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Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive Toxicity Study:

In a 28 days repeated dose toxicity study, the effect of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that the test chemical significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 125 mg/kg bw for male rats and LOAEL was considered to be 250 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.

From the NOAEL and LOAEL values obtained from the above experimental data for the test chemical for toxicity to reproduction as well as developmental toxicity, it is considered that the chemical is not likely to be classified as reproductive/developmental toxicant according to CLP regulations.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K1 level.The data has been obtained from the 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:

In different studies, the test chemical has been investigated for reproductive toxicity to a greater or lesser extent. Following studies represent the data on the reproductive toxicity data:

Reproductive Toxicity Study 1:

In a 28 days repeated dose toxicity study, the effect of the test chemical was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that the test chemical significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 125 mg/kg bw for male rats and LOAEL was considered to be 250 mg/kg body weight/day for female when Sprague Dawley male and female rats were exposed daily to the test chemical by oral route for 28 days.

Reproductive Toxicity Study 2:

The above study was performed to evaluate and assess the reproductive and the developmental toxicity of the test chemical by dosing the Sprague-Dawley rats. In this study, the test chemical was dissolved in the vehicle (corn-oil) and the doses used in this study were 0, 50, 150, and 450 mg/kg bw/day as the control group, Low dose group, Mid Dose group and High dose group respectively. The animals were obtained fromCharles River Laboratories, 1 NC, Raleigh, NC annd were quarantined for 7 days before the study. The males were also obtained from a different dose and were used for mating. The males and female animals were co-housed together for mating kept together overnight. The next morning the female rats were checked foror the presence of sperm by vaginal smear. The day of sperm detection was designated as gestational day (GD 0). The animals were then dosed with the test chemicals from Gestational Day 6 through Gestational Day 15. The animals were then observed the different parameters. Test chemical treated animals exhibited clinical signs of toxicity which were observed in all treatment groups on the first day of dosing. Lethargy, slow breathing, and prone body posture were the most comon clinical signs during the first five days of dosing, with the incidence of these effects showing a marked dose-dependence. Two dams died during dosing and both were in the 50 mg/kg/day group. Necropsy data indicated that the deaths were unrelated to dosing errors. Further, the test chemical also caused a significant dose-dependent decrease in maternal body weight and body weight gain; the effect was confined to the 150 mg/kg and 450 mg/kg groups. The test chemical also reduced maternal food and water consumption in the two highest dose groups. On GD 6 to 9, relative food intake was suppressed 25% by 150 mg/kg of the test chemical and 37% by the higher dose. However, by GD 9 to 12, food consumption in the two groups had returned to control levels. A significant elevation in food consumption was noted on gd 18 to 20 in the 450 mg/kg/day group. Relative water intake in both groups displayed a pattern similar to food consumption. From GD 6 to 9, a 19% decrease was observed in the 150 mg/kg/day group (significant) and a 13% reduction i n the 450 mg/kg/day group ( non significant ); water consumption in both groups showed significant elevations of 15%-25% on GD 9 to 12 through GD 15 t o 18, before returning  to control levels by GD 18 to 20. Absolute food and water consumption were similarly affected. Maternal liver weights (absolute or relative) were comparable across groups. There was a trend toward decreased gravid uterine weight with increasing dose of the test chemical. Gravid uterine weights of the 50, 150, and 450 mg/kg/day groups were 105%, 95%, and 89% of control values respectively, but there is no significant difference among groups by ANOVA. In reproductive parameters, the incidence of conceptuses was adversely affected ( i.e. nonlive or malformed) was 8%, 7%, 13% and 20% in the control through high-dose groups, respectively. In fetal parameters, the incidence of conceptuses adversely affected ( i e nonlive or malformed) was 8%, 7%, 13% and 20% in the control through high-dose groups, respectively. Thus, the an upward trend was observed in mortality/non-viability of the pups. Average fetal body weight per litter also exhibited a significant trend test. Fetal body weights in the 50, 150, and 450 mg/kg/day groups were 105%, 99% and 95%) of control values respectively. Thus, a reduction trend was observed in the weights of the fetuses. A treatment related change, on the incidence of enlarged ventricles of the brain was observed in fetuses. A separate statistical analysis of this malformation indicated that there was a significant dose-dependent increase in the percent fetuses per litter and the percent litters with enlarged ventricles (significant trend test for both). Thus, based on all the above observations and results, it was concluded that NOAEL for the test chemical for reproductive toxicity was found to be 50 mg/kg bw/day while the LOAEL for the test chemical based on the fetus observation was found out to be <= 50 mg/kg bw/day.

Reproductive Toxicity Study 3:

The study was designed to investigate the reproductive toxic effects of the test chemicalin male/female rats in an overall estimation period of one generation.Thetest chemicalwas given to rats in the doses of0, 100, 500 and 2500 ppm. In the one-generation study, significant decrease in the mean body weights were reported at 2500 ppm on weeks 2-6 and 8 and food intake on weeks 2 and 8 in males. In females, the body weights were significantly lower on few occasions during gestation and lactation period. There were no treatment-related changes in oestrous cyclicity, pre-coital time, gestation length, pups survivability, mating, fertility, fecundity or sperm parameters.There were no treatment-related changes in organ weights, gross or microscopic findings of parents. No treatment-related changes were observed in pups.Hence, NOAEL for reproductive toxicity study was considered to be 153.8 mg/kg bw/day for male rat and 393.6 mg/kg bw/day for female rats respectively, it is regarded that there is no reproductive toxicity at concentration 153.8 mg/kg bw/day and 393.6 mg/kg bw/day or lower.

Reproductive Toxicity Study 4:

The study was designed to investigate the maternal reproductive effects of the test chemical acid in rats by oral route.The test chemical was given orally to rats in the doses of 0, 10, 60, 300 mg/kg bw/day.Slight maternal toxicity was evident in the high-dose group of 300 mg/kg as indicated by the significant reduction in body weight change and food consumption.Thus the maternal NOAEL is therefore considered to be 60 mg/kg bw/day, it is regarded that there is no reprotoxic effects at concentration 60 mg/kg bw/day or lower.

Reproductive Toxicity Study 5:

The study was designed to investigate the maternal reproductive effects of the test chemical in rabbit by the oral (gavage) route.The test chemical was given orally to rabbits in the doses of 0, 3, 10, 50 mg/kg/day. Slight maternal toxicity was evident in female administered 50 mg/kg bw/day by gavage as indicated by significant reduction in body weight gain during the treatment period –from Day 6 to day 30.Hence the maternal NOAEL is therefore considered to be 10 mg/kg bw/day, it is regarded that there is no reprotoxic effects at concentration at 60 mg/kg bw/day or lower.

From the NOAEL and LOAEL values obtained from the above experimental data for the test chemical for toxicity to reproduction as well as developmental toxicity, it is considered that the chemical is not likely to be classified as reproductive/developmental toxicant according to CLP regulations.

Effects on developmental toxicity

Description of key information

The LOAEL for the test chemical based on developmental toxicity was found out to be <= 50 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The data is from Klimisch 2 level and is obtained from National Toxicology Program Report
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:

In different studies, the test chemical has been investigated for reproductive toxicity to a greater or lesser extent. Following studies represent the data on the developmental toxicity data:

Developmental Toxicity Study 1:

The above study was performed to evaluate and assess the reproductive and the developmental toxicity of the test chemical by dosing the Sprague-Dawley rats. In this study, the test chemical was dissolved in the vehicle (corn-oil) and the doses used in this study were 0, 50, 150, and 450 mg/kg bw/day as the control group, Low dose group, Mid Dose group and High dose group respectively. The animals were obtained fromCharles River Laboratories, 1 NC, Raleigh, NC annd were quarantined for 7 days before the study. The males were also obtained from a different dose and were used for mating. The males and female animals were co-housed together for mating kept together overnight. The next morning the female rats were checked foror the presence of sperm by vaginal smear. The day of sperm detection was designated as gestational day (GD 0). The animals were then dosed with the test chemicals from Gestational Day 6 through Gestational Day 15. The animals were then observed the different parameters. Test chemical treated animals exhibited clinical signs of toxicity which were observed in all treatment groups on the first day of dosing. Lethargy, slow breathing, and prone body posture were the most comon clinical signs during the first five days of dosing, with the incidence of these effects showing a marked dose-dependence. Two dams died during dosing and both were in the 50 mg/kg/day group. Necropsy data indicated that the deaths were unrelated to dosing errors. Further, the test chemical also caused a significant dose-dependent decrease in maternal body weight and body weight gain; the effect was confined to the 150 mg/kg and 450 mg/kg groups. The test chemical also reduced maternal food and water consumption in the two highest dose groups. On GD 6 to 9, relative food intake was suppressed 25% by 150 mg/kg of the test chemical and 37% by the higher dose. However, by GD 9 to 12, food consumption in the two groups had returned to control levels. A significant elevation in food consumption was noted on gd 18 to 20 in the 450 mg/kg/day group. Relative water intake in both groups displayed a pattern similar to food consumption. From GD 6 to 9, a 19% decrease was observed in the 150 mg/kg/day group (significant) and a 13% reduction i n the 450 mg/kg/day group ( non significant ); water consumption in both groups showed significant elevations of 15%-25% on GD 9 to 12 through GD 15 t o 18, before returning  to control levels by GD 18 to 20. Absolute food and water consumption were similarly affected. Maternal liver weights (absolute or relative) were comparable across groups. There was a trend toward decreased gravid uterine weight with increasing dose of the test chemical. Gravid uterine weights of the 50, 150, and 450 mg/kg/day groups were 105%, 95%, and 89% of control values respectively, but there is no significant difference among groups by ANOVA. In reproductive parameters, the incidence of conceptuses was adversely affected ( i.e. nonlive or malformed) was 8%, 7%, 13% and 20% in the control through high-dose groups, respectively. In fetal parameters, the incidence of conceptuses adversely affected ( i e nonlive or malformed) was 8%, 7%, 13% and 20% in the control through high-dose groups, respectively. Thus, the an upward trend was observed in mortality/non-viability of the pups. Average fetal body weight per litter also exhibited a significant trend test. Fetal body weights in the 50, 150, and 450 mg/kg/day groups were 105%, 99% and 95%) of control values respectively. Thus, a reduction trend was observed in the weights of the fetuses. A treatment related change, on the incidence of enlarged ventricles of the brain was observed in fetuses. Analysis of anatomical defects indicated that the test chemical treatment tended to increase the incidence of malformations. Both the percent fetuses malormed per litter (4%, 4%, 7% and 10%) and the percent litters with malformed fetuses (23%. 274, 33% and 50%) showed a significant trend test. The largest difference was seen in the 450 mg/kg/day group where the percent fetuses malformed per litter were 2.5 times greater than controls (ie., 10% vs. 4%).A separate statistical analysis of this malformation indicated that there was a significant dose-dependent increase in the percent fetuses per litter and the percent litters with enlarged ventricles (significant trend test for both). Thus, based on all the above observations and results, it was concluded that NOAEL for the test chemical for reproductive toxicity was found to be 50 mg/kg bw/day while the LOAEL for the test chemical based on the fetus observation was found out to be <= 50 mg/kg bw/day.

Developmental Toxicity Study 2:

The study was designed to investigate the teratogenic effects of the test chemical in rabbits by the oral (gavage) route.The test chemical was given orally to rabbits in the doses of 0, 3, 10, 50 mg/kg/day. The slight maternal toxicity was evident in female administered 50 mg/kgbw/day by gavage as indicated by significant reduction in body weight gain during the treatment period –from Day 6 to day 30. No test-related effects were observed in fetuses at any dose tested.Thus,the NOAEL (no observed adverse effect level) for teratogenicity study was considered to be 50 mg/kg and NOAEL (no observed adverse effect level) for maternal toxicity study was considered to be 10 mg/kg bw/day.

Developmental Toxicity Study 3:

The study was designed to investigate the teratogenic effects of the test chemical in rats by the oral route.The test chemical was given orally to rats in the doses0, 10, 60, 300mg/kg bw/day.Slight maternal toxicity was evident in the high-dose group of 300 mg/kg as indicated by the significant reduction in body weight change and food consumption. The increased number of small foetuses in the high dose group suggests slight foetotoxicity.Thus,the NOAEL (no observed adverse effect level) for both maternal and teratogenicity study was considered to be 60 mg/kg bw/day.

From the NOAEL and LOAEL values obtained from the above experimental data for the test chemical for toxicity to reproduction as well as developmental toxicity, it is considered that the chemical is not likely to be classified as reproductive/developmental toxicant according to CLP regulations.

Justification for classification or non-classification

From the NOAEL and LOAEL values obtained from the above experimental data for the test chemical for toxicity to reproduction as well as developmental toxicity, it is considered that the chemical is not likely to be classified as reproductive/developmental toxicant according to CLP regulations.

Additional information