Registration Dossier
Registration Dossier
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EC number: 226-999-5 | CAS number: 5590-18-1
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Reproductive toxicity study
In a study performed according to OECD 421 (2016) and GLP, the study-derived NOAEL for systemic, reproductive, and developmental toxicity was considered at 1000 mg/kg bw/day.
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:
- The data is from Study report.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- adopted on 29th July, 2016
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: PO190512; Shaanxi Pioneer Biotech Co., Ltd, Hengxianhe Town, Hanzhang City, Shaanxi Province, China
- Expiration date of the lot/batch: 12th May, 2021
- Purity: 99%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: NA
- Stability under storage conditions: Ambient (21 to 29°C).
- Stability under test conditions: NA
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: NA
- Reactivity of the test substance with the solvent/vehicle /test medium (if applicable): NA
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Rat is one of the standard laboratory rodent species used for toxicity assessment.
In-house bred animals - Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: In-house bred animals.
- Animals: 12 males + 12 females (total of 96 rats, 46 males + 46 females)
- Source: In-house bred animals.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study receipt: 10 weeks
- Weight at study initiation: Males: 240.18 to 285.03 g; Females: 200.76 to 249.63 g
- Fasting period before study: No
- 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.
- Bedding: Clean sterilized paddy husk was provided as bedding material.
- During acclimatization, two animals of same sex were housed.
- Pre-mating - Per cage, two animals of same sex and group were housed.
- Cohabitation Period (mating) - Per cage, two animals (one male and one female) of same group were housed.
- Post-mating - After confirmation of 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. Sterilized paper shreds were provided as nesting material for all females from gestation day 20 onwards.
- Diet (e.g. ad libitum): Altromin maintenance diet for rats and mice was available ad libitum.
- Water (e.g. ad libitum): Water was provided ad libitum. Deep bore-well water was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period: Five days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8 to 22.9°C
- Humidity (%): 49 to 65%
- Air changes (per hr): 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light and 12 hours dark cycle - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item formulations were prepared before dose administration and administered within the stability period. The following stock solutions were prepared: of 25, 50, and 100 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 item formulations.
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item was insoluble in distilled water and not suspended uniformly in 0.5% w/v Carboxymethyl cellulose at the concentration of 100 mg/mL. The test item was suspended uniformly in corn oil at the concentration of 100 mg/mL.
- Stock solutions of test item: 0 mg/mL, 25 mg/mL, 50 mg/mL and 100 mg/mL.
- Dose volume (if gavage): 10 ml/kg bw
- Lot/batch no. (if required): N12009002 - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: two weeks
- 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.
- Re-mating: Re-mating of females was not considered as all the females were confirmed with mating with the first male.
Non-pregnant females: Non-pregnant females were sacrificed after 24 days from the last day of confirmation of mating.
- After successful mating each pregnant female was caged (how): pregnant females were housed individually - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- Males - 29 days
Females - 63 days - Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- 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 dose levels were selected based on the dose-range finding study where animals were orally gavaged. No treatment related effects were observed at any of the dose levels in dose
- 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: -8.21 to 11.55%; Females: -10.72 to 8.51%) 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 weights of the animals were analyzed statistically for mean body weight and there were no statistically significant differences noted between groups within each sex.
- Fasting period before blood sampling for clinical biochemistry: No data available.
- Other: No data available. - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed at receipt, on the fist day of dosing, weekly thereafter and at termination. Females were weighed on GD 0, 7, 14 and 20 during pregnancy and on lactation day 1, 4, 7 and 13 during lactation period and on day 14.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, Feed consumption was measured for all animals once a week during premating period. Feed consumption was not measured during the mating period for either male or female rats. After mating, feed consumption for females was recorded during gestation day (GD) 0 to 7, 7 to 14 and 14 to 20 and during lactation day 1 to 4, 4 to 7 and 7 to 13.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data available
OTHER: No data available - Oestrous cyclicity (parental animals):
- Oestrous cyclicity was monitored for two weeks after five days of acclimatization. Vaginal smears were monitored daily from the beginning of treatment period until evidence of mating. 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); excess pups were killed and discarded.
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.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No data available
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No data available - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were sacrificed after 29 days of treatment
- Maternal animals: All surviving animals were sacrificed on Lactation day 14 (after 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 were prepared for microscopic examination and weighed, respectively are indicated in Table 1 - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed at PND 4 and or PND 13.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) are indicated in Table 2.
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 test item-related clinical signs of toxicity in all the groups during the experimental period.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All animals were survived to planned death.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no significant changes noted in mean body weight or mean body weight gain with respect to day 1 in any of the groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no significant changes noted in the mean feed consumption measured during pre-mating period (first 2 weeks) in treatment groups when compared to control groups.
There were no test item-related changes noted in mean gestational feed consumption in treatment groups when compared to control groups.
There were no significant changes noted in mean lactation feed consumption in treatment groups when compared to control groups. - 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 changes observed in serum Thyroxine (T4) hormone levels in treatment groups males when compared to control group males. As there were no changes noted in T4 levels of 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:
- no effects observed
- Description (incidence and severity):
- There were no treatment related histopthological changes observed in treatment group related to test item.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No neoplastic lesions were observed at 0 and 1000 mg/kg bw/day.
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no significant changes in mean gestational body weight or mean gestational body weight gain in the treatment groups when compared to control group.
There were no significant changes in mean lactation body weight or mean lactation body weight gain in the treatment groups when compared to control group. - Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- There were no cases of irregular oestrus cyclicity during pre-mating or mating. No significant changes in mean oestrus length were observed in treatment groups when compared to control group during pre-mating or mating periods.
- 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
- 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):
- There were no test item-related changes noted in mean pup weight on PND 1, 4, 7 or 13 in treatment groups when compared to control group.
- 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):
- There were no significant changes in serum Thyroxine (T4) hormone levels on PND 13 pups in treatment groups when compared to control group.
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- No significant changes were observed.
- Anogenital distance (AGD):
- no effects observed
- Description (incidence and severity):
- There were no test item-related effects noted on mean pup AGD (M/F) or AGD ratio (M/F) measured on PND 4 in treatment groups compared to control group.
- Nipple retention in male pups:
- no effects observed
- Description (incidence and severity):
- There were no cases of male nipple retention on PND 13 in all the dose 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
- 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 (Parent generation):All animals survived to planned death and there were no clinical signs of toxicity. No test item-related changes noted in body weight or body weight gain and feed consumption of both sexes from any of the dose levels during the experimental period. There were no significant changes noted in serum thyroxine hormone (T4) levels in all treatment groups compared to control groups. No significant changes in absolute or relative organ weights of both sexes in any of the dose levels were observed. There were no gross pathological changes observed during necropsy in all of the adult animals except in groups G3 and G4 wherein, both gastric and intestinal contents were found with yellow discoloration. This noted coloration was due to colored nature of test-item. Histopathological examinations of G1 (males and females) and G4 (males and females) animals did not reveal any treatment-related effects. 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 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 were observed at all the tested dose levels. No significant changes in AGD measurement/ratio were observed at all the tested dose levels. No significant changes in pup weight or AGD measurement/ratio were observed at all the tested dose levels. No cases of nipple retention were observed on PND 13 among male pups. Serum thyroxine (T4) hormone levels measured on PND 13 were unaffected by treatment. 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. Table for CLINICAL SIGNS OF TOXICITY AND MORTALITY RECORD (Males)
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.
Contd. CLINICAL SIGNS OF TOXICITY AND MORTALITY RECORD (Females)
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. Table for BODY WEIGHT (g) RECORD (Males)
Group, Sex & Dose (mg/kg body weight/day) |
Body Weight (g) on Day |
|||||
1 |
7 |
14 |
21 |
28 |
||
G1, M & 0 |
Mean |
344.92 |
364.74 |
380.43 |
401.18 |
413.79 |
±SD |
22.32 |
26.88 |
28.74 |
35.61 |
36.70 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
346.79 |
363.64 |
382.83 |
397.60 |
411.86 |
±SD |
22.18 |
23.83 |
22.16 |
25.73 |
27.90 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
348.51 |
369.31 |
387.54 |
399.54 |
413.68 |
±SD |
20.30 |
26.17 |
28.75 |
30.67 |
31.73 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
348.93 |
365.83 |
387.13 |
405.21 |
420.46 |
±SD |
19.36 |
21.24 |
23.17 |
26.89 |
30.10 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
M: Male; SD: Standard Deviation; n: Number of Animals.
Contd. Table for BODY WEIGHT (g) RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
Body Weight (g) on Day |
||||
1 |
7 |
14 |
21# |
||
G1, F & 0 |
Mean |
253.80 |
260.79 |
268.54 |
272.30 |
±SD |
16.30 |
16.43 |
15.99 |
15.79 |
|
n |
12 |
12 |
12 |
7 |
|
G2, F & 250 |
Mean |
253.72 |
261.62 |
267.91 |
284.49 |
±SD |
17.75 |
17.79 |
17.86 |
23.30 |
|
n |
12 |
12 |
12 |
3 |
|
G3, F & 500 |
Mean |
253.98 |
262.91 |
268.04 |
284.09 |
±SD |
16.19 |
16.48 |
15.51 |
21.72 |
|
n |
12 |
12 |
12 |
4 |
|
G4, F & 1000 |
Mean |
254.95 |
264.13 |
269.90 |
277.58 |
±SD |
17.65 |
17.20 |
16.74 |
20.86 |
|
n |
12 |
12 |
12 |
4 |
|
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. Table for 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 |
278.53 |
288.75 |
311.73 |
377.30 |
±SD |
20.06 |
20.06 |
20.97 |
20.61 |
|
n |
11 |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
273.15 |
285.52 |
308.59 |
372.18 |
±SD |
18.85 |
20.76 |
20.58 |
19.75 |
|
n |
12 |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
275.89 |
287.04 |
309.71 |
370.99 |
±SD |
18.68 |
18.93 |
19.81 |
20.26 |
|
n |
11 |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
276.32 |
289.94 |
312.84 |
375.40 |
±SD |
17.58 |
18.19 |
19.20 |
21.30 |
|
n |
11 |
11 |
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Dams.
Table 4. Table for 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 |
287.29 |
292.32 |
300.80 |
312.73 |
±SD |
19.07 |
18.20 |
17.69 |
16.16 |
|
n |
11 |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
285.03 |
289.58 |
297.82 |
310.76 |
±SD |
19.88 |
19.39 |
18.64 |
19.42 |
|
n |
12 |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
284.79 |
289.38 |
297.30 |
310.79 |
±SD |
17.71 |
17.41 |
16.90 |
16.58 |
|
n |
11 |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
288.68 |
293.09 |
302.35 |
315.11 |
±SD |
16.28 |
16.61 |
16.26 |
16.35 |
|
n |
11 |
11 |
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Dams.
Table 5. Table for PERCENT CHANGE IN BODY WEIGHT GAIN (%) WITH RESPECT TO DAY 1 RECORD (Males)
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight (%) Gain during Day |
||||
1 to 7 |
1 to 14 |
1 to 21 |
1 to 28 |
||
G1, M & 0 |
Mean |
5.70 |
10.23 |
16.16 |
19.81 |
±SD |
1.53 |
1.82 |
3.75 |
3.88 |
|
n |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
4.87 |
10.46 |
14.67 |
18.76 |
±SD |
1.68 |
2.67 |
2.37 |
2.60 |
|
n |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
5.91 |
11.13 |
14.56 |
18.63 |
±SD |
2.27 |
3.05 |
3.51 |
3.94 |
|
n |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
4.84 |
10.94 |
16.09 |
20.43 |
±SD |
1.35 |
2.06 |
2.67 |
3.34 |
|
n |
12 |
12 |
12 |
12 |
|
M: Male; SD: Standard Deviation; n: Number of Animals.
Contd. Table for PERCENT CHANGE IN BODY WEIGHT GAIN (%) WITH RESPECT TO DAY 1 RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight (%) Gain during Day |
|||
1 to 7 |
1 to 14 |
1 to 21# |
||
G1, F & 0 |
Mean |
2.77 |
5.85 |
8.27 |
±SD |
1.05 |
1.56 |
1.34 |
|
n |
12 |
12 |
7 |
|
G2, F & 250 |
Mean |
3.13 |
5.62 |
7.97 |
±SD |
0.88 |
1.05 |
1.45 |
|
n |
12 |
12 |
3 |
|
G3, F & 500 |
Mean |
3.53 |
5.58 |
9.87 |
±SD |
1.01 |
1.58 |
1.70 |
|
n |
12 |
12 |
4 |
|
G4, F & 1000 |
Mean |
3.63 |
5.92 |
9.42 |
±SD |
0.91 |
1.47 |
2.41 |
|
n |
12 |
12 |
4 |
|
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 6. Table for PERCENT CHANGE IN GESTATION BODY WEIGHT GAIN (%) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight Gain (%) during Gestation Day (GD) |
|||
0 to 7 |
7 to 14 |
14 to 20 |
||
G1, F & 0 |
Mean |
3.69 |
7.98 |
21.13 |
±SD |
0.74 |
0.90 |
1.76 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
4.50 |
8.12 |
20.72 |
±SD |
0.81 |
0.89 |
2.38 |
|
n |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
4.05 |
7.91 |
19.87 |
±SD |
0.95 |
0.63 |
2.57 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
4.94* |
7.91 |
20.04 |
±SD |
0.79 |
0.66 |
2.22 |
|
n |
11 |
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Dams.*: Statistically significant (P<0.05) change than the vehicle control group.
Table 7. Table for PERCENT CHANGE IN LACTATION BODY WEIGHT GAIN (%) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight Gain (%) during Lactation Day (LD) |
|||
1 to 4 |
4 to 7 |
7 to 13 |
||
G1, F & 0 |
Mean |
1.78 |
2.93 |
4.01 |
±SD |
0.60 |
0.78 |
0.97 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
1.62 |
2.88 |
4.35 |
±SD |
0.70 |
1.04 |
1.21 |
|
n |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
1.63 |
2.75 |
4.56 |
±SD |
0.59 |
0.93 |
1.31 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
1.53 |
3.17 |
4.23 |
±SD |
0.44 |
0.67 |
1.09 |
|
n |
11 |
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Dams.
Table 8. Table for FEED CONSUMPTION (g/animal/day) RECORD (Males)
Group, Sex & Dose (mg/kg body weight/day) |
Feed Consumption (g/animal/day) during Pre-mating Period |
||
Week 1 |
Week 2 |
||
G1, M & 0 |
Mean |
20.71 |
24.73 |
±SD |
1.68 |
1.27 |
|
n |
12 |
12 |
|
G2, M & 250 |
Mean |
21.29 |
23.50 |
±SD |
1.49 |
1.53 |
|
n |
12 |
12 |
|
G3, M & 500 |
Mean |
20.23 |
24.05 |
±SD |
2.49 |
1.12 |
|
n |
12 |
12 |
|
G4, M & 1000 |
Mean |
22.35 |
24.45 |
±SD |
1.99 |
1.06 |
|
n |
12 |
12 |
|
M: Male; SD: Standard Deviation; n: Number of Animals.
Contd. Table for FEED CONSUMPTION (g/animal/day) RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
Feed Consumption (g/animal/day) during Pre-mating Period |
||
Week 1 |
Week 2 |
||
G1, F & 0 |
Mean |
17.03 |
18.98 |
±SD |
0.73 |
1.41 |
|
n |
6 |
6 |
|
G2, F & 250 |
Mean |
16.31 |
18.27 |
±SD |
1.67 |
1.44 |
|
n |
6 |
6 |
|
G3, F & 500 |
Mean |
16.62 |
18.46 |
±SD |
0.60 |
1.56 |
|
n |
6 |
6 |
|
G4, F & 1000 |
Mean |
17.18 |
19.39 |
±SD |
2.85 |
1.57 |
|
n |
6 |
6 |
|
F: Female; SD: Standard Deviation; n: Number of Animals.
Table 9. Table for 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 |
19.09 |
22.90 |
26.29 |
±SD |
0.53 |
0.40 |
0.51 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
19.30 |
22.57 |
26.43 |
±SD |
0.58 |
0.38 |
0.57 |
|
n |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
19.15 |
22.64 |
26.71 |
±SD |
0.55 |
0.29 |
0.49 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
17.90 |
23.08 |
26.84* |
±SD |
4.44 |
0.57 |
0.47 |
|
n |
11 |
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Dams.*: Statistically significant (P<0.05) change than the vehicle control group.
Table 10. Table for 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 |
27.78 |
31.61 |
35.24 |
±SD |
0.96 |
0.59 |
1.45 |
|
n |
11 |
11 |
11 |
|
G2, F & 250 |
Mean |
28.34 |
31.71 |
36.47 |
±SD |
1.23 |
0.40 |
1.26 |
|
n |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
28.25 |
31.75 |
35.82 |
±SD |
0.86 |
0.99 |
1.17 |
|
n |
11 |
11 |
11 |
|
G4, F & 1000 |
Mean |
28.19 |
31.59 |
36.09 |
±SD |
0.93 |
0.93 |
1.23 |
|
n |
11 |
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Dams.
Table 11. Table for 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 |
4.45 |
% |
100.0 |
0.0 |
±SD |
0.23 |
||
n |
12 |
|||||
G2, F & 250 |
12 |
n |
12 |
0 |
Mean |
4.56 |
% |
100.0 |
0.0 |
±SD |
0.35 |
||
n |
12 |
|||||
G3, F & 500 |
12 |
n |
12 |
0 |
Mean |
4.44 |
% |
100.0 |
0.0 |
±SD |
0.26 |
||
n |
12 |
|||||
G4, F & 1000 |
12 |
n |
12 |
0 |
Mean |
4.47 |
% |
100.0 |
0.0 |
±SD |
0.27 |
||
n |
12 |
|||||
F: Female; SD: Standard Deviation; n: Number of Animals.
Table 12. Table for DELIVERY DATA (AT BIRTH) RECORD 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 |
12.73 |
6.00 |
6.55 |
12.55 |
0.00 |
0.00 |
0.00 |
0.18 |
0.00 |
0.00 |
0.18 |
0.97 |
98.70 |
|||||
±SD |
1.19 |
1.67 |
0.93 |
1.04 |
0.00 |
0.00 |
0.00 |
0.40 |
0.00 |
0.00 |
0.40 |
0.43 |
2.89 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G2, F & 250 |
Mean |
12.25 |
6.50 |
5.67 |
12.17 |
0.00 |
0.08 |
0.08 |
0.00 |
0.00 |
0.00 |
0.00 |
1.30 |
99.36 |
|||||
±SD |
1.82 |
0.90 |
1.97 |
1.80 |
0.00 |
0.29 |
0.29 |
0.00 |
0.00 |
0.00 |
0.00 |
0.59 |
2.22 |
||||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
||||||
G3, F & 500 |
Mean |
12.18 |
5.82 |
6.27 |
12.09 |
0.00 |
0.09 |
0.09 |
0.00 |
0.00 |
0.00 |
0.00 |
1.01 |
99.35 |
|||||
±SD |
1.17 |
1.40 |
1.42 |
1.04 |
0.00 |
0.30 |
0.30 |
0.00 |
0.00 |
0.00 |
0.00 |
0.49 |
2.15 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G4, F & 1000 |
Mean |
11.64 |
4.55* |
6.64 |
11.18 |
0.00 |
0.45 |
0.45 |
0.00 |
0.00 |
0.00 |
0.00 |
0.80 |
96.39 |
|||||
±SD |
1.69 |
1.44 |
2.06 |
1.72 |
0.00 |
1.04 |
1.04 |
0.00 |
0.00 |
0.00 |
0.00 |
0.49 |
8.17 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
F: Female; SD: Standard Deviation; n: Number of Dams; m/f: male/female.*: Statistically significant (P<0.05) change than the vehicle control group.
Table 13. Table for LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group, Sex & Dose weight/day) |
During LD 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 |
6.00 |
6.55 |
12.55 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.97 |
100.00 |
||||
±SD |
1.67 |
0.93 |
1.04 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.43 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G2, F & 250 |
Mean |
6.50 |
5.67 |
12.17 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.30 |
100.00 |
||||
±SD |
0.90 |
1.97 |
1.80 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.59 |
0.00 |
|||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
|||||
G3, F & 500 |
Mean |
5.82 |
6.27 |
12.09 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.01 |
100.00 |
||||
±SD |
1.40 |
1.42 |
1.04 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.49 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G4, F & 1000 |
Mean |
4.55* |
6.64 |
11.18 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.80 |
100.00 |
||||
±SD |
1.44 |
2.06 |
1.72 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.49 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
F: Female; SD: Standard Deviation; n: Number of Dams; m/f: male/female; LD: Lactation Day.
Contd. LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group, Sex & Dose weight/day) |
Pups Sacrificed for Litter Standardization (No.) |
Live Pups (No.) on LD 4 after Litter Standardization (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 |
1.91 |
1.91 |
6.00 |
4.64 |
10.64 |
6.00 |
4.64 |
10.64 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.44 |
100.00 |
||||||
±SD |
0.00 |
0.30 |
0.30 |
1.67 |
1.03 |
0.92 |
1.67 |
1.03 |
0.92 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.79 |
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 |
1.50 |
1.50 |
6.50 |
4.17 |
10.67 |
6.50 |
4.17 |
10.67 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.90 |
100.00 |
||||||
±SD |
0.00 |
0.80 |
0.80 |
0.90 |
1.70 |
1.37 |
0.90 |
1.70 |
1.37 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.09 |
0.00 |
|||||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
|||||||
G3, F & 500 |
Mean |
0.00 |
1.73 |
1.73 |
5.82 |
4.55 |
10.36 |
5.82 |
4.55 |
10.36 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.55 |
100.00 |
||||||
±SD |
0.00 |
0.65 |
0.65 |
1.40 |
1.44 |
0.67 |
1.40 |
1.44 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.09 |
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 |
1.00 |
1.00 |
4.55 |
5.64 |
10.18 |
4.55* |
5.64 |
10.18 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.97* |
100.00 |
||||||
±SD |
0.00 |
1.00 |
1.00 |
1.44 |
1.69 |
0.87 |
1.44 |
1.69 |
0.87 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.65 |
0.00 |
|||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||||
F: Female; SD: Standard Deviation; n: Number of Dams; LD: Lactation Day; m/f: male/female.*: Statistically significant (P<0.05) change than the vehicle control group.
Contd. LITTER OBSERVATION RECORD 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 |
6.00 |
4.64 |
10.64 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.44 |
100.00 |
||||
±SD |
1.67 |
1.03 |
0.92 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.79 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G2, F & 250 |
Mean |
6.50 |
4.17 |
10.67 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.90 |
100.00 |
||||
±SD |
0.90 |
1.70 |
1.37 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.09 |
0.00 |
|||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
|||||
G3, F & 500 |
Mean |
5.82 |
4.55 |
10.36 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.55 |
100.00 |
||||
±SD |
1.40 |
1.44 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
1.09 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G4, F & 1000 |
Mean |
4.55* |
5.64 |
10.18 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.97* |
100.00 |
||||
±SD |
1.44 |
1.69 |
0.87 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.65 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
F: Female; SD: Standard Deviation; n: Number of Dams; LD: Lactation Day; m/f: male/female.*: Statistically significant (P<0.05) change than the vehicle control group.
Table 14. Table for REPRODUCTIVE PERFORMANCE RECORD (Males)
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 |
12 (12) |
100.0 |
|
G3, M & 500 |
12 (12) |
100.0 |
11 (12) |
91.7 |
|
G4, M & 1000 |
12 (12) |
100.0 |
11 (12) |
91.7 |
M: Male.
Contd. Table for REPRODUCTIVE PERFORMANCE RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
|
Pre-coital Interval / Mean Time to Mating (Days) |
Gestation Length / Duration of Pregnancy (Days) |
|||
Pre-Coital Interval / Copulatory Interval |
Conceiving Days (1 to 5) |
Conceiving Days (5 to More) |
Gestation Length (Days) |
|||
G1, F & 0 |
Mean |
8.08 |
n |
3 |
9 |
22.45 |
±SD |
3.82 |
% |
27.27 |
81.82 |
0.52 |
|
n |
12 |
11 |
||||
G2, F & 250 |
Mean |
4.42 |
n |
9 |
3 |
22.33 |
±SD |
2.87 |
% |
75.00 |
25.00 |
0.49 |
|
n |
12 |
12 |
||||
G3, F & 500 |
Mean |
5.67 |
n |
7 |
5 |
22.45 |
±SD |
3.73 |
% |
63.64 |
45.45 |
0.52 |
|
n |
12 |
11 |
||||
G4, F & 1000 |
Mean |
5.25 |
n |
7 |
5 |
22.55 |
±SD |
4.86 |
% |
63.64 |
45.45 |
0.52 |
|
n |
12 |
11 |
||||
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).
Contd. Table for REPRODUCTIVE PERFORMANCE RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
Female Mating Index (%) |
Female Fertility Index (%) |
Female Fecundity or Pregnancy Index (%) |
||||||||
No. of Females with Evidence of Mating |
No. of Females used for Mating |
Female Mating Index (%) |
No. of Females confirmed as Fertile |
No. of Females used for Mating |
Female Fertility Index (%) |
No. of Pregnant Females |
No. of Females with confirmed Mating |
Female Fecundity or Pregnancy Index (%) |
|||
G1, F & 0 |
12 |
12 |
100.0 |
11 |
12 |
91.7 |
11 |
12 |
91.7 |
||
G2, F & 250 |
12 |
12 |
100.0 |
12 |
12 |
100.0 |
12 |
12 |
100.0 |
||
G3, F & 500 |
12 |
12 |
100.0 |
11 |
12 |
91.7 |
11 |
12 |
91.7 |
||
G4, F & 1000 |
12 |
12 |
100.0 |
11 |
12 |
91.7 |
11 |
12 |
91.7 |
||
Contd. Table for REPRODUCTIVE PERFORMANCE RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
Gestation index (%) |
|
Parturition index (%) |
||||
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 |
11 |
100.0 |
|
11 |
11 |
100.0 |
G2, F & 250 |
12 |
12 |
100.0 |
|
12 |
12 |
100.0 |
G3, F & 500 |
11 |
11 |
100.0 |
|
11 |
11 |
100.0 |
G4, F & 1000 |
11 |
11 |
100.0 |
|
11 |
11 |
100.0 |
Contd.Table for REPRODUCTIVE PERFORMANCE RECORD (Females)
Group, Sex & Dose (mg/kg body weight/day) |
|
Post-implantation Loss (%) |
|
Post-natal Loss (%) |
||||
No. of Implantations |
No. of Viable (Live) Pups |
Post-implantation Loss (No.) |
Post-implantation Loss (%) |
|
Total No. of Pups Found Dead/ Cannibalized during lactation period |
Post-natal Loss (%) |
||
G1, F & 0 |
Mean |
12.91 |
12.55 |
0.36 |
2.65 |
|
0.00 |
0.00 |
±SD |
1.22 |
1.04 |
0.50 |
3.68 |
|
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
|
11 |
11 |
|
G2, F & 250 |
Mean |
12.42 |
12.17 |
0.25 |
1.93 |
|
0.00 |
0.00 |
±SD |
1.83 |
1.80 |
0.45 |
3.50 |
|
0.00 |
0.00 |
|
n |
12 |
12 |
12 |
12 |
|
12 |
12 |
|
G3, F & 500 |
Mean |
12.36 |
12.09 |
0.27 |
1.86 |
|
0.00 |
0.00 |
±SD |
1.43 |
1.04 |
0.65 |
4.37 |
|
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
|
11 |
11 |
|
G4, F & 1000 |
Mean |
11.73 |
11.18 |
0.55 |
4.11 |
|
0.00 |
0.00 |
±SD |
1.79 |
1.72 |
1.29 |
9.53 |
|
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
|
11 |
11 |
|
F: Female; n: Number of Dams.
Table 15. Table for ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
|
Testes |
Epididymides |
Prostate |
Seminal vesicles with coagulating glands |
Thyroid along with parathyroid |
G1, M & 0 |
Mean |
3.2784 |
1.3315 |
1.1175 |
1.4823 |
0.0284 |
±SD |
0.2789 |
0.0716 |
0.1440 |
0.2196 |
0.0036 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
3.2778 |
1.3408 |
1.1698 |
1.6503 |
0.0277 |
±SD |
0.2537 |
0.0947 |
0.1620 |
0.1872 |
0.0023 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
3.2840 |
1.3214 |
1.1262 |
1.4692 |
0.0275 |
±SD |
0.2547 |
0.0952 |
0.1147 |
0.1836 |
0.0033 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
3.2368 |
1.3370 |
1.2206 |
1.4698 |
0.0283 |
±SD |
0.3159 |
0.1511 |
0.2052 |
0.1959 |
0.0029 |
|
n |
12 |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals; #: Weighed post fixation.
Contd. ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Ovaries |
Thyroid along |
|
G1, F & 0 |
Mean |
0.1429 |
0.0255 |
±SD |
0.0077 |
0.0017 |
|
n |
12 |
12 |
|
G2, F & 250 |
Mean |
0.1446 |
0.0244 |
±SD |
0.0082 |
0.0012 |
|
n |
12 |
12 |
|
G3, F & 500 |
Mean |
0.1465 |
0.0259 |
±SD |
0.0050 |
0.0019 |
|
n |
12 |
12 |
|
G4, F & 1000 |
Mean |
0.1412 |
0.0265 |
±SD |
0.0108 |
0.0016 |
|
n |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams; #: Weighed post fixation.
Table 16. Table for 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 |
Epididymides |
Prostate |
Seminal vesicles with coagulating glands |
Thyroid along with parathyroid |
G1, M & 0 |
Mean |
391.35 |
0.8413 |
0.3429 |
0.2875 |
0.3788 |
0.0073 |
±SD |
37.78 |
0.0692 |
0.0343 |
0.0444 |
0.0408 |
0.0009 |
|
n |
12 |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
391.42 |
0.8402 |
0.3434 |
0.3006 |
0.4235 |
0.0071 |
±SD |
27.39 |
0.0743 |
0.0266 |
0.0480 |
0.0548 |
0.0007 |
|
n |
12 |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
396.15 |
0.8339 |
0.3352 |
0.2880 |
0.3738 |
0.0070 |
±SD |
40.24 |
0.0787 |
0.0250 |
0.0485 |
0.0555 |
0.0008 |
|
n |
12 |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
402.50 |
0.8046 |
0.3322 |
0.3045 |
0.3653 |
0.0071 |
±SD |
30.92 |
0.0533 |
0.0275 |
0.0527 |
0.0416 |
0.0008 |
|
n |
12 |
12 |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals.
Contd. Table for 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 |
G1, F & 0 |
Mean |
302.15 |
0.0474 |
0.0085 |
±SD |
16.19 |
0.0029 |
0.0006 |
|
n |
12 |
12 |
12 |
|
G2, F & 250 |
Mean |
301.04 |
0.0482 |
0.0081 |
±SD |
17.62 |
0.0040 |
0.0005 |
|
n |
12 |
12 |
12 |
|
G3, F & 500 |
Mean |
300.99 |
0.0488 |
0.0086 |
±SD |
16.17 |
0.0035 |
0.0007 |
|
n |
12 |
12 |
12 |
|
G4, F & 1000 |
Mean |
304.73 |
0.0463 |
0.0087 |
±SD |
16.39 |
0.0027 |
0.0008 |
|
n |
12 |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of Dams.
Table 17. Table for SERUM THYROXINE (T4) HORMONE LEVELS (ng/mL) RECORD - MALES
Group, Sex & Dose |
Serum T4 Levels (ng/mL) |
||
G1, M & 0 |
Mean |
82.133 |
|
±SD |
9.622 |
||
n |
12 |
||
G2, M & 250 |
Mean |
82.175 |
|
±SD |
7.976 |
||
n |
12 |
||
G3, M & 500 |
Mean |
80.692 |
|
±SD |
8.452 |
||
n |
12 |
||
G4, M &1000 |
Mean |
81.318 |
|
±SD |
9.291 |
||
n |
12 |
M: Male;SD: Standard Deviation; n: Number of Animals.
Table 18. Table for PUP OBSERVATIONS RECORD DURING POSTNATAL PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
At Birth (PND 1) |
PND 1 to 4 |
Pups Sacrificed for Blood Collection on PND 4 (No.)* |
PND 5 to 7$ |
PND 8 to 13$ |
||||||||
G1, F & 0 |
No. of Dams / Litters# |
11 |
11 |
11 |
11 |
11 |
|||||||
No. of Live Pups |
138 |
138 |
21 |
117 |
117 |
||||||||
Pup Observation/ No. of Pups observed |
N/138 |
N/138 |
- |
N/117 |
N/117 |
||||||||
G2, F & 250 |
No. of Dams / Litters# |
12 |
12 |
10 |
12 |
12 |
|||||||
No. of Live Pups |
146 |
146 |
18 |
128 |
128 |
||||||||
Pup Observation/ No. of Pups observed |
N/146 |
N/146 |
- |
N/128 |
N/128 |
||||||||
G3, F & 500 |
No. of Dams / Litters# |
11 |
11 |
10 |
11 |
11 |
|||||||
No. of Live Pups |
133 |
133 |
19 |
114 |
114 |
||||||||
Pup Observation/ No. of Pups observed |
N/133 |
N/133 |
- |
N/114 |
N/114 |
||||||||
G4, F & 1000 |
No. of Dams / Litters# |
11 |
11 |
6 |
11 |
11 |
|||||||
No. of Live Pups |
123 |
123 |
11 |
112 |
112 |
||||||||
Pup Observation/ No. of Pups observed |
N/123 |
N/123 |
- |
N/112 |
N/112 |
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. Table for MEAN PUP WEIGHT (g) PER LITTER RECORD DURING LACTATION PERIOD
Group, Sex & Dose (mg/kg body weight/day) |
PND 1 |
PND 4 |
PND 7 |
PND 14 |
||||||||
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 |
7.19 |
6.78 |
11.20 |
10.88 |
15.12 |
14.97 |
25.75 |
24.86 |
|||
±SD |
0.23 |
0.24 |
0.25 |
0.26 |
0.32 |
0.19 |
0.42 |
0.36 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2, F & 250 |
Mean |
7.01 |
6.64 |
11.03 |
10.51* |
15.13 |
14.95 |
25.55 |
24.77 |
|||
±SD |
0.44 |
0.46 |
0.39 |
0.31 |
0.25 |
0.34 |
0.82 |
0.38 |
||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
||||
G3, F & 500 |
Mean |
7.13 |
6.81 |
11.07 |
10.73 |
15.01 |
15.05 |
25.57 |
24.77 |
|||
±SD |
0.19 |
0.22 |
0.22 |
0.31 |
0.20 |
0.32 |
0.63 |
0.52 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4, F & 1000 |
Mean |
7.12 |
6.75 |
11.05 |
10.84 |
15.19 |
15.10 |
26.15 |
24.95 |
|||
±SD |
0.42 |
0.34 |
0.34 |
0.23 |
0.26 |
0.20 |
0.69 |
0.43 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
F: Female; SD: Standard Deviation; n: Number of Litters; PND: Postnatal Day.
*: Statistically significant (P<0.05) change than the vehicle control group.
Table 20. Table for MEAN PUP ANOGENITAL DISTANCE (AGD) MEASUREMENT (mm) AND ANOGENITAL DISTANCE (AGD) RATIO PER LITTER RECORD ON POSTNATAL DAY 4
Group & Dose (mg/kg body weight/day) |
|
Mean Anogenital Distance Measurement (mm) |
|
Mean Anogenital Distance Ratio |
||
Male |
Female |
|
Male |
Female |
||
G1 & 0 |
Mean |
4.98 |
2.47 |
2.23 |
1.11 |
|
±SD |
0.12 |
0.06 |
0.06 |
0.03 |
||
n |
11 |
11 |
|
11 |
11 |
|
G2 & 250 |
Mean |
4.83* |
2.52 |
2.17 |
1.15 |
|
±SD |
0.15 |
0.11 |
0.08 |
0.05 |
||
n |
12 |
12 |
|
12 |
12 |
|
G3 & 500 |
Mean |
4.94 |
2.50 |
2.22 |
1.13 |
|
±SD |
0.11 |
0.11 |
0.05 |
0.06 |
||
n |
11 |
11 |
|
11 |
11 |
|
G4 & 1000 |
Mean |
4.97 |
2.59* |
2.23 |
1.17* |
|
±SD |
0.17 |
0.10 |
0.09 |
0.05 |
||
n |
11 |
11 |
|
11 |
11 |
|
F: Female; SD: Standard Deviation; n: Number of Litters; AGD: Anogenital Distance.
*: Statistically significant (P<0.05) change than the vehicle control group.
Table 21. Table for 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 |
12 |
||
G3 & 500 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
||
G4 & 1000 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
SD: Standard Deviation; n: Number of Litters.
Table 22. Table for SERUM THYROXINE (T4) HORMONE LEVELS (ng/mL) RECORD - POSTNATAL DAY 13 PUPS (PND)
Group, Sex & Dose |
Serum T4 Levels (ng/mL) |
||
G1 & 0 |
Mean |
68.196 |
|
±SD |
6.763 |
||
n |
11 |
||
G2 & 250 |
Mean |
71.669 |
|
±SD |
2.452 |
||
n |
12 |
||
G3 & 500 |
Mean |
72.121 |
|
±SD |
2.791 |
||
n |
11 |
||
G4 &1000 |
Mean |
65.087 |
|
±SD |
1.589 |
||
n |
11 |
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 Klimicsh 1.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Reproductive toxicity study
Study 1.
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 (Parent generation):All animals survived to planned death and there were no clinical signs of toxicity. No test item-related changes noted in body weight or body weight gain and feed consumption of both sexes from any of the dose levels during the experimental period. There were no significant changes noted in serum thyroxine hormone (T4) levels in all treatment groups compared to control groups. No significant changes in absolute or relative organ weights of both sexes in any of the dose levels were observed. There were no gross pathological changes observed during necropsy in all of the adult animals except in groups G3 and G4 wherein, both gastric and intestinal contents were found with yellow discoloration. This noted coloration was due to colored nature of test-item. Histopathological examinations of G1 (males and females) and G4 (males and females) animals did not reveal any treatment-related effects. 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 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 were observed at all the tested dose levels. No significant changes in AGD measurement/ratio were observed at all the tested dose levels. No significant changes in pup weight or AGD measurement/ratio were observed at all the tested dose levels. No cases of nipple retention were observed on PND 13 among male pups. Serum thyroxine (T4) hormone levels measured on PND 13 were unaffected by treatment. 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
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
The registered substance was given by oral gavage to 12 rats per sex per dose level at 0 (vehicle), 250, 500 and 1000 mg/kg bw/day. The study was performed according to OECD 421 (2016) and GLP. No adverse effect was observed. The study-derived NOAEL for systemic, reproductive, and developmental toxicity was considered at 1000 mg/kg bw/day. Considering the results of this OECD 421 study, the registered substance is regarded to be classified as Not Classified for reproductive toxicity according to Regulation EC 1272/2008.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
