Registration Dossier
Registration Dossier
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EC number: 211-889-1 | CAS number: 705-86-2
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
Reproductive Toxicity Study:
In a Reproduction/Developmental Toxicity Screening Test, Sprague Dawley rats were treated with test chemical at dose levels of 250, 500 and 1000 mg/kg body weight orally by gavage. Males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13 and females (dams) were sacrificed on lactation day 14 after overnight fasting (water allowed). All the tested dose group animals of either sex did not reveal any clinical signs of toxicity and no mortality/morbidity observed. The No Observed Adverse Effect Level (NOAEL) of the test chemical was considered to be 1000 mg/kg body weight when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13, under the experimental conditions.
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 study report
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- According to OECD 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- 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) x wks; (F1) x wks: 9 to 11 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: Males: 240.91 g to 288.02 g
Females: 200.02 g to 232.05 g
- Fasting period before study:
- 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 water bottle fitted with stainless steel sipper tube. Clean sterilized paddy husk was provided as bedding material.
i. Pre mating
Two animals of same sex and group per cage were housed.
ii. Mating
During mating, two animals (one male and one female) of same group were housed.
iii. Post mating
After confirming presence of sperm in the vaginal smear (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually. Sterilized paper shreds were provided as a nesting material from gestation day 20 onwards.
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): Altromin Maintenance diet for rats and mice 1324 manufactured by Altromin Spezialfutter GmbH & Co. KG was provided ad libitum to the animals throughout the experimental period.
- Water (e.g. ad libitum): Water was provided ad libitum throughout the acclimatization and experimental period. Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C):19.1 to 23.6oC
- Humidity (%):40 to 69%
- 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: 29 November 2017
To: 09 May 2018 - Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:The test item formulations were freshly prepared before dose administration on each treatment day. The required quantity of test item was weighed into a clean beaker and there by adding little volume of the vehicle into the beaker,mixed well using glass rod and transferred into measuring cylinder. This rinsing procedure was repeated until complete transfer of test item formulation into the measuring cylinder. Finally, the volume was made up to the required quantity with vehicle to get a desired concentration of 25, 50 and 100 mg/mL of test item for low, mid and high dose groups respectively.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item is not miscible with distilled water at a concentration of 100 mg/mL (high dose concentration selected for the study) and forms uniform suspension with corn oil. Hence, corn oil was selected as a vehicle for test item formulation.
- Concentration in vehicle: 0, 250, 500 and 1000 mg/kg bw
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): Batch No: A1708001
- Purity: - Details on mating procedure:
- - M/F ratio per cage:1:1 ratio
- Length of cohabitation: The female was placed with the same male until pregnancy occurs by evidence of sperm in vaginal smear until two weeks have elapsed.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Day ‘0’ pregnancy was confirmed by the presence of sperm in the vaginal smear.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: Not specified
- Further matings after two unsuccessful attempts: [no / yes (explain)]Not specified
- After successful mating each pregnant female was caged (how): females were housed individually. Sterilized paper shreds were provided as a nesting material from gestation day 20 onwards.
- Any other deviations from standard protocol: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability and Homogeneity were analysis.
- Duration of treatment / exposure:
- Male: 37 days
Female: Approx 62 days - Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Total: 96
0 mg/kg bw: 12 male, 12 female
250 mg/kg bw: 12 male, 12 female
500 mg/kg bw: 12 male, 12 female
1000 mg/kg bw: 12 male, 12 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses of 0, 250, 500 and 1000 mg/kg body weight for vehicle control, low dose, mid dose and high dose respectively were selected based on the NOAEL of test item is >1000 mg/kg body weight in a 28 days repeated dose study (oral) in rats
- 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% (+2.99% and -11.62% for males and +4.34% and -7.91% for females) of the mean body weight of each sex. The grouping was done one day prior to the initiation of treatment. Body weight of the animals was analyzed statistically for mean body weight to rule out the statistical significant difference between groups within each sex.
- Other: - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table [No.?] were included. : mortality and morbidity were examined.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed at receipt, on the first day of dosing, weekly thereafter (varied by -1 day) 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.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
OTHER: - Oestrous cyclicity (parental animals):
- Oestrus cycles were monitored for two weeks after five days of acclimatization to evaluate its normal oestrus cyclicity (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. Oestrus cyclicity was also monitored on the day of sacrifice for females.
- Litter observations:
- The number of pups born (dead and live) in a litter, sex, live births and external observations were recorded at birth. Individual body weight of live pups on lactation day 1 (within 24 hours of parturition), 4, 7 and 13 were recorded. The anogenital distance of each pup was measured on postnatal day 4 (lactation day 4) and the ratio of AGD to the cube root of pup body weight was calculated. All survived male pups were examined for appearance of nipples/areolae on postnatal day 13 (lactation day 13). The litter was observed daily in order to note the number of alive, dead and cannibalized pups.
- Postmortem examinations (parental animals):
- Hormone analysis, organ weight and external and internal gross pathological and histopathological examination.
- Postmortem examinations (offspring):
- organ weight and The pups were sacrificed on lactation day 13 and the sacrificed pups and dead pups were examined for gross abnormalities
- Statistics:
- The raw data was subjected to computer statistical processing. The computer printout of the data (in the form of appendix) was verified with the raw data. After verification, the data was subjected to various statistical analyses using SPSS software version 22.
All analysis and comparisons were evaluated at the 95% level of confidence (P<0.05), indicated by the aforementioned tests designated by the superscripts throughout the report as stated below:
* Statistically significant (P<0.05) change than the vehicle control group. - Reproductive indices:
- Male Mating Index, Male Fertility Index, Female Mating Index, Female Fertility Index, Gestation Index, Live Birth Index (%) per dam and Pup Survival index (%) on lactation day 4 were examined.
- Offspring viability indices:
- yes, on daye 0 and 13
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of toxicity observed at any of the tested dose group animals of either sex during the experimental period.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- no mortality/morbidity observed at any of the tested dose group animals of either sex during the experimental period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in mean body weight and percent change in body weight with respect to day 1 at all the tested group animals of either sex during gestation, lactation and the experimental period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no changes observed in feed consumption at any of the tested dose group animals of either sex during during gestation, lactation and the experimental period.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment related changes observed in serum T4 levels in adult males at any of the tested dose groups when compared with vehicle control group.
However, statistically significant increase in T4 levels at the high dose group males when compared with vehicle control group males was noted.
This significant variation could be due to two males in 1000 mg/kg bw with a serum T4 level of 142.851 and 140.210 respectively which are significantly more than other animals of same group. Hence, the variations observed in the T4 levels are considered to be incidental. - Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment related histopathological findings noticed in the present study.
Lesions considered spontaneous and incidental were observed in treated and control rats. These lesions consisted of unilateral interstitial mononuclear cell (MNC) infiltration in epididymides.
A detailed qualitative examination of the testes was made, taking into account the tubular stages of the spermatogenic cycle. The examination was conducted in order to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells into the lumen or any cell or stage specificity of testicular findings.
Testes and ovaries did not show any pathological findings/lesions. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in the oestrus cyclicity at any of the tested dose group females during pre-mating treatment, mating treatment and on lactation day 14.
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in number of corpora lutea, number of implantations and no changes were noted in pre and post-implantation loss, pre-natal loss, post-natal loss at any of the tested dose group animals when compared with vehicle control group animals. No resorptions were noted at all the dose group animals observed during necropsy.
- 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 performance
- Remarks on result:
- other: No effect observed
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs observed in any of the pups of tested dose group animals during lactation period.
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- There were no treatment related changes observed in the number of pups and pup survival index of each litter at any of the tested dose group animals during lactation period when compared with vehicle control group animals.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in mean pup (male and female) weight on lactation day 1, 4, 7 and 13 at any of the tested dose groups when compared with vehicle control group dams.
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment related changes observed in serum T4 levels in lactation day 13 pups at any of the tested dose groups when compared with vehicle control group.
- Urinalysis findings:
- not specified
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in ano-genital distance ratio on lactation day 4 and no occurrences of nipples in male pups of dams at any of the tested dose group litters and vehicle control group litters observed on lactation day 13.
- Anogenital distance (AGD):
- not specified
- Nipple retention in male pups:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological changes (both external and internal) observed at all the tested dose group pups of either sex at all the tested dose groups examined at termination.
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- 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
- Remarks on result:
- other: No effect observed
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) of the test chemical was considered to be 1000 mg/kg body weight when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13, under the experimental conditions
- Executive summary:
In a Reproduction/Developmental Toxicity Screening Test, Sprague Dawley rats were treated with test chemical at dose levels of 250, 500 and 1000 mg/kg body weight orally by gavage. Males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13 and females (dams) were sacrificed on lactation day 14 after overnight fasting (water allowed). All the tested dose group animals of either sex did not reveal any clinical signs of toxicity and no mortality/morbidity observed. There were no changes observed in mean body weight, percent change in body weight with respect to day 1 and feed consumption at all the tested dose group animals of either sex during the experimental period. No changes were observed in organ weights (both absolute and relative) at all the tested dose group animals. There were no treatment related changes observed in serum T4 levels of adult males and in serum T4 levels of lactation day 13 pups at any of the tested dose groups. Dams did not reveal any treatment related changes in oestrus cyclicity, copulatory interval, body weights and feed consumption during gestation and lactation periods, gestation length, live birth index, number of pups, sex ratio and pup survival index at all the tested dose groups throughout the lactation period. Similarly, all pups did not reveal any clinical signs or external anomalies throughout the lactation period. No treatment related changes in pup weights, ano-genital distance ratio were noted. No occurrences of nipples in male pups at any of the tested dose groups and vehicle control group. In addition, there were no gross pathological changes (both external and internal) observed at all the tested dose group adult animals and pups. There were no treatment related histopathological findings noticed during the microscopic examination. Testes were screened with special emphasis on stages of spermatogenesis and interstitial testicular cell structure, revealed normal progression of the spermatogenic cycle and presence of all germ layers (cells). In addition this, ovaries did not show any pathological findings/lesions. Therefore, The No Observed Adverse Effect Level (NOAEL) of the test chemical was considered to be 1000 mg/kg body weight when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13, under the experimental conditions.
Reference
SUMMARY OF THE STUDY
Parameters ↓ |
Group & Dose (mg/kg body weight/day) |
||||
G1 & 0 |
G2 & 250 |
G3 & 500 |
G4 & 1000 |
||
Reproductive Indices |
|||||
Mating Indices |
|||||
Pairs started (No.) |
12 |
12 |
12 |
12 |
|
Males showing evidence of mating (No.) within 14 days* |
12 |
12 |
10 |
11 |
|
Females showing evidence of copulation (No.) |
12 |
12 |
12 |
12 |
|
Male Mating Index (%) within 14 days* |
100.00 |
100.00 |
83.33 |
91.67 |
|
Female Mating Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Fertility Indices |
|||||
Females achieving pregnancy (No.) |
12 |
12 |
12 |
12 |
|
Male Fertility Index (%)* |
100.00 |
100.00 |
83.33 |
91.67 |
|
Female Fertility Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Copulatory Indices |
|||||
Conceiving days 1 to 5 (No.) |
7 |
6 |
6 |
5 |
|
Conceiving days >6 (No.) |
5 |
6 |
6 |
7 |
|
Mean Precoital Interval (Days) |
5.83 |
6.75 |
7.83 |
7.92 |
|
|
|||||
Gestation Indices |
|||||
Pregnancy≤21 days (No.) |
1 |
1 |
0 |
0 |
|
Pregnancy = 22 days (No.) |
4 |
6 |
6 |
4 |
|
Pregnancy≥23 days (No.) |
7 |
5 |
6 |
8 |
|
Mean Gestation length (Days) |
22.50 |
22.33 |
22.67 |
22.75 |
|
Gestation Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Dams with live young born (No.) |
12 |
12 |
12 |
12 |
|
Dams with live young at day 4 post-partum (No.) |
12 |
12 |
12 |
12 |
|
Dams with live young at day 13 post-partum (No.) |
12 |
12 |
12 |
12 |
|
|
|||||
Implantation Index and Pre and Post implantation Losses |
|||||
Implants/dam (Mean) |
10.58 |
11.75 |
11.17 |
11.00 |
|
Corpora luetea/dam (Mean) |
10.67 |
11.75 |
11.25 |
11.00 |
|
Implantation Index (%) |
99.17 |
100.00 |
99.07 |
100.00 |
|
Pre-Implantation Loss (%) |
0.83 |
0.00 |
0.93 |
0.00 |
|
Post-Implantation Loss (%) |
1.52 |
0.00 |
1.39 |
0.00 |
|
|
|||||
Offspring Viability Indices |
|||||
Live Birth Indices and Sex Ratio at Birth |
|||||
Live pups/dam at birth (mean) |
10.42 |
11.75 |
11.00 |
11.00 |
|
Litter Size (Total No. of pups born/dam) at birth (mean) |
10.58 |
11.75 |
11.00 |
11.00 |
|
Mean Live Birth Index/dam (%) |
98.48 |
100.00 |
100.00 |
100.00 |
|
Male Live pups/dam at birth (mean) |
4.92 |
5.92 |
4.83 |
4.92 |
|
Female Live pups/dam at birth (mean) |
5.50 |
5.83 |
6.17 |
6.08 |
|
Sex Ratio (male/female) |
1.23 |
1.22 |
0.90 |
1.05 |
|
*: The females were placed with proven male of same test group after 14 days of cohabitation period.
Parameters ↓ |
Group & Dose (mg/kg body weight/day) |
|||
G1 & 0 |
G2 & 100 |
G3 & 300 |
G4 & 1000 |
|
Pup Survival Indices and Sex Ratio during lactation |
||||
Mean No. of Pups survived per dam ( LD1 to 4) |
10.42 |
11.75 |
11.00 |
11.00 |
Mean No. of Pups dead per dam ( LD1 to 4) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam (LD1 to 4) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 4 |
1.23 |
1.22 |
0.90 |
1.05 |
Mean No. of Pups Sacrificed for Blood Collection on LD4 |
0.58 |
1.25 |
1.08 |
0.92 |
Mean No. of Pups survived per dam (LD4 to 7) |
9.83 |
10.50 |
9.92 |
10.08 |
Mean No. of Pups dead per dam (LD4 to 7) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam (LD4 to 7) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 7 |
1.22 |
1.55 |
1.14 |
1.21 |
Mean No. of Pups survived per dam (LD7 to 13) |
9.83 |
10.50 |
9.92 |
10.08 |
Mean No. of Pups dead per dam (LD7 to 13) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam ( LD7 to 13) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 13 |
1.22 |
1.55 |
1.14 |
1.21 |
|
||||
Pre and Postnatal loss |
||||
Mean Pre-natal (implantations minus live births) (No.) |
0.17 |
0.00 |
0.17 |
0.00 |
Females with 0 (No.) |
11 |
12 |
11 |
12 |
Females with 1 (No.) |
1 |
0 |
1 |
0 |
Post-natal (live births minus alive at post natal day 13) |
||||
Females with 0 (No.) |
12 |
12 |
12 |
12 |
Females with ≥ 1 (No.) |
0 |
0 |
0 |
0 |
|
||||
Litter Observations |
||||
Male Pup weight at birth (mean) in gram |
7.10 |
7.00 |
7.40 |
7.20 |
Female Pup weight at birth (mean) in gram |
6.68 |
6.38 |
6.83 |
6.39 |
Male Pup weight on LD4 (mean) in gram |
12.07 |
11.87 |
11.90 |
12.28 |
Female Pup weight on LD4 (mean) in gram |
11.20 |
10.89 |
10.60 |
10.61 |
Male Pup weight on LD7 (mean) in gram |
17.10 |
17.02 |
17.52 |
17.43 |
Female Pup weight on LD7 (mean) in gram |
15.88 |
15.59 |
15.58 |
15.22 |
Male Pup weight on LD13 (mean) in gram |
28.06 |
27.91 |
28.67 |
28.17 |
Female Pup weight on LD13 (mean) in gram |
25.98 |
25.95 |
25.89 |
25.60 |
SUMMARYOF CLINICAL SIGNSOF TOXICITY, DETAILED CLINICAL EXAMINATIONAND MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) |
No. of Animals |
Clinical Signs of Toxicity/ Detailed Clinical Examination |
Mortality (No. of Mortality / No. of Animals dosed) |
G1, M & 0 |
12 |
N |
0/12 |
G2, M & 250 |
12 |
N |
0/12 |
G3, M & 500 |
12 |
N |
0/12 |
G4, M & 1000 |
12 |
N |
0/12 |
M: Male; N: Normal
Group, Sex & Dose (mg/kg body weight/day) |
No. of Animals |
Clinical Signs of Toxicity/ Detailed Clinical Examination) |
Mortality (No. of Mortality / No. of Animals dosed) |
G1, F & 0 |
12 |
N |
0/12 |
G2, F & 250 |
12 |
N |
0/12 |
G3, F & 500 |
12 |
N |
0/12 |
G4, F & 1000 |
12 |
N |
0/12 |
SUMMARY OF ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose |
Epididymes |
Testes |
Prostate+Seminal vesicles with coagulating glands (PSC) |
Thyroid along with parathyroid# |
|
G1, M & 0 |
Mean |
1.5304 |
3.4862 |
3.0974 |
0.2577 |
±SD |
0.1461 |
0.2643 |
0.3581 |
0.0253 |
|
n |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
1.5855 |
3.3497 |
3.2505 |
0.2581 |
±SD |
0.1608 |
0.2477 |
0.3081 |
0.0202 |
|
n |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
1.6304 |
3.5343 |
3.1775 |
0.2575 |
±SD |
0.1677 |
0.2791 |
0.2398 |
0.0169 |
|
n |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
1.5877 |
3.2692 |
3.1080 |
0.2476 |
±SD |
0.1734 |
0.1988 |
0.3843 |
0.0207 |
|
n |
12 |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number of animals; #: Weighed post fixation
Group, Sex & Dose (mg/kg body weight/day) |
|
Thyroid along with parathyroid# |
G1, F & 0 |
Mean |
0.2341 |
±SD |
0.0105 |
|
n |
11 |
|
G2, F & 100 |
Mean |
0.2414 |
±SD |
0.0113 |
|
n |
10 |
|
G3, F & 300 |
Mean |
0.2457 |
±SD |
0.0126 |
|
n |
11 |
|
G4, F & 1000 |
Mean |
0.2354 |
±SD |
0.0162 |
|
n |
11 |
SUMMARY OF FASTING BODY WEIGHT (g) AND ORGAN WEIGHT (%) RELATIVE TO FASTING BODY WEIGHT RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Fasting Body Weight (g) |
Epididymes |
Testes |
Prostate+Seminal vesicles with coagulating glands (PSC) |
Thyroid along with parathyroid |
|
G1, M & 0 |
Mean |
379.21 |
0.4050 |
0.9226 |
0.8197 |
0.0678 |
±SD |
24.03 |
0.0477 |
0.0933 |
0.1089 |
0.0033 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
389.42 |
0.4070 |
0.8614 |
0.8382 |
0.0663 |
±SD |
23.79 |
0.0305 |
0.0584 |
0.1005 |
0.0031 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
386.93 |
0.4216 |
0.9129 |
0.8228 |
0.0665 |
±SD |
16.51 |
0.0410 |
0.0506 |
0.0725 |
0.0017 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
376.98 |
0.4211 |
0.8679 |
0.8237 |
0.0656 |
±SD |
21.53 |
0.0387 |
0.0384 |
0.0824 |
0.0020 |
|
n |
12 |
12 |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number of animals
Group, Sex & Dose (mg/kg body weight/day) |
|
Fasting Body Weight (g) |
Thyroid along with parathyroid |
G1, F & 0 |
Mean |
264.08 |
0.0886 |
±SD |
6.47 |
0.0024 |
|
n |
11 |
11 |
|
G2, F & 250 |
Mean |
272.77 |
0.0885 |
±SD |
13.04 |
0.0020 |
|
n |
10 |
10 |
|
G3, F & 500 |
Mean |
274.96 |
0.0894 |
±SD |
14.12 |
0.0014 |
|
n |
11 |
11 |
|
G4, F & 1000 |
Mean |
264.70 |
0.0889 |
±SD |
16.47 |
0.0015 |
|
n |
11 |
11 |
SUMMARY RECORD OF VAGINAL SMEAR EXAMINATION FOR DETERMINATION OF OESTRUS CYCLICITY
Group & Dose |
No. of Females |
No. of Females with Regular Oestrus Cyclicity during Pre-mating, Mating and on Lactation day 14 |
No. of Females with Irregular Oestrus Cyclicity during Pre-mating, Mating and on Lactation day 14 |
G1 & 0 |
12 |
12 |
0 |
G2 & 250 |
12 |
12 |
0 |
G3 & 500 |
12 |
12 |
0 |
G4 & 1000 |
12 |
12 |
0 |
SUMMARY RECORD OF GESTATION LENGTH (DAYS) AND DELIVERY DATA
Group & Dose |
|
Gestation Length (Days) |
|
Delivery Data |
||||||||||
Litter Size (No.) |
Live Pups (No.) |
Dead Pups (No.) |
|
Sex Ratio (M/F) at Birth |
Live Birth Index |
|||||||||
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
|||||||||
G1 & 0 |
Mean |
23.00 |
11.45 |
11.09 |
5.09 |
6.00 |
0.36 |
0.36 |
0.00 |
1.04 |
97.35 |
|||
±SD |
0.89 |
2.02 |
1.64 |
1.70 |
1.90 |
0.67 |
0.67 |
0.00 |
0.76 |
5.05 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2 & 250 |
Mean |
23.30 |
10.70 |
10.40 |
4.00 |
6.40 |
0.30 |
0.30 |
0.00 |
0.70 |
96.67 |
|||
±SD |
0.67 |
1.64 |
2.01 |
1.56 |
1.78 |
0.67 |
0.67 |
0.00 |
0.39 |
8.05 |
||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||
G3 & 500 |
Mean |
23.00 |
12.09 |
12.00 |
6.09 |
5.91 |
0.09 |
0.00 |
0.09 |
1.23 |
99.24 |
|||
±SD |
0.45 |
1.14 |
1.18 |
2.30 |
1.70 |
0.30 |
0.00 |
0.30 |
0.87 |
2.51 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4 & 1000 |
Mean |
23.64 |
11.18 |
10.82 |
4.45 |
6.36 |
0.36 |
0.09 |
0.27 |
0.76 |
96.74 |
|||
±SD |
0.50 |
2.18 |
2.27 |
1.51 |
1.86 |
0.67 |
0.30 |
0.65 |
0.34 |
6.11 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
M: Male; F: Female;SD: Standard Deviation; n: Number of dams
SUMMARY OF LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group & Dose |
|
No. of Live Pups At Birth |
During LD 1 to 4 |
Sex Ratio (M/F) at LD 4 |
No. of Survived Pups during LD 1 to 4 |
Pup Survival Index LD 1 to 4 |
||||||
Live Pups (No.) |
|
Dead Pups (No.) |
||||||||||
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
|||||||
G1 & 0 |
Mean |
11.09 |
11.09 |
5.09 |
6.00 |
0.00 |
0.00 |
0.00 |
1.04 |
11.09 |
100.00 |
|
±SD |
1.64 |
1.64 |
1.70 |
1.90 |
0.00 |
0.00 |
0.00 |
0.76 |
1.64 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||
G2 & 250 |
Mean |
10.40 |
10.40 |
4.00 |
6.40 |
0.00 |
0.00 |
0.00 |
0.70 |
10.40 |
100.00 |
|
±SD |
2.01 |
2.01 |
1.56 |
1.78 |
0.00 |
0.00 |
0.00 |
0.39 |
2.01 |
0.00 |
||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||
G3 & 500 |
Mean |
12.00 |
12.00 |
6.09 |
5.91 |
0.00 |
0.00 |
0.00 |
1.23 |
12.00 |
100.00 |
|
±SD |
1.18 |
1.18 |
2.30 |
1.70 |
0.00 |
0.00 |
0.00 |
0.87 |
1.18 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||
G4 & 1000 |
Mean |
10.82 |
10.82 |
4.45 |
6.36 |
0.00 |
0.00 |
0.00 |
0.76 |
10.82 |
100.00 |
|
±SD |
2.27 |
2.27 |
1.51 |
1.86 |
0.00 |
0.00 |
0.00 |
0.34 |
2.27 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||
M: Male: F: Female;SD: Standard Deviation; n: Number of dams; LD: Lactation Day
Group & Dose |
Animal No. |
Live Pups (No.) on LD 4 |
Pups Sacrificed for Blood Collection on LD 4 (No.) |
Live Pups (No.) on LD 4 after Sacrificed for Blood Collection |
During LD 4 to 7 |
Sex Ratio (M/F) at |
No. of Survived Pups during LD |
Pup Survival Index |
||||||||||||||||
Live Pups (No.) |
|
Dead Pups (No.) |
||||||||||||||||||||||
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
||||||||||
G1 & 0 |
Mean |
5.09 |
6.00 |
11.09 |
0.00 |
1.00 |
1.00 |
5.09 |
5.00 |
10.09 |
5.09 |
5.00 |
10.09 |
0.00 |
0.00 |
0.00 |
1.30 |
10.09 |
100.00 |
|||||
±SD |
1.70 |
1.90 |
1.64 |
0.00 |
0.89 |
0.89 |
1.70 |
1.67 |
0.94 |
1.70 |
1.67 |
0.94 |
0.00 |
0.00 |
0.00 |
1.05 |
0.94 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G2 & 250 |
Mean |
4.00 |
6.40 |
10.40 |
0.00 |
0.90 |
0.90 |
4.00 |
5.50 |
9.50 |
4.00 |
5.50 |
9.50 |
0.00 |
0.00 |
0.00 |
0.82 |
9.50 |
100.00 |
|||||
±SD |
1.56 |
1.78 |
2.01 |
0.00 |
0.88 |
0.88 |
1.56 |
1.51 |
1.35 |
1.56 |
1.51 |
1.35 |
0.00 |
0.00 |
0.00 |
0.46 |
1.35 |
0.00 |
||||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
G3 & 500 |
Mean |
6.09 |
5.91 |
12.00 |
0.00 |
1.64 |
1.64 |
6.09 |
4.27 |
10.36 |
6.09 |
4.27 |
10.36 |
0.00 |
0.00 |
0.00 |
2.27 |
10.36 |
100.00 |
|||||
±SD |
2.30 |
1.70 |
1.18 |
0.00 |
0.50 |
0.50 |
2.30 |
1.74 |
0.92 |
2.30 |
1.74 |
0.92 |
0.00 |
0.00 |
0.00 |
2.62 |
0.92 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G4 & 1000 |
Mean |
4.45 |
6.36 |
10.82 |
0.00 |
0.73 |
0.73 |
4.45 |
5.64 |
10.09 |
4.45 |
5.64 |
10.09 |
0.00 |
0.00 |
0.00 |
0.87 |
10.09 |
100.00 |
|||||
±SD |
1.51 |
1.86 |
2.27 |
0.00 |
1.01 |
1.01 |
1.51 |
1.36 |
1.38 |
1.51 |
1.36 |
1.38 |
0.00 |
0.00 |
0.00 |
0.44 |
1.38 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
Group & Dose |
Animal No. |
Live Pups (No.) on LD 7 |
During LD 7 to 13 |
|
Sex Ratio (M/F) at LD 13 |
No. of Survived Pups during LD 7 to 13 |
Pup Survival Index |
||||||||||
Live Pups (No.) |
|
Dead Pups (No.) |
|||||||||||||||
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
|||||||||
G1 & 0 |
Mean |
5.09 |
5.00 |
10.09 |
5.09 |
5.00 |
10.09 |
0.00 |
0.00 |
0.00 |
1.30 |
10.09 |
100.00 |
||||
±SD |
1.70 |
1.67 |
0.94 |
1.70 |
1.67 |
0.94 |
0.00 |
0.00 |
0.00 |
1.05 |
0.94 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G2 & 250 |
Mean |
4.00 |
5.50 |
9.50 |
4.00 |
5.50 |
9.50 |
0.00 |
0.00 |
0.00 |
0.82 |
9.50 |
100.00 |
||||
±SD |
1.56 |
1.51 |
1.35 |
1.56 |
1.51 |
1.35 |
0.00 |
0.00 |
0.00 |
0.46 |
1.35 |
0.00 |
|||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|||||
G3 & 500 |
Mean |
6.09 |
4.27 |
10.36 |
6.09 |
4.27 |
10.36 |
0.00 |
0.00 |
0.00 |
2.27 |
10.36 |
100.00 |
||||
±SD |
2.30 |
1.74 |
0.92 |
2.30 |
1.74 |
0.92 |
0.00 |
0.00 |
0.00 |
2.62 |
0.92 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G4 & 1000 |
Mean |
4.45 |
5.64 |
10.09 |
4.45 |
5.64 |
10.09 |
0.00 |
0.00 |
0.00 |
0.87 |
10.09 |
100.00 |
||||
±SD |
1.51 |
1.36 |
1.38 |
1.51 |
1.36 |
1.38 |
0.00 |
0.00 |
0.00 |
0.44 |
1.38 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
SUMMARY OF UTERI OBSERVATIONS RECORD
Group & Dose |
No. of Corpora lutea |
No. of Implantations |
Implantation Index |
Pre-Implantation Loss (%) |
Post-Implantation Loss (%) |
Pre-natal Loss (No.) |
Post-natal Loss (%) |
Post-natal Loss (No.) |
No. of Early Resorptions |
No. of Late Resorptions |
|
G1 & 0 |
Mean |
11.73 |
11.45 |
98.07 |
1.93 |
2.65 |
0.36 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
2.33 |
2.02 |
3.35 |
3.35 |
5.05 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G2 & 250 |
Mean |
10.70 |
10.70 |
100.00 |
0.00 |
3.33 |
0.30 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
1.64 |
1.64 |
0.00 |
0.00 |
8.05 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
G3 & 500 |
Mean |
12.27 |
12.09 |
98.59 |
1.41 |
0.76 |
0.09 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
1.19 |
1.14 |
3.14 |
3.14 |
2.51 |
0.30 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
11.36 |
11.18 |
98.78 |
1.22 |
3.26 |
0.36 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
2.46 |
2.18 |
2.72 |
2.72 |
6.11 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
SD: Standard Deviation; n: Number of animals
SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - MALES
Group, Sex & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1, M & 0 |
Mean |
87.991 |
|
±SD |
4.682 |
||
n |
12 |
||
G2, M & 250 |
Mean |
87.300 |
|
±SD |
4.919 |
||
n |
12 |
||
G3, M & 500 |
Mean |
95.705 |
|
±SD |
14.351 |
||
n |
12 |
||
G4, M & 1000 |
Mean |
104.278* |
|
±SD |
21.130 |
||
n |
12 |
M: Male; SD: Standard Deviation; n: Number of animals
* Statistically significant (P<0.05) change than the vehicle control group.
SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - LACTATION DAY 13 PUPS
Group & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1 & 0 |
Mean |
70.752 |
|
±SD |
9.415 |
||
n |
11 |
||
G2 & 250 |
Mean |
62.065 |
|
±SD |
8.076 |
||
n |
10 |
||
G3 & 500 |
Mean |
64.219 |
|
±SD |
7.606 |
||
n |
11 |
||
G4 & 1000 |
Mean |
62.132 |
|
±SD |
9.600 |
||
n |
11 |
SD: Standard Deviation; n: Number of Dams (Serum collected from pups per dam pooled for analysis)
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 and from study report
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In a Reproduction/Developmental Toxicity Screening Test, Sprague Dawley rats were treated with test chemical at dose levels of 250, 500 and 1000 mg/kg body weight orally by gavage. Males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13 and females (dams) were sacrificed on lactation day 14 after overnight fasting (water allowed). All the tested dose group animals of either sex did not reveal any clinical signs of toxicity and no mortality/morbidity observed. There were no changes observed in mean body weight, percent change in body weight with respect to day 1 and feed consumption at all the tested dose group animals of either sex during the experimental period. No changes were observed in organ weights (both absolute and relative) at all the tested dose group animals. There were no treatment related changes observed in serum T4 levels of adult males and in serum T4 levels of lactation day 13 pups at any of the tested dose groups. Dams did not reveal any treatment related changes in oestrus cyclicity, copulatory interval, body weights and feed consumption during gestation and lactation periods, gestation length, live birth index, number of pups, sex ratio and pup survival index at all the tested dose groups throughout the lactation period. Similarly, all pups did not reveal any clinical signs or external anomalies throughout the lactation period. No treatment related changes in pup weights, ano-genital distance ratio were noted. No occurrences of nipples in male pups at any of the tested dose groups and vehicle control group. In addition, there were no gross pathological changes (both external and internal) observed at all the tested dose group adult animals and pups. There were no treatment related histopathological findings noticed during the microscopic examination. Testes were screened with special emphasis on stages of spermatogenesis and interstitial testicular cell structure, revealed normal progression of the spermatogenic cycle and presence of all germ layers (cells). In addition this, ovaries did not show any pathological findings/lesions. Therefore, The No Observed Adverse Effect Level (NOAEL) of the test chemical was considered to be 1000 mg/kg body weight when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13, under the experimental conditions.
Effects on developmental toxicity
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- Data is from study report
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- According to OECD 421 (Reproduction / Developmental Toxicity Screening Test).
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:In-house bred animals
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) x wks; (F1) x wks: 9 to 11 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: Males:
240.91 g to 288.02 g
Females: 200.02 g to 232.05 g
- Fasting period before study:
- 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 water bottle fitted with stainless steel sipper tube. Clean sterilized paddy husk was provided as bedding material.
i. Pre mating
Two animals of same sex and group per cage were housed.
ii. Mating
During mating, two animals (one male and one female) of same group were housed.
iii. Post mating
After confirming presence of sperm in the vaginal smear (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually. Sterilized paper shreds were provided as a nesting material from gestation day 20 onwards.
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): Altromin Maintenance diet for rats and mice 1324 manufactured by Altromin Spezi alfutter GmbH & Co. KG was provided ad libitum to the animals throughout the experimental period.
- Water (e.g. ad libitum): Water was provided ad libitum throughout the acclimatization and experimental period. Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C):19.1 to 23.6oC
- Humidity (%):40 to 69%
- 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: 29 November 2017
To: 09 May 2018 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:The test chemical formulations were freshly prepared before dose administration on each treatment day. The required quantity of test chemical was weighed into a clean beaker and there by adding little volume of the vehicle into the beaker, mixed well using glass rod and transferred into measuring cylinder. This rinsing procedure was repeated until complete transfer of test item formulation into the measuring cylinder. Finally, the volume was made up to the required quantity with vehicle to get a desired concentration of 25, 50 and 100 mg/mL of test item for low, mid and high dose groups respectively.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item is not miscible with distilled
water at a concentration of 100 mg/mL (high dose concentration selected for the study) and forms unif
orm suspension with corn oil. Hence, corn oil was selected as a vehicle for test item formulation.
- Concentration in vehicle: 0, 250, 500 and 1000 mg/kg bw
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): Batch No: A1708001
- Purity: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability and Homogeneity were analysis.
- Details on mating procedure:
- - M/F ratio per cage:1:1 ratio
- Length of cohabitation: The female was placed with the same male until pregnancy occurs by evidence of sperm in vaginal smear until two weeks have elapsed.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Day ‘0’ pregnancy was confirmed by the presence of sperm in the vaginal smear.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: Not specified
- Further matings after two unsuccessful attempts: [no / yes (explain)]Not specified
- After successful mating each pregnant female was caged (how): females were housed individually.Sterilized paper shreds were provided as a nesting material from gestation day 20 onwards.
- Any other deviations from standard protocol: - Duration of treatment / exposure:
- Male: 37 days
Female: Approx 62 days - Frequency of treatment:
- Daily
- Duration of test:
- Males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13 and females (dams) were sacrificed on lactation day 14
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Total: 96
0 mg/kg bw: 12 male, 12 female
250 mg/kg bw: 12 male, 12 female
500 mg/kg bw: 12 male, 12 female
1000 mg/kg bw: 12 male, 12 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses of 0, 250, 500 and 1000 mg/kg body weight for vehicle control, low dose, mid dose and high dose respectively were selected based on the NOAEL of test item Delta Decalactone is >1000 mg/kg body weight in a 28 days repeated dose study (oral) in rats
- Rationale for animal assignment (if not random): The animals were weighed and arranged in ascendin g 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% (+2.99% and -11.62% for males and +4.34% and -7.91% for females) of the mean body weight of each sex. The grouping was done one day prior to the initiation of treatment. Body weight of the animals was analyzed statistically for mean body weight to rule out the statistical significant difference between groups within each sex.
- Other: - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table [No.?] were included. : mortality and morbidity were examined
.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed at receipt, on the first day of dosing, week
ly thereafter (varied by -1 day) 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.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/
kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain
data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
OTHER: - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data - Statistics:
- The raw data was subjected to computer statistical processing. The computer printout of the data (in the form of appendix) was verified with the raw data. After verification, the data was subjected to various statistical analyses using SPSS software version 22.
All analysis and comparisons were evaluated at the 95% level of confidence (P<0.05), indicated by the aforementioned tests designated by the superscripts throughout the report as stated below:
* Statistically significant (P<0.05) change than the vehicle control group. - Indices:
- Male Mating Index, Male Fertility Index, Female Mating Index, Female Fertility Index, Gestation Index, Live Birth Index (%) per dam and Pup Survival index (%) on lactation day 4 were examined.
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of toxicity observed at any of the tested dose group animals of either sex during the experimental period.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- no mortality/morbidity observed at any of the tested dose group animals of either sex during the experimental period.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in mean body weight and percent change in body weight with respect to day 1 at all the tested group animals of either sex during gestation, lactation and the experimental period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no changes observed in feed consumption at any of the tested dose group animals of either sex during during gestation, lactation and the experimental period.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment related changes observed in serum T4 levels in adult males at any of the tested dose groups when compared with vehicle control group. However, statistically significant increase in T4 levels at the high dose group males when compared with vehicle control group males was noted.
This significant variation could be due to two males in 1000 mg/kg bw with a serum T4 level of 142.851 and 140.210 respectively which are significantly more than other animals of same group. Hence, the variations observed in the T4 levels are considered to be incidental. - Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no effects observed in absolute and relative organ weights at any of the tested dose group animals of either sex when compared with vehicle control group
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological changes (both external and internal) observed at all the tested dose group adult animals and pups of either sex at all the tested dose groups examined at termination.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment related histopathological findings noticed in the present study.
Lesions considered spontaneous and incidental were observed in treated and control rats. These lesions consisted of unilateral interstitial mononuclear cell (MNC) infiltration in epididymides.
A detailed qualitative examination of the testes was made, taking into account the tubular stages of the spermatogenic cycle. The examination was conducted in order to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells into the lumen or any cell or stage specificity of testicular findings. Testes and ovaries did not show any pathological findings/lesions. - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in pre and post-implantation loss at any of the tested dose group animals when compared with vehicle control group animals.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in loss by resorptions at any of the tested dose group animals when compared with vehicle control group animals.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in early or late resorptions at any of the tested dose group animals when compared with vehicle control group animals.
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- early or late resorptions
- food consumption and compound intake
- gross pathology
- histopathology: non-neoplastic
- maternal abnormalities
- mortality
- necropsy findings
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
- Remarks on result:
- other: No effect observed
- Abnormalities:
- not specified
- Localisation:
- not specified
- Description (incidence and severity):
- not specified
- Fetal body weight changes:
- not specified
- Description (incidence and severity):
- There were no changes observed in mean pup (male and female) weight on lactation day 1, 4, 7 and 13 at any of the tested dose groups when compared with vehicle control group dams.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- There were no treatment related changes observed in the number of pups and pup survival index of each litter at any of the tested dose group animals during lactation period when compared with vehicle control group animals.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No effect on sex ratio of pup were observed as compared to control.
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- no effects observed
- Description (incidence and severity):
- There were no treatment related changes observed in the pup survival index of each litter at any of the tested dose group animals during lactation period of 13 days when compared with vehicle control group animals.
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological changes (both external and internal) observed at all the tested dose group pups of either sex at all the tested dose groups examined at termination.
- Skeletal malformations:
- not specified
- Visceral malformations:
- not specified
- Other effects:
- no effects observed
- Description (incidence and severity):
- Clinical biochemistry findings:
There were no treatment related changes observed in serum T4 levels in lactation day 13 pups at any of the tested dose groups when compared with vehicle control group.
Sexual maturation:
There were no changes observed in ano-genital distance ratio on lactation day 4 and no occurrences of nipples in male pups of dams at any of the tested dose group litters and vehicle control group litters ob served on lactation day 13. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- changes in sex ratio
- fetal/pup body weight changes
- changes in postnatal survival
- external malformations
- other: ano-genital distance ratio on lactation day 4 and nipples in male pups of dams
- Remarks on result:
- other: No effect observed
- Abnormalities:
- not specified
- Localisation:
- other: not specified
- Description (incidence and severity):
- not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) of the test chemical was considered to be 1000 mg/kg body weight for P and F1 generation when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13, under the experimental conditions.
- Executive summary:
In a experimental study conducted according to OECD 421 , Sprague Dawley rats were treated with test chemical at dose levels of 250, 500 and 1000 mg/kg body weight orally by gavage. Males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13 and females (dams) were sacrificed on lactation day 14 after overnight fasting (water allowed). All the tested dose group animals of either sex did not reveal any clinical signs of toxicity and no mortality/morbidity observed. There were no changes observed in mean body weight, percent change in body weight with respect to day 1 and feed consumption at all the tested dose group animals of either sex during the experimental period. No changes were observed in organ weights (both absolute and relative) at all the tested dose group animals. There were no treatment related changes observed in serum T4 levels of adult males and in serum T4 levels of lactation day 13 pups at any of the tested dose groups. Dams did not reveal any treatment related changes in oestrus cyclicity, copulatory interval, body weights and feed consumption during gestation and lactation periods, gestation length, live birth index, number of pups, sex ratio and pup survival index at all the tested dose groups throughout the lactation period. Similarly, no developmental effect were observed in all pups did not reveal any clinical signs or external anomalies throughout the lactation period. No treatment related changes in pup weights, ano-genital distance ratio were noted. No occurrences of nipples in male pups at any of the tested dose groups and vehicle control group. In addition, there were no gross pathological changes (both external and internal) observed at all the tested dose group adult animals and pups. There were no treatment related histopathological findings noticed during the microscopic examination. Testes were screened with special emphasis on stages of spermatogenesis and interstitial testicular cell structure, revealed normal progression of the spermatogenic cycle and presence of all germ layers (cells). In addition this, ovaries did not show any pathological findings/lesions. Therefore, The No Observed Adverse Effect Level (NOAEL) of the test chemical was considered to be 1000 mg/kg body weight for P and F1 generation when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13, under the experimental conditions.
Reference
SUMMARY OF THE STUDY
Parameters ↓ |
Group & Dose (mg/kg body weight/day) |
||||
G1 & 0 |
G2 & 250 |
G3 & 500 |
G4 & 1000 |
||
Reproductive Indices |
|||||
Mating Indices |
|||||
Pairs started (No.) |
12 |
12 |
12 |
12 |
|
Males showing evidence of mating (No.) within 14 days* |
12 |
12 |
10 |
11 |
|
Females showing evidence of copulation (No.) |
12 |
12 |
12 |
12 |
|
Male Mating Index (%) within 14 days* |
100.00 |
100.00 |
83.33 |
91.67 |
|
Female Mating Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Fertility Indices |
|||||
Females achieving pregnancy (No.) |
12 |
12 |
12 |
12 |
|
Male Fertility Index (%)* |
100.00 |
100.00 |
83.33 |
91.67 |
|
Female Fertility Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Copulatory Indices |
|||||
Conceiving days 1 to 5 (No.) |
7 |
6 |
6 |
5 |
|
Conceiving days >6 (No.) |
5 |
6 |
6 |
7 |
|
Mean Precoital Interval (Days) |
5.83 |
6.75 |
7.83 |
7.92 |
|
|
|||||
Gestation Indices |
|||||
Pregnancy≤21 days (No.) |
1 |
1 |
0 |
0 |
|
Pregnancy = 22 days (No.) |
4 |
6 |
6 |
4 |
|
Pregnancy≥23 days (No.) |
7 |
5 |
6 |
8 |
|
Mean Gestation length (Days) |
22.50 |
22.33 |
22.67 |
22.75 |
|
Gestation Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Dams with live young born (No.) |
12 |
12 |
12 |
12 |
|
Dams with live young at day 4 post-partum (No.) |
12 |
12 |
12 |
12 |
|
Dams with live young at day 13 post-partum (No.) |
12 |
12 |
12 |
12 |
|
|
|||||
Implantation Index and Pre and Post implantation Losses |
|||||
Implants/dam (Mean) |
10.58 |
11.75 |
11.17 |
11.00 |
|
Corpora luetea/dam (Mean) |
10.67 |
11.75 |
11.25 |
11.00 |
|
Implantation Index (%) |
99.17 |
100.00 |
99.07 |
100.00 |
|
Pre-Implantation Loss (%) |
0.83 |
0.00 |
0.93 |
0.00 |
|
Post-Implantation Loss (%) |
1.52 |
0.00 |
1.39 |
0.00 |
|
|
|||||
Offspring Viability Indices |
|||||
Live Birth Indices and Sex Ratio at Birth |
|||||
Live pups/dam at birth (mean) |
10.42 |
11.75 |
11.00 |
11.00 |
|
Litter Size (Total No. of pups born/dam) at birth (mean) |
10.58 |
11.75 |
11.00 |
11.00 |
|
Mean Live Birth Index/dam (%) |
98.48 |
100.00 |
100.00 |
100.00 |
|
Male Live pups/dam at birth (mean) |
4.92 |
5.92 |
4.83 |
4.92 |
|
Female Live pups/dam at birth (mean) |
5.50 |
5.83 |
6.17 |
6.08 |
|
Sex Ratio (male/female) |
1.23 |
1.22 |
0.90 |
1.05 |
|
*: The females were placed with proven male of same test group after 14 days of cohabitation period.
Parameters ↓ |
Group & Dose (mg/kg body weight/day) |
|||
G1 & 0 |
G2 & 100 |
G3 & 300 |
G4 & 1000 |
|
Pup Survival Indices and Sex Ratio during lactation |
||||
Mean No. of Pups survived per dam ( LD1 to 4) |
10.42 |
11.75 |
11.00 |
11.00 |
Mean No. of Pups dead per dam ( LD1 to 4) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam (LD1 to 4) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 4 |
1.23 |
1.22 |
0.90 |
1.05 |
Mean No. of Pups Sacrificed for Blood Collection on LD4 |
0.58 |
1.25 |
1.08 |
0.92 |
Mean No. of Pups survived per dam (LD4 to 7) |
9.83 |
10.50 |
9.92 |
10.08 |
Mean No. of Pups dead per dam (LD4 to 7) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam (LD4 to 7) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 7 |
1.22 |
1.55 |
1.14 |
1.21 |
Mean No. of Pups survived per dam (LD7 to 13) |
9.83 |
10.50 |
9.92 |
10.08 |
Mean No. of Pups dead per dam (LD7 to 13) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam ( LD7 to 13) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 13 |
1.22 |
1.55 |
1.14 |
1.21 |
|
||||
Pre and Postnatal loss |
||||
Mean Pre-natal (implantations minus live births) (No.) |
0.17 |
0.00 |
0.17 |
0.00 |
Females with 0 (No.) |
11 |
12 |
11 |
12 |
Females with 1 (No.) |
1 |
0 |
1 |
0 |
Post-natal (live births minus alive at post natal day 13) |
||||
Females with 0 (No.) |
12 |
12 |
12 |
12 |
Females with ≥ 1 (No.) |
0 |
0 |
0 |
0 |
|
||||
Litter Observations |
||||
Male Pup weight at birth (mean) in gram |
7.10 |
7.00 |
7.40 |
7.20 |
Female Pup weight at birth (mean) in gram |
6.68 |
6.38 |
6.83 |
6.39 |
Male Pup weight on LD4 (mean) in gram |
12.07 |
11.87 |
11.90 |
12.28 |
Female Pup weight on LD4 (mean) in gram |
11.20 |
10.89 |
10.60 |
10.61 |
Male Pup weight on LD7 (mean) in gram |
17.10 |
17.02 |
17.52 |
17.43 |
Female Pup weight on LD7 (mean) in gram |
15.88 |
15.59 |
15.58 |
15.22 |
Male Pup weight on LD13 (mean) in gram |
28.06 |
27.91 |
28.67 |
28.17 |
Female Pup weight on LD13 (mean) in gram |
25.98 |
25.95 |
25.89 |
25.60 |
SUMMARYOF CLINICAL SIGNSOF TOXICITY, DETAILED CLINICAL EXAMINATIONAND MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) |
No. of Animals |
Clinical Signs of Toxicity/ Detailed Clinical Examination |
Mortality (No. of Mortality / No. of Animals dosed) |
G1, M & 0 |
12 |
N |
0/12 |
G2, M & 250 |
12 |
N |
0/12 |
G3, M & 500 |
12 |
N |
0/12 |
G4, M & 1000 |
12 |
N |
0/12 |
M: Male; N: Normal
Group, Sex & Dose (mg/kg body weight/day) |
No. of Animals |
Clinical Signs of Toxicity/ Detailed Clinical Examination) |
Mortality (No. of Mortality / No. of Animals dosed) |
G1, F & 0 |
12 |
N |
0/12 |
G2, F & 250 |
12 |
N |
0/12 |
G3, F & 500 |
12 |
N |
0/12 |
G4, F & 1000 |
12 |
N |
0/12 |
SUMMARY OF ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose |
Epididymes |
Testes |
Prostate+Seminal vesicles with coagulating glands (PSC) |
Thyroid along with parathyroid# |
|
G1, M & 0 |
Mean |
1.5304 |
3.4862 |
3.0974 |
0.2577 |
±SD |
0.1461 |
0.2643 |
0.3581 |
0.0253 |
|
n |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
1.5855 |
3.3497 |
3.2505 |
0.2581 |
±SD |
0.1608 |
0.2477 |
0.3081 |
0.0202 |
|
n |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
1.6304 |
3.5343 |
3.1775 |
0.2575 |
±SD |
0.1677 |
0.2791 |
0.2398 |
0.0169 |
|
n |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
1.5877 |
3.2692 |
3.1080 |
0.2476 |
±SD |
0.1734 |
0.1988 |
0.3843 |
0.0207 |
|
n |
12 |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number of animals; #: Weighed post fixation
Group, Sex & Dose (mg/kg body weight/day) |
|
Thyroid along with parathyroid# |
G1, F & 0 |
Mean |
0.2341 |
±SD |
0.0105 |
|
n |
11 |
|
G2, F & 100 |
Mean |
0.2414 |
±SD |
0.0113 |
|
n |
10 |
|
G3, F & 300 |
Mean |
0.2457 |
±SD |
0.0126 |
|
n |
11 |
|
G4, F & 1000 |
Mean |
0.2354 |
±SD |
0.0162 |
|
n |
11 |
F: Female;SD: Standard Deviation; n: Number of animals;
#: Weighed post fixation (excluding non-pregnant animals)
SUMMARY OF FASTING BODY WEIGHT (g) AND ORGAN WEIGHT (%) RELATIVE TO FASTING BODY WEIGHT RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Fasting Body Weight (g) |
Epididymes |
Testes |
Prostate+Seminal vesicles with coagulating glands (PSC) |
Thyroid along with parathyroid |
|
G1, M & 0 |
Mean |
379.21 |
0.4050 |
0.9226 |
0.8197 |
0.0678 |
±SD |
24.03 |
0.0477 |
0.0933 |
0.1089 |
0.0033 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G2, M & 250 |
Mean |
389.42 |
0.4070 |
0.8614 |
0.8382 |
0.0663 |
±SD |
23.79 |
0.0305 |
0.0584 |
0.1005 |
0.0031 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G3, M & 500 |
Mean |
386.93 |
0.4216 |
0.9129 |
0.8228 |
0.0665 |
±SD |
16.51 |
0.0410 |
0.0506 |
0.0725 |
0.0017 |
|
n |
12 |
12 |
12 |
12 |
12 |
|
G4, M & 1000 |
Mean |
376.98 |
0.4211 |
0.8679 |
0.8237 |
0.0656 |
±SD |
21.53 |
0.0387 |
0.0384 |
0.0824 |
0.0020 |
|
n |
12 |
12 |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number of animals
Group, Sex & Dose (mg/kg body weight/day) |
|
Fasting Body Weight (g) |
Thyroid along with parathyroid |
G1, F & 0 |
Mean |
264.08 |
0.0886 |
±SD |
6.47 |
0.0024 |
|
n |
11 |
11 |
|
G2, F & 250 |
Mean |
272.77 |
0.0885 |
±SD |
13.04 |
0.0020 |
|
n |
10 |
10 |
|
G3, F & 500 |
Mean |
274.96 |
0.0894 |
±SD |
14.12 |
0.0014 |
|
n |
11 |
11 |
|
G4, F & 1000 |
Mean |
264.70 |
0.0889 |
±SD |
16.47 |
0.0015 |
|
n |
11 |
11 |
SUMMARY RECORD OF GESTATION LENGTH (DAYS) AND DELIVERY DATA
Group & Dose |
|
Gestation Length (Days) |
|
Delivery Data |
||||||||||
Litter Size (No.) |
Live Pups (No.) |
Dead Pups (No.) |
|
Sex Ratio (M/F) at Birth |
Live Birth Index |
|||||||||
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
|||||||||
G1 & 0 |
Mean |
23.00 |
11.45 |
11.09 |
5.09 |
6.00 |
0.36 |
0.36 |
0.00 |
1.04 |
97.35 |
|||
±SD |
0.89 |
2.02 |
1.64 |
1.70 |
1.90 |
0.67 |
0.67 |
0.00 |
0.76 |
5.05 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2 & 250 |
Mean |
23.30 |
10.70 |
10.40 |
4.00 |
6.40 |
0.30 |
0.30 |
0.00 |
0.70 |
96.67 |
|||
±SD |
0.67 |
1.64 |
2.01 |
1.56 |
1.78 |
0.67 |
0.67 |
0.00 |
0.39 |
8.05 |
||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||
G3 & 500 |
Mean |
23.00 |
12.09 |
12.00 |
6.09 |
5.91 |
0.09 |
0.00 |
0.09 |
1.23 |
99.24 |
|||
±SD |
0.45 |
1.14 |
1.18 |
2.30 |
1.70 |
0.30 |
0.00 |
0.30 |
0.87 |
2.51 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4 & 1000 |
Mean |
23.64 |
11.18 |
10.82 |
4.45 |
6.36 |
0.36 |
0.09 |
0.27 |
0.76 |
96.74 |
|||
±SD |
0.50 |
2.18 |
2.27 |
1.51 |
1.86 |
0.67 |
0.30 |
0.65 |
0.34 |
6.11 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
M: Male; F: Female;SD: Standard Deviation; n: Number of dams
SUMMARY OF LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group & Dose |
|
No. of Live Pups At Birth |
During LD 1 to 4 |
Sex Ratio (M/F) at LD 4 |
No. of Survived Pups during LD 1 to 4 |
Pup Survival Index LD 1 to 4 |
||||||
Live Pups (No.) |
|
Dead Pups (No.) |
||||||||||
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
|||||||
G1 & 0 |
Mean |
11.09 |
11.09 |
5.09 |
6.00 |
0.00 |
0.00 |
0.00 |
1.04 |
11.09 |
100.00 |
|
±SD |
1.64 |
1.64 |
1.70 |
1.90 |
0.00 |
0.00 |
0.00 |
0.76 |
1.64 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||
G2 & 250 |
Mean |
10.40 |
10.40 |
4.00 |
6.40 |
0.00 |
0.00 |
0.00 |
0.70 |
10.40 |
100.00 |
|
±SD |
2.01 |
2.01 |
1.56 |
1.78 |
0.00 |
0.00 |
0.00 |
0.39 |
2.01 |
0.00 |
||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||
G3 & 500 |
Mean |
12.00 |
12.00 |
6.09 |
5.91 |
0.00 |
0.00 |
0.00 |
1.23 |
12.00 |
100.00 |
|
±SD |
1.18 |
1.18 |
2.30 |
1.70 |
0.00 |
0.00 |
0.00 |
0.87 |
1.18 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||
G4 & 1000 |
Mean |
10.82 |
10.82 |
4.45 |
6.36 |
0.00 |
0.00 |
0.00 |
0.76 |
10.82 |
100.00 |
|
±SD |
2.27 |
2.27 |
1.51 |
1.86 |
0.00 |
0.00 |
0.00 |
0.34 |
2.27 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||
M: Male: F: Female;SD: Standard Deviation; n: Number of dams; LD: Lactation Day
Group & Dose |
Animal No. |
Live Pups (No.) on LD 4 |
Pups Sacrificed for Blood Collection on LD 4 (No.) |
Live Pups (No.) on LD 4 after Sacrificed for Blood Collection |
During LD 4 to 7 |
Sex Ratio (M/F) at |
No. of Survived Pups during LD |
Pup Survival Index |
||||||||||||||||
Live Pups (No.) |
|
Dead Pups (No.) |
||||||||||||||||||||||
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
||||||||||
G1 & 0 |
Mean |
5.09 |
6.00 |
11.09 |
0.00 |
1.00 |
1.00 |
5.09 |
5.00 |
10.09 |
5.09 |
5.00 |
10.09 |
0.00 |
0.00 |
0.00 |
1.30 |
10.09 |
100.00 |
|||||
±SD |
1.70 |
1.90 |
1.64 |
0.00 |
0.89 |
0.89 |
1.70 |
1.67 |
0.94 |
1.70 |
1.67 |
0.94 |
0.00 |
0.00 |
0.00 |
1.05 |
0.94 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G2 & 250 |
Mean |
4.00 |
6.40 |
10.40 |
0.00 |
0.90 |
0.90 |
4.00 |
5.50 |
9.50 |
4.00 |
5.50 |
9.50 |
0.00 |
0.00 |
0.00 |
0.82 |
9.50 |
100.00 |
|||||
±SD |
1.56 |
1.78 |
2.01 |
0.00 |
0.88 |
0.88 |
1.56 |
1.51 |
1.35 |
1.56 |
1.51 |
1.35 |
0.00 |
0.00 |
0.00 |
0.46 |
1.35 |
0.00 |
||||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||||
G3 & 500 |
Mean |
6.09 |
5.91 |
12.00 |
0.00 |
1.64 |
1.64 |
6.09 |
4.27 |
10.36 |
6.09 |
4.27 |
10.36 |
0.00 |
0.00 |
0.00 |
2.27 |
10.36 |
100.00 |
|||||
±SD |
2.30 |
1.70 |
1.18 |
0.00 |
0.50 |
0.50 |
2.30 |
1.74 |
0.92 |
2.30 |
1.74 |
0.92 |
0.00 |
0.00 |
0.00 |
2.62 |
0.92 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
G4 & 1000 |
Mean |
4.45 |
6.36 |
10.82 |
0.00 |
0.73 |
0.73 |
4.45 |
5.64 |
10.09 |
4.45 |
5.64 |
10.09 |
0.00 |
0.00 |
0.00 |
0.87 |
10.09 |
100.00 |
|||||
±SD |
1.51 |
1.86 |
2.27 |
0.00 |
1.01 |
1.01 |
1.51 |
1.36 |
1.38 |
1.51 |
1.36 |
1.38 |
0.00 |
0.00 |
0.00 |
0.44 |
1.38 |
0.00 |
||||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||||
Group & Dose |
Animal No. |
Live Pups (No.) on LD 7 |
During LD 7 to 13 |
|
Sex Ratio (M/F) at LD 13 |
No. of Survived Pups during LD 7 to 13 |
Pup Survival Index |
||||||||||
Live Pups (No.) |
|
Dead Pups (No.) |
|||||||||||||||
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
|||||||||
G1 & 0 |
Mean |
5.09 |
5.00 |
10.09 |
5.09 |
5.00 |
10.09 |
0.00 |
0.00 |
0.00 |
1.30 |
10.09 |
100.00 |
||||
±SD |
1.70 |
1.67 |
0.94 |
1.70 |
1.67 |
0.94 |
0.00 |
0.00 |
0.00 |
1.05 |
0.94 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G2 & 250 |
Mean |
4.00 |
5.50 |
9.50 |
4.00 |
5.50 |
9.50 |
0.00 |
0.00 |
0.00 |
0.82 |
9.50 |
100.00 |
||||
±SD |
1.56 |
1.51 |
1.35 |
1.56 |
1.51 |
1.35 |
0.00 |
0.00 |
0.00 |
0.46 |
1.35 |
0.00 |
|||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|||||
G3 & 500 |
Mean |
6.09 |
4.27 |
10.36 |
6.09 |
4.27 |
10.36 |
0.00 |
0.00 |
0.00 |
2.27 |
10.36 |
100.00 |
||||
±SD |
2.30 |
1.74 |
0.92 |
2.30 |
1.74 |
0.92 |
0.00 |
0.00 |
0.00 |
2.62 |
0.92 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G4 & 1000 |
Mean |
4.45 |
5.64 |
10.09 |
4.45 |
5.64 |
10.09 |
0.00 |
0.00 |
0.00 |
0.87 |
10.09 |
100.00 |
||||
±SD |
1.51 |
1.36 |
1.38 |
1.51 |
1.36 |
1.38 |
0.00 |
0.00 |
0.00 |
0.44 |
1.38 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
SUMMARY OF PUP OBSERVATIONS RECORD DURING LACTATION PERIOD
Group & Dose (mg/kg body weight/day) |
Pup Observation on LD 1 |
Pup Observation on LD 4 |
Pup Observation on LD 7 |
Pup Observation on LD 13 |
|
G1 & 0 |
N |
N |
N |
N |
|
G2 & 250 |
N |
N |
N |
N |
|
G3 & 500 |
N |
N |
N |
N |
|
G4 & 1000 |
N |
N |
N |
N |
|
LD: Lactation Day
SUMMARY RECORD OF MEAN PUP WEIGHT (g) DURING LACTATION PERIOD
Group& Dose |
Mean Pup Weight (g) on LD 1 |
|
Mean Pup Weight (g) on LD 4 |
Mean Pup Weight (g) on LD 7 |
Mean Pup Weight (g) on LD 13 |
|||||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|||||
G1 & 0 |
Mean |
6.22 |
5.41 |
9.93 |
8.48 |
14.94 |
12.86 |
25.50 |
21.12 |
|||
±SD |
0.24 |
0.30 |
0.59 |
0.51 |
0.88 |
1.00 |
1.66 |
1.20 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2 & 250 |
Mean |
6.34 |
5.73 |
10.61 |
9.03 |
15.03 |
12.85 |
26.62 |
22.15 |
|||
±SD |
0.41 |
0.37 |
1.13 |
0.94 |
0.95 |
1.21 |
1.98 |
1.88 |
||||
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
||||
G3 & 500 |
Mean |
6.15 |
5.48 |
9.50 |
8.45 |
14.80 |
41.51 |
25.87 |
20.38 |
|||
±SD |
0.50 |
0.32 |
1.29 |
1.14 |
0.37 |
97.30 |
1.14 |
2.82 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4 & 1000 |
Mean |
6.29 |
5.57 |
10.37 |
8.59 |
15.18 |
12.86 |
26.26 |
21.96 |
|||
±SD |
0.39 |
0.25 |
0.71 |
1.00 |
0.62 |
1.69 |
1.65 |
3.37 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
SD: Standard Deviation; n: Number of dams; LD: Lactation Day
SUMMARY OF UTERI OBSERVATIONS RECORD
Group & Dose |
No. of Corpora lutea |
No. of Implantations |
Implantation Index |
Pre-Implantation Loss (%) |
Post-Implantation Loss (%) |
Pre-natal Loss (No.) |
Post-natal Loss (%) |
Post-natal Loss (No.) |
No. of Early Resorptions |
No. of Late Resorptions |
|
G1 & 0 |
Mean |
11.73 |
11.45 |
98.07 |
1.93 |
2.65 |
0.36 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
2.33 |
2.02 |
3.35 |
3.35 |
5.05 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G2 & 250 |
Mean |
10.70 |
10.70 |
100.00 |
0.00 |
3.33 |
0.30 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
1.64 |
1.64 |
0.00 |
0.00 |
8.05 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
G3 & 500 |
Mean |
12.27 |
12.09 |
98.59 |
1.41 |
0.76 |
0.09 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
1.19 |
1.14 |
3.14 |
3.14 |
2.51 |
0.30 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
11.36 |
11.18 |
98.78 |
1.22 |
3.26 |
0.36 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
2.46 |
2.18 |
2.72 |
2.72 |
6.11 |
0.67 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
SD: Standard Deviation; n: Number of animals
SUMMARY RECORD OF ANO-GENITAL DISTANC RATIO ON LACTATION DAY 4
Group & Dose (mg/kg body weight/day) |
Mean Male AGD Ratio |
Mean Female AGD Ratio |
||
G1 & 0 |
Mean |
2.76 |
1.20 |
|
±SD |
0.14 |
0.10 |
||
n |
11 |
11 |
||
G2 & 250 |
Mean |
2.66 |
1.14 |
|
±SD |
0.18 |
0.08 |
||
n |
10 |
10 |
||
G3 & 500 |
Mean |
2.46 |
1.17 |
|
±SD |
0.84 |
0.40 |
||
n |
11 |
11 |
||
G4 & 1000 |
Mean |
2.69 |
1.23 |
|
±SD |
0.21 |
0.12 |
||
n |
11 |
11 |
SD: Standard Deviation; n: Number of animals
SUMMARY RECORD OF MALE PUP NIPPLE/AREOLAE RETENTION (no.) ON LACTATION DAY 13
Group & Dose (mg/kg body weight/day) |
No. of Nipples/Areolae |
||
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 |
11 |
SD: Standard Deviation; n: Number of anima
SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - MALES
Group, Sex & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1, M & 0 |
Mean |
87.991 |
|
±SD |
4.682 |
||
n |
12 |
||
G2, M & 250 |
Mean |
87.300 |
|
±SD |
4.919 |
||
n |
12 |
||
G3, M & 500 |
Mean |
95.705 |
|
±SD |
14.351 |
||
n |
12 |
||
G4, M & 1000 |
Mean |
104.278* |
|
±SD |
21.130 |
||
n |
12 |
M: Male; SD: Standard Deviation; n: Number of animals
* Statistically significant (P<0.05) change than the vehicle control group.
SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - LACTATION DAY 13 PUPS
Group & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1 & 0 |
Mean |
70.752 |
|
±SD |
9.415 |
||
n |
11 |
||
G2 & 250 |
Mean |
62.065 |
|
±SD |
8.076 |
||
n |
10 |
||
G3 & 500 |
Mean |
64.219 |
|
±SD |
7.606 |
||
n |
11 |
||
G4 & 1000 |
Mean |
62.132 |
|
±SD |
9.600 |
||
n |
11 |
SD: Standard Deviation; n: Number of Dams (Serum collected from pups per dam pooled for analysis)
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 Klimicsh 1 and from study report
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
Based on the data available from the study report, no adverse effects were observed on the reproductive and developmental parameter due to the test chemical. Thus, the test chemical is not likely to classifiy as a 'reproductive toxicant' as per CLP regulation.
Additional information
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