Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study:

The reproductive toxicity study ,No Observed Effect Level (NOEL) was considered to be 80 mg/kg/day, and LOAEL dose-level of 200 mg/kg/day was considered to be for reproductive and developmental toxicity. When female Sprague Dawley rats were treated with the test chemical orally.  Based on available experimental data for thetest chemical in different rodent species i.e mice, rats and rabbits , NOAEL was considered to be in rang of 30-120 mg/kg bw while LOAEL 90-1600 mg/kg bw ,Suggested that coexistence of adverse maternal effects and modifications in numbers of ribs and PSV .Hence From above available data it can be concluded that the test chemical has some reproductive toxicity and considerable developmental toxicity and thus should be classified in Category 2 for reproductive toxicity.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
80 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from an experimental study from the reliable journal.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In different studies, it has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments i.e. most commonly in rats for the test chemical the results are summarized as follows:

Reproductive Toxicity Study 1:

The experimental study conducted for assessment and evaluation of Reproductive and developmental toxicity study of the test chemical was performed on female Sprague Dawley rats. 86 rats were divided into 2 treatment group. 25 female rats in treatment group 1 while 16 in treatment group 2 .Test material mixed with 0.5% aqueous methyl cellulose as the vehicle and was administered in dose concentration 0, 20, 80 or 200 mg/kg bw day from days 15 through 21 of gestation by oral gavage route twice daily. One-half of the dose was given to the animals in the morning and the second half 6-8 h later. Dosing volume was maintained at 10 ml/kg per dosing. For mating purposes, one female and one male (from breeding stock) were housed together. The occurrence of copulation was determined by daily inspection for a copulatory plug. The day at which evidence of mating was detected was designated gestation day 0, after which the females was placed in an individual cage. The animals were observed twice daily throughout the study for mortality and signs of overt toxicity. Individual body weights were recorded on gestation days 0, 6, 15, 16, 17, 18, 19, 20 and 21. Beginning on day 21, Pups were examined for external abnormalities as soon as possible following delivery. The number of viable and nonviable pups was recorded for each female. All 11 pups were sexed and weighed individually on lactation day 0. All surviving F0 females and F1 pups were euthanized by carbon dioxide inhalation at lactation day 1. On gestation day 25, those females which failed to deliver were euthanized. The uterus and ovaries of all dams were exposed by an abdominal incision and grossly examined to determine the number of implantation sites present. No observations of adverse effects until the onset of parturition. As well, there were no apparent compound-related effects on gestational body weight gain in any of the treatment groups. One death occurred in the vehicle-treated group on gestation day 20. However, post-mortem examination revealed no abnormalities or signs of overt clinical toxicity. Both onset of labour and its duration were disrupted in the animals receiving the highest dose. Increased fetotoxicity and periparturition death also appeared to occur among foetuses from females treated with 200 mg/kg/day of the test chemical but this was not statistically significant of the test chemical (200 mg/kg) ,Labour times in these groups ranged from 1-14 h with a mean duration of 3.6 h for the SA-treated For comparison, labor times in control animals ranged from less than 1 h to 3 h with a mean labour time of 1.5 h. There were no observed differences in mean litter size, pup size, or sex ratio, associated with the test chemical. Since those pups which did survive delivery had no visible abnormalities or other signs of overt toxicity. Maternal perinatal death was significantly increased in animals treated with both 200 mg/kg/ day of the test chemical. Four animals in each of these treatment groups died or were euthanized because of extreme distress during parturition. Clinical signs of maternal physical distress during parturition included labored breathing, decreased activity, and blood staining in the abdominal, nasal, and oral areas. Notably, each of these seven animals failed to deliver some or all of their pups. Increased maternal mortality was also evidenced as a significant decrease in the gestational index (defined as the percentage of pregnant females producing live pups) for these same treatment groups. No evidence of increased maternal distress or peripatum mortality was noted in animals from either the mid-dose (80 mg/kg/day) or low-dose (20 mg/kg/day) of the test chemical. Hence No Observed Adverse Effect Level (NOAEL) was considered to be 80 mg/kg/day, and LOAEL dose-level of 200 mg/kg/day was considered to be for reproductive and developmental toxicity. When  female Sprague Dawley rats were treated with the test chemical orally.

Reproductive Toxicity Study 2:

In another experimental study, Reproductive and developmental toxicity study of the test chemical was performed on female Sprague-Dawley rats. Test material were administered in dose concentration 0, 30,90,180 mg/kg bw day from days 6 through 15 of gestation by oral route daily. 72 rats used in study. Vehicle control group also observed during study. Females were mated overnight with males of proven fertility in racks containing modified cages. Each cage was subdivided into two parts by a shutter, one part containing the female(s) and the other part containing the male. The sexes remained separated until about 02.00 h, when the shutter opened by means of an automatic device. From 07.00 to 09.00 h all the females showing either a vaginal plug or spermatozoa in the vaginal smear were allocated to the several groups of an experiment. The day of insemination, thus confirmed, was designated ‘day 0’ of pregnancy. Killing of maternal animals and examination of uterine contents was carried out on day 21 of pregnancy. i.e. a short time before expected parturition. The females of the 180-mg/kg dose group reacted to the treatment by some reduction in food consumption. The near-term fetuses of the 90mg/kg bw and 180mg/kg bw dose groups showed a dose-related delay in growth as indicated by a diminished body weight and retarded skeletal maturation marked increase in the rate of embryo and feto-lethality occurred in this 180mg/kg bw group. Teratogenicity was found to occur at the marginal incidence of 0.7% in the 90mg/kg bw dose group. Of the 290 fetuses from 19 litters, one was affected by a generalized oedema in combination with 'pig tail’; a further one from another litter showed unilateral anophthalmia. In the180mg/kg bwdose group, the teratogenicity rate rose to about 30%. Most prominent among the malformations observed was craniorachischisis. The occurrence of ‘bipartite’ thoracic vertebral centres at a low incidence in the 90mg/kg bw dose fetuses and an extremely high incidence in the 180mg/kg bw dose fetuses is considered to indicate delayed ossification rather than a persistent skeletal anomaly and is in accordance with reduced body weight. The test chemical was teratogenic in the rat following maternal peroral treatment at 180 mg/kg during embryonic organogenesis. Teratogenicity was closely associated with marked embryo toxicity, but only a very low maternal toxicity. At 90 mg/kg, a delay of fetal growth and ‘marginal’ teratogenicity became evident in the absence of embryotoxicity and maternal toxicity. At 30 mg/kg neither the dams nor their unborn offspring were affected adversely by the test chemical. Hence NOAEL was considered to be 30mg/kg bw and LOAEL was considered to be 90 mg/kg bw . When female rats were treated with the test chemical orally from days 6 through 15 of gestation.

Reproductive Toxicity Study 3:

In another experimental study, reproductive and developmental toxicity study of the test chemical was performed on female New Zealand White rabbits .The test chemical was dissolved in water and administered in dose concentration 0, 100 mg/kg bw day from days 4 through 7of gestation by oral gavage route daily. The animals were killed on either day 8 or 28 of gestation, and the number of implantations and corpora lutea or the incidence of malformations was determined, respectively The test material did not affect the preimplantation ratio in animals killed at 8 or 28 days, and it did not affect the average litter size of viable offspring or induce teratogenic effects in animals killed at 28 days. Hence NOAEL dose-level was considered to be 100 mg/kg/day for reproductive and developmental toxicity. When female rabbits were treated with the test chemical orally.

Reproductive Toxicity Study 4:

In another experimental study, Developmental toxicity study of the test chemical was performed on female albino rats bred (COBS).Test material was administered in dose concentration 0, 200 mg/kg bw day from days 6 through 15 of gestation by oral gavage route daily. 21 rats each in treatment group were used. All females were sacrificed on day 20 of gestation. Fetal swellings, implantation and resorption sites and any uterine abnormalities were noted and the number of viable fetuses present in the uterus was determined. Fetuses were removed and sacrificed for examination; an external examination of all fetuses was conducted to detect any gross abnormalities. Two-thirds of all fetuses of each sex from each litter were examined for skeletal development using the alizarin staining method. Internal development was evaluated in the remaining fetuses by the freehand razor blade sectioning technique. Incidence of resorptions was increased in 1 of the 2 groups of dams treated with the test chemical. The incidence of internal defects was increased in the group treated with test material. External abnormalities were comparitively more among pups from animals treated with the test chemical. These abnormalities included runts, craniorachischisis, gastroschisis, spiralled caudia and talipes. Deficient ossification of sternum sections, which occurred with high incidence among pups from animals treated with sodium salicylate.  The distribution of sexes was 177 males and 196 females (47.8% males) for the treatment groups. Hence LOAEL dose-level was considered to be 200 mg/kg/day for reproductive and developmental toxicity when female rats were treated with the test chemical orally.

Reproductive Toxicity Study 5:

In this experimental study, reproductive and developmental toxicity study of the test chemical was performed on female CD1 mice.Test chemical that is soluble in water were administered in dose concentration 0, 800 mg/kg bw day from days 8 through 12 of gestation by oral gavage route once daily. Dosing volume was 0.5 ml/kg per dosing occasion. 24 mice each in treatment group and vehicle control group.The change in maternal weight during the treatment period was calculated. Dams were allowed to give birth, and the litters were counted and weighed on postnatal day 1 and 3 (PD1 and PD3). Dead pups recovered from the nest were necropsied and abnormalities were noted. Dams that had not given birth by PD3 were killed and their uteri were examined for the presence of implantation sites.No mortality was observed. Number of pregnant mice were similar as compared to control. No effects on maternal body weight. No significant effects on Number of live foetuses on day 1 and 3. Test chemical induced statistically significant reductions in pup weight on PD1, 6 continued to show significant effects on PD3. Hence, NOAEL was considered to be 800mg/kg bw for reproductive toxicity and LOAEL dose-level was considered to be 800 mg/kg/day for developmental toxicity.When female CD 1 mice were treated with the test chemical orally.

Reproductive Toxicity Study 6:

In an experimental study, Reproductive and developmental toxicity study of the test chemical was performed on a group of 30 gravid female ICR/SIM mice. Test chemical dissolved in water was administered in dose concentration 0, 1600 mg/kg bw day from days 8 through 12 of gestation by oral gavage route daily and a control group of 30 gravid mice was given vehicle only. Mice were allowed to deliver, and Dams that had not given birth by gestation day 21 or 22 were necropsied and their uteri were examined and neonates were examined, counted, and weighed on the day of birth (day 1) and day 3. Dead neonates were recovered from the nest and externally examined for abnormalities. Seven animals died as a result of dosing. Maternal weight gain was significantly decreased compared to controls. Percent neonate survival (96%) was significantly decreased compared to controls. The average number of viable neonates per litter was significantly decreased on days 1 and 3 of parturition and the number of dead neonates per litter was significantly increased on day 1. Average neonatal weight was similar to controls. Hence LOAEL dose-level was considered to be 1600 mg/kg/day for reproductive and developmental toxicity, when female rats were treated with the test chemicals orally.

Based on all the above available experimental data for the test chemical in different rodent species i.e mice , rats and rabbits , NOAEL was considered to be in rang of 30-120 mg/kg bw while LOAEL 90-1600 mg/kg bw , which suggested that coexistence of adverse maternal effects and modifications in numbers of ribs and PSV. Hence From above available data it can be concluded that the test chemical has some reproductive toxicity and considerable developmental toxicity and thus should be classified in Category 2 for reproductive toxicity.

 

Effects on developmental toxicity

Description of key information

Developmental toxicity

The developmental toxicity study, No Observed Adverse Effect Level (NOAEL) was considered to be 80 mg/kg/day, and LOAEL dose-level of 200 mg/kg/day was considered to be for reproductive and developmental toxicity. When female Sprague Dawley rats were treated with the test chemical orally.  Based on available experimental data for the test chemical in different rodent species i.e mice , rats and rabbits , NOAEL was considered to be in rang of 30-120 mg/kg bw while LOAEL 90-1600 mg/kg bw , which suggested the coexistence of adverse maternal effects and modifications in numbers of ribs and PSV. Hence From above available data it can be concluded that the test chemical has some reproductive toxicity and considerable developmental toxicity and thus should be classified in Category 2 for reproductive toxicity.

 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
80 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from an experimental study from the reliable journal
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

In different studies, the test chemical has been investigated for developmental toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments i.e. most commonly in rats for the test chemical.

Developmental Toxicity Study 1:

The experimental study conducted on the test chemical to evaluate reproductive and developmental toxicity study of the test chemical was performed on female Sprague Dawley rats. 86 rats were divided into 2 treatment group. 25 female rats in treatment group 1 while 16 in treatment group 2 .Test chemical mixed with 0.5% aqueous methyl cellulose were administered in dose concentration 0, 20, 80 or 200 mg/kg bw day from days 15 through 21 of gestation by oral gavage route twice daily. One-half of the dose was given to the animals in the morning and the second half 6-8 h later. Dosing volume was 10 ml/kg per dosing occasion. For mating purposes, one female and one male (from breeding stock) were housed together. The occurrence of copulation was determined by daily inspection for a copulatory plug. The day at which evidence of mating was detected was designated gestation day 0, and the female animals were placed in an individual cage. The animals were observed twice daily throughout the study for mortality and signs of overt toxicity. Individual body weights were recorded on gestation days 0, 6, 15, 16, 17, 18, 19, 20 and 21. Beginning on day 21, Pups were examined for external abnormalities as soon as possible following delivery. The number of viable and nonviable pups was recorded for each female. All 11 pups were sexed and weighed individually on lactation day 0. All surviving F0 females and F1 pups were euthanized by carbon dioxide inhalation at lactation day 1. On gestation day 25, those females which failed to deliver were euthanized. The uterus and ovaries of all dams were exposed by an abdominal incision and grossly examined to determine the number of implantation sites present. No observations of adverse effects until the onset of parturition. As well, there were no apparent compound-related effects on gestational body weight gain in any of the treatment groups. One death occurred in the vehicle-treated group on gestation day 20. However, post-mortem examination revealed no abnormalities or signs of overt clinical toxicity. Both onset of labour and its duration were disrupted in the animals receiving the highest dose. Increased fetotoxicity and periparturn death also appeared to occur among foetuses from females treated with 200 mg/kg/day of the test chemical but this was not statistically significant of the test chemical. Labour durations in these groups ranged from 1-14 h with a mean duration of 3.6 h for the SA-treated. For comparison, labor duration in control animals ranged from less than 1 h to 3 h with a mean labour time of 1.5 h. There were no observed differences in mean litter size, pup size, or sex ratio, associated with the test chemical. Since those pups which did survive delivery had no visible abnormalities or other signs of overt toxicity. Maternal prenatal death was significantly increased in animals treated with both 200 mg/kg/ day of the test chemical. Four animals in each of these treatment groups died or were euthanized because of extreme distress during parturition. Clinical signs of maternal physical distress during parturition included labored breathing, decreased activity, and blood staining in the abdominal, nasal, and oral areas. Notably, each of these seven animals failed to deliver some or all of their pups. Increased maternal mortality was also evidenced as a significant decrease in the gestational index (defined as the percentage of pregnant females producing live pups) for these same treatment groups. No evidence of increased maternal distress or peripatum mortality was noted in animals from either the mid-dose (80 mg/kg/day) or low-dose (20 mg/kg/day) of the test chemical. Hence No Observed Effect Level (NOEL) was considered to be 80 mg/kg/day, and LOAEL dose-level of 200 mg/kg/day was considered to be for reproductive and developmental toxicity, when  female Sprague Dawley rats were treated with the test chemical orally.

Developmental Toxicity Study 2:

In another experimental study, the test chemical was dissolved in saline and was administered to pregnant rats orally with dose of 100 mg/kg from day 7 to 11 of gestation period. Control animals for both experiments were treated with equivalent doses of physiological saline. Animals were killed with an overdose of Nembutal (pentobarbitone sodium) either on day 15 or day 19 of pregnancy, No malformation in fetus observed and no maternal deaths observed. Thus the No observed adverse effect value is considered to be 100 mg/kg bw/day.

Developmental Toxicity Study 3:

In another experimental study, reproductive and developmental toxicity study of the test chemical was performed on female New Zealand White rabbits .Test chemical was dissolved in water and administered in dose concentration 0, 100 mg/kg bw day from days 4 through 7of gestation by oral gavage route daily. The animals were killed on either day 8 or 28 of gestation, and the number of implantations and corpora lutea or the incidence of malformations was determined, respectively The test chemical did not affect the preimplantation ratio in animals killed at 8 or 28 days, and it did not affect the average litter size of viable offspring or induce teratogenic effects in animals killed at 28 days. Hence NOAEL dose-level was considered to be 100 mg/kg/day for reproductive and developmental toxicity, when female rabbits were treated with the test chemical orally.

Developmental Toxicity Study 4:

In another experimental study, the fetotoxicity of the test chemical on pregnant female Crl:CD(SD)BR rats were studied where the rats were given a single dose of the test chemical via gavage on Day 9 after confirmed pregnancy at dose levels of 0, 120, 180, 240 or 300 mg/kg body weight. No statistically significant treatment-related effects on litter size or fetal weight or postimplantation loss were observed. after treatment with 120 mg/kg of the test chemical while treatment with 180 to 300 mg/kg/day caused the development of additional vertebra bearing ribs as all fetuses with 27 PSV had SNR. Hence, the fetotoxi LOAEL and NOAEL value was assessed to be 180 and 120mg/kg respectively.

Developmental Toxicity Study: 5

In an experimental study, reproductive and developmental toxicity study was performed on female Sprague-Dawley rats. Test chemical was administered in dose concentration 0, 30,90,180 mg/kg bw day from days 6 through 15 of gestation by oral route daily. 72 rats used in study. Vehicle control group also observed during study. Females were mated overnight with males of proven fertility in racks containing modified cages. Each cage was subdivided into two parts by a shutter, one part containing the female(s) and the other part containing the male. The sexes remained separated until about 02.00 h, when the shutter opened by means of an automatic device. From 07.00 to 09.00 h all the females showing either a vaginal plug or spermatozoa in the vaginal smear were allocated to the several groups of an experiment. The day of insemination, thus confirmed, was designated ‘day 0’ of pregnancy. Killing of maternal animals and examination of uterine contents was carried out on day 21 of pregnancy. i.e. a short time before expected parturition. The females of the 180-mg/kg dose group reacted to the treatment by some reduction in food consumption. The near-term fetuses of the 90mg/kg bw and 180mg/kg bw dose groups showed a dose-related delay in growth as indicated by a diminished body weight and retarded skeletal maturation marked increase in the rate of embryo and feto-lethality occurred in this 180mg/kg bw group. Teratogenicity was found to occur at the marginal incidence of 0.7% in the 90mg/kg bw dose group. Of the 290 fetuses from 19 litters, one was affected by a generalized oedema in combination with 'pig tail’; a further one from another litter showed unilateral anophthalmia. In the180 mg/kg bw dose group, the teratogenicity rate rose to about 30%. Most prominent among the malformations observed was craniorachischisis. The occurrence of ‘bipartite’ thoracic vertebral centres at a low incidence in the 90 mg/kg bw dose fetuses and an extremely high incidence in the180 mg/kg bw dose fetuses is considered to indicate delayed ossification rather than a persistent skeletal anomaly and is in accordance with reduced body weight. The test chemical was teratogenic in the rat following maternal peroral treatment at 180 mg/kg during embryonic organogenesis. Teratogenicity was closely associated with marked embryo toxicity, but only a very low maternal toxicity. At 90 mg/kg, a delay of fetal growth and ‘marginal’ teratogenicity became evident in the absence of embryotoxicity and maternal toxicity. At 30 mg/kg neither the dams nor their unborn offspring were affected adversely by the test chemical. Hence NOAEL was considered to be 30mg/kg bw and LOAEL was considered to be 90 mg/kg bw, when female rats were treated with the test chemical orally from days 6 through 15 of gestation.

Developmental Toxicity Study 6:

In an experimental data, developmental toxicity study of the test chemical was performed on female albino rats bred (COBS). Test chemical was administered in dose concentration 0, 200 mg/kg bw day from days 6 through 15 of gestation by oral gavage route daily. 21 rats each in treatment group were used. All females were sacrificed on day 20 of gestation. Fetal swellings, implantation and resorption sites and any uterine abnormalities were noted and the number of viable fetuses present in the uterus was determined. Fetuses were removed and sacrificed for examination; an external examination of all fetuses was conducted to detect any gross abnormalities. Two-thirds of all fetuses of each sex from each litter were examined for skeletal development using the alizarin staining method. Internal development was evaluated in the remaining fetuses by the freehand razor blade sectioning technique. Incidence of resorptions was increased in 1 of the females. External abnormalities were somewhat more numerous among pups from animals treated with the test chemical. These abnormalities included runt, craniorachischisis, gastroschisis, spiralled caudia and talipes. Deficient ossification of sternum sections, which occurred with high incidence among pups from animals treated with the test chemical. The distribution of sexes was 177 males and 196 females (47.8% males) for the treatment groups. Hence LOAEL dose-level was considered to be 200 mg/kg/day for reproductive and developmental toxicity, when female rats were treated with the test chemical orally.

Developmental Toxicity Study 7:

In reproductive and developmental toxicity study of the test chemical was performed on female Sprague-Dawley rats. Test chemical dissolved in distilled water was administered in dose concentration 0, 300 mg/kg bw day from on day 7, 8, 9, 10, or 11 of gestation by oral gavage route daily. Controls were dosed with vehicle. Rats were weighed and decapitated on day 21. Gravid uteri were removed, weighed, and examined to determine the number of live, dead, and resorbed fetuses. Maternal weight gain was calculated as the difference between the overall weight change during pregnancy and the gravid uterus weight. All live fetuses were removed, blotted dry, weighed, and examined for gross malformations. Litters were fixed in 65% ethanol before clearing with 1% KOH and staining with Alizarin red S to facilitate microscopic skeletal examination. None of the rats died on study, and maternal toxicity was not seen. Fetal weight gain and the number of implantation sites were not affected by dosing. Extra ribs were induced significantly more with dosing on day 10 than any other day, and ossification sites were also seen more frequently. Cervical ribs were significantly increased with dosing on day 8. Extra ribs were induced significantly more on day 10 compared to other treatment days (p<0.01). Ossification sites were also found more frequently on day 10 (p<0.01), and the percent of their mean induction surpassed that of extra rib formation. These data indicate that on day 10, both lumbar ribs and ossification sites can be induced. Cervical ribs were significantly increased on day 8 and also differed significantly (p <0.05) from any other treatment day implicating day 8 as a sensitive period for cervical rib induction. Hence LOAEL dose-level was considered to be 300 mg/kg/day for reproductive and developmental toxicity, when female rats were treated with the test chemical orally.

Developmental Toxicity Study 8:

 In another experimental study, developmental toxicity study of the test chemical was performed on female CD1 mice. Test chemical soluble in water were administers in dose concentration 0, 800 mg/kg bw day from days 8 through 12 of gestation by oral gavage route once daily. Dosing volume was 0.5 ml/kg per dosing occasion. 24 mice each in treatment group and vehicle control group. The change in maternal weight during the treatment period was calculated. Dams were allowed to give birth, and the litters were counted and weighed on postnatal day 1 and 3 (PD1 and PD3). Dead pups recovered from the nest were necropsied and abnormalities noted. Dams that had not given birth by PD3 were killed and their uteri examined for the presence of implantation sites. No mortality was observed. No of pregnant mice were similar compared to control. No effects on maternal body weight. No significant effects on Number of live foetuses on day 1 and 3. Test chemical produced statistically significant reductions in pup weight on PD1, 6 continued to show significant effects on PD3. Hence, LOAEL dose-level was considered to be 800 mg/kg/day for reproductive and developmental toxicity, when female CD 1 mice were treated with the test chemical orally.

Developmental Toxicity Study 9:

In an experimental study, reproductive and developmental toxicity study of the test chemical was performed on female CD1 mice .Test chemical dissolved in distilled water was administered in dose concentration 0, 1500 mg/kg bw day from on day 7, 8, 9, 10, or 11 of gestation by oral gavage route daily. Controls were dosed with vehicle. On day 18, mice were weighed and then killed by cervical dislocation. Gravid uteri were removed, weighed, and examined to determine the number of live, dead, and resorbed fetuses. Maternal weight gain was calculated as the difference between the overall weight change during pregnancy and the gravid uterus weight. All live fetuses were removed, blotted dry, weighed, and examined for gross malformations. Litters were fixed in 65% ethanol before clearing with 1% KOH and staining with Alizarin red S to facilitate microscopic skeletal examination. The 1,500mg/kg dose of the test chemical was lethal to some dams in every treatment group. Maternal toxicity was not seen in the surviving animals. Fetal weight gain was not affected, but fetal mortality was significantly increased with dosing on day 10. The number of extra ribs was significantly increased with dosing on days 8 and 9, and the combined effect of extra ribs and ossification sites was greater on day 9 than day 8. Hence LOAEL dose-level was considered to be 1500 mg/kg/day for reproductive and developmental toxicity. When female CD1 mice were treated with the test chemical orally.

Developmental Toxicity Study 10:

In an experimental study, reproductive and developmental toxicity study of the test chemical was performed on a group of 30 gravid female ICR/SIM rats. Test chemical dissolved in water was administered in dose concentration 0, 1600 mg/kg bw day from days 8 through 12 of gestation by oral gavage route daily and a control group of 30 gravid mice was given vehicle only. Mice were allowed to deliver, and Dams that had not given birth by gestation day 21 or 22 were necropsied and their uteri were examined and neonates were examined, counted, and weighed on the day of birth (day 1) and day 3. Dead neonates were recovered from the nest and externally examined for abnormalities. Seven animals died as a result of dosing. Maternal weight gain was significantly decreased compared to controls. Percent neonate survival (96%) was significantly decreased compared to controls. The average number of viable neonates per litter was significantly decreased on days 1 and 3 of parturition and the number of dead neonates per litter was significantly increased on day 1. Average neonatal weight was similar to controls. Hence LOAEL dose-level was considered to be 1600 mg/kg/day for reproductive and developmental toxicity, when female rats were treated with the test chemical orally.

Based on available experimental data for the test chemical different rodent species i.e mice, rats and rabbits, NOAEL was considered to be in range of 30-120 mg/kg bw while LOAEL 90-1600 mg/kg bw which suggested that coexistence of adverse maternal effects and modifications in numbers of ribs and PSV. Hence From above available data it can be concluded that the test chemical has some reproductive toxicity and considerable developmental toxicity and thus should be classified in Category 2 for reproductive toxicity.

 

Justification for classification or non-classification

From above available data it can be concluded that the test chemical has some reproductive toxicity and considerable developmental toxicity and thus comparing these value with the criteria of CLP regulation, it may be be classified in Category 2 for reproductive toxicity.