Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to bein range of 940 -1000mg /kg bw/day.When male and female 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:
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
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Species:
rat
Strain:
other: 1.Wistar 2.HanBrl:WIST (SPF)
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
No data available
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 1.1% carboxymethylcellulose in water 2.bi-distilled water containing 1% carboxymethylcellulose
Details on exposure:
Study 1
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
The test substance mixed in 1% carboxymethylcellulose
- Concentration in vehicle: 0, 100, 300 and 1000 mg/kg bw/day (0, 94, 282 or 940 mg active dye/kg bw/day)
- Amount of vehicle (if gavage): 10 ml/kg
Study 2
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
The test substance mixed in bi-destilled water containing 1% carboxymethylcellulose
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test substance mixed in bi-destilled water containing 1% carboxymethylcellulose

- Concentration in vehicle :0, 100, 300 and 1000 mg/kg bw/day (0, 86, 258, and 861 mg active
dye/kg bw/day)
- Amount of vehicle (if gavage): 10 ml/kg bw

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Study 1
12 days (6-17 of gestation period)
Study 2
14 days ( from day 6 (implantation) through to day 20 post coitum )
Frequency of treatment:
Daily
Details on study schedule:
A prenatal developmental study was conducted on female Wistar rats.
Remarks:
Study 1
Doses / Concentrations:
0, 100, 300 and 1000 mg/kg bw/day (0, 94, 282 or 940 mg active dye/kg bw/day)
Study 2
0, 100, 300 and 1000 mg/kg bw/day (0, 86, 258, and 861 mg active dye/kg bw/day)
No. of animals per sex per dose:
Study 1
Total number of animals-88
0 mg /kg bw/day -22 female rats
94 mg /kg bw/day -22 female rats
282 mg /kg bw/day -22 female rats
940 mg /kg bw/day-22 female rats
Study 2
Total:88
0 mg/kg bw/day:22
100mg/kg bw/day:22
300mg/kg bw/day:22
1000 mg/kg bw/day:22
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Parental animals: Observations and examinations:
Study 1
Parental animal: observation and examination- Clinical sign, body weight and food intake was observed.
Histopathology- About one half of the foetuses were examined for soft tissue anomalies whereas remaining foetuses were examined for skeletal anomalies following alizarin red staining.

Study 2
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: twice daily.


BODY WEIGHT: Yes
Time schedule for examinations: daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes on 3-day intervals
Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


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

OTHER:


Oestrous cyclicity (parental animals):
No data

Sperm parameters (parental animals):
No data
Litter observations:
Study 1:Foetuses were sexed and weighed.
Postmortem examinations (parental animals):
Study 1
Embryonic resorptions and implantation sites was observed.
Study 2
Postmortem examinations (Parent Animal)
SACRIFICE :On day 21 post-coitum, the dams were sacrificed
Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: No data
Maternal animals: yes (subjected to macroscopic examination.)
GROSS NECROPSY:
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.:
macroscopic examination was performed
Postmortem examinations (offspring):
Study 1:Foetuses were observed externely.
Study 2.
Postmortem examinations (offspring)
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: The foetuses were removed by Caesarean section, sexed, weighed, examined for gross external abnormalities, killed, and allocated to either visceral or skeletal (about one half of the foetuses for each examination).
Statistics:
No data
Reproductive indices:
No data
Offspring viability indices:
No data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Study 1
Discoloured faeces were observed at 940 mg/kg bw/day.
Study 2
Clinical signs included darker faeces (all treated groups, from day 7-21 post coitum), and discolouration of skin, eyes and bedding (generally only in the 1000mg/kg bw dose group)
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2
The mean body weight gain was slightly decreased and the corrected body weight gain (corrected for gravid uterus weight) was marginally lower in 1000mg/kg bw /day dose females compared to control females
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study 2:Food consumption was similar in treated and control groups.
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:
effects observed, treatment-related
Description (incidence and severity):
Study 2
At necropsy discolouration of intestinal contents, kidneys, fatty tissues, intrauterine fluids and foetuses was noted in all 1000mg/kg bw /day dose group dams
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
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):
Study 1
At the does group of 940mg /kg bw/day one female had only embryonic resorptions.At the dose group of 282 and 940 mg /kg bw/day two
Females were not pregnant, one female had only empty implantation sites and a further one only embryonic resorptions at Caesarean section. These findings were considered by the study authors to be incidental as a dose relation was missing.
Study 2
One low-dose female was not pregnant. The incidence of pre-implantation loss was slightly higher (statistically significant) in the high-dose group; this difference was considered as being incidental by the study authors because pre-implantation loss mainly occurred prior to onset of treatment. Post-implantation loss and number of foetuses per dam was not affected.
Study 1
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)-No mortality was observed.Clinical sign- Discoloured faeces were observed at 940 mg/kg bw/day.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)-No data available

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)-No data available

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)-No data available

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)-No data available

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)-No data available

ORGAN WEIGHTS (PARENTAL ANIMALS)-No data available

GROSS PATHOLOGY (PARENTAL ANIMALS)-At the does group of 94 mg /kg bw/day one female had only embryonic resorptions.
At the dose group of 282 and 940 mg /kg bw/day two
Females were not pregnant, one female had only empty implantation sites and a further one only embryonic resorptions at Caesarean section.

HISTOPATHOLOGY (PARENTAL ANIMALS)-No data available

OTHER FINDINGS (PARENTAL ANIMALS)-No data available
Dose descriptor:
NOAEL
Effect level:
> 940 - < 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Maternal toxicity was not observed at all dose level.
Remarks on result:
other: overall no effects on reproductive performance was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
Study 1 :No significannt change were observed in treated group compare to control group.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study 1&2 :No significannt change were observed in treated group compare to control group.
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):
Study 1&2 :No significant change was observed on external soft tissue and skeletal anomalies based in treated group compare to control group .
Histopathological findings:
no effects observed
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Study 1 :
VIABILITY (OFFSPRING)-No data available

CLINICAL SIGNS (OFFSPRING)-No significannt change were observed in treated group compare to control group.

BODY WEIGHT (OFFSPRING)-No significannt change were observed in treated group compare to control group.

SEXUAL MATURATION (OFFSPRING)-No data available

ORGAN WEIGHTS (OFFSPRING)-No data available

GROSS PATHOLOGY (OFFSPRING)-No significant change was observed on external soft tissue and skeletal anomalies based in treated group compare to control group .

HISTOPATHOLOGY (OFFSPRING)-No data available

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 940 - <= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant change were observed on litter parameters and foetal weight. No significant change were observed on external soft tissue and skeletal anomalies in treated group compare to control group
Remarks on result:
other: overall no developmental toxic effects observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Conclusions:
NOAEL was considered to be in range of 940 -1000mg /kg bw/day for test material in P0 female Wistar rats , when they were exposed with test material by oral (gavage) through gestation period .
Executive summary:

Reproductive toxicity

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

 

Study 1

Reproductive toxicity study was observed for test material in P0 female Wistar rats, when they were  exposed at the concentration of0, 94, 282 or 940mg /kg bw/day through  6-17of gestation period by oral (gavage).The test substance (in1%carboxymethylcellulose in water) was given daily at dose volumes of 10 ml/kg bw by oral gavage. Dams were observed daily for clinical signs, body weight and food intake recorded at designated intervals. The females were killed on gestation day 21, subjected to macroscopic examination, and foetuses were removed by Caesarean section. Common litter parameters were recorded and foetuses were sexed, weighed and submitted to external examination. About one half of the foetuses were also examined for soft tissue anomalies where as remaining foetuses were examined for skeletal anomalies following alizarin red staining. At the does group of 94 mg /kg bw/day one female had only embryonic resorptions.

At the dose group of 282 and 940 mg /kg bw/day two Females were not pregnant, one female had only empty implantation sites and a further one only embryonic resorptions at Caesarean section. These findings were considered by the study authors to be incidental as a dose relation was missing.No mortality was observed. Discoloured faeces were observed at 940mg/kg bw/day. No significant changes were observed on litter parameters and fetal weight. No significant changes were observed on external soft tissue and skeletal anomalies in treated group compare to control. Therefore NOAEL was considered to be 940 mg /kg bw/day for test material in P0 female Wistar rats.

Study 2

Reproductive and development toxicity study of  test material was performed on female  HanBrl:WIST (SPF) rats.22 mated females rats were divided into per dose group . The test substance in bi-distilled water containing 1% carboxymethyl cellulose was given daily at dose volumes of 10 ml/kg bw by oral gavage in dose0, 100, 300 and 1000 mg/kg bw/day (0, 86, 258, and 861 mg active dye/kg bw/day) from day 6 (implantation) through to day 20post coitum. Mortality, morbidity, signs of abortion, and clinical signs and/or symptoms was checked at least twice daily. Food consumption was recorded on 3-day intervals and body weights were recorded daily. The females were sacrificed on gestation day 21, subjected to macroscopic examination. The foetuses were removed by Caesarean section, sexed, weighed, examined for gross external abnormalities, killed, and allocated to either visceral or skeletal (about one half of the foetuses for each examination).

No mortalities occurred. Clinical signs included darker faeces (all treated groups, from day 7-21 post coitum), and discolouration of skin, eyes and bedding (generally only in the high dose group). The mean body weight gain was slightly decreased and the corrected body weight gain (corrected for gravid uterus weight) was marginally lower in high-dose females compared to control females. Food consumption was similar in treated and control groups. One low-dose female was not pregnant. The incidence of pre-implantation loss was slightly higher (statistically significant) in the high-dose group; this difference was considered as being incidental by the study authors because pre-implantation loss mainly occurred prior to onset of treatment. Post-implantation loss and number of foetuses per dam was not affected. At necropsy discolouration of intestinal contents, kidneys, fatty tissues, intrauterine fluids and foetuses was noted in all high-dose dams. No effects on litter parameters or foetal weight were observed. Incidences of external, visceral and skeletal findings were similar for control and treated groups. Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity is considered to be 300 mg/kg bw/day (258 mg active dye/kg bw/day) and the NOAEL for reproductive and developmental toxicity is considered to be 1000 mg/kg bw/day (861 mg active dye/kg bw/day).When femaleHanBrl:WIST (SPF)rats were treated with test material orally.

Based on the data available from different studies test chemical did not showedreproductive toxicityat dose concentration 940 -1000mg /kg bw/day.When male and female rats were treated with test material orally.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

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

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

 

Study 1

Reproductive toxicity study was observed for test material in P0 female Wistar rats, when they were  exposed at the concentration of0, 94, 282 or 940mg /kg bw/day through  6-17of gestation period by oral (gavage).The test substance (in1%carboxymethylcellulose in water) was given daily at dose volumes of 10 ml/kg bw by oral gavage. Dams were observed daily for clinical signs, body weight and food intake recorded at designated intervals. The females were killed on gestation day 21, subjected to macroscopic examination, and foetuses were removed by Caesarean section. Common litter parameters were recorded and foetuses were sexed, weighed and submitted to external examination. About one half of the foetuses were also examined for soft tissue anomalies where as remaining foetuses were examined for skeletal anomalies following alizarin red staining. At the does group of 94 mg /kg bw/day one female had only embryonic resorptions.

At the dose group of 282 and 940 mg /kg bw/day two Females were not pregnant, one female had only empty implantation sites and a further one only embryonic resorptions at Caesarean section. These findings were considered by the study authors to be incidental as a dose relation was missing.No mortality was observed. Discoloured faeces were observed at 940mg/kg bw/day. No significant changes were observed on litter parameters and fetal weight. No significant changes were observed on external soft tissue and skeletal anomalies in treated group compare to control. Therefore NOAEL was considered to be 940 mg /kg bw/day for test material in P0 female Wistar rats.

Study 2

Reproductive and development toxicity study of  test material was performed on female  HanBrl:WIST (SPF) rats.22 mated females rats were divided into per dose group . The test substance in bi-distilled water containing 1% carboxymethyl cellulose was given daily at dose volumes of 10 ml/kg bw by oral gavage in dose0, 100, 300 and 1000 mg/kg bw/day (0, 86, 258, and 861 mg active dye/kg bw/day) from day 6 (implantation) through to day 20post coitum. Mortality, morbidity, signs of abortion, and clinical signs and/or symptoms was checked at least twice daily. Food consumption was recorded on 3-day intervals and body weights were recorded daily. The females were sacrificed on gestation day 21, subjected to macroscopic examination. The foetuses were removed by Caesarean section, sexed, weighed, examined for gross external abnormalities, killed, and allocated to either visceral or skeletal (about one half of the foetuses for each examination).

No mortalities occurred. Clinical signs included darker faeces (all treated groups, from day 7-21 post coitum), and discolouration of skin, eyes and bedding (generally only in the high dose group). The mean body weight gain was slightly decreased and the corrected body weight gain (corrected for gravid uterus weight) was marginally lower in high-dose females compared to control females. Food consumption was similar in treated and control groups. One low-dose female was not pregnant. The incidence of pre-implantation loss was slightly higher (statistically significant) in the high-dose group; this difference was considered as being incidental by the study authors because pre-implantation loss mainly occurred prior to onset of treatment. Post-implantation loss and number of foetuses per dam was not affected. At necropsy discolouration of intestinal contents, kidneys, fatty tissues, intrauterine fluids and foetuses was noted in all high-dose dams. No effects on litter parameters or foetal weight were observed. Incidences of external, visceral and skeletal findings were similar for control and treated groups. Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity is considered to be 300 mg/kg bw/day (258 mg active dye/kg bw/day) and the NOAEL for reproductive and developmental toxicity is considered to be 1000 mg/kg bw/day (861 mg active dye/kg bw/day).When femaleHanBrl:WIST (SPF)rats were treated with test material orally.

Based on the data available from different studies test chemical did not showedreproductive toxicityat dose concentration 940 -1000mg /kg bw/day.When male and female rats were treated with test material orally.Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

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