Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 235-469-2 | CAS number: 12237-63-7 This substance is identified in the Colour Index by Colour Index Constitution Number, C.I. 45160:2.
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
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 chemicalwas considered to be in range of 1000-1500mg/kg bw/day .When male and female rats were treated with test chemiclorally. Thus, comparing this value with the criteria ofCLP regulation test chemicalisnot likely to classify as reproductive toxicant.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Data waiving:
- other justification
- Justification for data waiving:
- other:
- Justification for type of information:
- The study is ongoing and this information will be submitted later based on ECHA communication/decision number CCH-D-2114557769-27-01/F.
- Endpoint:
- reproductive toxicity, other
- Remarks:
- Teratogenicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from publication
- Qualifier:
- according to guideline
- Guideline:
- other: as below
- Principles of method if other than guideline:
- Teratogenic Potential study of test material in rats by oral administration.
- GLP compliance:
- not specified
- Limit test:
- no
- Justification for study design:
- No data available
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- CD
- Details on species / strain selection:
- No data available
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- 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
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- water
- 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:
- - 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:
- 14 days (days 6-19 of gestation)
- Frequency of treatment:
- Daily
- Details on study schedule:
- not specified
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 500 mg/kg bw/day
- No. of animals per sex per dose:
- 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 - Control animals:
- yes, concurrent vehicle
- Details on study design:
- not specified
- Positive control:
- not specified
- Parental animals: Observations and examinations:
- Survival, clinical sign and body weights were examined.
- Oestrous cyclicity (parental animals):
- not specified
- Sperm parameters (parental animals):
- not specified
- Litter observations:
- sex and body weight were examined.
- Postmortem examinations (parental animals):
- Gross pathology were examined.
- Postmortem examinations (offspring):
- Gross external malformations and variations were examined.
- Statistics:
- 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:
- 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):
- Orange discoloration of the urine was observed in all the treated rats as compared to control.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 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. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- When treated with 1500 mg/kg bw, slight reductions in body-weight gains as compared to controls, throughout the dosing period
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Orange discoloration of the urine was noted in all treated rats during the treatment period.
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- 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):
- 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.
- Dose descriptor:
- NOAEL
- Effect level:
- 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):
- 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):
- No effect on Body weight of fetuses were observed as compared to control.
- 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):
- 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. - Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 500 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
- 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 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.
- Executive summary:
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.
- Endpoint:
- fertility, other
- Remarks:
- Teratogenic toxicity study
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Justification for type of information:
- Data is from assessment report
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 414
- Principles of method if other than guideline:
- Female rats were administered test material by gavage for examining its Reproductive/Developmetal toxicity potential.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- not specified
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- not specified
- Route of administration:
- oral: gavage
- Vehicle:
- other: (bi-distilled water containing 1% carboxymethyl cellulose sodium salt
- Details on exposure:
- not specified
- Details on mating procedure:
- not specified
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 20 days
- Frequency of treatment:
- daily
- Details on study schedule:
- not specified
- Remarks:
- 0, 100, 300, 1000mg/kg body weight /day
- No. of animals per sex per dose:
- 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 - Control animals:
- yes, concurrent vehicle
- Details on study design:
- not specified
- Positive control:
- not specified
- Parental animals: Observations and examinations:
- 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:
- Feotus weight and sex were observed.
- Postmortem examinations (parental animals):
- On day 21 post coitum, the animals were killed and examined macroscopically. Foetuses were removed by Caesarean section.
- Postmortem examinations (offspring):
- Visceral and skeletal malformations were examination.
- Statistics:
- not specified
- Reproductive indices:
- not specified
- Offspring viability indices:
- not specified
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- violet discoloured urine, faeces and bedding material observed in all dosage groups, no reaction to treatment or clinical signs were observed in any female.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- No death occurred during the course of the study.
- Body weight and weight changes:
- not specified
- Description (incidence and severity):
- body weight was not affected by the test substance administration.
- Food consumption and compound intake (if feeding study):
- not specified
- Description (incidence and severity):
- Food consumption was 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
- 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):
- 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 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
- mortality
- reproductive function (sperm measures)
- Remarks on result:
- other: No effects on reproductive function
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- 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):
- 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 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- viability
- mortality
- gross pathology
- other: No external abnormalities were noted in any of the foetuses.
- Remarks on result:
- other: 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 1000 mg/kg body weight /day for F0 and F1 generation female wistar rats were treated with test material orally.
- Executive summary:
The teratogenic toxicity study was performed according to OECD 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. Hence NOAEL was considered to be 1000 mg/kg body weight /day for F0 and F1 generation female wistar rats were treated withtest material orally.
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from J- check
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- 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:
- Crj: CD(SD)
- Details on species / strain selection:
- No data available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- 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
- Vehicle:
- other: Water for injection
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with water at dose levels of 0, 40, 200 or 1000 mg/Kg/day (Recovery group: 0, 1000 mg/kg/day)
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): water
- Concentration in vehicle: 0, 40, 200 or 1000 mg/Kg/day (Recovery group: 0, 1000 mg/kg/day)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data - Details on mating procedure:
- No data available
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 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:
- No data available
- Remarks:
- Test group: 0, 40, 200 or 1000 mg/Kg/day
Recovery group: 0, 1000 mg/kg/day - No. of animals per sex per dose:
- 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:
- No data available
- Positive control:
- No data available
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. No data
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data
BODY WEIGHT: Yes
- Time schedule for examinations: No data
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data - Oestrous cyclicity (parental animals):
- No data available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- No data available
- Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]
GROSS NECROPSY: Yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- No data available
- Statistics:
- No data available
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- no abnormalities in general signs were observed in any dose groups
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- Neither death nor moribundity occurred in any dosed groups.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effects on body weight.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- 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):
- No effects on hematological parameters was observed in any dosed group
- Clinical biochemistry findings:
- not specified
- Description (incidence and severity):
- No effects on blood biochemical examination were observed in any dosed group.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- 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
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- 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):
- 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):
- 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 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- food consumption and compound intake
- haematology
- clinical biochemistry
- urinalysis
- organ weights and organ / body weight ratios
- histopathology: non-neoplastic
- reproductive performance
- Remarks on result:
- other: overall no effects on reproductive performance
- 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:
- no effects observed
- 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):
- Neither external abnormality nor macroscopic finding was detected in any pups at the necropsy.
- Histopathological findings:
- no effects observed
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- viability
- clinical signs
- body weight and weight gain
- gross pathology
- histopathology: non-neoplastic
- Remarks on result:
- other: overall no effects ondevelopmental parameters was observed
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity is considered to be 1000 mg/Kg/day. When male and female Crl:CD (SD) were treated with test material orally.
- Executive summary:
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.
- Endpoint:
- extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
- Data waiving:
- other justification
- Justification for data waiving:
- other:
Referenceopen allclose all
Summary of maternal and foetal observations in study of rats given test material by gavage on days 6-19 of gestation
Parameter
|
Observation |
|
|
||||||||||||||||||||||
0(control) |
100 |
500 |
1500 |
|
|||||||||||||||||||||
No. |
% |
SD |
No. |
% |
SD |
No. |
% |
SD |
No. |
% |
SD |
|
|||||||||||||
Animals on study
|
25 |
- |
- |
25 |
84.0 |
- |
25 |
- |
25 |
25 |
- |
- |
|||||||||||||
Animals that were gravid |
25 |
100.0 |
- |
21 |
0.0 |
- |
21 |
84.0 |
24 |
24 |
96.0 |
- |
|||||||||||||
Animals that died gravid |
0 |
0.0 |
- |
0 |
100 |
- |
0 |
0.0 |
6 |
6 |
24.0 |
- |
|||||||||||||
Animals examined at caesarean section |
25 |
100.0 |
- |
25 |
16.0 |
- |
25 |
100 |
19 |
19 |
76.0 |
- |
|||||||||||||
Non-gravid |
0 |
0.0 |
- |
4 |
84.0 |
- |
4 |
16 |
1 |
1 |
5.3 |
- |
|||||||||||||
Gravid |
25 |
100.0 |
- |
21 |
- |
2.55 |
21 |
84 |
18 |
18 |
94.7 |
- |
|||||||||||||
Dams with viable foetuses |
25 |
100.0 |
- |
21 |
- |
1.06 |
21 |
84 |
18 |
18 |
94.7 |
- |
|||||||||||||
Viable foetuses/dam |
13.3 |
- |
2.92 |
13.1 |
- |
2.16 |
12.6 |
- |
13.9 |
13.9 |
- |
1.30 |
|||||||||||||
Post-implantation loss/dam |
0.9 |
-[ |
1.78 |
0.9 |
- |
1.88 |
0.6 |
- |
2.89 |
0.5 |
- |
0.79 |
|||||||||||||
Total implantations/dam |
14.2 |
- |
2.24 |
14.0 |
- |
- |
13.1 |
- |
2.13 |
14.4 |
- |
1.10 |
|||||||||||||
Corpora lutea/dam |
15.6 |
- |
2.04 |
15.1 |
- |
- |
15.3 |
- |
- |
15.8 |
- |
1.56 |
|||||||||||||
Foetal sex: male Female |
178 154 |
53.6 46.4 |
- |
148 132 |
52.9 47.1 |
- |
130 134 |
49.2 50.8 |
- |
118 133 |
47.0 53.0 |
- |
|||||||||||||
Mean foetal body weight (g) |
3.4 |
- |
0.29 |
3.5 |
- |
0.36 |
3.5 |
- |
0.36 |
3.5 |
- |
0.45 |
Summary of the incidence of malformations and developmental and genetic variations
observed among foetuses from rats given test material by gavage on days 6-19 of gestation
Observations |
Dose (mg/kg/day)… |
No. of foetuses (no. of litters) |
|||
0 (control) |
100 |
500 |
1500 |
||
No. of litters examined No. of foetuses examined externally No. of foetuses examined viscerally No. of foetuses examined skeletally |
|
25 332 99 |
21 275 81 |
21 264 93 |
18 251 70 |
Malformations observed Skull anomaly Thoracoschisis Gastroschisis Sternoschisis Bent ribs Radius bent Carpal flexure Foetal anasarca Total foetuses (litters) with malformations: |
|
2 (1) 1(1) 2 (1) 1 ( 1 ) 1 (1) 2 (1)
2 (1) 3 (2)
|
6 (3)
6 (3) |
1 (1)
1 (1) |
0 (0) |
Variations observed 27 presacral vertebrae 14th rudimentary rib(s) 14th lull rib(s) 12 full pairs of ribs with bilateral 13th rudimentary ribs |
|
3 (2) 27 (11) 2 (1)
1 (1) |
23 (9) |
1(1) 17 (8) |
2 (1) 49 (14) 2 (1)
|
Skull reduced in ossification Hyoid unossified Vertebrae reduced in ossification Femur reduced in ossification Pubis unossified lschium unossified Femur unossified Metatarsals unossified Sternebrae no. 5 and/or no. 6 unossified Other sternebrae unossified Sternebrae misaligned Major vessel variation Renal papillae not developed and/or distended ureter |
|
4 (3) 7 (5) 2 (1) 1 (1) 2 (1) 2 (1) 1 (1) 1 (1)
33 (9)
8 (6) |
4 (2) 4 (3)
18 (8)
2 (2) |
5 (3) 2 (1)
33 (12) 1 (1) 1 (1) 1 (1)
1 (1) |
4 (2) 9 (3)
29 (11) 9 (4) 1 (1)
2 (2) |
Number of estrous cases and reproductive performance of male and female rats in combined repeat dose and reproductive/developmental toxicity screening test by oral administration
Dose (mg/kg) |
0 |
40 |
200 |
1000 |
Number of females |
12 |
12 |
12 |
12 |
Length of estrous cycle before mating (14days) Mean ±S.D. |
4.0 0.1 |
4.0 0.0 |
4.1 0.2 |
4.0 0.0 |
Number of females with abnormal estrous cycle before mating (14days)a) |
0/12 |
0/12 |
0/12 |
1/12 |
Number of pairs in 1st mating |
12 |
12 |
12 |
12 |
Number of pairs with successful copulation |
12 |
12 |
12 |
12 |
Copulation index (%)a) |
100 |
100 |
100 |
100 |
Number of conceiving days |
|
|
|
|
Mean ±S.D. |
2.6±1.4 |
2.5±0.9 |
2.6±1.0 |
2.7±0.9 |
Conceiving days 1-5 |
11 |
1 |
12 |
12 |
Conceiving days≧6 |
1 |
0 |
0 |
0 |
Number of pregnant females |
11 |
12 |
12 |
12 |
Fertility index (%)b) |
91.7 |
100 |
100 |
100 |
Number of pregnant females with live pups |
11 |
12 |
12 |
12 |
a) Number of females with abnormal estrous cycle/number of females examined.
b) (Number of pairs with successful copulation/number of pairs) ×100.
c) (Number of pregnant females/number of pairs with successful copulation) ×100.
Observation of pups in combined repeat dose and reproductive/developmental toxicity screening test by oral administration
Dose (mg/kg) |
0 |
40 |
200 |
1000 |
Number of dams |
11 |
12 |
12 |
12 |
Length of gestation (days) |
22.27±0.47 |
22.67±0.49 |
22.75±0.45 |
22.42±0.51 |
Corpora lutea |
18.1±3.2 |
20.4±2.3 |
19.1±2.9 |
20.9±3.4$ |
Implantation scars |
12.9±2.3 |
13.8±1.9 |
13.6±1.5 |
15.5±1.9**$ |
Implantation index (%)a) |
72.3±14.5 |
68.4±11.8 |
72.1±9.1 |
75.5±11.8 |
Gestation index (%)b) |
100 |
100 |
100 |
100 |
Pups born |
12.1±2.4 |
12.8±2.1 |
11.8±1.2 |
13.3±2.8 |
Stillbirths |
0.0 0.0 |
0.0 0.0 |
0.0 0.0 |
0.0 0.0 |
Live pups born |
12.1±2.4 |
12.8±2.1 |
11.8±1.2 |
13.3±2.8 |
Delivery index (%)c) |
93.3±6.4 |
92.3±9.3 |
87.6±8.2 |
85.0±15.7 |
Birth index (%)d) |
93.3±6.4 |
92.3±9.3 |
87.6±8.2 |
85.0±15.7 |
Live birth index (%)e) |
100.00± 0.0 |
100.00± 0.0 |
100.00 ±0.0 |
100.00±0.0 |
Live pups on day 4 of lactation |
11.5±3.8 |
12.5±2.1 |
11.8±1.3 |
13.2±2.8 |
Viability index (%)f) |
91.7±25.0 |
98.1±3.4 |
99.2±2.6 |
99.4±2.0 |
External anomalies (%)g) |
0.0±0.0 |
0.0±0.0 |
0.0±0.0 |
0.0±0.0 |
Sex ratio at birth (stillbirths included)h) |
68/133 |
67/153 |
68/142 |
80/159 |
Mean±S.D. |
0.51±0.14 |
0.46±0.18 |
0.48±0.11 |
0.51±0.08 |
Sex ratio at birth (stillbirths decluded)i) |
68/133 |
67/153 |
68/142 |
80/159 |
Mean±S.D. |
0.51±0.14 |
0.46±0.18 |
0.48±0.11 |
0.51±0.08 |
Sex ratio on day 4 of lactationj) |
65/127 |
67/150 |
67/141 |
79/158 |
Mean±S.D. |
0.48±0.20 |
0.46±0.18 |
0.48±0.11 |
0.50±0.09 |
Body weight of pups (g) |
|
|
|
|
Male Day 0 |
6.43±0.56 |
6.87±0.62 |
7.16±0.5$ |
6.74±0.78$ |
4 |
10.14±1.02 |
10.37±1.40 |
10.99±1.12 |
10.31±1.94 |
Female Day 0 |
6.08±0.49 |
6.56±0.61$ |
6.83±0.46*$ |
6.41±0.83$ |
4 |
9.43±0.99 |
10.05±1.47 |
10.58±1.06 |
9.88±2.00 |
Each values shows mean±S.D. per dam. a) (Number of implantation scars/number of corpora lutea)×100.
b) (Number of dams with live pups/number of pregnant dams)×100.
c) (Number of pups born/number of implantation scars)×100.
d) (Number of live pups born/number of implantation scars)×100.
e) (Number of live pups born/number of pups born)×100.
f) (Number of live pups onday 4/number of live pups born)×100.
g) (Number of pups with external anomalies/number of live pups)×100.
h) Total number of male pups born/total number of male and female pups born.
i) Total number of live males/total number of live males and females.
j) Total number of live males on day 4 of lactation/total number of live males and females on day 4 of lactation.
Significantly different from the control, * : p<0.05, **:P<0.01 (Dunnett's test).
Significantly different from the control, $ : p<0.05 (William's test).
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 500 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:
1.Due to COVID-19, the study is delayed and the related information is expected to be provided by 15 March 2023. Please also refer to the attachment.
2.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.
3.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.
4. 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.
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 -1500 mg/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
- 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 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 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 or test system 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:
- body weight and weight gain
- clinical signs
- early or late resorptions
- food consumption and compound intake
- gross pathology
- mortality
- pre and post implantation loss
- total litter losses by resorption
- 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
- 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.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 500 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 showed developmental toxicity at dose concentration 1000 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.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.