Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be in range of 300 -500 mg/kg bw/day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data from various test chemicals
Justification for type of information:
Weight of evidence approach based on the available information from various test chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
WoE report is based on reproductive toxicity studies on rats
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 2.Crl:CD (SD) 3.Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
2.Age at study initiation of dosing: 10 weeks old / - Recovery: 0, 500 mg/kg/day
3..TEST ANIMALS
- Source: Atsugi Breeding Center, Charles River Laboratories Japan, Inc.
- Age at study initiation:9 weeks of age
- Weight at study initiation: 325-386 g for males and 193-231 g for females
- Housing: bracket-type metallic wire-mesh cages/males and females excluding gestation and lact
ation periods (W 195 × D 325 × H 180 mm),
and polycarbonate cage during gestation and lactation periods/females (W 265 × D 426 × H 200 mm)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum excluding collected fresh urine
- Acclimation period:8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.4 to 23.7°C
- Humidity (%): 48.8 to 65.0%
- Air changes (per hr): 9 to 20 times per hour
- Photoperiod (hrs dark / hrs light):12-hour lighting per day
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
3.Details on exposure
PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in olive oil for injection.
VEHICLE
- Justification for use and choice of vehicle: No data
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): No data
- Dosing volume: 5 mL/kg
- Stability (test solutions): At least 7 days
- Storage condition of test solution: Stored in a refrigerator
Details on mating procedure:
Not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test suspensions at each concentration of initial and final preparations were analyzed by the GC method at Mitsubishi Safety Institute Ltd. Results showed that the concentration of the test article in each suspension was 95.0 to 106.2% of the nominal concentration and both values were within the acceptable range (concentration: percentage of the nominal concentration, 100 ± 10%)
Duration of treatment / exposure:
2..Male: 42 days / - Female: 42 - 58 days (from 14 days before mating to day 5 of lactation)
3.(P) Males: 42 days including 14 days pre-mating and mating periods (P) Females: Days including 14 days pre-mating, mating and gestation periods and the days until day 4 of lactation
Frequency of treatment:
2.daily
3.7 times / week
Details on study schedule:
Not specified
Remarks:
Study 2
1.0,80,200,500mg/kg bw/day
Study 3
0 (vehicle), 10, 60 and 300 mg/kg bw/day
No. of animals per sex per dose:
12 females/dose (0, 10, 60, 300 mg/kg), 7, 12, 12, 7 males of 0, 10, 60, 300 mg/kg, respectively, 5
males and 5 females at 0 and 300 mg/kg bw/day (recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
3..Dose selection rationale: A preliminary study was conducted to determine the doses to be employed. Three males and three female SD rats were receiving 0, 30, 100, 300, and 1000 mg/kg groups of the substance were administered for 14 days. As a result, death or dying was observed in all males and females receiving 1000 mg/kg groups. Salivation and increases in absolute and relative adrenal weights were observed in females receiving 300 mg/kg group. No clear changes related to the test substance were observed in males receiving 300 mg/kg group. Therefore, the high dose was set at 300 mg/ kg/day, and the middle and low dose were set at 60 and 10 mg/kg/day using common ratio 5. Vehicle control groups were set using olive oil only.
Positive control:
Not specified
Parental animals: Observations and examinations:
1.Clinical signs, Body weight, food consumption, Organ weights, Gross pathology, Histopathology, Hematology, Food chemistry, Urinalysis
Reproductive performance
2.CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
Males and females: once before the start of administration, two times/day during the administration
period, and once during the recovery period
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males: once before the start of administration, during the administration and recovery periods
Females: once before the start of administration, days 1, 7, 14 and 20 of gestation, and day 4 of
lactation
BODY WEIGHT: Yes
- Time schedule for examinations:
Males in the main and recovery groups were weighed on Day 1, 8, 15, 22, 29, 36, 42, and 43 of admi
nistration, and males of recovery groups were weighed on Day 50 and 56. Female satellite groups
were weighted same frequencies to male recovery groups. Females in the main groups were weigh
ed on Day 1, 8 and 15 of administration and copulated females were weighed on Day 0, 7, 14 and 20
of gestation, and days 0 and 4 of lactation.
FOOD CONSUMPTION: Yes
- Food consumption (g/day/rat) for each animal determined from the difference of the of the previous
day's feeding amount: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
Males in the main and recovery groups were measured on Day 1-8, 8-15, 15-22, 22-29, 29-36, 36-38,
43-50, and 50-52. Female satellite groups were measured on Day 1-8, 8-15, 15-22, 22-29, 29-36,
36-42, 43-50, and 50-56. Main females were measured same frequencies to body weighted days. It
is not measured during the mating.
FOOD INTAKE: No
COMPOUND INTAKE: No
FOOD EFFICIENCY: No
WATER CONSUMPTION: No
Oestrous cyclicity (parental animals):
23.Vaginal smears were collected from all females in the main groups and microscopically examined every day from the day after the start of administration until the day copulation was confirmed. Mean estrous cycle (day) and abnormal estrous cycle animals (not 4 to 6 day in estrous cycle) were examined by dams.
Sperm parameters (parental animals):
3..Parameters examined in P male parental generations: testes weight, epididymides weight
Litter observations:
3..PARAMETERS EXAMINED:The following parameters were examined in F1 offspring: Number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, and weight gain.
Postmortem examinations (parental animals):
3.SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]

GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS: yes
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
3.SACRIFICE: The F1 pups were euthanized on PND 4 by exsanguination pentobarbital sodium anesthesia, intraperitoneally.
GROSS NECROPSY: Yes
Statistics:
3.Parametric data such as grip strength, motor activity, body weight and gain, food consumption, urine volume, specific gravity, Hematology, blood biochemistry, and absolute and relative organ weights were analyzed by Bartlett’s test for homogeneity of distribution. When homogeneity was recognized, one-way analysis of variance was performed. When a significant difference was observed, Dunnett’s multiple comparison test was conducted for comparison between control and treated groups. If not homogenous, analysis was performed using the Kruskal-Wallis ranking test. In consequence, if not homogenous, Dunnett’s type mean rank sum test was conducted to compare to control and individual treatment groups. Qualitative value as the pathological findings was analyzed by Wilcoxon test and
Fisher’s exact test. Urinalyses data were analyzed by Kruskal-Wallis and Dunnet’s type mean rank test. Reproductive incidences of estrous cycle, fertility index, copulation index, delivery index, sex ratio, and external abnormalities were analysed by Fisher’s exact test. Significance level was set at 0.05 compared with the control group and among the groups.
Reproductive indices:
Not specifed
Offspring viability indices:
Not specifed
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
2.Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)
Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
2.Male: No effect
Female: Decrease in the food consumption (200 and 500 mg/kg/day)
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
2.Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)
Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2.Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the beta-glb (500 mg/kg/day)
Female: No effect
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.Male: No effect
Female: Atrophy of white pulp in the spleen (500 mg/kg/day)
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
3.There were no animals showing abnormal estrous cycles, and there were no significant differences in the average length of the estrous cycle between the control group and any treatment group.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
3.There were no significant differences in the incidence of females with irregular estrus cycle, mating period with the number of estrus and day of conceiving, copulation index, and fertility index between the control group and any treatment groups.There were no significant differences in the gestation length, number of corpora lutea, number of implantation sites, implantation index, and delivery index between the control group and any treatment groups.
2.No overall adverese effects were observed on rats (male/female) including reproductive performance.
Dose descriptor:
NOAEL
Effect level:
> 300 - <= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
haematology
organ weights and organ / body weight ratios
gross pathology
reproductive performance
Remarks on result:
other: No overall adverse effects
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not specified
Other effects:
no effects observed
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
No overall adverse effects observed.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 300 - <= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No overall adverse effects
Remarks on result:
other: No effects on reproductive performance was 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) in relation to reproductive toxicity for the test chemical was considered to be in range of 300-500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.
Executive summary:

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 2

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed on male and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes and reproductive performance.

in male decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)was observed while in female decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day) .in Female decrease in the food consumption (200 and 500 mg/kg/day) dose grop while male decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)In female atrophy of white pulp in the spleen (500 mg/kg/day) was observed .No overall adverese effects were observed on rats (male/female) including reproductive performance.

 On the basis of observations made, The No Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test chemical was considered to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.

Study 3

A combined repeated oral dose toxicity study and reproduction/developmental toxicity screening test was performed according to the OECD TG 422. Male and female rats (12 animals/sex/dose) were administered test chemical at 0, 10, 60, and 300 mg/kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating period and subsequent mating period. Females were dosed for up to 55 days, including 14 day pre-mating, mating, and gestation periods, and the time until lactation day 4. Five out of 12 males dosed at 0 and 300 mg/kg bw/day were treated as a recovery group. In addition,5 females/dose 0 and 300 mg/kg bw/day groups were dosed for 42 days without mating and examined after the recovery period. There were no effects on reproductive and developmental parameters at 300 mg/kg bw/day. The NOAEL for the rat reproductive/developmental toxicity of test chemical was considered to be 300 mg/kg bw/day, the highest dose tested.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
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

Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:

Study 2

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed on male and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes and reproductive performance.

in male decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)was observed while in female decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day) .in Female decrease in the food consumption (200 and 500 mg/kg/day) dose grop while male decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)In female atrophy of white pulp in the spleen (500 mg/kg/day) was observed .No overall adverese effects were observed on rats (male/female) including reproductive performance.

 On the basis of observations made, TheNo Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test chemical was considered to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.

Study 3

A combined repeated oral dose toxicity study and reproduction/developmental toxicity screening test was performed according to the OECD TG 422. Male and female rats (12 animals/sex/dose) were administered test chemical at 0, 10, 60, and 300 mg/kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating period and subsequent mating period. Females were dosed for up to 55 days, including 14 day pre-mating, mating, and gestation periods, and the time until lactation day 4. Five out of 12 males dosed at 0 and 300 mg/kg bw/day were treated as a recovery group. In addition,5 females/dose 0 and 300 mg/kg bw/day groups were dosed for 42 days without mating and examined after the recovery period. There were no effects on reproductive and developmental parameters at 300 mg/kg bw/day. The NOAEL for the rat reproductive/developmental toxicity of test chemical was considered to be 300 mg/kg bw/day, the highest dose tested.

Based on the data available from different studies, NOAEL for test material was considered to be in range of 300 -500 mg/kg bw/day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Effects on developmental toxicity

Description of key information

Developmental toxicity study

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be in range of 300 -500 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulation testchemical is not likely to classify as reproductive and developmental toxicant.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data from various test chemicals
Justification for type of information:
Weight of evidence approach based on the available information from various test chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Combined repeated dose and reproduction / developmental screening was performed for test chemical
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 2.Crl:CD (SD) 3.Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Atsugi Breeding Center, Charles River Laboratories Japan, Inc.
- Age at study initiation:9 weeks of age
- Weight at study initiation: 325-386 g for males and 193-231 g for females
- Housing: bracket-type metallic wire-mesh cages/males and females excluding gestation and lact
ation periods (W 195 × D 325 × H 180 mm),
and polycarbonate cage during gestation and lactation periods/females (W 265 × D 426 × H 200 mm)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum excluding collected fresh urine
- Acclimation period:8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.4 to 23.7°C
- Humidity (%): 48.8 to 65.0%
- Air changes (per hr): 9 to 20 times per hour
- Photoperiod (hrs dark / hrs light):12-hour lighting per day
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
3.Details on exposure
PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in olive oil for injection.
VEHICLE
- Justification for use and choice of vehicle: No data
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): No data
- Dosing volume: 5 mL/kg
- Stability (test solutions): At least 7 days
- Storage condition of test solution: Stored in a refrigerator
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
3.Test suspensions at each concentration of initial and final preparations were analyzed by the GC method at Mitsubishi Safety Institute Ltd. Results showed that the concentration of the test article in each suspension was 95.0 to 106.2% of the nominal concentration and both values were within the acceptable range (concentration: percentage of the nominal concentration, 100 ± 10%)
Details on mating procedure:
Not specified
Duration of treatment / exposure:
2.Male: 42 days / - Female: 42 - 58 days (from 14 days before mating to day 5 of lactation)
3.(P) Males: 42 days including 14 days pre-mating and mating periods (P) Females: Days including 14 days pre-mating, mating and gestation periods and the days until day 4 of lactation
Frequency of treatment:
2.daily
3.7 times / week
Duration of test:
58 days
Remarks:
Study 2
0,80,200,500mg/kg bw /day
Study 3
0 (vehicle), 10, 60 and 300 mg/kg bw/day
No. of animals per sex per dose:
Study 3
12 females/dose (0, 10, 60, 300 mg/kg), 7, 12, 12, 7 males of 0, 10, 60, 300 mg/kg, respectively, 5
males and 5 females at 0 and 300 mg/kg bw/day (recovery group)
Control animals:
not specified
Details on study design:
3.Dose selection rationale: A preliminary study was conducted to determine the doses to be employed. Three males and three female SD rats were receiving 0, 30, 100, 300, and 1000 mg/kg groups of the substance were administered for 14 days. As a result, death or dying was observed in all males and females receiving 1000 mg/kg groups. Salivation and increases in absolute and relative adrenal weights were observed in females receiving 300 mg/kg group. No clear changes related to the test substance were observed in males receiving 300 mg/kg group. Therefore, the high dose was set at 300 mg/ kg/day, and the middle and low dose were set at 60 and 10 mg/kg/day using common ratio 5. Vehicle control groups were set using olive oil only.
Maternal examinations:
2.Clinical signs, Body weight, food consumption, Organ weights, Gross pathology, Histopathology, Hematology, Food chemistry, Urinalysis
Reproductive performance
3.CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
Males and females: once before the start of administration, two times/day during the administration
period, and once during the recovery period
DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule:
Males: once before the start of administration, during the administration and recovery periods
Females: once before the start of administration, days 1, 7, 14 and 20 of gestation, and day 4 of
lactation
BODY WEIGHT: Yes
- Time schedule for examinations:
Males in the main and recovery groups were weighed on Day 1, 8, 15, 22, 29, 36, 42, and 43 of admi
nistration, and males of recovery groups were weighed on Day 50 and 56. Female satellite groups
were weighted same frequencies to male recovery groups. Females in the main groups were weigh
ed on Day 1, 8 and 15 of administration and copulated females were weighed on Day 0, 7, 14 and 20
of gestation, and days 0 and 4 of lactation.
FOOD CONSUMPTION: Yes
- Food consumption (g/day/rat) for each animal determined from the difference of the of the previous
day's feeding amount: Yes
Measurement of food consumption was conducted on all animals at the following frequencies:
Males in the main and recovery groups were measured on Day 1-8, 8-15, 15-22, 22-29, 29-36, 36-38,
43-50, and 50-52. Female satellite groups were measured on Day 1-8, 8-15, 15-22, 22-29, 29-36,
36-42, 43-50, and 50-56. Main females were measured same frequencies to body weighted days. It
is not measured during the mating.
FOOD INTAKE: No
COMPOUND INTAKE: No
FOOD EFFICIENCY: No
WATER CONSUMPTION: No
Ovaries and uterine content:
2&3The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
2&3- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
- Skeletal examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
Statistics:
Parametric data such as grip strength, motor activity, body weight and gain, food consumption, urine volume, specific gravity, Hematology, blood biochemistry, and absolute and relative organ weights were analyzed by Bartlett’s test for homogeneity of distribution. When homogeneity was recognized, one-way analysis of variance was performed. When a significant difference was observed, Dunnett’s multiple comparison test was conducted for comparison between control and treated groups. If not homogenous, analysis was performed using the Kruskal-Wallis ranking test. In consequence, if not homogenous, Dunnett’s type mean rank sum test was conducted to compare to control and individual treatment groups. Qualitative value as the pathological findings was analyzed by Wilcoxon test and
Fisher’s exact test. Urinalyses data were analyzed by Kruskal-Wallis and Dunnet’s type mean rank test. Reproductive incidences of estrous cycle, fertility index, copulation index, delivery index, sex ratio, and external abnormalities were analysed by Fisher’s exact test. Significance level was set at 0.05 compared with the control group and among the groups.
Indices:
1) Each parameter was determined by the following equations:
Mean estrus cycle, incidence of females with irregular estrus cycle, mating periods,Copulation index (%) = (No. of copulated animals/No. of co-housed animals) × 100
Fertility index (%) = (No. of pregnant females/No. of copulated females) × 100
Gestation length, number of corpora lutea, number of implantation sites, total number of offspring,
Implantation index (%) = (No. of implantation sites/No. of corpora lutea) × 100
Delivery index (%) = (No. of females delivered liveborn pups/No. of pregnant females) × 100
Gestation index (%) = (No. of pregnant animals delivered live offspring/number of pregnant animals) ×
100
Historical control data:
Total number of offspring at birth, number of live offspring at birth,
Number of live pups on day 0 of lactationBirth index (%) = (Number of live pups on day 0/Number of i
mplantation sites) ×100
Viability index = (Number of live pups on day 4 after birth/Number of live pups born) ×100
External examination of offspring, necropsy finding
Pups weight on day 0 of lactation
Sex ratio on day 0 of lactation
Number of live pups on day 4 of lactation
Pups weight on day 4 of lactation
Sex ratio on day 4 of lactation
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2.Male: Decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)
Female: Decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
2.Male: No effect
Female: Decrease in the food consumption (200 and 500 mg/kg/day)
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
2.Male: Decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)
Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2.Male: Decrease in the AST (200 mg/kg/day), Decrease in the ALT (200 and 500 mg/kg/day), Decrease in the creatinine (500 mg/kg/day), Decrease in the beta-glb (500 mg/kg/day)
Female: No effect
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
2.Male: Decrease in the spleen weight (Absolute and Relative) (200 mg/kg/day), Increase in the spleen weight (Absolute) (Recovery 500 mg/kg/day, tendency), Increase in the spleen weight (Relative) (Recovery 500 mg/kg/day), Decrease in the testes weight (Absolute)
(Recovery 500 mg/kg/day)
Female: Decrease in the spleen weight (Absolute and Relative) (500 mg/kg/day)
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.Male: No effect
Female: Atrophy of white pulp in the spleen (500 mg/kg/day)
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):
3.There were no significant differences in the number of implantation sites, implantation index, and delivery index between the control group and any treatment groups.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
3.There were no significant differences in the gestation length between the control group and any treatment groups.
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
2.No overall adverese effects were observed on rats (male/female) including reproductive performance.
3.There were no significant differences in the gestation length, number of corpora lutea, number of implantation sites, implantation index, and delivery index between the control group and any treatment groups.
Dose descriptor:
NOAEL
Effect level:
> 300 - <= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
organ weights and organ / body weight ratios
urinalysis
other: No overall adverese effects were observed on rats (male/female) including reproductive performance.
Remarks on result:
other: No overall adverese effects were observed on rats (male/female) including reproductive performance.
Abnormalities:
not specified
Localisation:
not specified
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
no effects observed
Description (incidence and severity):
No overall adverse effects observed.
Dose descriptor:
NOAEL
Effect level:
> 300 - <= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: No overall adverse effects observed.
Remarks on result:
other: No overall adverse effects observed.
Abnormalities:
not specified
Localisation:
other: not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Conclusions:
The No Observed Adverse effect level (NOAEL) in relation to developmental toxicity for the test chemical was considered to be in range of 300-500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.
Executive summary:

Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study2

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed on male and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes and reproductive performance.

in male decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)was observed while in female decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day) .in Female decrease in the food consumption (200 and 500 mg/kg/day) dose grop while male decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)In female atrophy of white pulp in the spleen (500 mg/kg/day) was observed .No overall adverese effects were observed on rats (male/female) including reproductive performance.

 On the basis of observations made, TheNo Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test chemical was considered to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.

Study3

A combined repeated oral dose toxicity study and reproduction/developmental toxicity screening test was performed according to the OECD TG 422. Male and female rats (12 animals/sex/dose) were administered test chemical at 0, 10, 60, and 300 mg/kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating period and subsequent mating period. Females were dosed for up to 55 days, including 14 day pre-mating, mating, and gestation periods, and the time until lactation day 4. Five out of 12 males dosed at 0 and 300 mg/kg bw/day were treated as a recovery group. In addition,5 females/dose 0 and 300 mg/kg bw/day groups were dosed for 42 days without mating and examined after the recovery period. There were no effects on reproductive and developmental parameters at 300 mg/kg bw/day. The NOAEL for the rat reproductive/developmental toxicity of test chemical was considered to be 300 mg/kg bw/day, the highest dose tested.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

 Developmental toxicity study

Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study2

Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test chemical upon repeated dosing by oral route. The test was performed on male and female Crl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes and reproductive performance.

in male decrease in the body weight gain (500 mg/kg/day, tendency), Decrease in the rate of body weight gain (500 mg/kg/day)was observed while in female decrease in the body weight (500 mg/kg/day), Decrease in the body weight gain(200, 500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the rate of body weight gain (Recovery 500 mg/kg/day) .in Female decrease in the food consumption (200 and 500 mg/kg/day) dose grop while male decrease in the WBC (200 and 500 mg/kg/day, tendency), Decrease in the RET (500 mg/kg/day), Decrease in the percentage of Eosinophil (500 mg/kg/day)Female: Decrease in the Hct (500 mg/kg/day and Recovery 500 mg/kg/day), Decrease in the WBC (500 mg/kg/day, tendency), Decrease in the percentage of Lymphocyte (500 mg/kg/day, tendency), Decrease in the RBC (Recovery 500 mg/kg/day), Increase in the MCHC (Recovery 500 mg/kg/day)In female atrophy of white pulp in the spleen (500 mg/kg/day) was observed .No overall adverese effects were observed on rats (male/female) including reproductive performance.

 On the basis of observations made, TheNo Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test chemical was considered to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.

Study3

A combined repeated oral dose toxicity study and reproduction/developmental toxicity screening test was performed according to the OECD TG 422. Male and female rats (12 animals/sex/dose) were administered test chemical at 0, 10, 60, and 300 mg/kg bw/day. Males were dosed for 42 days, including a 14 day pre-mating period and subsequent mating period. Females were dosed for up to 55 days, including 14 day pre-mating, mating, and gestation periods, and the time until lactation day 4. Five out of 12 males dosed at 0 and 300 mg/kg bw/day were treated as a recovery group. In addition,5 females/dose 0 and 300 mg/kg bw/day groups were dosed for 42 days without mating and examined after the recovery period. There were no effects on reproductive and developmental parameters at 300 mg/kg bw/day. The NOAEL for the rat reproductive/developmental toxicity of test chemical was considered to be 300 mg/kg bw/day, the highest dose tested.

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be in range of 300 -500 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation test chemical is not likely to classify as reproductive and developmental toxicant.

Additional information