Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) for test material was considered to be 1000 mg/kg/day for reproductive toxicity, when rats 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:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
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
Species:
rat
Strain:
other: 2. Wistar BOR:Wisw (SPFcpb) 3. Sprague-Dawley
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
2. Virgin females were used in the study.
3. TEST ANIMALS
- Age at study initiation: 9 weeks old male and female
- Weight at study initiation: (325.8 - 363.1 g for males and198.5 - 229.3 g for females
Route of administration:
oral: gavage
Vehicle:
other: 2. water 3. not specified
Details on exposure:
No data
Details on mating procedure:
2. No data
3. - M/F ratio per cage:No data available
- Length of cohabitation: 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:The day of positive proof for sperm in the vaginal rinse
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2. day 6 to 15 post coitum
3. Male :36 days
Copulated female:36-45 days
Not copulated female :51 days
Premating exposure:2 weeks
Frequency of treatment:
2. daily
3. daily
Details on study schedule:
No data
Remarks:
2. 0 and 1000 mg/kg bw
3. 0, 150, 350 and 750 mg/kg/day.
No. of animals per sex per dose:
2. Total:50
0 mg/kg bw (control group): 25 female rats
1000 mg/kg bw (test group): 25 female rats
3. Total:120
Male :60
Female:60
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Parental animals: Observations and examinations:
2. CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: No data
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):No data
- Time schedule for examinations: No data

OTHER: Following reproductive parameters were examined:
Corpora lutea
Implantations
Resorptions (complete, early and late)
3. CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: Clinical symptoms were observed once a day but were observed once a week in detail

BODY WEIGHT: Yes
Time schedule for examinations: body weight was observed once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of gestation period, date of delivery, and 4 days of the lactation day;
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes consumption rate of fodder was observed once a week except mating period.
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 / No / No data: No data available
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
2. No data
3. Parameters examined in [all/P/F1/F2] male parental generations:testes, epididymider (all males)
Litter observations:
2. No data
3. STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups, other:]The number of survivors and deaths during delivery,Body weight and Survival rate: measured on the day of delivery and on the day 4 of lactation and Sex ratio: It is determined by anogenital distance, for more than 2 mm and less than 1 mm were male and female, respectively.
Postmortem examinations (parental animals):
2. Animals were sacrificed on day 20 and necropsied.

GROSS NECROPSY: Yes

HISTOPATHOLOGY / ORGAN WEIGHTS: Yes
3. Postmortem examinations (Parent Animal)
SACRIFICE :On day 20 post-coitum, the dams were sacrificed
Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: No data
Maternal animals: yes
All surviving animals [describe when, e.g. after the last litter of each generation was weaned :

GROSS NECROPSY: - Organ weight: testes, epididymider (all males) liver, kidney, adrenals,
thymus, spleen, brain, and heart (5 male and female rats from each test group)
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.:
macroscopic examination was performed : 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals, brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or tibial), bone marrow
Postmortem examinations (offspring):
No data
Statistics:
2. No data
3. Statistical decision tree, but in case of recovery group, either two-side Student’s t-test or two-side Aspin-Welch t-test was used. In case of categorical data, two-sided Fisher’s exact test was used.
Reproductive indices:
No data
Offspring viability indices:
No data
Clinical signs:
no effects observed
Description (incidence and severity):
2. There were no signs of toxicity in dams.
3. effects observed, treatment-related - In male rats, intermittent (blood-like) salivation and 3 cases of staining around mouth were observed on the day 27 for the 150 mg/kg/day treatment group. In the 350 mg/kg/day treatment group, (bloodlike) salivation and staining around mouth were observed after the day 20 of administration; and 7 cases of (blood-like) staining around nose were observed after the day 21 of administration. After the day 3 of administration, intermittent soft stool and staining around anorectal region were observed for the most animals. In the 750 mg/kg/day treatment group, soft stool and staining around anorectal region for most animals; and 5 cases of loss of hair around tail region were observed after the day 3 and 14 of administration, respectively. After the day 7 and 21 of administration, (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose for most animals were observed, respectively. In the control groups, there were no specific clinical symptoms during test period. In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.
In female rats, after the day 15 of administration, intermittent (blood-like) salivation and 6 cases of staining around mouth; and from the day of delivery, difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection were observed for the 150 mg/kg/day treatment group. In the 350 mg/kg/day treatment group, (blood-like) salivation and staining around mouth were observed for all animals after the day 15 of administration; and 4 cases of intermittent (blood-like) staining around nose were observed after the day 28 of administration. In addition, 2 cases of soft stool and staining around anorectal region; and a case of difficult delivery, lacrimation, and irregular respiration were found after the day 4 of administration and from the delivery to death, respectively.
In the 750 mg/kg/day treatment group, (blood-like) salivation and staining around mouth for all animals; soft stool and staining around anorectal region for all animals; and 3 cases of intermittent diarrhea were observed after the day 5, 3 and 38 of administration, respectively. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawling position, hypoactivity, and abdominal swelling. In the control group, no specific clinical signs were observed during test period. In the recovery group, any other symptoms were not observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
2. No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found.
3. no effects observed - Pregnancy and delivery: All pregnant female rats were delivered pups not exceeding three day of the expected date and no significant difference between the treatment groups and the control group. There was no significant difference between the treatment groups and the control group in terms of the number of corpus luteum and implantation. In case of the percent of pre-implantation loss, total 4 cases were discovered at the 150 mg/kg/day and 350 mg/kg/day treatment group, but no significant difference between the treatment groups and the control group. In case of the percent of post-implantation loss, 6 cases were discovered at the 150 mg/kg/day, 350 mg/kg/day, and 750 mg/kg/day treatment group, but no significant difference between the treatment groups and the control group. In conclusion, although pre and post-implantation loss were quite high, these were spontaneous for SD rats.

Copulation index, both 150 mg/kg/day and 350 mg/kg/day treatment groups had 100 %, and 750 mg/kg/day treatment group had 90.9 %. In case of the fertility index, the control and every treatment group had 91.7 % and 100 %, respectively. Finally, gestation index for the control group, 150 mg/kg/day, 350 mg/kg/day and 750 mg/kg/day treatment group had 100 %, 91.7 %, 83.3 % and 90.0 %, respectively. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index. The sex mis-confirmation for new born pups in this test did not have relationship with test substance since its frequency was low and no dose-correlation.
Dose descriptor:
NOAEL
Effect level:
1 000 other: mg/kg bw
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
Remarks on result:
other: No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found.
Remarks:
2
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: No reproductive toxicity was observed
Remarks:
3
Critical effects observed:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
3. no effects observed - At the time of delivery for new born male pups, no significant difference was observed for bodyweights between the control and treatment groups. On the day 4 of lactation, in the 350 mg/kg/day treatment group, bodyweights of pups increased as compared with that of the control group. However, there was no finding for female pups on the day delivery and on the day 4 of lactation in terms of bodyweight.
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. Did not show any such malformations.
3. no effects observed
Histopathological findings:
no effects observed
Description (incidence and severity):
2. Skeletal variations were the same (nature and frequency) in test- and control group.
3. not specified
Other effects:
not specified
Description (incidence and severity):
3. No significant difference was observed between the treatment group and the control group at the time of the delivery and on the day 4 of the lactation. There were reconfirmed of sex ratio at the day 4 of the lactation since total 3 cases of sex were decided again.
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
2. Foetuses were weighed, inspected macroscopically for external malformations and prepared for inspection for visceral and skeletal malformations (by transverse section and double staining respectively). They did not show any such malformations. Skeletal variations were the same (nature and frequency) in test- and control group.
3. not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 other: mg/kg bw
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed on foetuses.
Remarks on result:
other: No developmental toxicity was observed
Remarks:
2
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: overall developmental effects
Remarks on result:
other: No developmental toxic effects was observed
Remarks:
3
Critical effects observed:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Conclusions:
Based on the data available from different studies, the No Observed Adverse Effect Level (NOAEL) for test material was considered to be 1000 mg/kg/day for reproductive toxicity, when rats 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:

 

The present study was conducted to determine the reproductive toxicity potential of test chemical when administered orally to rats. Virgin female rats were used for the study. Two dose groups (25 animals each) were used, one test- (1000 mg/kg bw) and one control group (0 mg/kg bw). They were dosed from day 6-15 post coitum and kept off-dose from day 16-19. There were no signs of toxicity in dams. Animals were sacrificed on day 20 and necropsied. Reproductive parameters were examined [viz. no. of corpora lutea, no. of implantations and resorptions (complete, early and late)]. Foetuses were weighed, inspected macroscopically for external malformations and prepared for inspection for visceral and skeletal malformations (by transverse section and double staining respectively). They did not show any such malformations. Skeletal variations were the same (nature and frequency) in test- and control group. No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found. Therefore, under the condition of this study, the no-observed-adverse-effect level (NOAEL) for dams and foetuses was considered to be 1000 mg/kg bw.

 

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test of the given test chemical was performed on Sprague Dawley rats. 60 male and 60 female animals were used also control animals (concurrent no treatment) were observed. All the animals were 9 weeks old and weighing 325.8 - 363.1 g for males and 198.5 - 229.3 g for females. The test material was given in dose concentration 0, 150, 350 and 750 mg/kg/day by oral gavage route. Male for 36 days, Copulated female for 36-45 days, Not copulated female for 51 days were exposed with test material while premating exposure period was 2 weeks. Each male and female rat was selected from the same test group in order to copulate. It spent 14 days in terms of mating. The day after the copulating, mating would be determined through the observation of sperm in a vaginal rinse. A period of pregnancy was calculated from mating date (day 0). Clinical symptoms were observed once a day but were observed once a week in detail; a death rate was observed twice a day and in case of animals with dying condition, they were allowed euthanasia to necropsy, if it is not possible immediately, they were refrigerated; body weight was observed once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of gestation period, date of delivery, and 4 days of the lactation day; and consumption rate of fodder was observed once a week except mating period. While female rats were necropsied, the number of corpus leteum and implantation were counted; and the former was measured in the ovary and the latter was measured in the uterus. Also testes, epididymider (all males) liver, kidney, adrenals, thymus, spleen, brain, and heart (5 male and female rats from each test group) were observed. 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals, brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes. In F1 generation the number of survivors and deaths during delivery, Body weight and Survival rate measured on the day of delivery and on the day 4 of lactation were observed. The sex ratio is determined by anogenital distance, for more than 2 mm and less than 1 mm were male and female, respectively.  Clinical signs in male rats, intermittent (blood-like) salivation and 3 cases of staining around mouth were observed on the day 27 for the 150 mg/kg/day treatment group. In the 350 mg/kg/day treatment group, (bloodlike) salivation and staining around mouth were observed after the day 20 of administration; and 7 cases of (blood-like) staining around nose were observed after the day 21 of administration. After the day 3 of administration, intermittent soft stool and staining around anorectal region were observed for the most animals. In the 750 mg/kg/day treatment group, soft stool and staining around anorectal region for most animals; and 5 cases of loss of hair around tail region were observed after the day 3 and 14 of administration, respectively. After the day 7 and 21 of administration, (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose for most animals were observed, respectively. In the control groups, there were no specific clinical symptoms during test period. In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period. In female rats, after the day 15 of administration, intermittent (blood-like) salivation and 6 cases of staining around mouth; and from the day of delivery, difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection were observed for the 150 mg/kg/day treatment group. In the 350 mg/kg/day treatment group, (blood-like) salivation and staining around mouth were observed for all animals after the day 15 of administration; and 4 cases of intermittent (blood-like) staining around nose were observed after the day 28 of administration. In addition, 2 cases of soft stool and staining around anorectal region; and a case of difficult delivery, lacrimation, and irregular respiration were found after the day 4 of administration and from the delivery to death, respectively. In the 750 mg/kg/day treatment group, (blood-like) salivation and staining around mouth for all animals; soft stool and staining around anorectal region for all animals; and 3 cases of intermittent diarrhea were observed after the day 5, 3 and 38 of administration, respectively. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawling position, hypoactivity, and abdominal swelling. In the control group, no specific clinical signs were observed during test period. In the recovery group, any other symptoms were not observed. All pregnant female rats were delivered pups not exceeding three day of the expected date and no significant difference between the treatment groups and the control group. There was no significant difference between the treatment groups and the control group in terms of the number ofcorpusluteum and implantation. In case of the percent of pre-implantation loss, total 4 cases were discovered at the 150 mg/kg/day and 350 mg/kg/day treatment group, but no significant difference between the treatment groups and the control group. In case of the percent of post-implantation loss, 6 cases were discovered at the 150 mg/kg/day, 350 mg/kg/day, and 750 mg/kg/day treatment group, but no significant difference between the treatment groups and the control group. In conclusion, although pre and post-implantation loss were quite high, these were spontaneous for SD rats. Copulation index, 150 mg/kg/day and 350 mg/kg/day treatment groups had 100 %, and 750 mg/kg/day treatment group had 90.9 %. In case of the fertility index, the control and every treatment group had 91.7 % and 100 %, respectively. Finally, gestation index for the control group, 150 mg/kg/day, 350 mg/kg/day and 750 mg/kg/day treatment group had 100 %, 91.7 %, 83.3 % and 90.0 %, respectively. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index. The sex mis-confirmation for new born pups in this test did not have relationship with test substance since its frequency was low and no dose-correlation. At the time of delivery for new born male pups, no significant difference was observed for bodyweights between the control and treatment groups. On the day 4 of lactation, in the 350 mg/kg/day treatment group, body weights of pups increased as compared with that of the control group. However, there was no finding for female pups on the day delivery and on the day 4 of lactation in terms of body weight. No significant difference was observed between the treatment group and the control group at the time of the delivery and on the day 4 of the lactation. There were reconfirmed of sex ratio at the day 4 of the lactation since total 3 cases of sex were decided again. There were no abnormalities in the treatment groups but in the control groups, a case of runt and 2 cases of blunt-tipped tail were observed. On the day 4 of lactation, 2 cases of blunt-tipped tail were observed but no abnormalities in the treatment groups. Under the condition of the study, No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 750 mg/kg/day, when male and female Sprague Dawley rats were treated with the given test chemical orally.

 

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

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 study

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

 

The present study was conducted to determine the reproductive toxicity potential of test chemical when administered orally to rats. Virgin female rats were used for the study. Two dose groups (25 animals each) were used, one test- (1000 mg/kg bw) and one control group (0 mg/kg bw). They were dosed from day 6-15 post coitum and kept off-dose from day 16-19. There were no signs of toxicity in dams. Animals were sacrificed on day 20 and necropsied. Reproductive parameters were examined [viz. no. of corpora lutea, no. of implantations and resorptions (complete, early and late)]. Foetuses were weighed, inspected macroscopically for external malformations and prepared for inspection for visceral and skeletal malformations (by transverse section and double staining respectively). They did not show any such malformations. Skeletal variations were the same (nature and frequency) in test- and control group. No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found. Therefore, under the condition of this study, the no-observed-adverse-effect level (NOAEL) for dams and foetuses was considered to be 1000 mg/kg bw.

 

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test of the given test chemical was performed on Sprague Dawley rats. 60 male and 60 female animals were used also control animals (concurrent no treatment) were observed. All the animals were 9 weeks old and weighing 325.8 - 363.1 g for males and 198.5 - 229.3 g for females. The test material was given in dose concentration 0, 150, 350 and 750 mg/kg/day by oral gavage route. Male for 36 days, Copulated female for 36-45 days, Not copulated female for 51 days were exposed with test material while premating exposure period was 2 weeks. Each male and female rat was selected from the same test group in order to copulate. It spent 14 days in terms of mating. The day after the copulating, mating would be determined through the observation of sperm in a vaginal rinse. A period of pregnancy was calculated from mating date (day 0). Clinical symptoms were observed once a day but were observed once a week in detail; a death rate was observed twice a day and in case of animals with dying condition, they were allowed euthanasia to necropsy, if it is not possible immediately, they were refrigerated; body weight was observed once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of gestation period, date of delivery, and 4 days of the lactation day; and consumption rate of fodder was observed once a week except mating period. While female rats were necropsied, the number of corpus leteum and implantation were counted; and the former was measured in the ovary and the latter was measured in the uterus. Also testes, epididymider (all males) liver, kidney, adrenals, thymus, spleen, brain, and heart (5 male and female rats from each test group) were observed. 22 kinds of tissues were fixed to do histopathologic tests such as testes, epididymides, ovaries, accessory sex organs for all animals, brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes. In F1 generation the number of survivors and deaths during delivery, Body weight and Survival rate measured on the day of delivery and on the day 4 of lactation were observed. The sex ratio is determined by anogenital distance, for more than 2 mm and less than 1 mm were male and female, respectively.  Clinical signs in male rats, intermittent (blood-like) salivation and 3 cases of staining around mouth were observed on the day 27 for the 150 mg/kg/day treatment group. In the 350 mg/kg/day treatment group, (bloodlike) salivation and staining around mouth were observed after the day 20 of administration; and 7 cases of (blood-like) staining around nose were observed after the day 21 of administration. After the day 3 of administration, intermittent soft stool and staining around anorectal region were observed for the most animals. In the 750 mg/kg/day treatment group, soft stool and staining around anorectal region for most animals; and 5 cases of loss of hair around tail region were observed after the day 3 and 14 of administration, respectively. After the day 7 and 21 of administration, (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose for most animals were observed, respectively. In the control groups, there were no specific clinical symptoms during test period. In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period. In female rats, after the day 15 of administration, intermittent (blood-like) salivation and 6 cases of staining around mouth; and from the day of delivery, difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection were observed for the 150 mg/kg/day treatment group. In the 350 mg/kg/day treatment group, (blood-like) salivation and staining around mouth were observed for all animals after the day 15 of administration; and 4 cases of intermittent (blood-like) staining around nose were observed after the day 28 of administration. In addition, 2 cases of soft stool and staining around anorectal region; and a case of difficult delivery, lacrimation, and irregular respiration were found after the day 4 of administration and from the delivery to death, respectively. In the 750 mg/kg/day treatment group, (blood-like) salivation and staining around mouth for all animals; soft stool and staining around anorectal region for all animals; and 3 cases of intermittent diarrhea were observed after the day 5, 3 and 38 of administration, respectively. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawling position, hypoactivity, and abdominal swelling. In the control group, no specific clinical signs were observed during test period. In the recovery group, any other symptoms were not observed. All pregnant female rats were delivered pups not exceeding three day of the expected date and no significant difference between the treatment groups and the control group. There was no significant difference between the treatment groups and the control group in terms of the number ofcorpusluteum and implantation. In case of the percent of pre-implantation loss, total 4 cases were discovered at the 150 mg/kg/day and 350 mg/kg/day treatment group, but no significant difference between the treatment groups and the control group. In case of the percent of post-implantation loss, 6 cases were discovered at the 150 mg/kg/day, 350 mg/kg/day, and 750 mg/kg/day treatment group, but no significant difference between the treatment groups and the control group. In conclusion, although pre and post-implantation loss were quite high, these were spontaneous for SD rats. Copulation index, 150 mg/kg/day and 350 mg/kg/day treatment groups had 100 %, and 750 mg/kg/day treatment group had 90.9 %. In case of the fertility index, the control and every treatment group had 91.7 % and 100 %, respectively. Finally, gestation index for the control group, 150 mg/kg/day, 350 mg/kg/day and 750 mg/kg/day treatment group had 100 %, 91.7 %, 83.3 % and 90.0 %, respectively. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index. The sex mis-confirmation for new born pups in this test did not have relationship with test substance since its frequency was low and no dose-correlation. At the time of delivery for new born male pups, no significant difference was observed for bodyweights between the control and treatment groups. On the day 4 of lactation, in the 350 mg/kg/day treatment group, body weights of pups increased as compared with that of the control group. However, there was no finding for female pups on the day delivery and on the day 4 of lactation in terms of body weight. No significant difference was observed between the treatment group and the control group at the time of the delivery and on the day 4 of the lactation. There were reconfirmed of sex ratio at the day 4 of the lactation since total 3 cases of sex were decided again. There were no abnormalities in the treatment groups but in the control groups, a case of runt and 2 cases of blunt-tipped tail were observed. On the day 4 of lactation, 2 cases of blunt-tipped tail were observed but no abnormalities in the treatment groups. Under the condition of the study, No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 750 mg/kg/day, when male and female Sprague Dawley rats were treated with the given test chemical orally.

 

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

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

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