.58 | 1.25 | 1.39 | 1.19 | 1.45 | 2.92 | 2.95 | 1.85 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
SD: Standard Deviation; n: Number of Dams. |
TABLE 4. SUMMARY OF GRAVID UTERUS WEIGHT (g) AND MATERNAL BODY WEIGHT CHANGE CORRECTED FOR GRAVID UTERINE WEIGHT (g)
Group & Dose (mg/kg body weight/day) |
| Body Weight Change (g) from GD 5 to 20 | Gravid Uterus Weight (g) | Corrected Body Weight | |
g | % | ||||
G1 & 0 | Mean ±SD | 93.21 | 70.87 | 22.34 | 8.43 |
21.52 | 19.66 | 10.17 | 3.81 | ||
| n | 22 | 22 | 22 | 22 |
G2 & 100 | Mean ±SD | 95.21 | 71.6 | 23.61 | 8.67 |
21.61 | 20.26 | 9.42 | 3.37 | ||
| n | 23 | 23 | 23 | 23 |
G3 & 300 | Mean ±SD | 99.55 | 74 | 25.55 | 9.62 |
18.69 | 15.96 | 11.52 | 4.35 | ||
| n | 22 | 22 | 22 | 22 |
G4 & 1000 | Mean ±SD | 99.8 | 73.06 | 26.74 | 9.89 |
23.15 | 21.85 | 10.02 | 3.9 | ||
| n | 23 | 23 | 23 | 23 |
SD: Standard Deviation; n: Number of Dams; GD: Gestation Day. *: Statistically significant (P<0.05) change than the control group. |
TABLE 5. SUMMARY OF AVERAGE GESTATION FEED CONSUMPTION (g/animal/day) RECORD
Group & Dose (mg/kg body weight/day) |
| Feed Consumption (g/animal/day) during Gestation Day (GD) | |||||||
0 to 3 | 3 to 5 | 5 to 8 | 8 to 11 | 11 to 14 | 14 to 17 | 17 to 19 | 19 to 20 | ||
G1 & 0 | Mean ±SD | 14.98 | 18.97 | 15.96 | 19.76 | 22.45 | 24.77 | 26.64 | 28.78 |
1.31 | 1.13 | 1.05 | 1.57 | 1.52 | 1.69 | 2.22 | 2.01 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G2 & 100 | Mean ±SD | 14.91 | 19.19 | 16.26 | 19.53 | 22.39 | 24.6 | 26.8 | 29.19 |
1.23 | 1.17 | 0.97 | 1.89 | 1.41 | 2.27 | 2.45 | 2.38 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
G3 & 300 | Mean ±SD | 14.71 | 19.52 | 16.83 | 19.62 | 22.28 | 24.85 | 25.79 | 28.62 |
1.59 | 1.76 | 1.27 | 1.55 | 1.23 | 1.33 | 2.65 | 2.37 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G4 & 1000 | Mean ±SD | 15.51 | 19.75 | 16.94 | 19.9 | 22.88 | 25.5 | 26.02 | 28.06 |
1.69 | 1.62 | 2.17 | 1.54 | 0.89 | 0.89 | 2.17 | 2.63 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
TABLE 6. SUMMARY OF UTERI OBSERVATIONS PER LITTER RECORD
Group & Dose (mg/kg body weight/day) | No. of Corpora lutea | No. of Implantations | Litter size | No. of Live Fetuses | No. of Dead Fetuses | No. of Early Resorptions | No. of Late Resorptions | |||
Total | Male | Female | ||||||||
G1 & 0 | Mean ±SD | 13 | 12.27 | 11.64 | 11.64 | 5.5 | 6.14 | 0 | 0.64 | 0 |
2.94 | 2.88 | 3.39 | 3.39 | 2.3 | 2.59 | 0 | 1.05 | 0 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G2 & 100 | Mean ±SD | 13.22 | 12.57 | 11.83 | 11.83 | 6.57 | 5.26 | 0 | 0.74 | 0 |
3.48 | 3.76 | 4.05 | 4.05 | 2.89 | 2.68 | 0 | 1.05 | 0 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
G3 & 300 | Mean ±SD | 13.5 | 12.73 | 11.86 | 11.77 | 5.59 | 6.18 | 0.09 | 0.86 | 0 |
2.86 | 2.6 | 2.95 | 2.91 | 1.76 | 2.17 | 0.43 | 1.25 | 0 | ||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 |
G4 & 1000 | Mean ±SD | 13.48 | 12.96 | 12.13 | 12.09 | 6.3 | 5.78 | 0.04 | 0.78 | 0.04 |
3.57 | 3.36 | 3.81 | 3.8 | 2.55 | 2.5 | 0.21 | 0.9 | 0.21 | ||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 |
TABLE 7. SUMMARY OF MATERNAL DATA PER LITTER RECORD
Group & Dose (mg/kg body weight/day) |
| Pre-Implantation Loss (%) | Post-Implantation Loss (%) | Percent of Dead Fetus (%) | Percent of Early Resorptions (%) | Percent of Late Resorptions (%) | Male/Female Sex Ratio | Male Fetuses (%) | Female Fetuses (%) | Percent of Live Fetuses |
| |
G1 & 0 | Mean ±SD | 5.57 | 6.23 | 0 | 6.23 | 0 | 1.06 | 47.55 | 52.45 | 100 | ||
6.11 | 10.88 | 0 | 10.88 | 0 | 0.61 | 14.03 | 14.03 | 0 | ||||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | ||
G2 & 100 | Mean ±SD | 6.13 | 7.32 | 0 | 7.32 | 0 | 1.69 | 56.19 | 43.81 | 100 | ||
8.5 | 11.88 | 0 | 11.88 | 0 | 1.28 | 15.94 | 15.94 | 0 | ||||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | ||
G3 & 300 | Mean ±SD | 5.51 | 8.04 | 0.65 | 7.4 | 0 | 1.02 | 48 | 52 | 99.35 | ||
4.82 | 11.95 | 3.05 | 11.98 | 0 | 0.46 | 11.41 | 11.41 | 3.05 | ||||
| n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | ||
G4 & 1000 | Mean ±SD | 3.71 | 8.28 | 0.33 | 7.61 | 0.33 | 1.14 | 53.02 | 46.98 | 99.67 | ||
5.74 | 12.48 | 1.6 | 12.5 | 1.6 | 0.65 | 16.95 | 16.95 | 1.6 | ||||
| n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | ||
SD: Standard Deviation; n: Number of Dams. |
TABLE 8. SUMMARY OF ABSOLUTE ORGAN WEIGHT (g) RECORD
Group & Dose (mg/kg body weight/day) | Absolute Thyroid along with Parathyroid Weight (g)# | |
G1 & 0 | Mean ±SD | 0.0183 |
0.0027 | ||
n | 22 | |
G2 & 100 | Mean ±SD | 0.0177 |
0.0025 | ||
n | 23 | |
G3 & 300 | Mean ±SD | 0.0185 |
0.0025 | ||
n | 22 | |
G4 & 1000 | Mean ±SD | 0.019 |
0.0019 | ||
n | 23 | |
SD: Standard Deviation; n: Number of Dams; #: Weighed post fixation. |
TABLE 9. SUMMARY OF TERMINAL BODY WEIGHT (g) AND ORGAN
WEIGHT (%) RELATIVE TO TERMINAL BODY WEIGHT RECORD
Group & Dose (mg/kg body weight/day) | Terminal Body Weight (g) | Relative Thyroid along with Parathyroid weight (%) | |
G1 & 0 | Mean ±SD | 358.5 | 0.0051 |
28.5 | 0.0008 | ||
n | 22 | 22 | |
G2 & 100 | Mean ±SD | 366.59 | 0.0049 |
27.52 | 0.0007 | ||
n | 23 | 23 | |
G3 & 300 | Mean ±SD | 365.92 | 0.0051 |
27.12 | 0.0006 | ||
n | 22 | 22 | |
G4 & 1000 | Mean ±SD | 372.98 | 0.0051 |
25.84 | 0.0006 | ||
n | 23 | 23 | |
SD: Standard Deviation; n: Number of Dams. |
TABLE 10. SUMMARY OF SERUM TRIIODOTHYRONINE (T3) LEVELS
(ng/mL) RECORD
Group & Dose (mg/kg body weight/day) |
| Serum T3 Levels (ng/mL) |
G1 & 0 | Mean ±SD | 2.587 |
0.249 | ||
| n | 22 |
G2 & 100 | Mean ±SD | 2.659 |
0.273 | ||
| n | 23 |
G3 & 300 | Mean ±SD | 3.082* |
0.225 | ||
| n | 22 |
G4 & 1000 | Mean ±SD | 2.849* |
0.535 | ||
| n | 23 |
SD: Standard Deviation; n: Number of Dams considered for mean calculations. |
TABLE 11. SUMMARY OF SERUM THYROXINE (T4) LEVELS (ng/mL)
RECORD
Group & Dose (mg/kg body weight/day) |
| Serum T4 Levels (ng/mL) |
G1 & 0 | Mean ±SD | 72.608 |
16.419 | ||
| n | 22 |
G2 & 100 | Mean ±SD | 71.998 |
13.244 | ||
| n | 23 |
G3 & 300 | Mean ±SD | 67.222 |
15.074 | ||
| n | 22 |
G4 & 1000 | Mean ±SD | 62.908 |
11.753 | ||
| n | 23 |
TABLE 12. SUMMARY OF SERUM THYROID STIMULATING HORMONE
(TSH) LEVELS (µIU/mL) RECORD
Group & Dose (mg/kg body weight/day) |
| Serum TSH Levels (µIU/mL) |
G1 & 0 | Mean ±SD | 3.853 |
4.033 | ||
| n | 20 |
G2 & 100 | Mean ±SD | 3.441 |
3.896 | ||
| n | 20 |
G3 & 300 | Mean ±SD | 7.357 |
6.235 | ||
| n | 21 |
G4 & 1000 | Mean ±SD | 6.445 |
5.991 | ||
| n | 21 |
TABLE 13. SUMMARY OF MEAN FETAL WEIGHT, MEAN FETAL CROWN RUMP LENGTH, MEAN FETAL ANOGENITAL DISTANCE AND RATIO RECORD
Group & Dose (mg/kg body weight/day) | Fetal Weight (g) | Crown Rump Length (mm) | Anogenital Distance | Anogenital Distance Ratio |
| ||||||
Male | Female | Male | Female | Male | Female | Male | Female |
| |||
G1 & 0 | Mean ±SD | 4.24 | 4.06 | 37.28 | 36.61 | 4.25 | 2.47 | 2.61 | 1.55 | ||
0.33 | 0.31 | 0.57 | 0.67 | 0.18 | 0.12 | 0.18 | 0.07 | ||||
n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | |||
G2 & 100 | Mean ±SD | 4.2 | 4.01 | 37.4 | 36.96 | 4.3 | 2.51 | 2.67 | 1.58 | ||
0.38 | 0.4 | 0.56 | 0.59 | 0.23 | 0.1 | 0.14 | 0.08 | ||||
n | 23 | 23 | 23 | 23 | 23 | 23 | 23 | 23 | |||
G3 & 300 | Mean ±SD | 4.25 | 4.02 | 37.56 | 36.79 | 4.2 | 2.57* | 2.6 | 1.62* | ||
0.33 | 0.21 | 0.5 | 0.65 | 0.27 | 0.12 | 0.18 | 0.07 | ||||
n | 22 | 22 | 22 | 22 | 22 | 22 | 22 | 22 | |||
G4 & 1000 | Mean ±SD | 4.22 0.30 | 3.93 0.28 | 37.67* | 36.92 | 4.28 | 2.59* | 2.65 0.17 | 1.64* | ||
0.49 | 0.6 | 0.24 | 0.1 | 0.07 | |||||||
| n | 23 | 22 | 23 | 22 | 23 | 22 | 23 | 22 |
Table 14 SUMMARY RECORD OF FETAL EXTERNAL EXAMINATION PER LITTER
Group | G1 | G2 | G3 | G4 | |||||||
Dose (mg/kg body weight/dry) | 0 | 100 | 300 | 1000 | |||||||
Litters Evaluated for External Examination | No | 22 | 23 | 22 | 23 | ||||||
Fetuses Evaluated for External Examination | No | 256 | 272 | 259 | 278 | ||||||
Variations | |||||||||||
Region/Tissue | Alteration | ||||||||||
General | Subcutaneous hemorrhagic spot/s beneach the skin on different regions of the body | ||||||||||
Litter Incidences | No (%) | 7 | (31.8) | 10 | (43.5) | 6 | (27.3) | 8 | (34.8) | ||
Fetal Incidences | No (%) | 9 | (3.5) | 14 | (5.1) | 8 | (3.1) | 10 | (3.6) | ||
General | Pale colored skin | ||||||||||
Litter Incidences | No (%) | 2 | (9.1) | 1 | (4.3) | 1 | (4.5) | 3 | (13.0) | ||
Fetal Incidences | No (%) | 2 | (0.8) | 1 | (0.4) | 1 | (0.4) | 3 | (1.1) | ||
Tail | Kinked | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.4) | ||
Malformations | |||||||||||
Region/Tissue | Alteration | ||||||||||
Hindlimb | Supernumerary digit (unilateral) | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.4) | 0 | (0.0) | 0 | (0.0) | ||
Hindlimb | Fused digits (unilateral) | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.4) | 0 | (0.0) | 1 | (0.4) | ||
Forelimb | Hyperextension (unilateral) | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 2 | (0.8) | 0 | (0.0) | ||
Head | Misshappen (flat shaped) | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.4) | ||
Forelimb | Short (unilateral) | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.4) |
TABLE 15. SUMMARY OF FETAL VISCERAL EXAMINATION PER LITTER
RECORD
Group | G1 | G2 | G3 | G4 | |||||||
Dose (mg/kg body weight/dry) | 0 | 100 | 300 | 1000 | |||||||
Litters Evaluated for External Examination | No | 22 | 23 | 22 | 23 | ||||||
Fetuses Evaluated for External Examination | No | 123 | 129 | 124 | 133 | ||||||
Variations | |||||||||||
Region/Tissue | Alteration | ||||||||||
Adrenals | Pale/Discoloration | ||||||||||
Litter Incidences | No (%) | 1 | 4.5 | 0 | 0 | 0 | 0 | 0 | |||
Fetal Incidences | No (%) | 1 | 0.8 | 0 | 0 | 0 | 0 | 0 | |||
Kidneys | Dilatation of renal pelvis | ||||||||||
Litter Incidences | No (%) | 4 | 18.2 | 2 | 8.7 | 0 | 13.6 | 3 | 13 | ||
Fetal Incidences | No (%) | 6 | 4.8 | 4 | 3.1 | 0 | 4 | 5 | 3.8 | ||
Liver | Pale/Discoloration | ||||||||||
Litter Incidences | No (%) | 4 | 18.2 | 3 | 13 | 3 | 4.5 | 2 | 8.7 | ||
Fetal Incidences | No (%) | 5 | 4 | 3 | 2.3 | 5 | 0.8 | 3 | 2.3 | ||
Liver | Fused Lobes | ||||||||||
Litter Incidences | No (%) | 1 | 4.5 | 0 | 0 | 1 | 0 | 0 | 0 | ||
Fetal Incidences | No (%) | 1 | 0.8 | 0 | 0 | 1 | 0 | 0 | 0 | ||
Lungs | Pale/Discoloration | ||||||||||
Litter Incidences | No (%) | 0 | 0 | 1 | 4.3 | 0 | 0 | 1 | 4.3 | ||
Fetal Incidences | No (%) | 0 | 0 | 1 | 0.8 | 0 | 0 | 2 | 1.5 | ||
Ureters | Dilatation | ||||||||||
Litter Incidences | No (%) | 2 | 9.1 | 4 | 17.4 | 4 | 18.2 | 3 | 13 | ||
Fetal Incidences | No (%) | 3 | 2.4 | 5 | 3.9 | 4 | 3.2 | 5 | 3.8 |
TABLE 16. SUMMARY OF SKELETAL EXAMINATION OF FETUSES PER LITTER RECORD
Group | G1 | G2 | G3 | G4 | |||||||
Dose (mg/kg body weight/dry) | 0 | 100 | 300 | 1000 | |||||||
Litters Evaluated for External Examination | No | 22 | 23 | 22 | 23 | ||||||
Fetuses Evaluated for External Examination | No | 132 | 143 | 136 | 146 | ||||||
Variations | |||||||||||
Region/Tissue | Alteration | ||||||||||
Skull | Parietal bones Incomplete ossification | ||||||||||
Litter Incidences | No (%) | 2 | (9.1) | 1 | (4.3) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 2 | (1.5) | 1 | (0.7) | 1 | (0.7) | 0 | (0.0) | ||
Interparietal bones Incomplete ossification |
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Litter Incidences | No (%) | 1 | (4.5) | 4 | (17.4) | 2 | (9.1) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 5 | (3.5) | 2 | (1.5) | 1 | (0.7) | ||
Supraoccipital bones Incomplete ossification | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 2 | (9.1) | 2 | (8.7) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 2 | (1.5) | 2 | (1.4) | ||
Exoccipital bones Incomplete ossification | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 2 | (8.7) | 1 | (4.5) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 2 | (1.4) | 1 | (0.7) | 1 | (0.7) | ||
Mandibular bones Incomplete ossification | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | ||
Zygomatic Arch Incomplete ossification | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | 2 | (8.7) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | 2 | (1.4) | ||
Sternum | Sternebra No. 3 Bipartite ossification | ||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | 0 | (0.0) | ||
Sternebra No. 4 Bipartite ossification | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | 1 | (0.7) | ||
Sternebra No. 5 Bipartite ossification | |||||||||||
Litter Incidences | No (%) | 1 | (4.5) | 1 | (4.3) | 2 | (9.1) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 1 | (0.7) | 2 | (1.5) | 1 | (0.7) | ||
Sternebra No. 6 Bipartite ossification |
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Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 1 | (0.7) | 0 | (0.0) | ||
Sternebra No. 2 Bipartite ossification |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | ||
Sternebra No. 2 Incomplete ossification | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | 0 | (0.0) | ||
Sternebra No. 5 Incomplete ossification |
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Litter Incidences | No (%) | 10 | (45.5) | 12 | (52.2) | 8 | (36.4) | 4 | (17.4) | ||
Fetal Incidences | No (%) | 14 | (10.6) | 15 | (10.5) | 11 | (8.1) | 5 | (3.4) | ||
Sternebra No. 6 Incomplete ossification |
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Litter Incidences | No (%) | 8 | (36.4) | 15 | (65.2) | 12 | (54.5) | 14 | (60.9) | ||
Fetal Incidences | No (%) | 14 | (10.6) | 25 | (17.5) | 18 | (13.2) | 22 | (15.1) | ||
Sternebra No. 5 Unossified |
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Litter Incidences | No (%) | 2 | (9.1) | 6 | (26.1) | 6 | (27.3) | 6 | (26.1) | ||
Fetal Incidences | No (%) | 2 | (1.5) | 8 | (5.6) | 7 | (5.1) | 6 | (4.1) | ||
Sternebra No. 6 Unossified |
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Litter Incidences | No (%) | 2 | (9.1) | 5 | (21.7) | 4 | (18.2) | 5 | (21.7) | ||
Fetal Incidences | No (%) | 2 | (1.5) | 10 | (7.0) | 4 | (2.9) | 5 | (3.4) | ||
Ribs | Rib No. 9 Wavy (Unilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 10 Wavy (Unilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 5 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 6 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 7 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 8 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 9 Wavy (bilateral) | |||||||||||
Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 10 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 11 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 12 Wavy (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.3) | 1 | (4.5) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 13 Wavy (bilateral) |
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Litter Incidences | No (%) | 1 | (4.5) | 2 | (8.7) | 3 | (13.6) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 3 | (2.1) | 3 | (2.2) | 0 | (0.0) | ||
Ossification Site at First Lumbar Vertebra (Unilateral) |
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Litter Incidences | No (%) | 2 | (8.7) | 3 | (13.6) | 4 | (17.4) | 4 | (18.2) | ||
Fetal Incidences | No (%) | 2 | (1.5) | 4 | (2.8) | 5 | (3.7) | 5 | (3.4) | ||
Ossification Site at First Lumbar Vertebra (Bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 2 | (9.1) | 2 | (8.7) | 2 | (9.1) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 2 | (1.4) | 3 | (2.2) | 3 | (2.1) | ||
Thoracic Vertebra | Centrum No. 8 Dumbbellshaped |
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Litter Incidences | No (%) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Centrum No. 9 Dumbbellshaped |
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Litter Incidences | No (%) | 0 | (0.0) | 2 | (9.1) | 3 | (13.0) | 3 | (13.6) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 2 | (1.4) | 3 | (2.2) | 3 | (2.1) | ||
Centrum No. 10 Dumbbellshaped |
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Litter Incidences | No (%) | 6 | (26.1) | 7 | (31.8) | 9 | (39.1) | 9 | (40.9) | ||
Fetal Incidences | No (%) | 6 | (4.5) | 11 | (7.7) | 9 | (6.6) | 9 | (6.2) | ||
Centrum No. 11 Dumbbellshaped |
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Litter Incidences | No (%) | 7 | (30.4) | 2 | (9.1) | 8 | (34.8) | 8 | (36.4) | ||
Fetal Incidences | No (%) | 10 | (7.6) | 3 | (2.1) | 10 | (7.4) | 12 | (8.2) | ||
Centrum No. 12 Dumbbellshaped |
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Litter Incidences | No (%) | 7 | (30.4) | 8 | (36.4) | 9 | (39.1) | 10 | (45.5) | ||
Fetal Incidences | No (%) | 10 | (7.6) | 10 | (7.0) | 9 | (6.6) | 14 | (9.6) | ||
Centrum No. 13 Dumbbellshaped |
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Litter Incidences | No (%) | 4 | (17.4) | 4 | (18.2) | 2 | (8.7) | 6 | (27.3) | ||
Fetal Incidences | No (%) | 4 | (3.0) | 4 | (2.8) | 2 | (1.5) | 8 | (5.5) | ||
Centrum No. 11 Hemicentric |
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Litter Incidences | No (%) | 0 | (0.00 | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Centrum No. 12 Hemicentric |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Sacral Vertebra | Arch No. 1 Ossification Site |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | ||
Lumbar Vertebra | Centrum No. 2 Dumbbellshaped |
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Litter Incidences | No (%) | 0 | (0.00 | 1 | (4.5) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | 0 | (0.0) | ||
Forelimb | Metacarpal No. 5 Unossified (Bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 3 | (13.6) | 2 | (8.70 | 3 | (13.6) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 4 | (2.8) | 2 | (1.5) | 3 | (2.1) | ||
Metacarpal No. 5 Incomplete |
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Litter Incidences | No (%) | 1 | (4.3) | 2 | (9.1) | 0 | (0.0) | 4 | (18.2) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 2 | (1.4) | 0 | (0.0) | 4 | (2.7) | ||
Proximal Phalanges Unossified |
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Litter Incidences | No (%) | 18 | (78.3) | 12 | (54.5) | 10 | (43.5) | 15 | (68.2) | ||
Fetal Incidences | No (%) | 20 | (15.2) | 18 | (12.6) | 14 | (10.3) | 18 | (12.3) | ||
Proximal Phalanges Incomplete |
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Litter Incidences | No (%) | 1 | (4.3) | 3 | (13.6) | 3 | (13.0) | 1 | (4.5) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 3 | 92.1) | 4 | (2.9) | 1 | (0.7) | ||
Pelvic Girdle | Pubis Incomplete ossification |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (4.5) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | ||
Malformations | |||||||||||
Skull | Parietal bones - fused |
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Litter Incidences | No (%) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Ribs | Rib No. 12 - Absent (unilateral) |
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Litter Incidences | No (%) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Rib No. 11 and 12 - Fused |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) | ||
Rib No. 12 and 13 - Fused |
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Litter Incidences | No (%) | 1 | (4.3) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | ||
Rudimentary (bilateral) |
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Litter Incidences | No (%) | 0 | (0.0) | 1 | (4.5) | 1 | (4.3) | 1 | (4.5) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 1 | (0.7) | 1 | (0.7) | 1 | (0.7) | ||
Thoracic Vertebra | Centrum No. 10 - Split |
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Litter Incidences | No (%) | 1 | (4.3) | 2 | (9.1) | 0 | (0.0) | 1 | (4.5) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 2 | (1.4) | 0 | (0.0) | 1 | (0.7) | ||
Centrum No. 11 - Split |
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Litter Incidences | No (%) | 0 | (0.0) | 2 | (9.1) | 2 | (8.7) | 3 | (13.6) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 2 | (1.4) | 2 | (1.5) | 3 | (2.1) | ||
Centrum No. 12 - Split |
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Litter Incidences | No (%) | 1 | (4.3) | 1 | (4.5) | 1 | (4.3) | 2 | (9.1) | ||
Fetal Incidences | No (%) | 1 | (0.8) | 1 | (0.7) | 1 | (0.7) | 2 | (1.4) | ||
Centrum No. 13 - Split |
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Litter Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (4.3) | 0 | (0.0) | ||
Fetal Incidences | No (%) | 0 | (0.0) | 0 | (0.0) | 1 | (0.7) | 0 | (0.0) |
Applicant's summary and conclusion
- Conclusions:
- In a pre-natal developmental toxicity study conducted in Sprague Dawley Rats, the NOAEL of the test substance for both maternal and fetal toxicity was determined to be 1000 mg/kg body weight/day under the experimental conditions employed.
- Executive summary:
The developmental toxicity of the test item was determined using OECD Guideline 414 under GLP conditions. The study used spraque dawley rats from an in-house line to test the daily oral administration via gavage of the test item using Carboxymethyl cellulose as vehicle. Based on a preliminary dose range study doses of 100, 300 and 1000 mg/kg bw/day were set with a concurrent vehicle control. On day 5 until day 19 of gestation, the test item was administered orally once daily to 25 pregnant females per group. During this time weight, food consumption, clinical signs of toxicity, mortality were observed. On day 20 all animals were euthanized, and tissue, organs and fetuses extracted and examined. There were no clinical signs of toxicity, mortality, morbidity, changes in body weight, food consumption changes, gross pathological or visceral changes in any group of maternal animals. Pregnancy rate, mean gravid uterus weight, live fetuses, mean litter size, mean sex ratio, mean number of implantation sites, mean number of resorptions, mean number of corpora lutae were similarly not affected by the treatment. Also unaffected were pre-and post- implantation losses, mean absolute and relative thyroid along with parathyropid weight, histopathology of the thryoid along with the parathyroid. The fetal toxicity assessment concluded no effect on mean fetal weight or crown-rump length in either sex. No test item related effects on developmental or structural alterations could be observed. Some visceral and skeletal alterations are considered incidental and not related to the test item as they occur in all groups, including the control and are not dose dependent. During the study no test item related effects in maternal or offspring animals could be observed. Therefore the "no observed adverse effect level (NOAEL) for reproduction and developmental toxicity is the highest dose used in this study of 1000mg/kg bw /day for maternal animals and offspring in rats.
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