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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 the test chemical was considered to be 1000mg/kg bw/day .When male and female rats were treated with the test chemical orally. Thus, comparing this value with the criteria of CLP regulation, the test chemical 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:
subacute
Species:
rat
Quality of whole database:
Data is Klimicsh 1 and data from study report.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study:

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

Reproductive Toxicity Study 1:

In 28 days repeated dose toxicity study, the effect of test material was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 250, 500 and 1000 mg/kg/ body weight/day. The results showed no effect on mortality, no changes were in food consumption and ophthalmology. Changes were observed in clinical signs like soft stool, nasal discharge, red crust around nostrils, perineum soiled with fecal matter. Significant decreased were observed in water consumption and locomotor activity of female rat in1000 mg/kg dose group. Body weight was increased significantly in male and female rats. Significant changes were observed in the level of testosterone, sodium, total proteins, total cholesterol, SGOT, SGPT, albumin, Blood urea nitrogen (BUN) and Creatinine when treated with 500 and 1000 mg/kg/day. Significant changes were observed in absolute and relative weight of brain, adrenals, spleen, thymus, epididymides, heart, kidneys, ovaries, uterus and liver in 500 and 1000 mg/kg/day. In addition, minimal to mild gross pathological and histopathological changes were observed in liver, spleen and intestine. However, the biological significance of these findings are not related to test chemical. Therefore, NOAEL was considered to be 1000 mg/kg/day when Sprague-Dawley rat exposed to test substance orally.

Reproductive Toxicity Study 2:

Combined Repeat Dose and Reproductive / Developmental Toxicity Screening Test of test material were performed onmale and female Sprague Dawley rats. The test material was suspended in corn oil in dose concentration0 ,100, 300 and 1,000 mg/kg bw/day and administered via oral gavage route in dose volume 5ml/kg bw. Dose selected on the bases of preliminary test by the previously repeated 14-day oral administration. 13 male and 13 female each were placed in each group. Administration period for each males, 2 weeks before mating, and 42 days from the end of the mating period to the day before the necropsy for males, and for female 2 weeks before mating and a maximum of 2 weeks mating period (Until mating) and once daily for the entire gestation period and 3 days after nursing (delivery day = nursing 0 day) in mating females. Matings were made with the same sex of the same group living together within the same group for up to two weeks from the evening on 15th day of administration. Mating was confirmed every morning by examining the presence of sperm in the vaginal plug and vaginal smear and females confirmed to be mated were separated from male starting from that day as the 0th day of pregnancy and raised individually. All the animals were observed for Clinical signs, body weight and food consumption. No deaths in male and female were observed. In males, no abnormalities in general conditions were observed. In females, there was only one change from day 42 of administration (day of delivery) to the one in 100 mg / kg administration group (administration 42 days: piloerection, blood-like fluid discharge from the vaginal opening; administration 43 to 44 days: coat contamination) But it recovered on day 45 of administration. In other females, no abnormalities in the general condition were observed. In male, the body weight gain increased from 8 to 15 days in the 100 mg / kg administration group significantly (p <0.01) compared with the control group, However, in the group administered with 300 mg / kg or more, there was no significant difference between the control group and treated group. In females, there was no significant difference in body weight and body weight gain between control group and treated group before breeding, pregnancy period and nursing period. There was no significant difference between the control group and treated group for males and female at any time of feeding intake. There was no significant difference between the control group and treated group in the mating rate, conception rate, the number of days taken from the start of cohabitation to mating and the number of estrus periods recurred during that period. An abnormality in labor condition (not treated with placenta) and abnormality in nursing condition (not collecting children, poor protrusion of nipple, poor protrusion of infant, child's fetus) was administered to one of 100 mg / kg administration group, The decrease in body surface temperature) was observed, and all children died on nursing day 2, but no abnormality was observed in other mother animals. For male In the 100 mg / kg administration group, the actual weight and the specific body weight value of the liver increased significantly (p <0.05) compared to the control group, but not the dose-dependent change. Atrophy of seminiferous tubules was found in 2 animals in the 1000 mg / kg administration group, one on both sides and one on one side, but both were localized and extremely mildly changed. There were no other abnormalities. Sperm granuloma was observed in one of the control group, and there was no abnormality. There were no abnormalities in the ovaries of the unexpanded and infertile cases. For female In the 100 mg / kg administration group, the actual weight of the kidney decreased significantly (p <0.05) compared to the control group, but not the dose-dependent change. For other organs in male and female, no significant difference was observed between the control group and treated group. Birth rate was 100% in all administration groups, and no significant difference was observed between gestation period between control group and treated group. No significant difference was observed between the control group and treated group for the number of luteinism, the number of implantation and the implantation rate of pregnant animals.There was no significant difference between the control group and treated group for the number of births, delivery rate, birth rate, fertility rate, and survival rate on 4th day of newborn. In addition, no significant difference was observed between the control group and treated group for sex ratio.There was no significant difference between the control group and thetreated grouponbody weight at 0 and 4 days of nursing. Births that showed morphological abnormalities were not observed in the external table observation on thebirthday, necropsy of the dead child, and necropsy on the 4th day of nursing. Hence, No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000mg/kg bw .When male and female Sprague Dawley rats were treated with test material orally.

 

Reproductive Toxicity Study 3:

The reproductive and developmental toxicity study of test material was performed on male and female Sprague Dawley rats according to OECD TG 421. The test material dissolved in corn oil in dose concentration 0, 250, 500 and 1,000 mg/kg bw/day via oral gavage route. The male rats treated with test material from two weeks prior to mating, during the mating period and, approximately, two weeks post mating (at least 28 days), and to female rats from two weeks prior to mating, during the mating period, gestation period and 3 days after lactation. Ten males and ten females were used in each group. All the animals were observed for clinical signs, mortality and body weight. There were no treatment-related effects on clinical examination, on body weights, necropsy findings or organ weights. There were no treatment-related changes in mating, fertility and pregnant indices, or in the number of corpora luteaand implantations, pre-implantation loss, post-implantation loss, litter size at birth, neonatal death, sex ratio of pups, viability ratio, body weights of pups on day 0 and day 4 of lactation or gross findings at the doses tested. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000mg/kg bw .When male and femaleSprague Dawley rats were treated with test material orally. Based on the data available from different studies, the test chemical did not show reproductive toxicity at dose concentration 1000mg/kg bw/day by oral route.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

Effects on developmental toxicity

Description of key information

Developmental toxicity study

The data available for the test chemical was reviewed to determine the developmental toxicity. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 1000 mg/kg bw /day. When male and female rats were treated with the test chemical orally. Thus, comparing this value with the criteria of CLP regulation, the test chemical is not likely to classify as reproductive and developmental toxicant.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimicsh 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 were reviewed to determine the developmental toxicity of the test chemical.The studies are as mentioned below:

Developmental Toxicity Study 1:

The reproductive and developmental toxicity study of the test chemical was performed on male and female Sprague Dawley rats according to OECD TG 421. The test material dissolved in corn oil in dose concentration 0, 250, 500 and 1,000 mg/kg bw/day via oral gavage route. The male rats treated with test material from two weeks prior to mating, during the mating period and, approximately, two weeks post mating (at least 28 days), and to female rats from two weeks prior to mating, during the mating period, gestation period and 3 days after lactation.Ten males and ten females were used in each group. All the animals were observed for clinical signs, mortality and body weight. There were no treatment-related effects on clinical examination, on body weights, necropsy findings or organ weights. There were no treatment-related changes in mating, fertility and pregnant indices, or in the number of corpora lutea and implantations, pre-implantation loss, post-implantation loss, litter size at birth, neonatal death, sex ratio of pups, viability ratio, body weights of pups on day 0 and day 4 of lactation or gross findings at the doses tested. Hence, No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000mg/kg bw .When male and femaleSprague Dawley rats were treated with the tet chemical orally.

Developmental Toxicity Study 2:

Combined Repeated Dose and Reproductive / Developmental Toxicity Screening Test of test material were performed on male and female Sprague Dawley rats. The test material was suspended in corn oil in dose concentration 0 ,100, 300 and 1,000 mg/kg bw/day and administered via oral gavage route in dose volume 5ml/kg bw. Dose selected on the bases of preliminary test by the previously repeated 14-day oral administration. 13 male and 13 female each were placed in each group. Administration period For each males, 2 weeks before mating, and 42 days from the end of the mating period to the day before the necropsy for males, and for female 2 weeks before mating and a maximum of 2 weeks mating period (Until mating) and once daily for the entire gestation period and 3 days after nursing (delivery day = nursing 0 day) in mating females. Matings were made with the same sex of the same group living together within the same group for up to two weeks from the evening on 15th day of administration. Mating was confirmed every morning by examining the presence of sperm in the vaginal plug and vaginal smear and females confirmed to be mated were separated from male starting from that day as the 0th day of pregnancy and raised individually. All the animals were observed for Clinical signs, body weight and food consumption. No deaths in male and female were observed. In males, no abnormalities in general conditions were observed. In females, there was only one change from day 42 of administration (day of delivery) to the one in 100 mg / kg administration group (administration 42 days: piloerection, blood-like fluid discharge from the vaginal opening; administration 43 to 44 days: coat contamination) But it recovered on day 45 of administration. In other females, no abnormalities in the general condition were observed. In male, the body weight gain increased from 8 to 15 days in the 100 mg / kg administration group significantly (p <0.01) compared with the control group, However, in the group administered with 300 mg / kg or more, there was no significant difference between the control group and treated group. In females, there was no significant difference in body weight and body weight gain between control group and treated group before breeding, pregnancy period and nursing period. There was no significant difference between the control group and treated group for males and female at any time of feeding intake. There was no significant difference between the control group and treated group in the mating rate, conception rate, the number of days taken from the start of cohabitation to mating and the number of estrus periods recurred during that period. An abnormality in labor condition (not treated with placenta) and abnormality in nursing condition (not collecting children, poor protrusion of nipple, poor protrusion of infant, child's fetus) was administered to one of 100 mg / kg administration group, The decrease in body surface temperature) was observed, and all children died on nursing day 2, but no abnormality was observed in other mother animals. For male In the 100 mg / kg administration group, the actual weight and the specific body weight value of the liver increased significantly (p <0.05) compared to the control group, but not the dose-dependent change. Atrophy of seminiferous tubules was found in 2 animals in the 1000 mg / kg administration group, one on both sides and one on one side, but both were localized and extremely mildly changed. There were no other abnormalities. Sperm granuloma was observed in one of the control group, and there was no abnormality. There were no abnormalities in the ovaries of the unexpanded and infertile cases. For female In the 100 mg / kg administration group, the actual weight of the kidney decreased significantly (p <0.05) compared to the control group, but not the dose-dependent change. For other organs in male and female, no significant difference was observed between the control group and treated group. Birth rate was 100% in all administration groups, and no significant difference was observed between gestation period between control group and treated group. No significant difference was observed between the control group and treated group for the number of luteinism, the number of implantation and the implantation rate of pregnant animals. There was no significant difference between the control group and treated group for the number of births, delivery rate, birth rate, fertility rate, and survival rate on 4th day of newborn. In addition, no significant difference was observed between the control group and treated group for sex ratio. There was no significant difference between the control group and the treated group on body weight at 0 and 4 days of nursing. Births that showed morphological abnormalities were not observed in the external table observation on the birth day, necropsy of the dead child, and necropsy on the 4th day of nursing. Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000mg/kg bw .When male and female Sprague Dawley rats were treated with test material orally. Based on the data available from different studies, the test chemical did not showed developmental toxicity at dose concentration1000 mg/kg bw/day. Hence the test chemical is not likely to classify as a reproductive and developmental toxicant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

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