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EC number: 204-485-1 | CAS number: 121-60-8
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
Toxicity to Reproduction:
No adverse effects on reproduction or development were observed at 250, 500 or 1000 mg/kg bw/day in the performed OECD 421 with rats.
Link to relevant study records
- Endpoint:
- screening for reproductive / 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 a study report
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- Adopted 29 July 2016
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Name: N-Acetylsulphanilyl chloride
IUPAC Name: Benzenesulfonyl chloride, 4-(acetylamino)-
CAS No.: 121-60-8
Molecular Formula: C8-H8-Cl-N-O3-S
Molecular Weight: 233.67 g/mol
SMILES: CC(=O)Nc1ccc(cc1)S(=O)(=O)Cl - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat is a standard laboratory rodent species used for toxicity assessment and is recommended to be used in OECD 421.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: In house bred animals
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) 9 to 10 weeks;
- Weight at study initiation: (P) Males: 220.33 to 250.60 g; Females: 200.31 to 240.79 g;
- Fasting period before study: No data available
- Housing: Animals were housed in a standard polypropylene cage (size: L 430 x B 285 x H 150 mm) with stainless steel mesh top grill having facilities for holding pelleted food and drinking water in a water bottle fitted with a stainless steel sipper tube. Clean sterilized paddy husk was provided as bedding material.
- During acclimatization, a maximum of two animals of the same sex were housed.
- Pre mating - Per cage, two animals of the same sex and group were housed.
- Cohabitation Period (mating) - Per cage, two animals (one male and one female) of the same group were housed.
- Post-mating - After confirming the 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.
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): Altromin maintenance diet for rats and mice (manufactured by Altromin Spezialfutter GmbH & Co. KG) was available ad libitum to the animals throughout the acclimatization and experimental periods.
- Water (e.g. ad libitum): Water was available ad libitum throughout the acclimatization and experimental periods. Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6 to 23.4 °C
- Humidity (%): 46 to 68%
- 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: 16 June 2020
To: 07 September 2020 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test chemical was dissolved in corn oil and formed uniform suspension at the concentration of 200 mg/mL (considering the highest dose of 1000 mg/kg body weight with a dose volume of 5 mL/kg body weight).
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil was used as a vehicle.
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 5ml/kg bw
- Lot/batch no. (if required): L32011001
- Purity: No data available - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: sperm in vaginal smear] referred to as day 0 of pregnancy
- 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
- After successful mating each pregnant female was caged (how): Individually
- Any other deviations from standard protocol: No - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The required quantity of the test chemical was weighed and triturated well in a mortar with a small quantity of vehicle until a homogenous suspension was formed, and after that, 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 the required quantity with the vehicle to get the desired concentration of 50, 100, and 200 mg/mL of test item for low, mid and high dose groups, respectively.
The test formulations were maintained under stirring conditions using a magnetic stirrer to maintain homogeneity of the test chemical formulations.
The test chemical formulations were stable and homogeneous for 6 hours at room temperature and 48 hours at 2 to 8˚C with concentrations of 10.0 mg/mL and 250.0 mg/mL in corn oil. Prepared test item formulations were administered to the animals within established stability conditions.
The samples were collected in duplicates (5 mL each) from the top, middle, and bottom layers from low, mid, and high dose concentrations and in duplicates from a single layer from vehicle control.
The prepared test item formulations were stirred using magnetic stirrer during sampling.
One set of aliquots of each formulation was analyzed. The second aliquot was stored for backup purpose at established stability conditions. The second set of samples were discarded as the analysis results of first set of samples were within the limits. Formulations were considered acceptable, since the mean results were within the range of 85 to 115% of the nominal concentration and the relative standard deviation (% RSD) is <10%.
Chromatographic Conditions:
Column : Zorbax Eclipse plus C18, 4.6 ×250 mm, 5 μm
Flow rate : 0.8 mL/min
Injection volume : 10 μL
Wavelength : 264 nm
Run time : 10 minutes
Column Oven Temperature: 25°C
Mobile Phase: Acetonitrile: Milli-Q water (80:20 %, v/v)
Diluent: Acetonitrile - Duration of treatment / exposure:
- Males: 29 days
Females: 63 days - Frequency of treatment:
- Once Daily
- Details on study schedule:
- No data available
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Control Group
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Remarks:
- Low Dose Group
- Dose / conc.:
- 500 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:
- 12 animals per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The doses were selected based on available data of the substance and of read-across substances.
- Rationale for animal assignment (if not random): The animals were weighed and arranged in ascending order of their body weights. These body weight stratified animals were distributed to all the groups using Microsoft Excel Spreadsheet, such that body weight variation of animals selected for the study did not exceed ±20% (Males: -12.09 to 14.54%; Females: -13.49 to 7.51%) of the mean body weight of each sex. The grouping was done one day prior to the initiation of treatment by randomization based on the body weights. Body weight of the animals were analyzed statistically for mean body weight to rule out statistically significant differences between groups within each sex prior to dosing.
- Fasting period before blood sampling for clinical biochemistry: No Data Available
- Other: No Data Available - Positive control:
- No positive control chemical was used.
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All the animals were observed once daily for clinical signs of toxicity and twice daily for mortality and morbidity.
DETAILED CLINICAL OBSERVATIONS: No
- Time schedule: No Data Available
BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed at receipt, on the first day of dosing, weekly thereafter and at termination. The females were weighed on gestation days 0, 7, 14 and 20 during pregnancy and on days 1, 4, 7 and 13 during lactation period and on day 14 (fasting body weight).
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Feed consumption was measured for all animals once a week during premating and weekly once for males during post mating period. Feed consumption was not measured during mating period for both males and females. Thereafter, the feed consumption for females was recorded during gestation days 0 to 7, 7 to 14 and 14 to 20 and on lactation days 1 to 4, 4 to 7 and 7 to 13.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data
OTHER: No data - Oestrous cyclicity (parental animals):
- Oestrus cyclicity was monitored for two weeks after the five days of acclimatization to evaluate the normal oestrus cycle (4 to 5 days). Only females with normal oestrus cyclicity were selected for the treatment. Vaginal smears were monitored daily from the beginning of the treatment period until evidence of mating. When obtaining vaginal/cervical cells, care was taken to avoid disturbance of mucosa, which may induce pseudopregnancy. The status of oestrus cyclicity of females was determined on termination day (lactation day 14).
- Sperm parameters (parental animals):
- A detailed histopathological examination was performed on the ovaries, testes, and epididymides. Particular emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure of the animals was given.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 10 pups/litter (5/sex/litter as nearly as possible);
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups, other. Particular attention should be paid to the external reproductive genitals which should be examined for signs of altered development; gross evaluation of external genitalia
GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No Data Available
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No Data Available - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving males were sacrificed after 29 days of treatment
- Maternal animals: All surviving females were sacrificed on lactation day 14 (i.e. after approx. 63 days of treatment)
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [1] were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
The F1 pups were sacrificed on PND 4 or 13.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as provided in Table 2 below.
GROSS NECROPSY
- The pups, which were sacrificed on PND 4 or 13 were examined for gross abnormalities with particular attention to the external reproductive genitals.
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [2] were prepared for microscopic examination and weighed, respectively. - Statistics:
- The statistical analysis was followed to the parameters in the table 3 given below.
- Reproductive indices:
- Mating and Fertility Indexes (both genders), Gestation Index, Parturition Index, and Pregnancy Index.
- Offspring viability indices:
- Litter Index and Pup Viability Index
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of toxicity in any of the groups.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All animals survived to planned death.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no significant changes in body weight or body weight gain with respect to day 1 of treatment in any of the groups.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant changes in food intake were observed, with the exception of a significant increase in food intake during the pre-mating period in male rats treated at 1000 mg/kg bw/day. This change was considered incidental and toxicological insignificant since the increase was minimal and could not be correlated with any changes in body weight or body weight gain.
- 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:
- no effects observed
- Description (incidence and severity):
- There were no significant changes in serum Thyroxine (T4) hormone levels in any of the male groups. As there were no significant changes observed in serum T4 levels in adult males, the assessment was not extended to adult females (dams).
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related histopathological findings at 1000 mg/kg bw/day (MF/F). A single incidence of minimal, multifocal, degeneration/atrophy of seminiferous tubules in testes was observed in high dose male without any correlating findings in epididymides of the same animal. This change was considered to be an expected spontaneous finding in rats of this age.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No neoplastic lesions were observed at 0 or 1000 mg/kg bw/day.
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- There were no irregularities observed in the oestrus cyclicity in any of the female groups during the pre-mating or mating period. No significant changes in mean oestrus cycle length were observed between the groups during the pre-mating or mating period.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- No treatment related adverse effects on the stages of spermatogenesis were observed during the microscopic examination of interstitial testicular cell structure.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No treatment related adverse effects on male or female mating index, male or female fertility index, pre-coital interval, gestational length, gestation index, parturition index, pregnancy index, live birth index, post implantation loss, mean number of Implantations were observed.
- 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:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive function (oestrous cycle)
- reproductive function (sperm measures)
- reproductive performance
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- All pups showed normal behaviour during the daily inspections.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No significant changes in live birth index (%) were observed and no cases of unscheduled mortality were observed during the post-natal period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant changes in pup weight (M/F) were observed on PND 1, PND 4, PND 7 or PND 13.
- Food consumption and compound intake (if feeding study):
- not examined
- 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:
- no effects observed
- Description (incidence and severity):
- No significant changes in serum Thyroxine (T4) hormone levels were observed on PND 13 in any of the groups.
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- No significant changes were observed.
- Anogenital distance (AGD):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant changes in mean pup anogenital distance (AGD) or AGD ratio were observed in any of the groups, with the exception of a significant decrease in AGD in male pups from the 1000 mg/kg dose group (mean 4.30 mm) versus the control group (mean 4.45 mm). AGD in male pups from the 1000 mg/kg dose group was within the historical control range of the test facility. Therefore, this small change in AGD at 1000 mg/kg was not considered to be an adverse effect of treatment.
- Nipple retention in male pups:
- no effects observed
- Description (incidence and severity):
- There were no male pups with retention of nipples/areolae on PND 13 in any of the groups.
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological findings in any of the groups.
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- sexual maturation
- clinical signs
- mortality
- body weight and weight gain
- clinical biochemistry
- gross pathology
- other: Anogenital Distance and Nipple Retention in Male Pups
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Treatment related:
- no
- Conclusions:
- The study-derived NOAEL for systemic, reproductive, and developmental toxicity was considered at 1000 mg/kg bw/day.
- Executive summary:
The study was performed according to OECD 421 (2016) and according to GLP. The substance was given to 12 rats per sex per dose level at 0 (corn oil), 250, 500 and 1000 mg/kg bw/day. Male rats were treated before mating and during mating for a total of 29 days. Female rats were treated before mating, during mating, during pregnancy, and up to day 13 of lactation for a total of approx. 63 days. Results (parental generation): All animals survived to planned death and there were no clinical signs of toxicity. No significant changes in body weight or body weight gain with respect to day 1 of treatment were observed. No significant changes in food intake were observed, with the exception of a significant increase in food intake during the pre-mating period in male rats treated at 1000 mg/kg bw/day. This change was considered incidental and toxicological insignificant since the increase was minimal and could not be correlated with any changes in body weight or body weight gain. There were no significant changes in serum Thyroxine (T4) hormone levels in any of the male groups. As there were no significant changes observed in serum T4 levels in adult males, the assessment was not extended to adult females (dams). There were no significant changes in absolute or relative weight of testes, epididymis, prostate with seminal vesicle and coagulation gland, ovaries, or thyroid with parathyroidinin any of the groups.There were no gross pathological findings in any of the groups. There were no treatment-related histopathological findings at 1000 mg/kg bw/day (MF/F). A single incidence of minimal, multifocal, degeneration/atrophy of seminiferous tubules in testes was observed in high dose male without any correlating findings in epididymides of the same animal. This change was considered to be an expected spontaneous finding in rats of this age. There were no irregularities observed in the oestrus cyclicity in any of the female groups during the pre-mating or mating period. No significant changes in mean oestrus cycle length were observed between the groups during the pre-mating or mating period. No treatment related adverse effects on the stages of spermatogenesis were observed during the microscopic examination of interstitial testicular cell structure. No treatment related adverse effects on male or female mating index, male or female fertility index, pre-coital interval, gestational length, gestation index, parturition index, pregnancy index, live birth index, post implantation loss, mean number of Implantations were observed. Results (F1 generation): All pups showed normal behaviour during the daily inspections. No significant changes in live birth index (%) were observed and no cases of unscheduled mortality were observed during the post-natal period. No significant changes in pup weight (M/F) were observed on PND 1, PND 4, PND 7 or PND 13. No significant changes in serum Thyroxine (T4) hormone levels were observed on PND 13 in any of the groups. No significant changes in mean pup anogenital distance (AGD) or AGD ratio were observed in any of the groups, with the exception of a significant decrease in AGD in male pups from the 1000 mg/kg dose group (mean 4.30 mm) versus the control group (mean 4.45 mm). AGD in male pups from the 1000 mg/kg dose group was within the historical control range of the test facility. Therefore, this small change in AGD at 1000 mg/kg was not considered to be an adverse effect of treatment. There were no male pups with retention of nipples/areolae on PND 13 in any of the groups. No significant changes in sex ratio were observed. There were no gross pathological findings in any of the groups. Conclusion: NOAEL for systemic, reproductive, and developmental toxicity was considered at 1000 mg/kg bw/day.
Reference
Table 1. CLINICAL SIGNS OF TOXICITY AND MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Total No. of Animals |
Clinical Signs of Toxicitya: Observation |
Mortalityb: No. of Mortalities |
G1, M & 0 |
12 |
Day 1 to termination:N (12) |
0 (12) |
G2, M & 250 |
12 |
Day 1 to termination:N (12) |
0 (12) |
G3, M & 500 |
12 |
Day 1 to termination:N (12) |
0 (12) |
G4, M & 1000 |
12 |
Day 1 to termination:N (12) |
0 (12) |
M: Male; N: Normal; a: observed daily once; b: observed twice daily
Table 1. (Contd…) CLINICAL SIGNS OF TOXICITY AND MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Total No. of Animals |
Clinical Signs of Toxicitya: Observation |
Mortalityb No. of Mortalities |
G1, F & 0 |
12 |
Day 1 to termination:N (12) |
0 (12) |
G2, F & 250 |
12 |
Day 1 to termination:N (12) |
0 (12) |
G3, F & 500 |
12 |
Day 1 to termination:N (12) |
0 (12) |
G4, F & 1000 |
12 |
Day 1 to termination:N (12) |
0 (12) |
F: Female; N: Normal; a: observed daily once; b: observed twice daily
Table 2. BODY WEIGHT (g) RECORD
Group, Sex & Dose |
Body Weight (g) on Day |
|||||
1 |
7 |
14 |
21 |
28 |
||
G1, M & 0 |
Mean |
308.34 |
317.29 |
330.05 |
341.22 |
354.20 |
±SD |
27.07 |
29.54 |
31.52 |
30.98 |
30.62 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
309.84 |
320.97 |
335.04 |
347.24 |
358.49 |
±SD |
27.78 |
30.67 |
33.73 |
38.29 |
39.14 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
309.10 |
315.94 |
331.53 |
341.09 |
357.44 |
±SD |
26.85 |
30.34 |
34.01 |
37.59 |
41.82 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
310.77 |
318.10 |
334.03 |
344.30 |
359.74 |
±SD |
24.54 |
22.14 |
19.72 |
20.07 |
22.00 |
|
n |
12 |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals
TABLE 2. (Contd…) BODY WEIGHT (g) RECORD
Group, Sex & Dose |
Body Weight (g) on Day |
||||
1 |
7 |
14 |
21# |
||
G1, F & 0 |
Mean |
238.06 |
241.92 |
249.61 |
258.80 |
±SD |
12.86 |
13.25 |
13.50 |
8.01 |
|
n |
12 |
12 |
12 |
5 |
|
G2, F & 250 |
Mean |
239.90 |
244.46 |
251.08 |
253.10 |
±SD |
12.67 |
14.54 |
13.61 |
7.61 |
|
n |
12 |
12 |
12 |
7 |
|
G3, F & 500 |
Mean |
239.99 |
242.97 |
248.77 |
245.89 |
±SD |
11.44 |
13.34 |
14.54 |
5.02 |
|
n |
12 |
12 |
12 |
5 |
|
G4, F & 1000 |
Mean |
240.24 |
245.24 |
250.28 |
254.92 |
±SD |
11.06 |
11.93 |
11.13 |
5.19 |
|
n |
12 |
12 |
12 |
3 |
F: Female; SD: Standard Deviation; n: Number of Animals; #: The data obtained from females in cohabitation only considered for mean calculations. The data of Day 21 body weight was not subjected to statistical analysis due to uneven number of variables.
Table 3. PERCENT CHANGE IN BODY WEIGHT (%) WITH RESPECT TO DAY 1
Group, Sex & Dose |
Percent Change in Body Weight (%) during Day |
||||
1 to 7 |
1 to 14 |
1 to 21 |
1 to 28 |
||
G1, M & 0 |
Mean |
2.86 |
6.99 |
10.66 |
14.90 |
±SD |
1.33 |
2.26 |
2.37 |
2.21 |
|
n |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
3.54 |
8.10 |
12.05 |
15.74 |
±SD |
1.26 |
4.30 |
7.06 |
8.02 |
|
n |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
2.15 |
7.14 |
10.17 |
15.40 |
±SD |
1.83 |
3.11 |
3.81 |
4.96 |
|
n |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
2.44 |
7.69 |
11.09 |
16.12 |
±SD |
1.94 |
3.97 |
6.42 |
7.99 |
|
n |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals
Table 3. (Contd…) PERCENTCHANGE IN BODY WEIGHT (%) WITH RESPECT TO DAY 1
Group, Sex & Dose |
Percent Change in Body Weight (%) during Day |
|||
1 to 7 |
1 to 14 |
1 to 21# |
||
G1, F & 0 |
Mean |
1.62 |
4.86 |
8.47 |
±SD |
1.04 |
1.64 |
2.45 |
|
n |
12 |
12 |
5 |
|
G2, F & 250 |
Mean |
1.87 |
4.66 |
7.82 |
±SD |
1.05 |
1.45 |
1.39 |
|
n |
12 |
12 |
7 |
|
G3, F & 500 |
Mean |
1.21 |
3.62 |
5.52 |
±SD |
1.32 |
1.74 |
1.96 |
|
n |
12 |
12 |
5 |
|
G4, F & 1000 |
Mean |
2.08 |
4.24 |
9.05 |
±SD |
1.07 |
3.40 |
5.51 |
|
n |
12 |
12 |
3 |
F: Female; SD: Standard Deviation; n: Number of Animals; #: The data obtained from females in cohabitation only considered for mean calculations. The data of Day 21 body weight was not subjected to statistical analysis due to uneven number of variables.
Table 4. FEED CONSUMPTION (g/animal/day) RECORD
Group, Sex & Dose |
|
Feed Consumption (g/animal/day) during Pre-mating Period |
|
Week 1 |
Week 2 |
||
G1, M & 0 |
Mean |
21.40 |
22.44 |
±SD |
0.68 |
1.12 |
|
n |
12 |
12 |
|
G2, M & 250 |
Mean |
20.88 |
22.97 |
±SD |
1.47 |
0.70 |
|
n |
12 |
12 |
|
G3, M & 500 |
Mean |
20.67 |
23.26 |
±SD |
1.03 |
0.88 |
|
n |
12 |
12 |
|
G4, M & 1000 |
Mean |
21.16 |
23.91* |
±SD |
0.70 |
0.74 |
|
n |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals;*: Statistically significant (P<0.05) change than the concurrent vehicle control group
Table 4. (Contd…) FEED CONSUMPTION (g/animal/day) RECORD
Group, Sex & Dose |
|
Feed Consumption (g/animal/day) during Pre-mating Period |
|
Week 1 |
Week 2 |
||
G1, F & 0 |
Mean |
16.44 |
17.73 |
±SD |
1.24 |
1.35 |
|
n |
12 |
12 |
|
G2, F & 250 |
Mean |
15.55 |
16.26 |
±SD |
1.10 |
1.36 |
|
n |
12 |
12 |
|
G3, F & 500 |
Mean |
15.26 |
16.89 |
±SD |
1.09 |
0.70 |
|
n |
12 |
12 |
|
G4, F & 1000 |
Mean |
15.97 |
17.38 |
±SD |
1.33 |
1.08 |
|
n |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Animals
Table 5. VAGINAL SMEAR EXAMINATION FOR DETERMINATION OF OESTRUS CYCLICITY
Determination of Oestrus Cyclicity during Pre-Mating Treatment Period |
||||||
Group, Sex & Dose |
Total No. of Females Evaluated |
No. of Females with Complete Regular Oestrus Cycle |
No. of Females with at least one Irregular Oestrus Cycle |
Average Length of Oestrus Cycle (Days) |
||
G1, F & 0 |
12 |
n |
12 |
0 |
Mean |
4.96 |
% |
100.0 |
0.0 |
±SD |
0.14 |
||
n |
12 |
|||||
G2, F & 250 |
12 |
n |
12 |
0 |
Mean |
5.00 |
% |
100.0 |
0.0 |
±SD |
0.00 |
||
n |
12 |
|||||
G3, F & 500 |
12 |
n |
12 |
0 |
Mean |
5.00 |
% |
100.0 |
0.0 |
±SD |
0.00 |
||
n |
12 |
|||||
G4, F & 1000 |
12 |
n |
12 |
0 |
Mean |
4.92 |
% |
100.0 |
0.0 |
±SD |
0.19 |
||
n |
12 |
F: Female; SD: Standard Deviation; n: Number of Animals
Table 6. GESTATION BODY WEIGHT (g)
Group, Sex & Dose (mg/kg body weight/day) |
Body Weight (g) on Gestation Day (GD) |
||||
0 |
7 |
14 |
20 |
||
G1, F & 0 |
Mean |
255.89 |
265.36 |
287.90 |
350.03 |
±SD |
14.75 |
14.26 |
12.93 |
15.45 |
|
n |
11 |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
259.51 |
272.15 |
296.43 |
355.73 |
±SD |
14.04 |
13.24 |
10.69 |
10.17 |
|
n |
10 |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
255.30 |
265.51 |
289.00 |
353.63 |
±SD |
12.00 |
11.63 |
14.22 |
20.46 |
|
n |
11 |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
255.13 |
265.39 |
291.32 |
349.51 |
±SD |
10.99 |
12.46 |
14.26 |
14.57 |
|
n |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; Note: Excluded the data of non-pregnant females for mean calculations and statistical analysis
Table 7. PERCENT CHANGE IN BODY WEIGHT (%) DURING GESTATION PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight (%) during Gestation Day (GD) |
|||
0 to 7 |
7 to 14 |
14 to 20 |
||
G1, F & 0 |
Mean |
3.73 |
8.55 |
21.60 |
±SD |
1.11 |
1.96 |
2.39 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
4.91 |
9.00 |
20.07 |
±SD |
1.54 |
2.52 |
3.36 |
|
n |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
4.02 |
8.83 |
22.34 |
±SD |
1.32 |
1.65 |
3.09 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
4.01 |
9.77 |
20.12 |
±SD |
1.22 |
1.56 |
5.45 |
|
n |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams;Note: Excluded the data of non-pregnant females for mean calculations and statistical analysis
Table 8. FEED CONSUMPTION (g/animal/day) DURING GESTATION PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
|
Feed Consumption (g/animal/day) during Gestation Day (GD) |
||
0 to 7 |
7 to 14 |
14 to 20 |
||
G1, F & 0 |
Mean |
18.83 |
20.07 |
22.26 |
±SD |
1.36 |
1.07 |
0.87 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
17.78 |
19.30 |
22.09 |
±SD |
0.79 |
0.75 |
1.24 |
|
n |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
18.69 |
19.91 |
22.77 |
±SD |
1.43 |
1.58 |
1.16 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
19.08 |
21.06 |
22.55 |
±SD |
1.07 |
1.12 |
2.13 |
|
n |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams;Note: Excluded the data of non-pregnant females for mean calculations and statistical analysis
Table 9. LACTATION BODY WEIGHT (g)
Group, Sex & Dose (mg/kg body weight/day) |
Body Weight (g) on Lactation Day (LD) |
||||
1 |
4 |
7 |
13 |
||
G1, F & 0 |
Mean |
266.00 |
272.73 |
287.58 |
307.40 |
±SD |
15.39 |
15.24 |
13.98 |
17.20 |
|
n |
11 |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
271.21 |
278.63 |
294.88 |
315.58 |
±SD |
10.75 |
10.27 |
9.75 |
11.90 |
|
n |
10 |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
270.12 |
276.19 |
292.81 |
313.45 |
±SD |
18.66 |
18.87 |
20.60 |
17.26 |
|
n |
11 |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
269.63 |
273.55 |
288.30 |
308.16 |
±SD |
10.61 |
11.45 |
11.16 |
13.53 |
|
n |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams
Table 10. PERCENT CHANGE IN BODY WEIGHT (%) DURING LACTATION PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight (%) during Lactation Day (LD) |
|||
1 to 4 |
4 to 7 |
7 to 13 |
||
G1, F & 0 |
Mean |
2.55 |
5.50 |
6.88 |
±SD |
1.39 |
1.81 |
2.62 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
2.75 |
5.86 |
7.02 |
±SD |
1.21 |
1.90 |
2.25 |
|
n |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
2.26 |
6.02 |
7.18 |
±SD |
1.27 |
2.10 |
3.18 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
1.45 |
5.42 |
6.90 |
±SD |
1.36 |
2.07 |
2.75 |
|
n |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams
Table 11. FEED CONSUMTION (g/animal/day) DURING LACTATION PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
|
Feed Consumption (g/animal/day) during Lactation Day (LD) |
||
1 to 4 |
4 to 7 |
7 to 13 |
||
G1, F & 0 |
Mean |
25.76 |
31.06 |
34.70 |
±SD |
0.97 |
2.24 |
1.17 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
27.07 |
32.23 |
36.14 |
±SD |
1.25 |
2.76 |
1.11 |
|
n |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
25.95 |
31.39 |
35.59 |
±SD |
1.42 |
2.86 |
1.59 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
26.12 |
31.92 |
35.55 |
±SD |
1.93 |
2.89 |
1.45 |
|
n |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams
Table 12. SUMMARY OF DELIVERYDATA (AT BIRTH) PER LITTER
Group, Sex & Dose weight/day) |
Litter Delivered (No.) |
||||||||||||||||||
Total Litter Size (No.) |
Live Pups (No.) |
Dead Pups (No.) |
Cannibalized Pups (No.) |
Sex Ratio (m/f) at Birth |
Live Birth Index (%) |
||||||||||||||
Male |
Female |
Total |
Male |
Female |
Total |
Undetermined |
Male |
Female |
Total |
||||||||||
G1, F & 0 |
Mean |
10.09 |
5.27 |
4.73 |
10.00 |
0.09 |
0.00 |
0.09 |
0.00 |
0.00 |
0.00 |
0.00 |
1.21 |
99.09 |
|||||
±SD |
1.97 |
1.90 |
1.27 |
2.00 |
0.30 |
0.00 |
0.30 |
0.00 |
0.00 |
0.00 |
0.00 |
0.53 |
3.02 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G2, F & 250 |
Mean |
10.80 |
5.30 |
5.40 |
10.70 |
0.10 |
0.00 |
0.10 |
0.00 |
0.00 |
0.00 |
0.00 |
1.28 |
99.00 |
|||||
±SD |
1.69 |
1.25 |
2.12 |
1.77 |
0.32 |
0.00 |
0.32 |
0.00 |
0.00 |
0.00 |
0.00 |
1.05 |
3.16 |
||||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
G3, F & 500 |
Mean |
9.82 |
4.91 |
4.91 |
9.82 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.15 |
100.00 |
|||||
±SD |
1.17 |
1.22 |
1.58 |
1.17 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.57 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G4, F & 1000 |
Mean |
10.33 |
5.92 |
4.42 |
10.33 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.52 |
100.00 |
|||||
±SD |
1.44 |
1.51 |
1.51 |
1.44 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.64 |
0.00 |
||||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; m/f: male/female
Table 13. LITTER OBSERVATION DURING LACTATION PERIOD
Group, Sex & Dose weight/day) |
During Lactation Day 1 to 4 |
Sex Ratio (M/F) on LD 4 |
Pup Survival Index (%) during LD 1 to 4 |
||||||||||||||
Live Pups (No.) |
Dead Pups (No.) |
Cannibalized Pups (No.) |
|||||||||||||||
Male |
Female |
Total |
Male |
Female |
Total |
Male |
Female |
Total |
|||||||||
G1, F & 0 |
Mean |
5.27 |
4.73 |
10.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.21 |
100.00 |
|||||
±SD |
1.90 |
1.27 |
2.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.53 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G2, F & 250 |
Mean |
5.30 |
5.40 |
10.70 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.28 |
100.00 |
|||||
±SD |
1.25 |
2.12 |
1.77 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.05 |
0.00 |
||||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
G3, F & 500 |
Mean |
4.91 |
4.91 |
9.82 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.15 |
100.00 |
|||||
±SD |
1.22 |
1.58 |
1.17 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.57 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G4, F & 1000 |
Mean |
5.92 |
4.42 |
10.33 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.52 |
100.00 |
|||||
±SD |
1.51 |
1.51 |
1.44 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.64 |
0.00 |
||||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; M/F: Male/Female; LD: Lactation Day
Table 13. (Contd...) LITTER OBSERVATION DURING LACTATION PERIOD
Group, Sex & Dose |
Pups Sacrificed for blood collection (No.) |
Live Pups (No.) on LD 4 after blood collection (No.) |
During LD 5 to 7 |
Sex Ratio (M/F) on LD 7 |
Pup Survival Index (%) during LD 5 to 7 |
|||||||||||||||||||
Live Pups (No.) |
Dead Pups (No.) |
Cannibalized (No.) |
||||||||||||||||||||||
Male |
Female |
Total |
Male |
Female |
Total |
Male |
Female |
Total |
Male |
Female |
Total |
Male |
Female |
Total |
||||||||||
G1, F & 0 |
Mean |
0.00 |
0.73 |
0.73 |
5.27 |
4.00 |
9.27 |
5.27 |
4.00 |
9.27 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.62 |
100.00 |
||||||
±SD |
0.00 |
1.01 |
1.01 |
1.90 |
1.48 |
1.19 |
1.90 |
1.48 |
1.19 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.07 |
0.00 |
|||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||||
G2, F & 250 |
Mean |
0.00 |
0.90 |
0.90 |
5.30 |
4.50 |
9.80 |
5.30 |
4.50 |
9.80 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.41 |
100.00 |
||||||
±SD |
0.00 |
0.88 |
0.88 |
1.25 |
1.35 |
1.03 |
1.25 |
1.35 |
1.03 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.99 |
0.00 |
|||||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|||||||
G3, F & 500 |
Mean |
0.00 |
0.36 |
0.36 |
4.91 |
4.55 |
9.45 |
4.91 |
4.55 |
9.45 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.24 |
100.00 |
||||||
±SD |
0.00 |
0.50 |
0.50 |
1.22 |
1.37 |
0.82 |
1.22 |
1.37 |
0.82 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.63 |
0.00 |
|||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||||
G4, F & 1000 |
Mean |
0.00 |
0.58 |
0.58 |
5.92 |
3.83 |
9.75 |
5.92 |
3.83 |
9.75 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.83 |
100.00 |
||||||
±SD |
0.00 |
0.79 |
0.79 |
1.51 |
1.34 |
0.87 |
1.51 |
1.34 |
0.87 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.06 |
0.00 |
|||||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; LD: Lactation Day; M/F: Male/Female
Table 13. (Contd...) LITTER OBSERVATION DURING LACTATION PERIOD
Group, Sex & Dose weight/day) |
During LD 8 to 13 |
Sex Ratio (M/F) on LD 13 |
Pup Survival Index (%) during LD 8 to 13 |
|||||||||||||
Live Pups (No.) |
Dead Pups (No.) |
Cannibalized (No.) |
||||||||||||||
Male |
Female |
Total |
Male |
Female |
Total |
Male |
Female |
Total |
||||||||
G1, F & 0 |
Mean |
5.27 |
4.00 |
9.27 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.62 |
100.00 |
||||
±SD |
1.90 |
1.48 |
1.19 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.07 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G2, F & 250 |
Mean |
5.30 |
4.50 |
9.80 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.41 |
100.00 |
||||
±SD |
1.25 |
1.35 |
1.03 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.99 |
0.00 |
|||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|||||
G3, F & 500 |
Mean |
4.91 |
4.55 |
9.45 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.24 |
100.00 |
||||
±SD |
1.22 |
1.37 |
0.82 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.63 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G4, F & 1000 |
Mean |
5.92 |
3.83 |
9.75 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.83 |
100.00 |
||||
±SD |
1.51 |
1.34 |
0.87 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.06 |
0.00 |
|||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; LD: Lactation Day; M/F: Male/Female
Table 14. REPRODUCTIVE PERFORMANCE
Group, Sex & Dose (mg/kg body weight/day) |
No. of Males with Evidence of Mating |
Male Mating Index (%) |
No. of Males Capable of Impregnating a Female |
Male Fertility Index (%) |
|
G1, M & 0 |
12 (12) |
100.0 |
11 (12) |
91.7 |
|
G2, M & 250 |
12 (12) |
100.0 |
10 (12) |
83.3 |
|
G3, M & 500 |
12 (12) |
100.0 |
11 (12) |
91.7 |
|
G4, M & 1000 |
12 (12) |
100.0 |
12 (12) |
100.0 |
M: Male
Table 14. (Contd…) REPRODUCTIVE PERFORMANCE
Group, Sex & Dose (mg/kg body weight/day) |
|
Copulatory interval / Pre-coital interval (Mean Time to Mating) / Cohabitation Record |
|
Gestation Length / Duration of Pregnancy (Days) |
|||
Pre-coital Interval |
Conceiving Days (1 to 5) |
Conceiving Days (5 to More) |
|||||
G1, F & 0 |
Mean |
6.83 |
n |
5 |
7 |
22.09 |
|
±SD |
3.79 |
% |
41.7 |
58.3 |
0.30 |
||
n |
12 |
11 |
|||||
G2, F & 250 |
Mean |
7.75 |
n |
3 |
9 |
22.50 |
|
±SD |
3.14 |
% |
25 |
75 |
0.71 |
||
n |
12 |
10 |
|||||
G3, F & 500 |
Mean |
6.50 |
n |
6 |
6 |
22.45 |
|
±SD |
3.87 |
% |
50 |
50 |
0.52 |
||
n |
12 |
11 |
|||||
G4, F & 1000 |
Mean |
5.33 |
n |
7 |
5 |
22.42 |
|
±SD |
3.85 |
% |
58.3 |
41.7 |
0.51 |
||
n |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Females confirmed with mating (in case ofPre-Coital Interval) /Number of Females confirmed with pregnancy (in case ofgestation length)
Table 14. (Contd…)REPRODUCTIVE PERFORMANCE
Group, Sex & Dose (mg/kg body weight/day) |
No. of Females with Evidence of Mating (No. of Females used for Mating) |
Female Mating Index (%) |
|
No. of Females Confirmed as Fertile |
Female Fertility Index (%) |
G1, F & 0 |
12 (12) |
100.0 |
11 (12) |
91.7 |
|
G2, F & 250 |
12 (12) |
100.0 |
10 (12) |
83.3 |
|
G3, F & 500 |
12 (12) |
100.0 |
11 (12) |
91.7 |
|
G4, F & 1000 |
12 (12) |
100.0 |
12 (12) |
100.0 |
F: Female
Table 14. (Contd…)REPRODUCTIVE PERFORMANCE
Group, Sex & Dose (mg/kg body weight/day) |
Pregnancy Index (%) |
|
Gestation Index (%) |
|
Parturition Index (%) |
||||||
No. of Pregnant Females |
No. of Females Confirmed with Mating |
Female Fecundity or Pregnancy Index (%) |
Females with Live Born Pups at Parturition |
No. of Females with Evidence of Pregnancy |
Gestation Index (%) |
No. of females littered |
No. of Females with Evidence of Pregnancy |
Parturition Index (%) |
|||
G1, F & 0 |
11 |
12 |
91.7 |
11 |
11 |
100.0 |
11 |
11 |
100.0 |
||
G2, F & 250 |
10 |
12 |
83.3 |
10 |
10 |
100.0 |
10 |
10 |
100.0 |
||
G3, F & 500 |
11 |
12 |
91.7 |
11 |
11 |
100.0 |
11 |
11 |
100.0 |
||
G4, F & 1000 |
12 |
12 |
100.0 |
12 |
12 |
100.0 |
12 |
12 |
100.0 |
F: Female
Table 14. (Contd…)REPRODUCTIVE PERFORMANCE
Group, Sex & Dose (mg/kg body weight/day) |
Post-implantation Loss (%) |
|
Postnatal Loss (%) |
|||||
No. of Implantations |
No. of Viable Pups |
Post-implantation Loss (No.) |
Post-implantation Loss (%) |
Total No. of Deaths/ Cannibalized during Lactation Period |
Postnatal Loss (%) |
|||
G1, F & 0 |
Mean |
10.36 |
10.00 |
0.36 |
3.76 |
0.00 |
0.00 |
|
±SD |
1.75 |
2.00 |
0.67 |
7.22 |
0.00 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
||
G2, F & 250 |
Mean |
11.60 |
10.70 |
0.90 |
7.83 |
0.00 |
0.00 |
|
±SD |
1.17 |
1.77 |
1.29 |
11.08 |
0.00 |
0.00 |
||
n |
10 |
10 |
10 |
10 |
10 |
10 |
||
G3, F & 500 |
Mean |
10.36 |
9.82 |
0.55 |
5.14 |
0.00 |
0.00 |
|
±SD |
1.12 |
1.17 |
0.82 |
7.55 |
0.00 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
||
G4, F & 1000 |
Mean |
10.83 |
10.33 |
0.50 |
4.62 |
0.00 |
0.00 |
|
±SD |
1.19 |
1.44 |
0.90 |
8.43 |
0.00 |
0.00 |
||
n |
12 |
12 |
12 |
12 |
12 |
12 |
F: Female; n: Number of Dams
Table 15. ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
|
Testes |
Epididymis |
Prostate (P) + Seminal vesicles with coagulating glands (SC) |
Thyroid along with parathyroid# |
G1, M & 0 |
Mean |
3.2035 |
1.3530 |
2.6717 |
0.0242 |
±SD |
0.3542 |
0.0968 |
0.2587 |
0.0046 |
|
n |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
3.2802 |
1.3835 |
2.8051 |
0.0237 |
±SD |
0.2207 |
0.1027 |
0.5185 |
0.0043 |
|
n |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
3.2392 |
1.3028 |
2.9552 |
0.0233 |
±SD |
0.4203 |
0.1243 |
0.5374 |
0.0040 |
|
n |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
3.1350 |
1.3175 |
2.7737 |
0.0247 |
±SD |
0.2501 |
0.0992 |
0.4644 |
0.0046 |
|
n |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals; #: Weighed post fixation
Table 15. (Contd…) ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
|
Ovaries |
Thyroid along with parathyroid# |
G1, F & 0 |
Mean |
0.1194 |
0.0206 |
±SD |
0.0247 |
0.0023 |
|
n@ |
11 |
11 |
|
G2, F & 250 |
Mean |
0.1346 |
0.0222 |
±SD |
0.0316 |
0.0020 |
|
n@ |
10 |
10 |
|
G3, F & 500 |
Mean |
0.1209 |
0.0208 |
±SD |
0.0192 |
0.0019 |
|
n@ |
11 |
11 |
|
G4, F & 1000 |
Mean |
0.1189 |
0.0217 |
±SD |
0.0122 |
0.0027 |
|
n |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; #: Weighed post fixation; @: the data of non-pregnant females one from G1, G3, and two from G2 were excluded from mean calculations and statistical analysis.
Table 16. 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) |
Testes |
Epididymis |
Prostate (P) + Seminal vesicles with coagulating glands (SC) |
Thyroid along with parathyroid |
|
G1, M & 0 |
Mean |
335.21 |
0.9598 |
0.4055 |
0.8034 |
0.0072 |
±SD |
28.97 |
0.1121 |
0.0350 |
0.1113 |
0.0012 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
338.95 |
0.9751 |
0.4111 |
0.8310 |
0.0070 |
±SD |
36.37 |
0.0930 |
0.0401 |
0.1418 |
0.0008 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
337.71 |
0.9765 |
0.3906 |
0.8837 |
0.0069 |
±SD |
40.42 |
0.1944 |
0.0586 |
0.1789 |
0.0006 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
334.56 |
0.9406 |
0.3950 |
0.8272 |
0.0073 |
±SD |
22.99 |
0.0917 |
0.0349 |
0.1092 |
0.0010 |
|
n |
12 |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals
Table 16. (Contd…) 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) |
Ovaries |
Thyroid along with parathyroid |
G1, F & 0 |
Mean |
297.21 |
0.0402 |
0.0069 |
±SD |
17.41 |
0.0081 |
0.0005 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
305.00 |
0.0440 |
0.0073 |
±SD |
10.46 |
0.0098 |
0.0006 |
|
n |
10 |
10 |
10 |
|
G3, F & 500 |
Mean |
303.50 |
0.0399 |
0.0069 |
±SD |
17.07 |
0.0063 |
0.0005 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
299.36 |
0.0398 |
0.0072 |
±SD |
14.82 |
0.0038 |
0.0008 |
|
n |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams
Table 17. SERUM THYROXINE (T4) HORMONE LEVELS (ng/mL) RECORD - MALES
Group, Sex & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
|
G1, M & 0 |
Mean |
76.973 |
±SD |
21.316 |
|
n |
11 |
|
G2, M & 250 |
Mean |
72.150 |
±SD |
14.877 |
|
n |
12 |
|
G3, M & 500 |
Mean |
79.823 |
±SD |
13.505 |
|
n |
12 |
|
G4, M & 1000 |
Mean |
89.738 |
±SD |
25.060 |
|
n |
9 |
M: Male;SD: Standard Deviation; n: Number of Animals
Table 18. PUP OBSERVATIONS DURING POSTNATAL PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
At Birth (PND 1) |
PND 5 to 7 |
Pups Sacrificed for Blood Collection on PND 4 (No.)* |
PND 4 to 7$ |
PND 8 to 13$ |
||||||||
G1, F & 0 |
No. of Dams / Litters# |
11 |
11 |
4 |
11 |
11 |
|||||||
No. of Live Pups |
110 |
110 |
8 |
102 |
102 |
||||||||
Pup Observation/ No. of Pups observed |
N/110 |
N/110 |
- |
N/102 |
N/102 |
||||||||
G2, F & 250 |
No. of Dams / Litters# |
10 |
10 |
6 |
10 |
10 |
|||||||
No. of Live Pups |
107 |
107 |
9 |
98 |
98 |
||||||||
Pup Observation/ No. of Pups observed |
N/107 |
N/107 |
- |
N/98 |
N/98 |
||||||||
G3, F & 500 |
No. of Dams / Litters# |
11 |
11 |
4 |
11 |
11 |
|||||||
No. of Live Pups |
108 |
108 |
4 |
104 |
104 |
||||||||
Pup Observation/ No. of Pups observed |
N/108 |
N/108 |
- |
N/104 |
N/104 |
||||||||
G4, F & 1000 |
No. of Dams / Litters# |
12 |
12 |
5 |
12 |
12 |
|||||||
No. of Live Pups |
124 |
124 |
7 |
117 |
117 |
||||||||
Pup Observation/ No. of Pups observed |
N/124 |
N/124 |
- |
N/117 |
N/117 |
F: Female; N: Normal; PND: Postnatal Day;#: confirmed with live pups*: Pups selected for blood collection from dams with litter size of more than 10; $: Pups sacrificed on PND 4 were excluded
Table 19. MEAN PUP WEIGHT (g) PER LITTER DURING LACTATION PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
|
PND 1 |
|
PND 4 |
|
PND 7 |
|
PND 13 |
||||
Mean Pup Weight (g) |
Mean Pup Weight (g) |
Mean Pup Weight (g) |
Mean Pup Weight (g) |
|||||||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|||||
G1, F & 0 |
Mean |
6.54 |
5.58 |
10.91 |
10.07 |
14.49 |
13.33 |
25.03 |
23.85 |
|||
±SD |
0.34 |
0.20 |
0.27 |
0.30 |
0.57 |
0.60 |
0.46 |
0.43 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2, F & 250 |
Mean |
6.54 |
5.73 |
10.85 |
10.02 |
14.27 |
13.45 |
24.78 |
23.71 |
|||
±SD |
0.41 |
0.15 |
0.17 |
0.30 |
0.37 |
0.93 |
0.44 |
0.38 |
||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||
G3, F & 500 |
Mean |
6.50 |
5.62 |
10.86 |
9.96 |
14.58 |
13.57 |
25.02 |
23.98 |
|||
±SD |
0.34 |
0.27 |
0.40 |
0.35 |
0.64 |
0.71 |
0.29 |
0.47 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4, F & 1000 |
Mean |
6.40 |
5.63 |
10.76 |
9.92 |
14.34 |
13.47 |
25.00 |
24.00 |
|||
±SD |
0.38 |
0.26 |
0.36 |
0.40 |
0.49 |
0.95 |
0.47 |
0.33 |
||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Litters; PND: Postnatal Day
Table 20. MEAN PUP ANOGENITAL DISTANCE (AGD) MEASUREMENT (mm) AND ANOGENITAL DISTANCE (AGD) RATIO PER LITTER ON POSTNATAL DAY 4
Group & Dose (mg/kg body weight/day) |
|
Mean Male Pup |
Mean Female Pup |
|
Mean Male Pup |
Mean Female Pup |
G1 & 0 |
Mean |
4.45 |
2.48 |
2.01 |
1.15 |
|
±SD |
0.16 |
0.08 |
0.08 |
0.04 |
||
n |
11 |
11 |
11 |
11 |
||
G2 & 250 |
Mean |
4.34 |
2.44 |
1.96 |
1.13 |
|
±SD |
0.15 |
0.14 |
0.06 |
0.06 |
||
n |
10 |
10 |
10 |
10 |
||
G3 & 500 |
Mean |
4.38 |
2.40 |
1.98 |
1.12 |
|
±SD |
0.15 |
0.11 |
0.08 |
0.06 |
||
n |
11 |
11 |
11 |
11 |
||
G4 & 1000 |
Mean |
4.30* |
2.37 |
1.95 |
1.10 |
|
±SD |
0.09 |
0.11 |
0.03 |
0.05 |
||
n |
12 |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Litters; AGD: Anogenital Distance
*: Statistically significant (P<0.05) change than the concurrent vehicle control group
Table 21. MALE PUP NIPPLE/AREOLAE RETENTION (no.) RECORD PER LITTER
Group & Dose |
Mean No. of Pups with Retention of Nipples/ Areolae on Postnatal Day 13 |
||
G1 & 0 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
||
G2 & 250 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
10 |
||
G3 & 500 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
||
G4 & 1000 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
12 |
SD: Standard Deviation; n: Number of Litters
Table 22. SERUM THYROXINE (T4) HORMONE LEVELS (ng/mL) RECORD - POSTNATAL DAY 13 PUPS (PND)
Group & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1 & 0 |
Mean |
82.863 |
|
±SD |
18.754 |
||
n |
11 |
||
G2 & 250 |
Mean |
81.388 |
|
±SD |
16.661 |
||
n |
10 |
||
G3 & 500 |
Mean |
88.978 |
|
±SD |
15.694 |
||
n |
11 |
||
G4 & 1000 |
Mean |
80.389 |
|
±SD |
14.195 |
||
n |
12 |
SD: Standard Deviation; n: Number of Litters; PND: Postnatal Day
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is from a Klimisch 1 database and provides a robust study summary.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Toxicity to Reproduction:
The study was performed according to OECD 421 (2016) and according to GLP. The substance was given to 12 rats per sex per dose level at 0 (corn oil), 250, 500 and 1000 mg/kg bw/day. Male rats were treated before mating and during mating for a total of 29 days. Female rats were treated before mating, during mating, during pregnancy, and up to day 13 of lactation for a total of approx. 63 days.Results (parental generation): All animals survived to planned death and there were no clinical signs of toxicity. No significant changes in body weight or body weight gain with respect to day 1 of treatment were observed. No significant changes in food intake were observed, with the exception of a significant increase in food intake during the pre-mating period in male rats treated at 1000 mg/kg bw/day. This change was considered incidental and toxicological insignificant since the increase was minimal and could not be correlated with any changes in body weight or body weight gain. There were no significant changes in serum Thyroxine (T4) hormone levels in any of the male groups. As there were no significant changes observed in serum T4 levels in adult males, the assessment was not extended to adult females (dams). There were no significant changes in absolute or relative weight of testes, epididymis, prostate with seminal vesicle and coagulation gland, ovaries, or thyroid with parathyroidinin any of the groups.There were no gross pathological findings in any of the groups. There were no treatment-related histopathological findings at 1000 mg/kg bw/day (MF/F). A single incidence of minimal, multifocal, degeneration/atrophy of seminiferous tubules in testes was observed in high dose male without any correlating findings in epididymides of the same animal. This change was considered to be an expected spontaneous finding in rats of this age. There were no irregularities observed in the oestrus cyclicity in any of the female groups during the pre-mating or mating period. No significant changes in mean oestrus cycle length were observed between the groups during the pre-mating or mating period. No treatment related adverse effects on the stages of spermatogenesis were observed during the microscopic examination of interstitial testicular cell structure. No treatment related adverse effects on male or female mating index, male or female fertility index, pre-coital interval, gestational length, gestation index, parturition index, pregnancy index, live birth index, post implantation loss, mean number of Implantations were observed.Results (F1 generation):All pups showed normal behaviour during the daily inspections. No significant changes in live birth index (%) were observed and no cases of unscheduled mortality were observed during the post-natal period. No significant changes in pup weight (M/F) were observed on PND 1, PND 4, PND 7 or PND 13. No significant changes in serum Thyroxine (T4) hormone levels were observed on PND 13 in any of the groups. No significant changes in mean pup anogenital distance (AGD) or AGD ratio were observed in any of the groups, with the exception of a significant decrease in AGD in male pups from the 1000 mg/kg dose group (mean 4.30 mm) versus the control group (mean 4.45 mm). AGD in male pups from the 1000 mg/kg dose group was within the historical control range of the test facility. Therefore, this small change in AGD at 1000 mg/kg was not considered to be an adverse effect of treatment. There were no male pups with retention of nipples/areolae on PND 13 in any of the groups. No significant changes in sex ratio were observed. There were no gross pathological findings in any of the groups.Conclusion:NOAEL for systemic, reproductive, and developmental toxicity was considered at 1000 mg/kg bw/day.
Effects on developmental toxicity
Description of key information
Developmental Toxicity:
No adverse effects on reproduction or development were observed at 250, 500 or 1000 mg/kg bw/day in the performed OECD 421 with rats.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is from a Klimisch 1 database and provides a robust study summary.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Developmental Toxicity:
The study was performed according to OECD 421 (2016) and according to GLP. The substance was given to 12 rats per sex per dose level at 0 (corn oil), 250, 500 and 1000 mg/kg bw/day. Male rats were treated before mating and during mating for a total of 29 days. Female rats were treated before mating, during mating, during pregnancy, and up to day 13 of lactation for a total of approx. 63 days.Results (parental generation): All animals survived to planned death and there were no clinical signs of toxicity. No significant changes in body weight or body weight gain with respect to day 1 of treatment were observed. No significant changes in food intake were observed, with the exception of a significant increase in food intake during the pre-mating period in male rats treated at 1000 mg/kg bw/day. This change was considered incidental and toxicological insignificant since the increase was minimal and could not be correlated with any changes in body weight or body weight gain. There were no significant changes in serum Thyroxine (T4) hormone levels in any of the male groups. As there were no significant changes observed in serum T4 levels in adult males, the assessment was not extended to adult females (dams). There were no significant changes in absolute or relative weight of testes, epididymis, prostate with seminal vesicle and coagulation gland, ovaries, or thyroid with parathyroidinin any of the groups.There were no gross pathological findings in any of the groups. There were no treatment-related histopathological findings at 1000 mg/kg bw/day (MF/F). A single incidence of minimal, multifocal, degeneration/atrophy of seminiferous tubules in testes was observed in high dose male without any correlating findings in epididymides of the same animal. This change was considered to be an expected spontaneous finding in rats of this age. There were no irregularities observed in the oestrus cyclicity in any of the female groups during the pre-mating or mating period. No significant changes in mean oestrus cycle length were observed between the groups during the pre-mating or mating period. No treatment related adverse effects on the stages of spermatogenesis were observed during the microscopic examination of interstitial testicular cell structure. No treatment related adverse effects on male or female mating index, male or female fertility index, pre-coital interval, gestational length, gestation index, parturition index, pregnancy index, live birth index, post implantation loss, mean number of Implantations were observed.Results (F1 generation):All pups showed normal behaviour during the daily inspections. No significant changes in live birth index (%) were observed and no cases of unscheduled mortality were observed during the post-natal period. No significant changes in pup weight (M/F) were observed on PND 1, PND 4, PND 7 or PND 13. No significant changes in serum Thyroxine (T4) hormone levels were observed on PND 13 in any of the groups. No significant changes in mean pup anogenital distance (AGD) or AGD ratio were observed in any of the groups, with the exception of a significant decrease in AGD in male pups from the 1000 mg/kg dose group (mean 4.30 mm) versus the control group (mean 4.45 mm). AGD in male pups from the 1000 mg/kg dose group was within the historical control range of the test facility. Therefore, this small change in AGD at 1000 mg/kg was not considered to be an adverse effect of treatment. There were no male pups with retention of nipples/areolae on PND 13 in any of the groups. No significant changes in sex ratio were observed. There were no gross pathological findings in any of the groups.Conclusion:NOAEL for systemic, reproductive, and developmental toxicity was considered at 1000 mg/kg bw/day.
Justification for classification or non-classification
No adverse effects on reproduction or development were observed at 250, 500 or 1000 mg/kg bw/day in the performed OECD 421 with rats.
The chemical is therefore regarded to be classified as Not Classified for toxicity to reproduction (category 1A, 1B or 2) as per CLP (Regulation (EC) No 1272/2008).
Additional information
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