Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive Toxicity

Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents were treated with test material orally by gavage. 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 data of the read-across chemicals.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on 2 reproductive toxicity studies i.e. WoE-2 and WoE-3.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data
Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
2. - Source: Charles River Japan Co., Ltd
- Age at study initiation: 9 weeks
- Weight at study initiation: 309 to 355 g for males and from 206 to 232 g for females
- Fasting period before study: No data available
- Housing: Rat were housed stainless steel hanging type wire mesh cage, excluded for the period of pregnancy /nursing period. During pregnancy / nursing female were housed in polycarbonate cage with a floor covering for laboratory animals.
- Diet (e.g. ad libitum): Solid feed for experimental animals irradiated with ultraviolet rays after autoclave sterilized nd filtering with a pore size of 5 μm, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
-Temperature (°C): 22 ± 2 ° C.
- Humidity (%):55 ± 15%
- Air changes (per hr): 12 times / hour
- Photoperiod (hrs dark / hrs light): lighting 12 hours / day (7: 00-19: 00)
3. TEST ANIMALS
- Age at study initiation: 9 weeks
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 2. 0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80 3. Water
Details on exposure:
2. VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5 % Sodium carboxymethylcellulose mixed with 0.1 % Tween 80
- Concentration in vehicle: 0 (vehicle), 100, 300, 1000 mg/kg
- Amount of vehicle (if gavage): 10 mL / kg
3. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with water at dose levels of 0, 40, 200 or 1000 mg/Kg/day (Recovery group: 0, 1000 mg/kg/day)
VEHICLE
- Justification for use and choice of vehicle (if other than water): water
- Concentration in vehicle: 0, 40, 200 or 1000 mg/Kg/day (Recovery group: 0, 1000 mg/kg/day)
Details on mating procedure:
2. - M/F ratio per cage: 1:1
- Length of cohabitation: 14th day
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Plug formation or sperm in vaginal smear referred to as day 0 of pregnancy
3. not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
2. not specified
3. yes - Spectrophotometer: UV-2400PC
The UV-visible absorption spectrum and the absorbance were measured.
Duration of treatment / exposure:
2. 42 to 47 days
3. Male: 42 days / - Female: 41 - 47 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
2. Daily
3. Daily
Details on study schedule:
2. not specified
3. not specified
Remarks:
2. 0, 100, 300 and 1000 mg/kg bw/day
3. Test group: 0, 40, 200 or 1000 mg/Kg/day
Recovery group: 0, 1000 mg/kg/day
No. of animals per sex per dose:
2. Total: 96
0 (vehicle) mg/kg: 12 male, 12 female
100 mg/kg: 12 male, 12 female
300 mg/kg: 12 male, 12 female
1000 mg/kg: 12 male, 12 female
3. not specified
Control animals:
yes, concurrent vehicle
Details on study design:
2. - Dose selection rationale: Test substance was repeatedly administered orally to SD rats of 3 male and 3 female at 0, 100, 300 and 1000 mg / kg doses for 14 days, and as a result, No effect on in general condition, body weight, food consumption. No clear toxicity change due to administration of the test substance was observed in both organ weight and necropsy.
Based on these findings, the high dose was set at the upper limit of 1000 mg / kg prescribed in the OECD guidelines, three doses of 300 mg / kg for the medium dose and 100 mg / kg for the low dose were set at a tolerance of about 3 .
3. not specified
Positive control:
2. not specified
3. not specified
Parental animals: Observations and examinations:
2. Mortality, clinical sign, body weight and feed Consumption were examined.
3. DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: No data
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Oestrous cyclicity (parental animals):
2. Estrous cyclicity were examined.
Number of corpus luteums and the number of landings were examined
3. not specified
Sperm parameters (parental animals):
2. Not specified
3. not specified
Litter observations:
2. Not specified
3. not specified
Postmortem examinations (parental animals):
2. Hematology, clinical chemistry, Gross pathology and histopathology were examined.
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
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
2. Number of births, sex and Body weight were examined.
3. not specified
Statistics:
2. Regarding the weighing data, parametric data was tested for equal variance by the Bartlett method, and one-way ANOVA was performed when variance was equal. Where the variances are not equal and nonparametric data were tested by Kruskal-Wallis. When significant difference was observed between groups, multiple comparisons of Dunnett method or Dunnett type were performed. Pathological findings in counting data were examined by χ 2 for a × b . When significant difference was observed, comparison was made between control group and each test substance administered group by Armitage χ 2 test. Other counting data were tested by Fisher's direct stochastic method. The significance level of each test was 5%. For the data on newborn babies, the average value calculated for each mother was set as a sample unit.
3. not specified
Reproductive indices:
2. Breast feeding, nesting, and the presence or absence of feeding, birth rate, implantation rate, delivery rate were examined.
3. not specified
Offspring viability indices:
2. Viability on day 0 and 4 were examined.
3. not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
2. effects observed, treatment-related - Red feces exhibiting the same color tone as the test substance administered in all sexes were observed daily from the day following the administration start date. When treated wtih 1000 mg/kg bw, in 2 male loose stools were observed transiently on 22 days after the start of administration, but abnormalities in general conditions considered to be toxic changes.
3. no effects observed - no evidence of toxicity attributable to the test substance in all test items for both sexes was observed.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
2. no mortality observed - No effect on survival of treated male and female rat were observed as compared to control.
3. no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2. no effects observed - No significant effect on body weight and body weight gain of treated male and female rats were observed as compared to control.
3. no effects observed - In the 200 mg / kg group, female weight at birth was significantly higher than that in the vehicle control group.
Female weight at birth day in 40 and 1000 mg / kg groups, male weight at birth day in each treatment group and 4 days after birth, there was no significant difference in male and female body weight between the vehicle control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
2. no effects observed - No effect on food consumption of treated male and female rats was observed as compared to control.
3. no effects observed - Male - In the measurement of food intake during the administration period, vehicle control was performed on day 29 in the 40 and 200 mg / kg administration groups. A significantly lower value was found compared to the group. During the recovery period, No significant difference was found between the 1000 mg / kg group and the vehicle control recovery group. Female - Before mating, during pregnancy and during the lactation period of the mother animal, each administration group is compared with the vehicle control group. There was no significant difference between them. Between the 1000 mg / kg dose group and the vehicle control recovery group in the recovery group that did not carry out mating. There was no significant difference.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
2. effects observed, non-treatment-related - When treated wtih 100 mg / kg, significant decrease in prothrombin time were observed in male rats, but no change was observed in the 300 and 1000 mg / kg group, so it was judged to be an accidental change. In females, there was no significant difference between the test substance administered group and the control group.
3. no effects observed - In the male 1000 mg / kg dose group, significant low values ​​of AST and glucose, Significant highs, A significant increase in glucose was noted in the female 1000 mg / kg group. Also, In the female 1000 mg / kg group, hematological examination showed a significant increase in eosinophil ratio
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
2. effects observed, non-treatment-related - When treated wtih 1000 mg / kg, significant incrase in A / G ratio were observed in male rats. However, since the total protein and albumin were not changed and were slightly high, it was considered to be fluctuating within the physiological range and it was judged that it was not caused by administration of the test substance.
When treated wtih 100 mg / kg, significant incrase in ASAT (GOT) in female rats, but no change was observed in the 300 and 1000 mg / kg group, so it was judged to be an accidental change .
3. not specified
Urinalysis findings:
no effects observed
Description (incidence and severity):
2. not specified
3. no effects observed - Both male and female, each administration at the end of the administration period and at the end of the recovery period, there was no significant difference between the group and the vehicle control group.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
2. no effects observed - No histopathological changes were observed in treated male and female rats as compared to control.
3. no effects observed - In histopathological examination, calcification of the pulmonary artery, hepatocellular necrosis in the liver, small granuloma in the liver, kidney, Visceral cyst formation, adrenal cortical vacuolation and intrastromal lymphocyte infiltration of the prostate were found in a few cases. In addition,histopathological changes observed in the histopathological examination of males in the 1000 mg / kg dose group
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
2. no effects observed - No effect on sexual cycle of treated female rat were observed as compared to control.
3. not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
2. no effects observed - No significant difference was observed in mating index, fertility index, numbers of corpora lutea or implantations, implantation index, delivery index, gestation index, gestation length, parturition or maternal behavior, numbers of offspring or live offspring of treated rats as compared to control.
3. no effects observed - Pregnancy lupus number, implantation rate, birth rate, gestational age, parturition status and lactation status are increased by test substance administration.The number of implantations in the 1000 mg / kg dose group compared to the vehicle control group
There was a significant increase in the number of pregnant women, but the number of pregnant corpus corpora lutea and implantation rate differed between each treatment group and vehicle control group. Because there was no significant difference between the two, it is considered to be a change that has no toxicological significance.
Dose descriptor:
NOAEL
Remarks:
2
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
haematology
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
Dose descriptor:
NOAEL
Remarks:
3
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
haematology
urinalysis
histopathology: non-neoplastic
reproductive performance
Remarks on result:
other: overall no effects on reproductive performance
Critical effects observed:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
2. no effects observed - No abnormal clinical signs were observed in offspring.
3. no effects observed - There was no difference in the general condition of pups, no abnormality was found in any group.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
2. no mortality observed - No effect on numbers of live offspring of were observed as compared to control.
3. no mortality observed - There were no cases where all children died during the nursing period. There was no significant difference between the group and the vehicle control group. The number of survivors at 4 days after birth and the 4 days survival rate of neonates were significant between each treatment group and vehicle control group.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
2. no effects observed - No significant change in body weights of offspring were observe as compared to control.
3. 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:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
2. no effects observed - No gross pathological changes were observed in offsprings.
3. no effects observed - No abnormal cases were found in any group.
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Remarks:
2
Generation:
F1
Effect level:
1 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
Remarks on result:
other: No effect observed
Dose descriptor:
NOAEL
Remarks:
3
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
body weight and weight gain
gross pathology
Remarks on result:
other: overall no effects on developmental parameters was observed
Critical effects observed:
not specified
Reproductive effects observed:
not specified
Conclusions:
Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents were treated with test material orally by gavage. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.
Executive summary:

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

 

In a Combined Repeat Dose and Reproductive / Developmental Toxicity Screening Test, Crj:CD(SD) male and female rats were treated with test material in the concentration of 0 (vehicle), 100, 300, 1000 mg/kg orally by gavage for 42 to 47 days according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test). No effect on survival of treated male and female rat was observed as compared to control. Red feces exhibiting the same color tone as the test substance administered in all sexes were observed daily from the day following the administration start date. At 1000 mg/kg bw, in 2 male loose stools were observed transiently on 22 days after the start of administration, but abnormalities in general conditions considered to be toxic changes. No significant effect on body weight and body weight gain and food consumption of treated male and female rats were observed as compared to control. Significant decrease in prothrombin time were observed in male rats at 100 mg / kg/day, but no change was observed in the 300 and 1000 mg / kg group, so it was judged to be an accidental change. In females, there was no significant difference between the test substances administered group and the control group. Significant increase in A / G ratio were observed in male rats at 1000 mg / kg/day. However, since the total protein and albumin were not changed and were slightly high, it was considered to be fluctuating within the physiological range and it was judged that it was not caused by administration of the test substance. Significant increase in ASAT (GOT) in female rats at 100 mg / kg/day, but no change was observed in the 300 and 1000 mg / kg group, so it was judged to be an accidental change. Similarly, No effect on reproductive parameters such as sexual cycle, mating index, the fertility index, numbers of corpora lutea or implantations, the implantation index, the delivery index, the gestation index, gestation length, parturition or maternal behavior, numbers of offspring or live offspring of treated rats as compared to control. Significant increase in relative liver weight in male and absolute and relative weight in female were observed at 1000 mg / kg bw as compared to control. Significant decrease in absolute spleen weight and significant increase in relative adrenal gland weight were observed at 300 mg / kg bw in male rats. Significant increase in relative adrenal gland weight were observed in male rats at 100 mg / kg bw. But, since there was no change in the 1000 mg / kg group, it was judged to be an accidental change. Colored stomach at 1000 mg / kg and red, colored contents were observed in small intestine and large intestine at 100 mg / kg. Focal bleeding of the lung, contraction failure and white spots, stomach tar-like contents, white spots of the liver, dilation of the renal pelvic cavity, uterine bloating, vaginal distension and ventricular dilation were observed. However, since there was no certain tendency in its expression status, it was judged to be an accidental change unrelated to administration of the test substance. No histopathological changes were observed in treated male and female rats as compared to control. In addition, No effect on numbers of live offspring, clinical signs and body weight of offspring were observed as compared to control. No gross pathological changes were observed in offspring. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Crj:CD (SD) male and female rats treated with test material orally by gavage for 42 to 47 days.

 

In another study, combined repeated dose and reproduction / developmental screening test was performed to evaluate the toxic nature of the given test chemical according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test). Male and female Crl:CD (SD) were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, body weight, food consumption, urinalysis, hematology, blood chemistry, organ weight changes and histopathology reproductive and developmental parameters. No mortality observed. No evidence of toxicity attributable to the test substance in all test items for both sexes was observed. In the 200 mg / kg group, female weight at birth was significantly higher than that in the vehicle control group. Female weight at birth day in 40 and 1000 mg / kg groups, male weight at birth day in each treatment group and 4 days after birth, there was no significant difference in male and female body weight between the vehicle control groups. In the measurement of food intake during the administration period, vehicle control was performed on day 29 in the 40 and 200 mg / kg administration groups. A significantly lower value was found compared to the group for males. During the recovery period, No significant difference was found between the 1000 mg / kg group and the vehicle control recovery group. Before mating, during pregnancy and during the lactation period of the mother animal, each administration group is compared with the vehicle control group. There was no significant difference between them. Between the 1000 mg / kg dose group and the vehicle control recovery group in the recovery group that did not carry out mating. There was no significant difference. In the male 1000 mg / kg dose group, significant low values ​​of AST and glucose. A significant increase in glucose was noted in the female 1000 mg / kg group. Also, in the female 1000 mg / kg group, hematological examination showed a significant increase in eosinophil ratio. Both male and female, each administration at the end of the administration period and at the end of the recovery period, there was no significant difference between the group and the vehicle control group was observed in urinalysis. In histopathological examination, calcification of the pulmonary artery, hepatocellular necrosis in the liver, small granuloma in the liver, kidney, visceral cyst formation, adrenal cortical vacuolation and intrastromal lymphocyte infiltration of the prostate were found in a few cases. In addition,histopathological changes observed in the histopathological examination of males in the 1000 mg / kg dose group. Pregnancy lupus number, implantation rate, birth rate, gestational age, parturition status and lactation status are increased by test substance administration. The number of implantations in the 1000 mg / kg dose group compared to the vehicle control group. There was a significant increase in the number of pregnant women, but the number of pregnant corpus corpora lutea and implantation rate differed between each treatment group and vehicle control group. Because there was no significant difference between the two, it is considered to be a change that has no toxicological significance. There was no difference in the general condition of pups, no abnormality was found in any group. There were no cases where all children died during the nursing period. There was no significant difference between the group and the vehicle control group. The number of survivors at 4 days after birth and the 4 days survival rate of neonates were significant between each treatment group and vehicle control group. No abnormal cases were found in any group. Hence, the No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity is considered to be 1000 mg/Kg/day, when male and female Crl:CD (SD) were treated with the given test chemical orally. 

 

Based on the data available from different studies, NOAEL was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents 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.

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 2 and from handbook or collection of data.
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

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

 

In a Combined Repeat Dose and Reproductive / Developmental Toxicity Screening Test, Crj:CD(SD) male and female rats were treated with test material in the concentration of 0 (vehicle), 100, 300, 1000 mg/kg orally by gavage for 42 to 47 days according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test). No effect on survival of treated male and female rat was observed as compared to control. Red feces exhibiting the same color tone as the test substance administered in all sexes were observed daily from the day following the administration start date. At 1000 mg/kg bw, in 2 male loose stools were observed transiently on 22 days after the start of administration, but abnormalities in general conditions considered to be toxic changes. No significant effect on body weight and body weight gain and food consumption of treated male and female rats were observed as compared to control. Significant decrease in prothrombin time were observed in male rats at 100 mg / kg/day, but no change was observed in the 300 and 1000 mg / kg group, so it was judged to be an accidental change. In females, there was no significant difference between the test substances administered group and the control group. Significant increase in A / G ratio were observed in male rats at 1000 mg / kg/day. However, since the total protein and albumin were not changed and were slightly high, it was considered to be fluctuating within the physiological range and it was judged that it was not caused by administration of the test substance. Significant increase in ASAT (GOT) in female rats at 100 mg / kg/day, but no change was observed in the 300 and 1000 mg / kg group, so it was judged to be an accidental change. Similarly, No effect on reproductive parameters such as sexual cycle, mating index, the fertility index, numbers of corpora lutea or implantations, the implantation index, the delivery index, the gestation index, gestation length, parturition or maternal behavior, numbers of offspring or live offspring of treated rats as compared to control. Significant increase in relative liver weight in male and absolute and relative weight in female were observed at 1000 mg / kg bw as compared to control. Significant decrease in absolute spleen weight and significant increase in relative adrenal gland weight were observed at 300 mg / kg bw in male rats. Significant increase in relative adrenal gland weight were observed in male rats at 100 mg / kg bw. But, since there was no change in the 1000 mg / kg group, it was judged to be an accidental change. Colored stomach at 1000 mg / kg and red, colored contents were observed in small intestine and large intestine at 100 mg / kg. Focal bleeding of the lung, contraction failure and white spots, stomach tar-like contents, white spots of the liver, dilation of the renal pelvic cavity, uterine bloating, vaginal distension and ventricular dilation were observed. However, since there was no certain tendency in its expression status, it was judged to be an accidental change unrelated to administration of the test substance. No histopathological changes were observed in treated male and female rats as compared to control. In addition, No effect on numbers of live offspring, clinical signs and body weight of offspring were observed as compared to control. No gross pathological changes were observed in offspring. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Crj:CD (SD) male and female rats treated with test material orally by gavage for 42 to 47 days.

 

In another study, combined repeated dose and reproduction / developmental screening test was performed to evaluate the toxic nature of the given test chemical according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test). Male and female Crl:CD (SD) were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, body weight, food consumption, urinalysis, hematology, blood chemistry, organ weight changes and histopathology reproductive and developmental parameters. No mortality observed. No evidence of toxicity attributable to the test substance in all test items for both sexes was observed. In the 200 mg / kg group, female weight at birth was significantly higher than that in the vehicle control group. Female weight at birth day in 40 and 1000 mg / kg groups, male weight at birth day in each treatment group and 4 days after birth, there was no significant difference in male and female body weight between the vehicle control groups. In the measurement of food intake during the administration period, vehicle control was performed on day 29 in the 40 and 200 mg / kg administration groups. A significantly lower value was found compared to the group for males. During the recovery period, No significant difference was found between the 1000 mg / kg group and the vehicle control recovery group. Before mating, during pregnancy and during the lactation period of the mother animal, each administration group is compared with the vehicle control group. There was no significant difference between them. Between the 1000 mg / kg dose group and the vehicle control recovery group in the recovery group that did not carry out mating. There was no significant difference. In the male 1000 mg / kg dose group, significant low values ​​of AST and glucose. A significant increase in glucose was noted in the female 1000 mg / kg group. Also, in the female 1000 mg / kg group, hematological examination showed a significant increase in eosinophil ratio. Both male and female, each administration at the end of the administration period and at the end of the recovery period, there was no significant difference between the group and the vehicle control group was observed in urinalysis. In histopathological examination, calcification of the pulmonary artery, hepatocellular necrosis in the liver, small granuloma in the liver, kidney, visceral cyst formation, adrenal cortical vacuolation and intrastromal lymphocyte infiltration of the prostate were found in a few cases. In addition,histopathological changes observed in the histopathological examination of males in the 1000 mg / kg dose group. Pregnancy lupus number, implantation rate, birth rate, gestational age, parturition status and lactation status are increased by test substance administration. The number of implantations in the 1000 mg / kg dose group compared to the vehicle control group. There was a significant increase in the number of pregnant women, but the number of pregnant corpus corpora lutea and implantation rate differed between each treatment group and vehicle control group. Because there was no significant difference between the two, it is considered to be a change that has no toxicological significance. There was no difference in the general condition of pups, no abnormality was found in any group. There were no cases where all children died during the nursing period. There was no significant difference between the group and the vehicle control group. The number of survivors at 4 days after birth and the 4 days survival rate of neonates were significant between each treatment group and vehicle control group. No abnormal cases were found in any group. Hence, the No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity is considered to be 1000 mg/Kg/day, when male and female Crl:CD (SD) were treated with the given test chemical orally. 

 

Based on the data available from different studies, NOAEL was considered to be 1000 mg/kg/day for reproductive toxicity, when rodents 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

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Comparing the NOAEL value and effects observed on rodents, with the criteria of CLP regulation the given test chemical is not likely to classify as reproductive toxicant.

Additional information