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EC number: 234-324-0 | CAS number: 11099-06-2
- 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 material was considered to be 100mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Remarks:
- Experimental data from various test chemicals
- Justification for type of information:
- Weight of evidence approach based on the available information from various test chemicals
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: As mentioned below
- Principles of method if other than guideline:
- WoE report is based on reproductive toxicity studies on rats
- GLP compliance:
- not specified
- Limit test:
- no
- Justification for study design:
- No data available
- Species:
- rat
- Strain:
- other: 2.Sprague-Dawley 3.Charles River Crl:CD® VAF/Plus®
- Details on species / strain selection:
- No data available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- No data available
- Route of administration:
- oral: gavage
- Vehicle:
- other: 2.corn oil 3.peanut oil
- Details on exposure:
- 2.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in corn oil.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in corn oil.
- Concentration in vehicle: 0,10, 50 and 100 mg/kg bw/day
3.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in peanut oil
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in peanut oil
- Concentration in vehicle: 20, 100 or 600 mg/kg/day - Amount of vehicle (if gavage): - Details on mating procedure:
- 2.Details of mating
- M/F ratio per cage:1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available
3.- M/F ratio per cage: 1:1
- Length of cohabitation:
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy proof of pregnancy was an in situ copulatory plug or vaginal smear for sperm.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 2.28 days in males; up to 53 days in females
3.15 days (day 6 of gestation through day 20 of gestation) - Frequency of treatment:
- daily
- Details on study schedule:
- No data available
- Remarks:
- Study 2
0,10, 50 and 100 mg/kg bw/day
Study 3
0,20, 100 or 600 mg/kg/day - No. of animals per sex per dose:
- 2.Total :80
0 mg/kg /day: 10males and 10 females
10 mg/kg /day: 10males and 10 females
50mg/kg /day:10males and 10 females
100 mg/kg /day:10males and 10 females
3.Total :240
0 mg/kg /day: 60 females
20 mg/kg /day: 60 females
100mg/kg /day:60 females
600 mg/kg /day:60 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Positive control:
- No data available
- Parental animals: Observations and examinations:
- 2&3Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: Body weight were recorded at designated intervals
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): food consumption were recorded at
designated intervals
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations - Oestrous cyclicity (parental animals):
- No data available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- 2.the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum
- Postmortem examinations (parental animals):
- 2.At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females.
- Postmortem examinations (offspring):
- No data available
- Statistics:
- 3.One-way analysis of variance (ANOVA) was used to analyze mean maternal gestation body weights, body weight changes, and food consumption, mean number of corpora lutea, implantation sites, live fetuses(male and female), postimplantation losses, resorptions (early and late), mean fetal weights (male and female), gravid uterine weights, carcass weights, and net weight change from day 0. If the ANOVA was significant, pairwise comparisons to the vehicle control were performed using Dunnett's test. A Kruskal-Wallis test was used to analyze mean percent preimplantation losses and live fetuses (male and female) per animal, mean percent postimplantation losses, dead fetuses, and resorptions (early and late) expressed as percentages of implantations per animal, mean percent affected fetuses per litter for external, visceral, and skeletal malformations and developmental variations, and mean percent affected fetuses per liter for external, visceral, and skeletal malformations and developmental variations. If the Kruskal-Wallis test was significant, pairwise comparisons to the vehicle control were made using a Mann-Whitney U test. A Pearson chi-square test was used to analyze fetal and litter incidence of fetal external, visceral and skeletal malformations and developmental variations, as well as litter incidence of total fetal external, visceral and skeletal malformations and developmental variations. If the chi-square test was significant, pairwise comparisons to the vehicle control were performed using a Fischer's exact test.
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 3.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 3.Increased incidence of mortality at 600 mg/kg/day. No significant maternal effects at 100 or 20 mg/kg/day.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 2.induced a transient decrease in body weight gain during lactation at 100 mg/kg/day. Slight transient decrease in body weight gain was also noted in females of the toxicity group at 100 mg/kg/day but no change in body weight was noted in males of the principal group at any dose-level.
3.No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 3.A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 2.slightly lower sodium, potassium and glucose levels in males given 100 mg/kg/day and 50mg/kg/day dose group.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 2.Tubular nephropathy was observed among some treated males (principal group) at 50 and 100 mg/kg/day and females (toxicity group) at 100 mg/kg/day. This was associated with slightly lower plasma levels of sodium, potassium and glucose. No signs of substance-induced maternal or paternal toxicity occurred at the low dose-level (10 mg/kg/day).
3.No significant findings at any dose level - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- 2.There were no effects on mating performance or fertility
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- body weight and weight gain
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive performance
- Remarks on result:
- other: There were no effects on mating performance or fertility
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Anogenital distance (AGD):
- not specified
- Nipple retention in male pups:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- 3.Slight fetal toxicity, as exhibited by a statistically significant increase in the incidences of minor skeletal variations, 27 presacral vertebrae and sternebra unossified at 600 mg/kg/day. No significant developmental effects at 100 or 20 mg/kg/day.
- Histopathological findings:
- not specified
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- viability
- clinical signs
- mortality
- gross pathology
- other: There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development
- Remarks on result:
- other: There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.
- Executive summary:
Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:
Study 2
The combined repeated reprductive and developmental toxicity study of test chemical was performed on male and female Sprague-Dawley rats. The test chemical was dissolved in corn oil and administered via oral gavage route throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total)and throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females. Three groups of 10 males and 10 females received the test chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A group of 10 males and 10 females was given the vehicle (corn oil) under the same experimental conditions and acted as a control group.
Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Females were paired with males from the same dose-level group until mating occurred or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females. There were no effects on mating performance or fertility. There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development. There were no clinically observable signs of toxicity in offspring from treated animals.Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.Study 3
The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.
No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals.
No significant findings at any dose level in gross pathology incidence.No significant effect on gravid uterine weights at any dose level. No significant findings at any dose level in histopathology incidence.
No significant treatment related effect at any dose level in Litter size and weights.No significant treatment related effect at any dose level in number viable (number alive and number dead). Sex ratio remains unaffected by treatment by test chemical No significant effects on fetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations 27 presacral vertebrae and sternebra unossified were observed at 600 mg/kg/day were attributed to treatment and considered manifestations of slight fetal toxicity. Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption were observed at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg/day. Therefore, the maternal and developmental NOAEL was considered to be 100 mg/kg/day.
Based on the data available from different studies, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Reproductive toxicity study
Data available from different studies were reviewed to determine the reproductive toxicity of testchemical.The studies are as mentioned below:
Study 2
The combined
repeated reprductive and developmental toxicity study of test chemical
was performed on male and female Sprague-Dawley
rats. The test chemical was dissolved in corn oil and administered via
oral gavage route throughout the pre-mating period (15 days), during the
mating and post-mating periods until final sacrifice for the males (at
least 4 weeks in total)and throughout pre-mating (15 days) and mating
period, during pregnancy and lactation, until day 4 post-partum
inclusive (or until sacrifice for un-mated females) for the
females. Three groups of 10 males and 10 females received the test
chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A
group of 10 males and 10 females was given the vehicle (corn oil) under
the same experimental conditions and acted as a control group.
Mortality and clinical signs were checked daily in all animals. Body
weight and food consumption were recorded at designated
intervals. Females were paired with males from the same dose-level group
until mating occurred or 2 weeks had elapsed. Gestation was monitored.
Females were allowed to deliver normally and to rear their progeny until
day 5 post-partum. During the lactation period, the pups were examined
daily for survival, external abnormalities and clinical signs. Pup body
weights were recorded on days 1 and 4 post-partum. At final sacrifice of
the parents, specified organs were weighed and a complete macroscopic
post-mortem examination was performed. A microscopic examination was
performed on a range of sampled tissue and organs for all males of the
principal groups and females of the toxicity groups; a microscopic
examination was not performed on the principal group females. There were
no effects on mating performance or fertility. There were no intergroup
differences for litter size, sex ratio or viability. There were no
effects on offspring development. There were no clinically observable
signs of toxicity in offspring from treated animals.Hence No
Observed Adverse Effect Level (NOAEL) for reproductive and developmental
toxicity was considered to be 100mg/kg/day, When male and femaleratswere
treated withtest chemicalorally.
Study 3
The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.
No significant body weight effects at
any dose level. Slight decrease in body weight gain observed gd 6
through 9 at 600 mg/kg/day considered treatment related. This decrease
was not statistically significant but was consistent with significant
decreases in food consumption. A statistically significant decrease in
food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other
significant treatment related effects on food consumption observed at
any dose level during the treatment period.An increased incidence of the
following clinical signs were observed in the 600 mg/kg/day group:
decreased activity, cold to touch, body surface stained, and material
around the nose and eye. Respiratory signs including labored breathing,
gasping, and rales observed in the 600 mg/kg/day group. Most of these
signs were observed in moribund animals.
No significant findings at any dose level in gross pathology
incidence.No significant effect on gravid uterine weights at any dose
level. No significant findings at any dose level in histopathology
incidence.
No significant treatment related effect at any dose level in Litter size
and weights.No significant treatment related effect at any dose level in
number viable (number alive and number dead). Sex ratio remains
unaffected by treatment by test chemical No significant effects on fetal
external or visceral malformations or developmental variations at any
dose level. Statistically significant increases in the incidences of the
variations 27 presacral vertebrae and sternebra unossified were observed
at 600 mg/kg/day were attributed to treatment and considered
manifestations of slight fetal toxicity. Increased incidences of
mortality and clinical observations, as well as slight decreases in body
weight gain and food consumption were observed at 600 mg/kg/day. The
occurrence of maternal toxicity at 600 mg/kg/day was accompanied by
slight fetal toxicity, as exhibited by 27 presacral vertebrae and
sternebra unossified. No significant maternal or developmental effects
were observed at 20 or 100 mg/kg/day. Therefore, the maternal and
developmental NOAEL was considered to be 100 mg/kg/day.
Based on the data available from different studies, NOAEL for test material was considered to be 100mg/kg /day for reproductive toxicity, when male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.
Effects on developmental toxicity
Description of key information
Developmental toxicity study
Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Remarks:
- Experimental data from various test chemicals
- Justification for type of information:
- Weight of evidence approach based on the available information from various test chemicals.
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: As mentioned below
- Principles of method if other than guideline:
- WoE report is based on developmental toxicity studies on rats
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: 2.Sprague-Dawley 3.Charles River Crl:CD® VAF/Plus®
- Details on test animals or test system and environmental conditions:
- No data available
- Route of administration:
- oral: gavage
- Vehicle:
- other: 2.corn oil 3.peanut oil
- Details on exposure:
- 2.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in corn oil.
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in corn oil.
- Concentration in vehicle: 0,10, 50 and 100 mg/kg bw/day
3.Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test chemical dissolved in peanut oil
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test chemical dissolved in peanut oil
- Concentration in vehicle: 20, 100 or 600 mg/kg/day - Amount of vehicle (if gavage): - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- 2.Details of mating
- M/F ratio per cage:1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available
3.Details of mating
- M/F ratio per cage:1:1
- Length of cohabitation:
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy proof of pregnancy was an in situ copulatory plug or vaginal smear for sperm.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol: No data available - Duration of treatment / exposure:
- 2.28 days in males; up to 53 days in females
3.15 days(day 6 of gestation through day 20 of gestation) - Frequency of treatment:
- Daily
- Duration of test:
- 2.54 days
3.20 days - Remarks:
- Study 2.
0,10, 50 and 100 mg/kg bw/day
Study 3.
0,20, 100 or 600 mg/kg/day - No. of animals per sex per dose:
- 2.Total :80
0 mg/kg /day: 10males and 10 females
10 mg/kg /day: 10males and 10 females
50mg/kg /day:10males and 10 females
100 mg/kg /day:10males and 10 females
3.Total :240
0 mg/kg /day: 60 females
20 mg/kg /day: 60 females
100mg/kg /day:60 females
600 mg/kg /day:60 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Maternal examinations:
- 2.&3 Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: Body weight were recorded at designated intervals
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): food consumption were recorded at
designated intervals
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations: - Ovaries and uterine content:
- 2.&3The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: - Fetal examinations:
- 2.&3- External examinations: Yes: all per litter
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data - Statistics:
- No data available
- Indices:
- No data available
- Historical control data:
- No data available
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 3.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 3.Increased incidence of mortality observed at 600 mg/kg/day. No significant maternal effects at 100 or 20 mg/kg/day.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 2.Induced a transient decrease in body weight gain during lactation at 100 mg/kg/day. Slight transient decrease in body weight gain was also noted in females of the toxicity group at 100 mg/kg/day but no change in body weight was noted in males of the principal group at any dose-level.
3.No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 3.A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- slightly lower sodium, potassium and glucose levels in males given 100 mg/kg/day,
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- 3.No significant effect on gravid uterine weights at any dose level.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- 3.No significant findings at any dose level
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 2.Tubular nephropathy was observed among some treated males (principal group) at 50 and 100 mg/kg/day and females (toxicity group) at 100 mg/kg/day. This was associated with slightly lower plasma levels of sodium, potassium and glucose. No signs of substance-induced maternal or paternal toxicity occurred at the low dose-level (10 mg/kg/day).
3. No significant findings at any dose level - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- not specified
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- changes in pregnancy duration
- clinical signs
- dead fetuses
- food consumption and compound intake
- histopathology: non-neoplastic
- mortality
- number of abortions
- Remarks on result:
- other: There were no effects on mating performance or fertility
- Abnormalities:
- not specified
- Localisation:
- not specified
- Fetal body weight changes:
- not specified
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- not specified
- Description (incidence and severity):
- 3.Slight fetal toxicity, as exhibited by a statistically significant increase in the incidences of minor skeletal variations, 27 presacral vertebrae and sternebra unossified at 600 mg/kg/day. No significant developmental effects at 100 or 20 mg/kg/day.
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- changes in sex ratio
- fetal/pup body weight changes
- changes in postnatal survival
- external malformations
- Remarks on result:
- other: No effects on developmental parameters was observed
- Abnormalities:
- not specified
- Localisation:
- other: not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.
- Executive summary:
Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:
Study 2
The combined repeated reprductive and developmental toxicity study of test chemical was performed on male and female Sprague-Dawley rats. The test chemical was dissolved in corn oil and administered via oral gavage route throughout the pre-mating period (15 days), during the mating and post-mating periods until final sacrifice for the males (at least 4 weeks in total)and throughout pre-mating (15 days) and mating period, during pregnancy and lactation, until day 4 post-partum inclusive (or until sacrifice for un-mated females) for the females. Three groups of 10 males and 10 females received the test chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A group of 10 males and 10 females was given the vehicle (corn oil) under the same experimental conditions and acted as a control group.
Mortality and clinical signs were checked daily in all animals. Body weight and food consumption were recorded at designated intervals. Females were paired with males from the same dose-level group until mating occurred or 2 weeks had elapsed. Gestation was monitored. Females were allowed to deliver normally and to rear their progeny until day 5 post-partum. During the lactation period, the pups were examined daily for survival, external abnormalities and clinical signs. Pup body weights were recorded on days 1 and 4 post-partum. At final sacrifice of the parents, specified organs were weighed and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on a range of sampled tissue and organs for all males of the principal groups and females of the toxicity groups; a microscopic examination was not performed on the principal group females.There were no effects on mating performance or fertility. There were no intergroup differences for litter size, sex ratio or viability. There were no effects on offspring development. There were no clinically observable signs of toxicity in offspring from treated animals.Hence No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 100mg/kg/day, When male and female rats were treated with test chemical orally.Study 3
The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.
No significant body weight effects at any dose level. Slight decrease in body weight gain observed gd 6 through 9 at 600 mg/kg/day considered treatment related. This decrease was not statistically significant but was consistent with significant decreases in food consumption. A statistically significant decrease in food consumption was observed gd 6 through 9 at 600 mg/kg/day. No other significant treatment related effects on food consumption observed at any dose level during the treatment period.An increased incidence of the following clinical signs were observed in the 600 mg/kg/day group: decreased activity, cold to touch, body surface stained, and material around the nose and eye. Respiratory signs including labored breathing, gasping, and rales observed in the 600 mg/kg/day group. Most of these signs were observed in moribund animals.
No significant findings at any dose level in gross pathology incidence.No significant effect on gravid uterine weights at any dose level. No significant findings at any dose level in histopathology incidence.
No significant treatment related effect at any dose level in Litter size and weights.No significant treatment related effect at any dose level in number viable (number alive and number dead). Sex ratio remains unaffected by treatment by test chemical No significant effects on fetal external or visceral malformations or developmental variations at any dose level. Statistically significant increases in the incidences of the variations 27 presacral vertebrae and sternebra unossified were observed at 600 mg/kg/day were attributed to treatment and considered manifestations of slight fetal toxicity. Increased incidences of mortality and clinical observations, as well as slight decreases in body weight gain and food consumption were observed at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day was accompanied by slight fetal toxicity, as exhibited by 27 presacral vertebrae and sternebra unossified. No significant maternal or developmental effects were observed at 20 or 100 mg/kg/day. Therefore, the maternal and developmental NOAEL was considered to be 100 mg/kg/day.
Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from authoritative database
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Developmental toxicity study
Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:
Study 2
The combined
repeated reprductive and developmental toxicity study of test chemical
was performed on male and female Sprague-Dawley
rats. The test chemical was dissolved in corn oil and administered via
oral gavage route throughout the pre-mating period (15 days), during the
mating and post-mating periods until final sacrifice for the males (at
least 4 weeks in total)and throughout pre-mating (15 days) and mating
period, during pregnancy and lactation, until day 4 post-partum
inclusive (or until sacrifice for un-mated females) for the
females. Three groups of 10 males and 10 females received the test
chemical by oral gavage once a day at 10, 50 or 100 mg/kg/day while A
group of 10 males and 10 females was given the vehicle (corn oil) under
the same experimental conditions and acted as a control group.
Mortality and clinical signs were checked daily in all animals. Body
weight and food consumption were recorded at designated
intervals. Females were paired with males from the same dose-level group
until mating occurred or 2 weeks had elapsed. Gestation was monitored.
Females were allowed to deliver normally and to rear their progeny until
day 5 post-partum. During the lactation period, the pups were examined
daily for survival, external abnormalities and clinical signs. Pup body
weights were recorded on days 1 and 4 post-partum. At final sacrifice of
the parents, specified organs were weighed and a complete macroscopic
post-mortem examination was performed. A microscopic examination was
performed on a range of sampled tissue and organs for all males of the
principal groups and females of the toxicity groups; a microscopic
examination was not performed on the principal group females.There were
no effects on mating performance or fertility. There were no intergroup
differences for litter size, sex ratio or viability. There were no
effects on offspring development. There were no clinically observable
signs of toxicity in offspring from treated animals.Hence No
Observed Adverse Effect Level (NOAEL) for reproductive and developmental
toxicity was considered to be 100mg/kg/day, When male and femalerats
were treated withtest chemicalorally.
Study 3
The reproductive and developmental toxicity study of test chemical was performed on female Charles River Crl:CD® VAF/Plus®. The test chemical dssolved in peanut oil in dose concentration 20, 100 or 600 mg/kg/day and administered via oral gavage once per day, day 6 of gestation through day 20 of gestation . Each test and control group contain 60 female rats. cageside observations performed twice per day; detaile d clinical observations daily. body weight, food consumption, laparohysterectomic exam, location of viable and nonviable fetuses, early and late resorptions, number of total implantations and corpora lutea were noted .fetal parameters like - weight, sex, external malformations and variations, soft-tissue defects, skeletal examination were performed.
No significant
body weight effects at any dose level. Slight decrease in body weight
gain observed gd 6 through 9 at 600 mg/kg/day considered treatment
related. This decrease was not statistically significant but was
consistent with significant decreases in food consumption. A
statistically significant decrease in food consumption was observed gd 6
through 9 at 600 mg/kg/day. No other significant treatment related
effects on food consumption observed at any dose level during the
treatment period.An increased incidence of the following clinical signs
were observed in the 600 mg/kg/day group: decreased activity, cold to
touch, body surface stained, and material around the nose and eye.
Respiratory signs including labored breathing, gasping, and rales
observed in the 600 mg/kg/day group. Most of these signs were observed
in moribund animals.
No significant findings at any dose level in gross
pathology incidence.No significant effect on gravid uterine weights at
any dose level. No significant findings at any dose level in histopathology
incidence.
No significant treatment related effect at any dose level in Litter
size and weights.No significant treatment related effect at any dose
level in number viable (number alive and number dead). Sex ratio remains
unaffected by treatment by test chemical No
significant effects on fetal external or visceral malformations or
developmental variations at any dose level. Statistically significant
increases in the incidences of the variations 27 presacral vertebrae and
sternebra unossified were observed at 600 mg/kg/day were attributed to
treatment and considered manifestations of slight fetal toxicity.
Increased incidences of mortality and clinical observations, as well as
slight decreases in body weight gain and food consumption were observed
at 600 mg/kg/day. The occurrence of maternal toxicity at 600 mg/kg/day
was accompanied by slight fetal toxicity, as exhibited by 27 presacral
vertebrae and sternebra unossified. No significant maternal or
developmental effects were observed at 20 or 100 mg/kg/day. Therefore,
the maternal and developmental NOAEL was considered to be 100 mg/kg/day.
Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 100 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria ofCLP regulation testchemical isnot likelyto classify as reproductive and developmental toxicant.
Justification for classification or non-classification
Thus, comparing this value with the criteria ofCLP regulation testchemical is not likely to classify as reproductive and developmental toxicant.
Additional information
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