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EC number: 204-857-3 | CAS number: 127-68-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Data is from study report
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- (Adopted on January 22, 2001)
- Principles of method if other than guideline:
- According to OECD Guideline 414 (Prenatal Developmental Toxicity Study) (Adopted on January 22, 2001)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Sodium 3-nitrobenzenesulphonate
- EC Number:
- 204-857-3
- EC Name:
- Sodium 3-nitrobenzenesulphonate
- Cas Number:
- 127-68-4
- Molecular formula:
- C6H5NO5S.Na
- IUPAC Name:
- sodium 3-nitrobenzenesulphonate
- Test material form:
- solid: granular
- Details on test material:
- - Name of test material (as cited in study report):hair dye formulation containing 2.25% sodium m-Nitrobenzenesulphonate
- Molecular formula (if other than submission substance):C6H4NNaO5S(sodium m-nitrobenzenesulphonate)
- Molecular weight (if other than submission substance):225.15 (sodium m-nitrobenzenesulphonate)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Vivo Bio Tech Ltd, Sy # 349/A, Pregnapur-502311, Gajwel Mandal, Medak District, Telangana
- Age at study initiation: 13 to 14 weeks
- Weight at study initiation: 214.952 ± 13.13 to 196.16 to 246.01
- Fasting period before study:
- Housing: Rats were housed in standard polysulfone rat cages (size: Length 425 mm x Breadth 266 mm x Height 185 mm) with stainless steel top grill having facilities for pellet food and drinking water in polycarbonate bottle with stainless steel sipper tube. Additionally, polycarbonate rat huts were placed inside the cage as environmental enrichment objects which were replaced once a week.
Following was the housing pattern during different periods of the experiment:
i. Pre mating / Acclimatization: Two rats of the same sex per cage were housed per cage.
ii. Mating: Female rats were cohabited with males in a 1:1 ratio in same cage.
iii. Post-mating / Treatment: After mating confirmation, females were housed individually.
Steam sterilized corn cob was used as bedding and was changed along with the cage at least twice a week.
- Diet (e.g. ad libitum): Teklad Certified (2014C) Global 14% Protein Rodent Maintenance Diet – pellet (Certified), ad libitum
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in ‘Aquaguard’ on-line water filter-cum-purifier, ad libitum
- Acclimation period: five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 23 °C
- Humidity (%): 65 – 66 %
- Air changes (per hr): adequate fresh air supply (12 to 15 air changes/hour).
- Photoperiod (hrs dark / hrs light):12 hours light and 12 hours dark cycle.
IN-LIFE DATES: From: 27 October 2017
To:29 March 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- water
- Remarks:
- Milli-Q®
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:The dose formulations were freshly prepared daily before dosing and were used within the stability period.
The required quantity of test item was weighed in pre-calibrated beaker*. A small volume (3 to 40 mL) of vehicle (Milli-Q® water) was added and mixed well using a glass rod. The final volume was made up with the vehicle to get the required final concentration. The volume was made up to the upper meniscus during dose formulation preparation.
*Pre-calibration of the beaker to desired volume: Milli-Q® water was measured in a graduated measuring cylinder to the final volume of the batch size (example if batch size was 70 mL, water was taken till 70 mL mark in graduated measuring cylinder). The measured water was transferred into a clean beaker (to be pre-calibrated) and upper and lower meniscus of water were marked on the beaker using a marker. Once these lines were marked, the water was discarded and the beaker was dried.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on the solubility test conducted under study, the test item is soluble in Milli-Q® water. Hence, Milli-Q® water was used as vehicle for dose formulation preparation.
- Concentration in vehicle: 0, 100, 300 and 1000 mg/kg bw
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentration and stability of the test chemical in vehicle was established at the concentrations of 0.7 mg/mL and 125 mg/mL. Based on the results, the test item was stable and homogenous in the vehicle up to 48 hours when stored at room temperature.
- Details on mating procedure:
- - Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]: Cohoused
- If cohoused: the female rats were cohabited with males
- M/F ratio per cage: 1:1 ratio
- Length of cohabitation: On the first day, after vaginal smear examination, all the females with proestrous and estrous stages were retained with the males; while the other females were separated from males. Subsequently females were cohabited in batches of required numbers. These females were cohabited with respective males in a 1:1 ratio. The details were recorded in raw data. This procedure was continued until there were sufficient numbers of Day 0 pregnant rats for the study.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No Data Available
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: [yes, vaginal smear were examination]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0] of pregnancy
- Any other deviations from standard protocol: Not specified. - Duration of treatment / exposure:
- 15 days
- Frequency of treatment:
- Daily
- Duration of test:
- From GD 5 to GD 19 of presumed gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Control Group
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- Low Dose Group
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- Mid Dose Group
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- High Dose Group
- No. of animals per sex per dose:
- Total: 96
0 mg/kg bw: 24 female
100 mg/kg bw: 24 female
300 mg/kg bw: 24 female
1000 mg/kg bw: 24 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose range finding study was carried out at Test Facility using seven day ‘0’ pregnant rats per group at the doses of 100 (G2), 300 (G3) and 1000 (G4) mg/kg/day along with the concurrent vehicle control (G1). No effect were observed in treated female and Fetal examination. Therefore, based on the results of dose range finding study doses were selected as 0, 100, 300 and 1000 mg/kg bw.
- Rationale for animal assignment (if not random): Rats were randomly distributed to different groups by body weight stratification. Based on the body weight, Day ‘0’ pregnant rats were arranged in the ascending order. These rats were then assigned to the groups starting either from control and treatment group/s in the increasing order of dose or vice-versa on GD 0. As far as possible rats were assigned equally to the study groups, the extra animals remaining were also assigned to groups. This difference was negated on subsequent day/s by assigning rats in such a way that there were equal numbers of rats in all the groups.
- Other: No Data Available
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day - pre dose and post dose (30 minutes to one hour post dose, approx.) during treatment days and once on non-treatment days
- Cage side observations checked in table [No.?] were included. : morbidity and mortality i.e., once in the morning and once in the afternoon.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day
BODY WEIGHT: Yes
- Time schedule for examinations: weighed on gestation days 0, 3, 5, 8, 11, 14, 17 and 20.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day # : On gestation day 20
- Organs examined: all visceral organs of dams were examined.
OTHER: - 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: Gross evaluation of placenta - Fetal examinations:
- - External examinations: Yes:All the fetuses were examined
- Soft tissue examinations: Yes: Approximately one half of the fetuses from each litter were subjected to visceral
- Skeletal examinations: Yes: the remaining half of the fetuses were subjected to skeletal evaluation.
- Head examinations: No data - Statistics:
- The data on maternal body weight, body weight change in interval, gravid uterine weight, body weight change corrected to gravid uterine weight, maternal food consumption were analyzed using Analysis of Variance (ANOVA) after testing for homogeneity for intra group variance using Levene’s test. Where intra group variances were heterogeneous, ANOVA was performed after suitable transformation of data. Dunnett’s pairwise comparison of the treated group means with the control group mean was performed, when the group differences were found significant.
Fetal weight for male and female were analyzed using Analysis of Covariance (ANCOVA) taking litter size as covariate for group.
Number of corpora lutea, number of implantations, early and late resorptions, pre-implantation and post-implantation loss, external, visceral and skeletal observations for variations were analyzed using Kruskal wallis test for group comparison.
The incidence of with and without resorptions in dams will be tested using Cochran Armitage trend test followed by Fisher’s exact test for group association.
Statistically significant differences (p<0.05), indicated by the aforementioned tests were designated as * throughout the report. - Indices:
- Embryonic resorption index, Fetal resorption index, Implantation index (%), Live fetus index, Dead fetus index were examined.
- Historical control data:
- Not specified
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs observed throughout the experimental period at any of the doses tested.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- There was no morbidity or mortality throughout the experimental period in the 100, 300 and 1000 mg/kg/day dose groups.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The maternal group mean body weights and maternal body weight gain were unaffected by the administration of test chemical at the doses of 100, 300 and 1000 mg/kg/day and were statistically comparable to vehicle control group.
The corrected body weight gain was statistically significantly increased at 1000 mg/kg/day as compared to vehicle control group indicating that body weights of rats were not affected by treatment with test chemical up to the high dose of 1000 mg/kg/day. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- The maternal food consumption was comparable to vehicle control group during different periods of gestation up to the high dose of 1000 mg/kg/day.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No effect on gravid uterine weights were observed in treated female rat as compared to control.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological findings in any of the tested doses.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No effect on pre and post-implantation loss rates were observed in treated female rats as compared to control.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- No effect on loss rates were observed in treated female rats as compared to control.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- No effect on early and late resorptions were observed in treated female rats as compared to control.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were observed in dead fetuses as compaed to control.
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- No effect on preganacy duration were observed in treated female rats as compared to control.
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- changes in pregnancy duration
- clinical signs
- dead fetuses
- early or late resorptions
- effects on pregnancy duration
- food consumption and compound intake
- gross pathology
- maternal abnormalities
- mortality
- number of abortions
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were observed in weight of male and female fetuses at 100, 300 and 1000 mg/kg /day.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- No reduction in the number of live male and female fetuses were observed due to the administration of the test chemical.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were observed in sex ratio of male and female fetuses at 100, 300 and 1000 mg/kg /day.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- No adverse effects or changes in the mean litter sizes and weights were observed due to the administration of the test chemical.
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were observed during external observations of fetuses of dams treated up to 1000 mg/kg/day.
Normal variants: There was no incidence of normal variant in any of the doses tested.
Minor anomalies: There was an incidence of a small fetus each in the vehicle control and low dose group. This finding was not of any toxicological significance as this is commonly observed in rat fetuses. - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were observed during skeletal examination of fetuses of dams treated up to 1000 mg/kg/day.
Normal Variants: Incidences of normal variants were comparable between the vehicle control and the treatment groups.
Minor anomalies: The incidences of minor anomalies were statistically comparable to vehicle control group at all the doses tested.
Major malformations: There were no incidences of major malformations in any of the treatment groups. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No changes were observed during visceral examination of fetuses of dams treated up to 1000 mg/kg/day.
Normal Variants, Minor anomalies and Major malformations: There were no incidences of normal variants, minor anomalies and major malformations in any of the doses tested. - Other effects:
- not specified
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in litter size and weights
- external malformations
- skeletal malformations
- visceral malformations
- Remarks on result:
- not determinable due to absence of adverse toxic effects
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
Summary of Clinical Signs and Mortality
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Observations |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
|
Total No. of rats found sperm positive |
24 |
24 |
24 |
24 |
|
|
|
|
|
|
Clinical signs |
NAD |
NAD |
NAD |
NAD |
|
|
|
|
|
|
|
Mortality |
-------------None------------ |
||||
|
|
Summary of maternal group mean body weight (g)
Group No. |
Dose (mg/kg/day) |
No. of Rats |
Group mean body weight (g) on GD |
||||||||
|
0 |
3 |
5 |
8 |
11 |
14 |
17 |
20 |
|||
G1 |
0 |
21 |
Mean |
214.18 |
222.98 |
229.95 |
238.57 |
252.79 |
263.87 |
288.02 |
314.65 |
|
|
|
SD |
14.23 |
14.95 |
14.68 |
15.39 |
16.72 |
16.62 |
18.80 |
22.58 |
|
|
|
|
|
|
|
|
|
|
|
|
G2 |
100 |
23 |
Mean |
216.39 |
226.08 |
234.32 |
242.56 |
256.20 |
267.26 |
291.98 |
320.04 |
|
|
|
SD |
15.37 |
17.51 |
18.91 |
20.47 |
22.54 |
24.88 |
27.77 |
32.57 |
|
|
|
|
|
|
|
|
|
|
|
|
G3 |
300 |
23 |
Mean |
216.68 |
226.07 |
233.55 |
241.12 |
255.23 |
266.69 |
289.97 |
319.69 |
|
|
|
SD |
14.73 |
17.20 |
18.51 |
19.99 |
22.27 |
22.58 |
23.32 |
25.81 |
|
|
|
|
|
|
|
|
|
|
|
|
G4 |
1000 |
24 |
Mean |
214.93 |
223.73 |
230.53 |
239.52 |
252.39 |
262.80 |
285.57 |
317.15 |
|
|
|
SD |
13.14 |
15.71 |
17.55 |
20.17 |
22.05 |
23.02 |
27.70 |
31.98 |
|
|
|
|
|
|
|
|
|
|
|
|
Summary of maternal body weight gain (g)
Period of treatment (days of gestation) |
Group No. |
G1 |
G2 |
G3 |
G4 |
|
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
||
No. of Rats |
21 |
23 |
23 |
24 |
||
|
|
|
|
|
|
|
Pre-treatment period (Days 0-5) |
Mean |
15.77 |
17.93 |
16.88 |
15.60 |
|
SD |
3.97 |
5.36 |
5.59 |
5.91 |
||
|
|
|
|
|
|
|
Treatment Period (Days 5-20) |
Mean |
84.70 |
85.72 |
86.13 |
86.62 |
|
SD |
11.05 |
15.85 |
11.20 |
19.02 |
||
|
|
|
|
|
|
|
Entire gestation (Days 0-20) |
Mean |
100.47 |
103.65 |
103.01 |
102.21 |
|
SD |
13.57 |
19.70 |
15.14 |
22.16 |
||
|
|
|
|
|
|
|
Summary of Corrected Body Weight and Body Weight Gain (g)
Group No. |
Dose (mg/kg/day) |
No. of Rats |
|
Gestation Day 5 |
Terminal body wt on GD 20 |
Uterine Wt (g) |
Carcass weight (corrected body weight on GD 20) |
Corrected Bwt gain. (g) |
G1 |
0 |
21 |
Mean |
58.07 |
26.63 |
70.64 |
244.01 |
14.06 |
|
|
|
SD |
7.33 |
6.78 |
7.69 |
20.84 |
11.60 |
|
|
|
|
|
|
|
|
|
G2 |
100 |
23 |
Mean |
57.65 |
28.07 |
64.08 |
255.97 |
21.64 |
|
|
|
SD |
11.05 |
6.96 |
12.29 |
25.60 |
11.09 |
|
|
|
|
|
|
|
|
|
G3 |
300 |
23 |
Mean |
56.41 |
29.72 |
65.39 |
254.30 |
20.75 |
|
|
|
SD |
8.28 |
6.40 |
12.49 |
23.09 |
10.63 |
|
|
|
|
|
|
|
|
|
G4 |
1000 |
24 |
Mean |
55.04 |
31.58 |
60.94 |
256.21 |
25.67* |
|
|
|
SD |
13.67 |
7.59 |
20.30 |
23.17 |
9.44 |
|
|
|
|
|
|
|
|
|
*: Significantly different from G1 GD: Gestation day
Corrected body weight on gestation day
20 (Carcass weight) = Terminal body weight on
day 20 - unopened uterine weight.
Corrected body weight gain = carcass weight - body weight on day 5.
Summary of Maternal Data
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
|
No. of Rats |
21 |
23 |
23 |
24 |
|
|
|
|
|
|
Gravid uterine weight (g) |
Mean |
70.64 |
64.08 |
65.39 |
60.94 |
|
SD |
7.69 |
12.29 |
12.49 |
20.30 |
|
|
|
|
|
|
Number of Corpora lutea |
Mean |
14.38 |
13.52 |
13.70 |
13.13 |
SD |
1.32 |
1.50 |
2.08 |
2.05 |
|
|
|
|
|
|
|
Number of Implantations |
Mean |
13.43 |
12.74 |
12.83 |
11.42 |
SD |
1.60 |
2.32 |
2.62 |
3.90 |
|
|
|
|
|
|
|
Early Resorptions |
Mean |
0.43 |
0.61 |
0.57 |
0.25 |
SD |
0.68 |
0.89 |
0.73 |
0.44 |
|
|
|
|
|
|
|
Late Resorptions |
Mean |
0.05 |
0.13 |
0.09 |
0.13 |
SD |
0.22 |
0.34 |
0.29 |
0.34 |
|
|
|
|
|
|
|
Pre-implantation Loss |
Mean |
0.95 |
0.78 |
0.87 |
1.71 |
SD |
1.32 |
1.31 |
1.01 |
2.26 |
|
|
|
|
|
|
|
Post-implantation Loss |
Mean |
0.48 |
0.74 |
0.65 |
0.38 |
SD |
0.68 |
0.92 |
0.71 |
0.49 |
|
|
|
|
|
|
|
Dams with any Resorption |
Total |
8 |
11 |
12 |
9 |
|
|
|
|
|
|
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
|
No. of Rats |
21 |
23 |
23 |
24 |
|
|
|
|
|
|
Early Resorptions (%) |
Mean |
3.02 |
5.12 |
4.20 |
2.10 |
|
SD |
4.76 |
7.26 |
5.35 |
3.77 |
|
|
|
|
|
|
Late Resorptions (%) |
Mean |
0.34 |
0.98 |
1.30 |
0.94 |
|
SD |
1.56 |
2.60 |
4.58 |
2.54 |
|
|
|
|
|
|
Pre-implantation Loss (%) |
Mean |
6.46 |
6.32 |
7.06 |
15.85 |
|
SD |
8.78 |
11.86 |
9.82 |
24.98 |
|
|
|
|
|
|
Post-implantation Loss (%) |
Mean |
3.36 |
6.10 |
5.50 |
3.03 |
|
SD |
4.79 |
7.43 |
6.17 |
4.06 |
|
|
|
|
|
|
Implantation Index (%) |
Mean |
93.54 |
93.68 |
92.94 |
84.15 |
|
SD |
8.78 |
11.86 |
9.82 |
24.98 |
|
|
|
|
|
|
Summary of Litter Data
|
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
|
No. of Rats |
21 |
23 |
23 |
24 |
|
|
|
|
|
|
No. of litters |
|
21 |
23 |
23 |
24 |
|
|
|
|
|
|
Total no. of fetuses |
|
272 |
276 |
280 |
265 |
|
|
|
|
|
|
Mean litter size |
|
13.0 |
12.0 |
12.2 |
11.0 |
|
|
|
|
|
|
Total live fetuses |
|
|
|
|
|
a. Number |
|
272 |
276 |
280 |
265 |
|
|
|
|
|
|
b. Weight (g) |
Mean |
3.57 |
3.48 |
3.49 |
3.66 |
|
SD |
0.24 |
0.21 |
0.29 |
0.47 |
|
|
|
|
|
|
Live male fetuses |
|
|
|
|
|
a. Number |
|
146 |
134 |
142 |
137 |
|
|
|
|
|
|
b. Weight (g) |
Mean |
3.66 |
3.56 |
3.58 |
3.73 |
|
SD |
0.26 |
0.23 |
0.30 |
0.48 |
|
|
|
|
|
|
Live female fetuses |
|
|
|
|
|
a. Number |
|
126 |
142 |
138 |
128 |
|
|
|
|
|
|
b. Weight (g) |
Mean |
3.46 |
3.41 |
3.41 |
3.52 |
|
SD |
0.22 |
0.21 |
0.30 |
0.23 |
|
|
|
|
|
|
Sex Ratio - Male : Female |
|
1:0.86 |
1:1.06 |
1:0.97 |
1:0.93 |
(% of male fetuses) |
|
(53.7%) |
(48.6%) |
(50.7%) |
(51.7%) |
Summary of Gross Pathological Findings
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
1. No. of rats subjected to caesarean section
|
24 |
24 |
24 |
24 |
2. No. of rats pregnant at caesarean section
|
21 |
23 |
23 |
24 |
3. No. of rats showing gross pathology |
0 |
0 |
0 |
0 |
|
|
|
|
|
Summary of Fetal External Observations (Incidence and Percentage)
Group No. |
G1 |
G2 |
G3 |
G4 |
||||||||||||
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
||||||||||||
No. of litters examined |
21 |
23 |
23 |
24 |
||||||||||||
No. of fetuses examined |
272 |
276 |
280 |
265 |
||||||||||||
Fetus |
Litter |
Fetus |
Litter |
Fetus |
Litter |
Fetus |
Litter |
|||||||||
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Normal Variant |
None |
|||||||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Minor Anomalies |
|
|||||||||||||||
Small fetus |
1 |
0.37 |
1 |
4.76 |
1 |
0.36 |
1 |
4.35 |
0 |
0.00 |
0 |
0.00 |
0 |
0.00 |
0 |
0.00 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Major Malformations |
None |
|||||||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Summary of Fetal Visceral Observations (Incidence and Percentage)
Group No. |
G1 |
G2 |
G3 |
G4 |
||||||||||||
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
||||||||||||
No. of litters examined |
21 |
23 |
23 |
24 |
||||||||||||
No. of fetuses examined |
131 |
132 |
132 |
126 |
||||||||||||
Fetus |
Litter |
Fetus |
Litter |
Fetus |
Litter |
Fetus |
Litter |
|||||||||
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
Inc. |
% |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Normal Variant |
None |
|||||||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Minor Anomalies |
None |
|||||||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Major Malformations |
None |
|||||||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Applicant's summary and conclusion
- Conclusions:
- Based on the above findings, it is concluded that, No Observed Adverse Effect Level (NOAEL) for Maternal toxicity and fetal developmental toxicity is 1000 mg/kg/day in Wistar rats when the test chemical was administered orally by gavage during GD 5 to 19 under the test conditions and doses employed in this study.
- Executive summary:
The objective of this study was to evaluate the embryo-fetal developmental toxicity of test chemical when administered to pregnant Wistar rats by oral route during gestation days GD 5 to GD 19. The results of this study helped to establish the No Observed Adverse Effect Level (NOAEL) of the test item for maternal and developmental toxicity in rats. In this study, each group (G1, G2, G3 and G4) consisted of 24 presumed pregnant Wistar rats (gestation day 0). Day '0' of gestation for each individual female rat in the study was considered as the day on which vaginal plug was observed or vaginal smear was found sperm positive. The test chemical was dissolved in vehicle - Milli-Q water and administered orally (by gavage) to presumed pregnant rats once daily from GD 5 to 19 at the dose levels of 100, 300 and 1000 mg/kg/day for low (G2), mid (G3) and high (G4) dose group rats, respectively. The rats in the vehicle control (G1) group received the vehicle alone. A constant dose volume of 10 mL/kg body weight was administered to all groups. The dose formulation solutions were analyzed for active ingredient concentrations at the initiation and termination of treatment. The results of analysis of formulations revealed that the analyzed concentrations were within the acceptable limits. The mated females were observed twice daily for clinical signs, mortality and morbidity. Body weights and food consumption were monitored during the different periods of gestation. The intermittent body weight gain and food consumption was calculated and presented for rats found pregnant at caesarean section. Caesarean section was performed for all the rats on GD 20 and dams were examined for gross pathological changes. The uterus from all the dams was removed (by laparotomy) and the contents were examined. The uteri were weighed and examined for the number of implantation sites, early and late resorptions, and number of live and dead fetuses. The number of corpora lutea was counted on each ovary. All the fetuses were sexed, weighed and examined for external malformations. Approximately half the number of fetuses from each litter was examined for visceral malformations and the remaining half was evaluated for skeletal malformations. During observations, there were no mortalities and clinical signs at all the doses tested. The maternal body weights and food consumption were comparable to vehicle control group up to the highest dose of 1000 mg/kg/day. The maternal data parameters comprising of mean number of corpora lutea, implantations, number of early and late resorptions, pre and post implantation loss and dams with any resorptions were comparable to vehicle control group at all the doses tested. Gross evaluation of placenta revealed no findings. The litter data parameters comprising of total number of fetuses, mean weights of male and female fetuses and sex ratio were comparable to vehicle control group at all the doses tested. Fetal, external, visceral and skeletal observations were comparable to vehicle control group at all the doses tested. Visceral and skeletal examinations revealed no signs of teratogenicity in any of the tested doses. Therefore, based on the above findings, it is concluded that, No Observed Adverse Effect Level (NOAEL) for Maternal toxicity and fetal developmental toxicity is 1000 mg/kg/day in Wistar rats when the test chemical was administered orally by gavage during GD 5 to 19 under the test conditions and doses employed in this study.
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