Registration Dossier

Administrative data

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 chemical was considered to be in range of 1000-1500mg/kg bw/day .When male and female rats were treated with test chemicl orally. Thus, comparing this value with the criteria of CLP regulation test chemical 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 of read across substances
Justification for type of information:
Weight of evidence approach based on structurally similar chemicals
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats
1&2.Teratogenic Potential study of test material in rats by oral administration.
3.Combined repeated dose and reproduction / developmental screening was performed to evaluate the toxic nature of test material.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
rat
Strain:
other: 1.Sprague-Dawley 2.Wistar 3.Crj: CD(SD)
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
1.Details on test animal
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: (P) x wks; (F1) x wks: P- 18 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: P-246 to 379 g
- Fasting period before study: No data available
- Housing: Animals were housed individually and identified by ear tag.
- Diet (e.g. ad libitum): Animals were housed individually
- Water (e.g. ad libitum): water, ad lib.
- Acclimation period: 4 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.22 ± 15 °C
- Humidity (%):50 ± 15%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle.

IN-LIFE DATES: From: To: No data available
3.TEST ANIMALS
- Source: No data
- Age at study initiation: 9 weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 1.Water 2.(bi-distilled water containing 1% carboxymethyl cellulose sodium salt 3.Water for injection
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with vehicle at dose levels of 0, 100, 500 or 1500 mg/kg body weight and prepared daily

DIET PREPARATION
- Rate of preparation of diet (frequency):No data
- Mixing appropriate amounts with (Type of food):No data
- Storage temperature of food:No data

VEHICLE
- Justification for use and choice of vehicle (if other than water):No data
- Concentration in vehicle:0, 100, 500 or 1500 mg/kgbw
- Amount of vehicle (if gavage):10 mL/Kg
- Lot/batch no. (if required):No data
- Purity:No data
Details on mating procedure:
1.- M/F ratio per cage: 1: 1.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Copulatory plug or presence of sperm in vaginal washings was designated as day 0 of gestation
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 1.14 days (days 6-19 of gestation)
Study2.20 days
Study3.Male: 42 days / - Female: 41 - 47 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Details on study schedule:
not specified
Remarks:
Study1.
0.0,100.0,500.0,1500mg/kg bw/day
Study2
.0, 100, 300, 1000mg/kg body weight /day
Study3.Test group: 0, 40, 200 or 1000 mg/Kg/day
Recovery group: 0, 1000 mg/kg/day
No. of animals per sex per dose:
Study1.
Total: 100 females
0 mg/Kg bw: 25 females
100 mg/Kg bw: 25 females
500 mg/Kg bw: 25 females
1500 mg/Kg bw: 25 females
Study2.
Total: 88
0 mg/kgbw/day: 22 female
100 mg/kgbw/day: 22 female
300 mg/kgbw/day: 22 female
1000 mg/kgbw/day: 22 female
Study3.Total :106
0mg/kg :12 male and 12 female
40mg/kg :12 male and 12 female
200mg/kg :12 male and 12 female
1000mg/kg :12 male and 12 female
recovery group
5 male and 5 female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified
Parental animals: Observations and examinations:
Study1.Survival, clinical sign and body weights were examined.
Study2.Animals were checked twice daily for mortality/morbidity, and once daily for clinical signs.
Food consumption and body weight were recorded at designated intervals during pregnancy
Oestrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
Study1.& 2.sex and body weight were examined.
Postmortem examinations (parental animals):
Study1.Gross pathology were examined.
Study2.On day 21 post coitum, the animals were killed and examined macroscopically. Foetuses were removed by Caesarean section.
Postmortem examinations (offspring):
Study1.Gross external malformations and variations were examined.
Study2.Visceral and skeletal malformations were examination.
Statistics:
Study1.Differences in the fetal sex distribution and the number of litters with malformations between control and treated groups wcre compared using the Chi-square test criterion with Yates" correction for 2 x 2 contingency lables and, or Fisher's exact probability test as described by Sicgel (1956). The numbers of early and late resorptions, dead foetuses and post-implantation losses were compared between groups by the Mann Whitney U test as described by Siegel (1956) and Well (1970). The mean numbers of viable foetuses, total implantations, corpora lutca and mean t\)etal weights were compared between groups by analysis of variance (oneway classification), Bartlett's test l\~r homogeneity of variances, and the appropriate t test (for equal or unequal variances) as described by Steel & Torric (1960) using Dunnctt's multiple comparison tables (1964).
Reproductive indices:
Study1.Viable and non-viable foetuses, early and late resorptions, total implantations and corpora lutea were examined.
Offspring viability indices:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Study2.violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female.
Study3.no abnormalities in general signs were observed in any dose groups
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Study1.When treated with 1500 mg/kg bw, Six rats died during the dosing period as compared to control.
Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye.
Study2.No death occurred during the course of the study.
Study3.Neither death nor moribundity occurred in any dosed groups.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Study1.When treated with 1500 mg/kg bw, slight reductions in body-weight gains as compared to controls, throughout the dosing period.
Study2.body weight was not affected by the test substance administration.
Study3.No effects on body weight.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study2.Food consumption was not affected by the test substance administration.
Study3.No effects on food consumption were observed in any dose group
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Study3.No effects on hematological parameters was observed in any dosed group
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Study3.No effects on blood biochemical examination were observed in any dosed group
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Study1.Orange discoloration of the urine was noted in all treated rats during the treatment period.
Study3.No effects on urinalysis were observed in any dosed group
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Study3.No effects in organ weights were observed in any groups.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Study1.Green discoloration of the amniotic fluid was observed in 1, 10 and 16 rats at 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats at 500 mg/Kg group.
Study2.No abnormal macroscopically findings were noted during necropsy.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Study3.no changes in histopathological examination were observed in any males or females given 1000 mg/kg.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Study3.No adverse effect of the compound was observed at any dose level on the estrous cycle
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Study1.No effect on Viable and non-viable foetuses, early and late resorptions, total implantations and corpora lutea and sex ratio of fetuses were observed as compared to control.
Study3.No adverse effect of the compound was observed at any dose level on the reproductive performances, such as the estrous cycle, copulation index, fertility index, or pairing days until copulation.No significant changes were observed in gestation length, delivery or lactation. All pregnant females delivered live pups.No adverse effect of the compound was observed on the developmental performances, such as the number of corpora lutea or implantations, implantation index, number of pups born or live pups, delivery index, birth index.
Dose descriptor:
NOAEL
Effect level:
> 1 000 - <= 1 500 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
mortality
body weight and weight gain
urinalysis
gross pathology
reproductive performance
other: No effect observed
Remarks on result:
other: No effects on reproductive performance
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
Study1.No effect on Viable and non-viable fetuses were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study1.No effect on Body weight of fetuses were observed as compared to control.
Study 2.The mean body weights of foetuses, the ratio of male and female foetuses gave no indication of effects caused by administration of the test material.
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
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Study1.When treated with 1500 mg/kg bw, A slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14th rib(s) was observed however, these values fell within the ranges of historical control data.
No biologically meaningful or statistically significant differences in the number of litters and number of fetuses with malformations and number of fetuses or litters with developmental variations were observed in treated rats as compared to control.
Study2.The external, visceral and skeletal examinations of foetuses gave no indication of effects caused by administration of the test material.

Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 - <= 1 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
gross pathology
other: No effect observed
Remarks on result:
other: No developmental toxic effects observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be in range of 100-1500 mg/kg/day for P and F1 generation when male and female rats treated with test chemical orally.
Executive summary:

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

Study 1.

In a Teratogenic Potential Test, CD Sprague-Dawley female rats treated with test material in the concentration of 0, 100, 500 or 1500 mg/kg bw orally by gavage in water for 14 days (days 6-19 of gestation). Six rats died during the dosing period at 1500 mg/kg bw as compared to control. Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Slight reductions in body-weight gains at 1500 mg/kg bw and Orange discoloration of the urine was noted in all treated rats during the treatment period. No effect on reproductive parameters such as Viable and non-viable fetuses, early and late resorptions, total implantations and corpora lutea and sex ratio of fetuses were observed in treated female rats as compared to control. Green discoloration of the amniotic fluid was observed in 1, 10 and 16 rats at 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats at 500 mg/Kg group. In addition, No effect on Body weight of fetuses were observed as compared to control. A slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14th rib(s) was observed at 1500 mg/kg bw however, these values fell within the ranges of historical control data. No biologically meaningful or statistically significant differences in the number of litters and number of fetuses with malformations and number of fetuses or litters with developmental variations were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1500 mg/kg/day for P and F1 generation when CD Sprague-Dawley female rats treated with test material orally by gavage for 14 days. 

Study 2.

The teratogenic toxicity study was performed according toOECD 414guideline. Thepregnantfemale wistarratswere treated with test material in dose concentration 0,100,300,1000mg/kg bw /day by oral gavage route fromday 6 through day 17 post coitum.22 pregnantfemale /dose group werereceived test material while a group of 22 pregnant rats received the vehicle only (bi-distilled water containing 1% carboxymethylcellulose sodium salt) and served as a control group. Animals were checked twice daily for mortality/morbidity, and once daily for clinical signs. Food consumption and body weight were recorded at designated intervals during pregnancy. On day 21 post coitum, the animals were killed and examined macroscopically. Foetuses were removed by Caesarean section.

 All animals survived until Caesarean section and with the exception of violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female. Food consumption and body weighty development were not affected by the test material administration. No abnormal macroscopically findings were noted during necropsy. The differences amongst the relevant reproduction data (post-implantation loss, number of implantations and foetuses) of the vehicle control group and the dose groups gave no indication of test article related effects. The mean body weights of foetuses, the ratio of male and female foetuses and the results of external, visceral and skeletal examinations of foetuses gave no indication of effects caused by administration of the test material. HenceNOAEL was considered to be 1000 mg/kg body weight /day for F0 and F1 generation female wistar rats were treated withtest material orally.

3.

Combined repeated dose and reproduction / developmental screening was performed to evaluate the toxic nature of test material . Male and female Crl:CD (SD) were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, functional battery observations, body weight, food consumption, urinalysis, haematology, blood chemistry, organ weight changes and histopathology reproductive and developmental parameters.

No adverse effect of the compound was observed at any dose level on the reproductive performances, such as the estrous cycle, copulation index, fertility index, or pairing days until copulation. No significant changes were observed in gestation length, delivery or lactation. All pregnant females delivered live pups. No adverse effect of the compound was observed on the developmental performances, such as the number of corpora lutea or implantations, implantation index, number of pups born or live pups, delivery index, birth index, live birth index, sex ratio or body weight on day 0 of lactation, or viability index or body weight on day 4 of lactation. Neither external abnormality nor macroscopic finding was detected in any pups at the necropsy.No adverse effects were noted in the various parameters studied. Based on the observations made,The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity is considered to be 1000 mg/Kg/day. When male and femaleCrl:CD (SD)were treated with test material orally.

 

Based on the data available from different studies test chemical did not showed reproductive toxicityat dose concentration 1000mg/kg bw/day by oral route.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

 

 

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

Study 1.

In a Teratogenic Potential Test, CD Sprague-Dawley female rats treated with test material in the concentration of 0, 100, 500 or 1500 mg/kg bw orally by gavage in water for 14 days (days 6-19 of gestation). Six rats died during the dosing period at 1500 mg/kg bw as compared to control. Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Slight reductions in body-weight gains at 1500 mg/kg bw and Orange discoloration of the urine was noted in all treated rats during the treatment period. No effect on reproductive parameters such as Viable and non-viable fetuses, early and late resorptions, total implantations and corpora lutea and sex ratio of fetuses were observed in treated female rats as compared to control. Green discoloration of the amniotic fluid was observed in 1, 10 and 16 rats at 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats at 500 mg/Kg group. In addition, No effect on Body weight of fetuses were observed as compared to control. A slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14th rib(s) was observed at 1500 mg/kg bw however, these values fell within the ranges of historical control data. No biologically meaningful or statistically significant differences in the number of litters and number of fetuses with malformations and number of fetuses or litters with developmental variations were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1500 mg/kg/day for P and F1 generation when CD Sprague-Dawley female rats treated with test material orally by gavage for 14 days. 

Study 2.

The teratogenic toxicity study was performed according toOECD 414guideline. Thepregnantfemale wistarratswere treated with test material in dose concentration 0,100,300,1000mg/kg bw /day by oral gavage route fromday 6 through day 17 post coitum.22 pregnantfemale /dose group werereceived test material while a group of 22 pregnant rats received the vehicle only (bi-distilled water containing 1% carboxymethylcellulose sodium salt) and served as a control group. Animals were checked twice daily for mortality/morbidity, and once daily for clinical signs. Food consumption and body weight were recorded at designated intervals during pregnancy. On day 21 post coitum, the animals were killed and examined macroscopically. Foetuses were removed by Caesarean section.

 All animals survived until Caesarean section and with the exception of violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female. Food consumption and body weighty development were not affected by the test material administration. No abnormal macroscopically findings were noted during necropsy. The differences amongst the relevant reproduction data (post-implantation loss, number of implantations and foetuses) of the vehicle control group and the dose groups gave no indication of test article related effects. The mean body weights of foetuses, the ratio of male and female foetuses and the results of external, visceral and skeletal examinations of foetuses gave no indication of effects caused by administration of the test material. HenceNOAEL was considered to be 1000 mg/kg body weight /day for F0 and F1 generation female wistar rats were treated withtest material orally.

Study 3.

Combined repeated dose and reproduction / developmental screening was performed to evaluate the toxic nature of test material . Male and female Crl:CD (SD) were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, functional battery observations, body weight, food consumption, urinalysis, haematology, blood chemistry, organ weight changes and histopathology reproductive and developmental parameters.

No adverse effect of the compound was observed at any dose level on the reproductive performances, such as the estrous cycle, copulation index, fertility index, or pairing days until copulation. No significant changes were observed in gestation length, delivery or lactation. All pregnant females delivered live pups. No adverse effect of the compound was observed on the developmental performances, such as the number of corpora lutea or implantations, implantation index, number of pups born or live pups, delivery index, birth index, live birth index, sex ratio or body weight on day 0 of lactation, or viability index or body weight on day 4 of lactation. Neither external abnormality nor macroscopic finding was detected in any pups at the necropsy.No adverse effects were noted in the various parameters studied. Based on the observations made,The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity is considered to be 1000 mg/Kg/day. When male and femaleCrl:CD (SD)were treated with test material orally.

 

Based on the data available from different studies test chemical did not showedreproductive toxicityat dose concentration 1000mg/kg bw/day by oral route.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

 

 

Effects on developmental toxicity

Description of key information

Developmental toxicity study

The data available for test chemical was reviewed to determine the developmental toxicity. No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be in range of 1000 -1500mg/kg bw /day. When female rats were treated with test chemical orally.Thus, comparing this value with the criteria of CLP regulation test chemical is not likely to 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 of read across substances
Justification for type of information:
Weight of evidence approach based on structurally similar chemicals
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats
1&2. Teratogenic toxicity study of test material was performed on rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 1.wistar 2.CD Sprague-Dawley
Details on test animals and environmental conditions:
2.Details on test animal
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: (P) x wks; (F1) x wks: P- 18 weeks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: P-246 to 379 g
- Fasting period before study: No data available
- Housing: Animals were housed individually and identified by ear tag.
- Diet (e.g. ad libitum): Animals were housed individually
- Water (e.g. ad libitum): water, ad lib.
- Acclimation period: 4 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.22 ± 15 °C
- Humidity (%):50 ± 15%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12-hr light/dark cycle.

IN-LIFE DATES: From: To: No data available
Route of administration:
oral: gavage
Vehicle:
other: bi-distilled water containing 1% carboxymethylcellulose sodium salt
Details on exposure:
1.PREPARATION OF DOSING SOLUTIONS: Test material dissolved in bi-distilled water containing 1% carboxymethylcellulose
sodium salt


Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation:
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:Copulatory plug or presence of sperm in vaginal washings day 0 of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
Study 1.
11 days (from day 6 through day 17 post coitum)
Study 2.
14 days
Frequency of treatment:
Daily
Duration of test:
20 days
Remarks:
Study 1.
0, 100, 300, 1000mg/kg body weight /day
Study 2.
0, 100, 500 or 1500 mg/kg body weight/day
No. of animals per sex per dose:
Study 1
Total: 88
0 mg/kgbw/day: 22 female
100 mg/kgbw/day: 22 female
300 mg/kgbw/day: 22 female
1000 mg/kgbw/day: 22 female
Study 2.
Total: 100
0 mg/kgbw/day: 25 female
100 mg/kgbw/day: 25 female
500 mg/kgbw/day: 25 female
1500 mg/kgbw/day: 25 female

Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Maternal examinations:
Study1&2
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were checked twice daily for mortality/morbidity, and once daily for clinical signs.
- 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 during pregnancy


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes :Food consumption were recorded at designated intervals during
pregnancy

- 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:

POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day #
- Organs examined:

OTHER:
Ovaries and uterine content:
Study 1&2
The 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:
Study 1&2
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
Study 2.Statistical analysis were performed by using Chi-square test criterion with Yates" correction for 2 x 2 contingency lables and, or Fisher's exact probability test as described by Sicgel (1956) to Differences in the foetal sex distribution and the number of litters with malformations between control and treated groups. The numbers of early and late resorptions, dead foetuses and post-implantation losses were compared between groups by the Mann Whitney U test as described by Siegel (1956) and Well (1970). The mean numbers of viable foetuses, total implantations, corpora lutca and mean foetal weights were compared between groups by analysis of variance (one way classification), Bartlett's test for homogeneity of variances, and the appropriate t- test (for equal or unequal variances) as described by Steel & Torric (1960) using Dunnctt's multiple comparison tables (1964).
Indices:
No data available
Historical control data:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Study1.violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female.
Study 2. Orange discoloration of the urine was observed in all the treated rats as compared to control.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
Study 1.All animals survived until Caesarean section
Study 2.When treated with 1500 mg/kg bw/day, Six rats died during the dosing period as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study 1.body weighty were not affected by the test substance administration
Study 2.When treated with 1500 mg/kg bw/day, decrease in body weight gain was observed in treated rats as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study 1.Food consumption were not affected by the test substance administration
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Study 1.No abnormal macroscopically findings were noted during necropsy.
Study 2.When treated with 1500 mg/kg bw/day, green discoloration of the amniotic fluid and green colored small intestines were observed in treated rats as compared to control.

When treated with 100 and 500 mg/kg bw/day, green discoloration of the amniotic fluid was observed in treated rats as compared to control.

Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Study 2.No effect on Post-implantation loss/dam, Total implantations/dam and Corpora lutea/dam were observed in treated rats as compared to control.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Study 1.The differences amongst the relevant reproduction data (post-implantation loss, number of implantations and foetuses) of the vehicle control group and the dose groups gave no indication of test article related effects.
Dose descriptor:
NOAEL
Effect level:
> 1 000 - <= 1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
gross pathology
pre and post implantation loss
total litter losses by resorption
early or late resorptions
Remarks on result:
other: No effects on reproductive performance
Abnormalities:
not specified
Localisation:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Study 1.The mean body weights of foetuses gave no indication of effects caused by administration of the test article.
Study 2.No effect on foetal body weight was observed in treated rats as compared to control.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Study 2.No effect on viability of foetuse were observed in treated rats as compared to control.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Study 1.the ratio of male and female foetuses gave no indication of effects caused by administration of the test article.
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
Study 1.The external examinations of foetuses gave no indication of effects caused by administration of the test article.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Study 1.The skeletal examinations of foetuses gave no indication of effects caused by administration of the test article.
Study 2.When treated wtih 1500 mg/kg bw/day, slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14th rib(s) was observed in feotus of treated rats as compared to control, but the observed effect fell within the ranges of historical control data.
Visceral malformations:
no effects observed
Description (incidence and severity):
Study 1.The visceral examinations of foetuses gave no indication of effects caused by administration of the test article.
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Remarks on result:
other: No developmental toxic effects were observed
Abnormalities:
not specified
Localisation:
other: not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be in range of 1000-1500 mg/kg body weight /day for F0 and F1 generation female rats were treated with test chemical orally.
Executive summary:

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

Study 1.

The teratogenic toxicity study was performed according to OECD 414 guideline. The pregnant female wistar ratswere treated with test material in dose concentration 0,100,300,1000mg/kg bw /day by oral gavage route fromday 6 through day 17 post coitum.22 pregnantfemale /dose group werereceived test material while a group of 22 pregnant rats received the vehicle only (bi-distilled water containing 1% carboxymethylcellulose sodium salt) and served as a control group. Animals were checked twice daily for mortality/morbidity, and once daily for clinical signs. Food consumption and body weight were recorded at designated intervals during pregnancy. On day 21 post coitum, the animals were killed and examined macroscopically. Foetuses were removed by Caesarean section.

 All animals survived until Caesarean section and with the exception of violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female. Food consumption and body weighty development were not affected by the test material administration. No abnormal macroscopically findings were noted during necropsy. The differences amongst the relevant reproduction data (post-implantation loss, number of implantations and foetuses) of the vehicle control group and the dose groups gave no indication of test article related effects. The mean body weights of foetuses, the ratio of male and female foetuses and the results of external, visceral and skeletal examinations of foetuses gave no indication of effects caused by administration of the test material. Hence NOAEL was considered to be 1000 mg/kg body weight /day for F0 and F1 generation female wistar rats were treated with test material orally.

Study 2.

In a Teratogenic toxicity study, CD Sprague-Dawley female rats were treated with test material in the concentration of 0, 100, 500 and 1500 mg/kg body weight/day by oral gavage. Six rats died during the dosing period and at 1500 mg/kg bw/day and Orange discoloration of the urine was observed in all the treated rats as compared to control. Similarly, green discoloration of the amniotic fluid and green colored small intestines were observed at 1500 mg/kg bw/day and green discoloration of the amniotic fluid was observed at 100 and 500 mg/kg bw/day treated rats as compared to control. No effect on Post-implantation loss/dam, Total implantations/dam, Corpora lutea/dam and There were no biologically meaningful or statistically significant differences in the number of litters and Foetal sex of treated rats were observed as compared to control. In addition, No effect on viability of foetuse, number of fetuses with malformations, number of foetuses or litters with developmental variations was observed in any of the treated groups. Slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14thrib(s) was observed in feotus of 1500 mg/kg bw/day treated rats as compared to control, but the observed effect fell within the ranges of historical control data. Therefore, NOAEL was considered to be 1500 mg/kg body weight /day for F0 and F1 generation when CD Sprague-Dawley female rats were treated with test material orally.

 

Based on the data available from different studies,test chemical did not showed developmental toxicity at dose concentration1000 mg/kg bw/day.Hence the test chemical is not likely to classify as a reproductive and developmental toxicant as per the criteria mentioned in CLP regulation.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

 Developmental toxicity study

Data available from different studies were reviewed to determine thedevelopmental toxicityof  test chemical.The studies are as mentioned below:

Study 1.

The teratogenic toxicity study was performed according toOECD 414guideline. Thepregnantfemale wistarratswere treated with test material in dose concentration 0,100,300,1000mg/kg bw /day by oral gavage route fromday 6 through day 17 post coitum.22 pregnantfemale /dose group werereceived test material while a group of 22 pregnant rats received the vehicle only (bi-distilled water containing 1% carboxymethylcellulose sodium salt) and served as a control group. Animals were checked twice daily for mortality/morbidity, and once daily for clinical signs. Food consumption and body weight were recorded at designated intervals during pregnancy. On day 21 post coitum, the animals were killed and examined macroscopically. Foetuses were removed by Caesarean section.

 All animals survived until Caesarean section and with the exception of violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female. Food consumption and body weighty development were not affected by the test material administration. No abnormal macroscopically findings were noted during necropsy. The differences amongst the relevant reproduction data (post-implantation loss, number of implantations and foetuses) of the vehicle control group and the dose groups gave no indication of test article related effects. The mean body weights of foetuses, the ratio of male and female foetuses and the results of external, visceral and skeletal examinations of foetuses gave no indication of effects caused by administration of the test material. HenceNOAEL was considered to be 1000 mg/kg body weight /day for F0 and F1 generation female wistar rats were treated withtest material orally.

Study 2.

In a Teratogenic toxicity study, CD Sprague-Dawley female rats were treated with test material in the concentration of 0, 100, 500 and 1500 mg/kg body weight/day by oral gavage. Six rats died during the dosing period and at 1500 mg/kg bw/day and Orange discoloration of the urine was observed in all the treated rats as compared to control. Similarly, green discoloration of the amniotic fluid and green colored small intestines were observed at 1500 mg/kg bw/day and green discoloration of the amniotic fluid was observed at 100 and 500 mg/kg bw/day treated rats as compared to control. No effect on Post-implantation loss/dam, Total implantations/dam, Corpora lutea/dam and There were no biologically meaningful or statistically significant differences in the number of litters and Foetal sex of treated rats were observed as compared to control. In addition, No effect on viability of foetuse, number of fetuses with malformations, number of foetuses or litters with developmental variations was observed in any of the treated groups. Slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14thrib(s) was observed in feotus of 1500 mg/kg bw/day treated rats as compared to control, but the observed effect fell within the ranges of historical control data. Therefore, NOAEL was considered to be 1500 mg/kg body weight /day for F0 and F1 generation when CD Sprague-Dawley female rats were treated with test material orally.

 

Based on the data available from different studies,test chemical did not showeddevelopmental toxicityat dose concentration1000 mg/kg bw/day.Hence the test chemical is not likely to classify as a reproductive and developmental toxicant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

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