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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 test material was considered to be 1000 mg/kg Bwt/day .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.

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 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 1.

The reproductive and developmental toxicity study of test material was performed in femaleCOBS CD rats. The test material was dissolved in corn oil and administered in dose concentration 0,200,1000mg/kg bw by oral gavage route from days 6-15 of gestation. 25 females /dose group were used in study. All the animals were observed forClinical signs, body weight and food consumoption.The dams were sacrificed and sectioned on gestation day 20. Intrauterine survival, foetal weight and external, skeletal and visceral anomalies were recorded. In dams clinical signs of intoxication were observed also reduced body weight was observed at 1000mg/kg bw dose group. Effects on the foetus were confined to an increase in numbers of litters with the skeletal variant 'malaligned sternebrae' which occurred at 200 mg/kg/day only and a slight decrease in foetal weight at 1000 mg/kg/day which was within the historical control range. As an increased incidence of 'malaligned sternebrae' was not observed at 1000 mg/kg/day the observation at 200 mg/kg/day was considered incidental. Hencethe no observed adverse effect level (NOAEL) was considered to be 1000mg/kg bw/day for reproductive and developmental toxicity .When female rats were treated with test material by orally during gestation days 6-15.

Study 3.

Combined Repeat 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 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 ofpreliminary 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 forClinical 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. HenceNo 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.

 Study 4

The reproductive and developmental toxicity study of test material was performed on female wistar rats.The chemicals were freshly prepared for gavage administration every day in aqueous emulsions under rapid stirring in doubly-distilled water containing approximately 0.005% Cremophor EL". The test material in dose concentration0,130,650,975,1300mg/kg day was adminstered fromday 6 to day 15 post-coitum (pc). Two control groups, treated with either doubly-distilled water alone (1) or water plus approximately 0.005% Cremophor EL as emulsifier (2), were employed.one to four untreated females were mated with one untreated fertile male of the same breed. Mating took place overnight. If sperm was detected microscopically in the vaginal smears in the morning, the animals were considered to be fertilized. This day was designated as 'day 0' (beginning of the study) and the following day 'day 1' post-coitum (pc).Food consumption, body weights and clinical signs were recorded daily throughout the study. On day 20 pc all surviving females were killed and subjected to gross pathology.The foetuses were dissected from the uterus, weighed and further investigated for external, visceral and skeletal findings. Approximately one-half of the foetuses of all groups was fixed in Bouin's solution and examined according to the method of Barrow and Taylor (1969). For skeletal findings approximately one-half of the foetuses was fixed in ethyl alcohol and stained according to a modified method of Dawson (1926).

A dose-related increase in maternal toxicity with increasing severeness of clinical signs (lateral and abdominal position, unsteady gait, salivation, piloerection, nasal discharge and pneumonia) was observed. A slight decrease in food consumption and body weight gain was observed at650,975,1300mg/kg day dose group. Uterine and placental weights, foetal weights and data were not influenced by administration of this material. No dead foetuses were observed. There was no indication of developmental toxicity. All foetal values were within the range of biological variation; any differences in malformations and retardations were statistically insignificant or without a dose-response relationship and mostly occurred in animals of the treated and untreated groups as well as the historical control group at comparable frequency. A single cheiloschisis and one anophthalmy in the 1300mg/kg bw dose group was considered coincidental and not biologically significant. Hencethe no observed adverse effect level (NOALE) was considered to be 1300mg/kg bw/day for  reproductive and developmental toxicity .When female rats were treated with test material orally during gestation day 6-15.

 

Based on the data available from different studies test chemical did not showedreproductive toxicityat dose concentration 1000mg/kg bw/day .When male and female rats were treated with test material orally.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

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 material is not likely to classify as reproductive toxicant.