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EC number: 263-058-8 | CAS number: 61789-40-0
- 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
![](https://chesar.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology, when male and female Sprague Dawley rats were treated with test chemical orally for 90 days.
Link to relevant study records
- Endpoint:
- reproductive toxicity, other
- Remarks:
- sub chronic 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 from secondary source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD guideline 408
- Principles of method if other than guideline:
- Reproductive toxicity study of test material was performed on Sprague Dawley rats
- GLP compliance:
- not specified
- Limit test:
- no
- Justification for study design:
- No data available
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl: CD(SD)BR)
- Details on species / strain selection:
- No data available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Age: 5/6 weeks
- Weight at study initiation: male : 115-174 g, female : 97-150 g - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled water
- Details on exposure:
- Details on exposure
PREPARATION OF DOSING SOLUTIONS:Test material soluble in distilled water
DIET PREPARATION- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 250, 500, 1000 mg /kg-
Amount of vehicle (if gavage):10ml /kg bw
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- 5 days/week
- Details on study schedule:
- No data available
- Remarks:
- 0, 250, 500, 1000 mg /kg
- No. of animals per sex per dose:
- Total:800 mg/kg :
10 male and 10 female 250mg/kg:
10 male and 10 female: 500mg/kg
10 male and 10 female: 1000 mg/kg:
10 male and 10 female: 0 mg/kg - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Positive control:
- No data available
- Parental animals: Observations and examinations:
- Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: daily
BODY WEIGHT: Yes
Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes twice/week
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 available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- No data available
- Postmortem examinations (parental animals):
- Postmortem examinations (Parent Animal)
SACRIFICE :On day 92
GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS : yes - Postmortem examinations (offspring):
- No data available
- Statistics:
- Levene´s test (body weight, body weight gain, food consumption), ANOVA, Dunnett´s test (both for multiple group comparisons), Student-Newman-Keul (organ weight, chlinical chemistry, hematology data organ/body weight ratio with each one factor treatment)
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related clinical signs were observed
- Dermal irritation (if dermal study):
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- There were no treatment-related mortalities
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- 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 treatment related effects on histopathology of testes, accessory sex organs, ovaries, uterus, prostate
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
- 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
- mortality
- organ weights and organ / body weight ratios
- histopathology: non-neoplastic
- Remarks on result:
- other: No effects on reproductive organ
- 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:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- other: not specified
- Generation:
- other: not specified
- Based on:
- not specified
- Sex:
- not specified
- Basis for effect level:
- other: not specified
- Remarks on result:
- not measured/tested
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology, When male and female Sprague Dawley rats were treated with test chemical orally for 90 days.
- Executive summary:
- A 90 days subchronic toxicity study of test chemical was performed according to OECD TG 408 on male and female Sprague-Dawley rats. The test material was dissolved in distilled water at dose levels of 0, 250, 500 or 1000 mg/kg-day and administered via oral gavage route once a day for 5 days/week in dose volume 10ml/kg bw in Sprague-Dawley rats 10/sex/dose was used in the study. All the animals were observed for Clinical signs and mortality daily. Body weight and food consumption were noted twice a week. On day 92, all the animals were sacrificed and Gross pathology and Histopathology were performed. There were no treatment-related mortalities in any test group. No effects on Body weight and food consumption were noted. No effects on testes and ovaries weights were noted. No treatment related effects on histopathology of testes, accessory sex organs, ovaries, uterus and prostate were noted. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology were observed, when male and female Sprague Dawley rats were treated with test chemical orally for 90 days.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Data available for the read across chemicals was reviewed to determine the reproductive toxicity of test chemical. The studies are as mentioned below:
Study 1: A 90 days subchronic toxicity study of test chemical was performed according to OECD TG 408 on male and female Sprague-Dawley rats. The test material was dissolved in distilled water at dose levels of 0, 250, 500 or 1000 mg/kg-day and administered via oral gavage route once a day for 5 days/week in dose volume 10ml/kg bw in Sprague-Dawley rats 10/sex/dose was used in the study. All the animals were observed for Clinical signs and mortality daily. Body weight and food consumption were noted twice a week. On day 92, all the animals were sacrificed and Gross pathology and Histopathology were performed. There were no treatment-related mortalities in any test group. No effects on Body weight and food consumption were noted. No effects on testes and ovaries weights were noted. No treatment related effects on histopathology of testes, accessory sex organs, ovaries, uterus and prostate were noted. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology were observed, when male and female Sprague Dawley rats were treated with test chemical orally for 90 days.
Study 2: The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.
Study 3: In a reproductive toxicity study, Sprague-Dawley female rats were treated with test chemical in the concentration of 0, 100, 300, or 1000 mg/kg/day orally by gavage in corn oil. No maternal mortality and clinical signs or behavioral changes were observed in treated female rats as compared to control. No effect on body weight and feed consumption changes were observed in treated female rats as compared to control. Similarly, no effect on reproductive parameters such as number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length was observed in treated rats. Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related. Slight but significant increase in relative liver weight of treated female rats was observed as compared to control. In addition, No effect on viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence. They occurred in low frequency and were distributed randomly across the test chemical treated and control groups. Therefore, NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawley female rats were treated with test chemical orally by gavage from day 6 to 15 of gestation.
Based on the data available from different studies, test chemical did not showed reproductive toxicity at dose concentration between 300- 1000mg/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.
Effects on developmental toxicity
Description of key information
The NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean foetal body weight were considered to be secondary to maternal toxicity when female CD were treated with test chemical orally from day 5 - 19 of pregnancy.
Link to relevant study records
- Endpoint:
- developmental toxicity
- 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 from secondry source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Principles of method if other than guideline:
- Developmental toxicity study of test material was performed on female CD rats.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: CD
- Details on test animals or test system and environmental conditions:
- Age at day 0 of pregnancy: 8 - 9 weeks- Body weight at day 0 of pregnancy: 205 - 254 g
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- (aqua ad iniectabilia)
- Details on exposure:
- Details on exposure
PREPARATION OF DOSING SOLUTIONS:Test material soluble in water (aqua ad iniectabilia)
DIET PREPARATION
- Rate of preparation of diet (frequency):- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 330, 990 or3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively)
- Amount of vehicle (if gavage):10ml /kg bw
- Lot/batch no. (if required)
:- Purity: - 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: during the dark period.
- 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
- Any other deviations from standard protocol: - Duration of treatment / exposure:
- 15 days (from day 5 - 19 of pregnancy)
- Frequency of treatment:
- Daily
- Duration of test:
- 20 days
- Remarks:
- 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively)
- No. of animals per sex per dose:
- Total:
1000 mg/kg : 25 female
95 mg/kg:25 female
286 mg/kg:25 female
950 mg/kg:25 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Maternal examinations:
- Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: daily
BODY WEIGHT: Yes, Time schedule for examinations: daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes daily Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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 - Ovaries and uterine content:
- 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:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data - Statistics:
- Postmortem examinations (Parent Animal)
SACRIFICE : on days 20
GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS : yes - Indices:
- No data available
- Historical control data:
- No data available
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- At 3300 mg/kg bw dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One dam at 3300 mg/kg day died on gestation day 15
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- >= 990 mg/kg bw dose group reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%). At 3300 mg/kg bw dose group reduced body weight (up to 17 % below control) and decreased body weight change were observed
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- >= 990 mg/kg bw dose group reduced food consumption (up to 12 % gestation days 8, 10, 19)and at 3300 mg/kg bw dose group up to 65% each day
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- In 3300 mg/kg bw dose group reduced gravid uterus weight by 22% (caused by lowered fetal weights)
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At 990 mg/kg bw dose group 4/20: ulcers, thickened mucosa and in 3300 mg/kg bw dose group 20/21: thickened mucosa, greyish discoloured in 2/21; ulcers (also in the prematurely deceased dam) were observed.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in the 3300 mg/kg bw dose group.
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of early, late and total resorptions was increased in the 3300 mg/kg bw group.
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 95 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- gross pathology
- mortality
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
- Remarks on result:
- other: No toxic effects observed at given dose group
- Abnormalities:
- not specified
- Localisation:
- not specified
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- a statistically significant reduction in fetal weights as compared to the control was observed At 3300 mg/kg bw dose group
- Description (incidence and severity):
- a statistically significant reduction in number of viable fetuses as compared to the control was observed At 3300 mg/kg bw dose group
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Description (incidence and severity):
- No external malformations and no external variations were seen in controls or in dosed groups.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- No skeletal were seen in controls or in dosed groups.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No soft tissue malformations were seen in controls or in dosed groups.
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw). The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw)
- Dose descriptor:
- NOAEL
- Effect level:
- > 950 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- external malformations
- skeletal malformations
- visceral malformations
- Remarks on result:
- other: No developmental toxic effects observed
- Abnormalities:
- not specified
- Localisation:
- other: not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean foetal body weight were considered to be secondary to maternal toxicity when female CD were treated with test chemical orally from day 5 - 19 of pregnancy.
- Executive summary:
The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 950 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from authoritative database
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Data available for the read across chemicals was reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:
Study 1:
The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.
Study 2: The developmental toxicity study of test chemical was performed on female pregnant rats. The test material was administered in dose concentration 0, 30, 90 or 300 mg/kg bw on days 6 through 17 of gestation via gavage. Clinical signs, gestational body weights, food consumption, gravid uterine weight, total number of corpora lutea, implantation, early and late resorptions, were noted in dams while live and dead fetuses, sex, individual body weights of fetuses, visceral (50 %) and skeletal (50 %) abnormalities were observed in fetuses. No treatment-related effects on the incidence of fetal external, visceral, or skeletal malformations or developmental variations were observed among litters from dams in any of the treated groups. Hence the maternal and developmental no-observed-effect level (NOEL) was considered to be 300 mg/kg bw/d, the highest level, when female rats were treated with test chemical orally on days 6 through 17 of gestation.
Study 3: In a developmental toxicity reproductive toxicity was evaluated in Sprague-Dawley female rats by using test chemical in the concentration of 0, 100, 300, or 1000 mg/kg/day orally by gavage in corn oil. No maternal mortality and clinical signs or behavioral changes were observed in treated female rats as compared to control. No effect on body weight and feed consumption changes were observed in treated female rats as compared to control. Similarly, no effect number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length was observed in treated rats. Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related. Slight but significant increase in relative liver weight of treated female rats was observed as compared to control. In addition, No developmental parameter such as viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence. They occurred in low frequency and were distributed randomly across the test chemical treated and control groups. Therefore, NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawley female rats were treated with test chemical orally by gavage from day 6 to 15 of gestation.
Based on the data available from different studies, test chemical did not showed developmental toxicity at dose concentration between 300- 1000mg/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, the test chemical is not likely to classify as reproductive and developmental toxicant.
Additional information
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