Silicic acid, ethyl ester

Endpoint summary

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, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, 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.

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 available information from various test chemicals

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on reproductive toxicity studies on rats

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Species:

rat

Strain:

other: 2.Sprague-Dawley 3.Charles River Crl:CD® VAF/Plus®

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

other: 2.corn oil 3.peanut oil

Details on exposure:

2.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in corn oil.

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in corn oil.
- Concentration in vehicle: 0,10, 50 and 100 mg/kg bw/day
3.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in peanut oil

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in peanut oil
- Concentration in vehicle: 20, 100 or 600 mg/kg/day - Amount of vehicle (if gavage):

Details on mating procedure:

2.Details of mating
- M/F ratio per cage:1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available
3.- M/F ratio per cage: 1:1
- Length of cohabitation:
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy proof of pregnancy was an in situ copulatory plug or vaginal smear for sperm.

- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available

- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available

- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2.28 days in males; up to 53 days in females
3.15 days (day 6 of gestation through day 20 of gestation)

Frequency of treatment:

daily

Details on study schedule:

No data available

Remarks:

Study 2
0,10, 50 and 100 mg/kg bw/day
Study 3
0,20, 100 or 600 mg/kg/day

No. of animals per sex per dose:

2.Total :80
0 mg/kg /day: 10males and 10 females
10 mg/kg /day: 10males and 10 females
50mg/kg /day:10males and 10 females
100 mg/kg /day:10males and 10 females
3.Total :240
0 mg/kg /day: 60 females
20 mg/kg /day: 60 females
100mg/kg /day:60 females
600 mg/kg /day:60 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

2&3Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight were recorded at designated intervals
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): food consumption were recorded at
designated intervals
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

2.the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum

Postmortem examinations (parental animals):

2.At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females.

Postmortem examinations (offspring):

No data available

Statistics:

3.One-way analysis of variance (ANOVA) was used to analyze mean maternal gestation body weights, body weight changes, and food consumption, mean number of corpora lutea, implantation sites, live fetuses(male and female), postimplantation losses, resorptions (early and late), mean fetal weights (male and female), gravid uterine weights, carcass weights, and net weight change from day 0. If the ANOVA was significant, pairwise comparisons to the vehicle control were performed using Dunnett's test. A Kruskal-Wallis test was used to analyze mean percent preimplantation losses and live fetuses (male and female) per animal, mean percent postimplantation losses, dead fetuses, and resorptions (early and late) expressed as percentages of implantations per animal, mean percent affected fetuses per litter for external, visceral, and skeletal malformations and developmental variations, and mean percent affected fetuses per liter for external, visceral, and skeletal malformations and developmental variations. If the Kruskal-Wallis test was significant, pairwise comparisons to the vehicle control were made using a Mann-Whitney U test. A Pearson chi-square test was used to analyze fetal and litter incidence of fetal external, visceral and skeletal malformations and developmental variations, as well as litter incidence of total fetal external, visceral and skeletal malformations and developmental variations. If the chi-square test was significant, pairwise comparisons to the vehicle control were performed using a Fischer's exact test.

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

3.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

3.Increased incidence of mortality at 600 mg/kg/day. No significant maternal effects at 100 or 20 mg/kg/day.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

2.induced a transient decrease in body weight gain during lactation at 100 mg/kg/day. Slight transient decrease in body weight gain was also noted in females of the toxicity group at 100 mg/kg/day but no change in body weight was noted in males of the principal group at any dose-level.
3.No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

3.A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

2.slightly lower sodium, potassium and glucose levels in males given 100 mg/kg/day and 50mg/kg/day dose group.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

2.Tubular nephropathy was observed among some treated males (principal group) at 50 and 100 mg/kg/day and females (toxicity group) at 100 mg/kg/day. This was associated with slightly lower plasma levels of sodium, potassium and glucose. No signs of substance-induced maternal or paternal toxicity occurred at the low dose-level (10 mg/kg/day).
3.No significant findings at any dose level

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.There were no effects on mating performance or fertility

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

body weight and weight gain

clinical biochemistry

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

reproductive performance

Remarks on result:

other: There were no effects on mating performance or fertility

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

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

Sexual maturation:

not specified

Anogenital distance (AGD):

not specified

Nipple retention in male pups:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

3.Slight fetal toxicity, as exhibited by a statistically significant increase in the incidences of minor skeletal variations, 27 presacral vertebrae and sternebra unossified at 600 mg/kg/day. No significant developmental effects at 100 or 20 mg/kg/day.

Histopathological findings:

not specified

Other effects:

no effects observed

Description (incidence and severity):

There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

clinical signs

mortality

gross pathology

other: There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development

Remarks on result:

other: There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.

Executive summary:

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

Study 2

The combined repeated reprductive and developmental toxicity study of test chemical was performed on male and female Sprague-Dawley rats. The test chemical was dissolved in corn oil and administered via oral gavage route throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total)and throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females. Three groups of 10 males and 10 females received the test chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A group of 10 males and 10 females was given the vehicle (corn oil) under the same experimental conditions and acted as a control group.
 Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Females were paired with males from the same dose-level group until mating occurred or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females. There were no effects on mating performance or fertility. There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development. There were no clinically observable signs of toxicity in offspring from treated animals.Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.

 Study 3

The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.

No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals.
No significant findings at any dose level in gross pathology incidence.No significant effect on gravid uterine weights at any dose level. No significant findings at any dose level in histopathology incidence.
No significant treatment related effect at any dose level in Litter size and weights.No significant treatment related effect at any dose level in number viable (number alive and number dead). Sex ratio remains unaffected by treatment by test chemical No significant effects on fetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations 27 presacral vertebrae and sternebra unossified were observed at 600 mg/kg/day were attributed to treatment and considered manifestations of slight fetal toxicity.   Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption were observed at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg/day. Therefore, the maternal and developmental NOAEL was considered to be 100 mg/kg/day.  
Based on the data available from different studies, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, 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

100 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 2

The combined repeated reprductive and developmental toxicity study of test chemical was performed on male and female Sprague-Dawley rats. The test chemical was dissolved in corn oil and administered via oral gavage route throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total)and throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females. Three groups of 10 males and 10 females received the test chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A group of 10 males and 10 females was given the vehicle (corn oil) under the same experimental conditions and acted as a control group.
 Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Females were paired with males from the same dose-level group until mating occurred or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females. There were no effects on mating performance or fertility. There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development. There were no clinically observable signs of toxicity in offspring from treated animals.Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and femaleratswere treated withtest chemicalorally.

 Study 3

The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.

No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals.
No significant findings at any dose level in gross pathology incidence.No significant effect on gravid uterine weights at any dose level. No significant findings at any dose level in histopathology incidence.
No significant treatment related effect at any dose level in Litter size and weights.No significant treatment related effect at any dose level in number viable (number alive and number dead). Sex ratio remains unaffected by treatment by test chemical No significant effects on fetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations 27 presacral vertebrae and sternebra unossified were observed at 600 mg/kg/day were attributed to treatment and considered manifestations of slight fetal toxicity.   Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption were observed at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg/day. Therefore, the maternal and developmental NOAEL was considered to be 100 mg/kg/day.  

Based on the data available from different studies, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, 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.

Effects on developmental toxicity

Description of key information

Developmental toxicity study

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.

Link to relevant study records

Reference

Endpoint:

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 available information from various test chemicals.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on developmental toxicity studies on rats

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: 2.Sprague-Dawley 3.Charles River Crl:CD® VAF/Plus®

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

other: 2.corn oil 3.peanut oil

Details on exposure:

2.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in corn oil.

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in corn oil.
- Concentration in vehicle: 0,10, 50 and 100 mg/kg bw/day
3.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in peanut oil

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in peanut oil
- Concentration in vehicle: 20, 100 or 600 mg/kg/day - Amount of vehicle (if gavage):

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

2.Details of mating
- M/F ratio per cage:1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available

- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available

- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available
3.Details of mating
- M/F ratio per cage:1:1
- Length of cohabitation:
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy proof of pregnancy was an in situ copulatory plug or vaginal smear for sperm.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available

- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available

Duration of treatment / exposure:

2.28 days in males; up to 53 days in females
3.15 days(day 6 of gestation through day 20 of gestation)

Frequency of treatment:

Daily

Duration of test:

2.54 days
3.20 days

Remarks:

Study 2.
0,10, 50 and 100 mg/kg bw/day
Study 3.
0,20, 100 or 600 mg/kg/day

No. of animals per sex per dose:

2.Total :80
0 mg/kg /day: 10males and 10 females
10 mg/kg /day: 10males and 10 females
50mg/kg /day:10males and 10 females
100 mg/kg /day:10males and 10 females
3.Total :240
0 mg/kg /day: 60 females
20 mg/kg /day: 60 females
100mg/kg /day:60 females
600 mg/kg /day:60 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Maternal examinations:

2.&3 Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight were recorded at designated intervals
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): food consumption were recorded at
designated intervals
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

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

Ovaries and uterine content:

2.&3The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:

Fetal examinations:

2.&3- External examinations: Yes: all per litter
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data

Statistics:

No data available

Indices:

No data available

Historical control data:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

3.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

3.Increased incidence of mortality observed at 600 mg/kg/day. No significant maternal effects at 100 or 20 mg/kg/day.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

2.Induced a transient decrease in body weight gain during lactation at 100 mg/kg/day. Slight transient decrease in body weight gain was also noted in females of the toxicity group at 100 mg/kg/day but no change in body weight was noted in males of the principal group at any dose-level.
3.No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

3.A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.

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:

effects observed, treatment-related

Description (incidence and severity):

slightly lower sodium, potassium and glucose levels in males given 100 mg/kg/day,

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

3.No significant effect on gravid uterine weights at any dose level.

Gross pathological findings:

no effects observed

Description (incidence and severity):

3.No significant findings at any dose level

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

2.Tubular nephropathy was observed among some treated males (principal group) at 50 and 100 mg/kg/day and females (toxicity group) at 100 mg/kg/day. This was associated with slightly lower plasma levels of sodium, potassium and glucose. No signs of substance-induced maternal or paternal toxicity occurred at the low dose-level (10 mg/kg/day).
3. No significant findings at any dose level

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

not specified

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

changes in pregnancy duration

clinical signs

dead fetuses

food consumption and compound intake

histopathology: non-neoplastic

mortality

number of abortions

Remarks on result:

other: There were no effects on mating performance or fertility

Abnormalities:

not specified

Localisation:

not specified

Fetal body weight changes:

not specified

Reduction in number of live offspring:

not specified

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

not specified

Description (incidence and severity):

3.Slight fetal toxicity, as exhibited by a statistically significant increase in the incidences of minor skeletal variations, 27 presacral vertebrae and sternebra unossified at 600 mg/kg/day. No significant developmental effects at 100 or 20 mg/kg/day.

Visceral malformations:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

changes in sex ratio

fetal/pup body weight changes

changes in postnatal survival

external malformations

Remarks on result:

other: No effects on developmental parameters was observed

Abnormalities:

not specified

Localisation:

other: not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.

Executive summary:

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

Study 2

The combined repeated reprductive and developmental toxicity study of test chemical was performed on male and female Sprague-Dawley rats. The test chemical was dissolved in corn oil and administered via oral gavage route throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total)and throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females. Three groups of 10 males and 10 females received the test chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A group of 10 males and 10 females was given the vehicle (corn oil) under the same experimental conditions and acted as a control group.
 Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Females were paired with males from the same dose-level group until mating occurred or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females.There were no effects on mating performance or fertility. There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development. There were no clinically observable signs of toxicity in offspring from treated animals.Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.

Study 3

The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.

No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals.
No significant findings at any dose level in gross pathology incidence.No significant effect on gravid uterine weights at any dose level. No significant findings at any dose level in histopathology incidence.
No significant treatment related effect at any dose level in Litter size and weights.No significant treatment related effect at any dose level in number viable (number alive and number dead). Sex ratio remains unaffected by treatment by test chemical No significant effects on fetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations 27 presacral vertebrae and sternebra unossified were observed at 600 mg/kg/day were attributed to treatment and considered manifestations of slight fetal toxicity.   Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption were observed at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg/day. Therefore, the maternal and developmental NOAEL was considered to be 100 mg/kg/day.  

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 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 for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study 2

The combined repeated reprductive and developmental toxicity study of test chemical was performed on male and female Sprague-Dawley rats. The test chemical was dissolved in corn oil and administered via oral gavage route throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total)and throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females. Three groups of 10 males and 10 females received the test chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A group of 10 males and 10 females was given the vehicle (corn oil) under the same experimental conditions and acted as a control group.
 Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Females were paired with males from the same dose-level group until mating occurred or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females.There were no effects on mating performance or fertility. There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development. There were no clinically observable signs of toxicity in offspring from treated animals.Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and femalerats were treated withtest chemicalorally.

Study 3

The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.

No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals.
No significant findings at any dose level in gross pathology incidence.No significant effect on gravid uterine weights at any dose level. No significant findings at any dose level in histopathology incidence.
No significant treatment related effect at any dose level in Litter size and weights.No significant treatment related effect at any dose level in number viable (number alive and number dead). Sex ratio remains unaffected by treatment by test chemical No significant effects on fetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations 27 presacral vertebrae and sternebra unossified were observed at 600 mg/kg/day were attributed to treatment and considered manifestations of slight fetal toxicity.   Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption were observed at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg/day. Therefore, the maternal and developmental NOAEL was considered to be 100 mg/kg/day.  

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.

Justification for classification or non-classification

Thus, comparing this value with the criteria ofCLP regulation testchemical is not likely to classify as reproductive and developmental toxicant.