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EC number: - | CAS number: 1309389-73-8
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2016-07-29 to 2017-04-13
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Adopted 2001-01-22
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: ICH Harmonized Tripartite Guideline, Detection of Toxicity to Reproduction for Medicinal Products. Study for Effects on Embryo-Fetal Developmental (Segment II), S5(R2), Guideline 4.1.3.Step 4 version
- Version / remarks:
- 1993-06-24
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998-08
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (2E)-3-(2H-1,3-benzodioxol-5-yl)-N,N-diphenylprop-2-enamide
- Cas Number:
- 1309389-73-8
- Molecular formula:
- C22H17NO3
- IUPAC Name:
- (2E)-3-(2H-1,3-benzodioxol-5-yl)-N,N-diphenylprop-2-enamide
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- CRL Sprague-Dawley CD® IGS rats
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 8 weeks at mating
- Weight at study initiation: The weight variation did not exceed ± 20% of the mean weight.
- Fasting period before study: No
- Housing: Individually in suspended stainless steel cages, which conform to the size recommendations in the latest Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011).
- Diet: Ad libitum (2016 Certified Envigo Teklad Global Rodent Diet®)
- Water: Ad libitum (filtered tap water)
- Acclimation period: Animals arrived on gestation day 1,2 or 3. The test started on gestation day 5.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-24
- Humidity (%): 48-70
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: August 2 – September 19, 2016
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance was mixed weight to volume (w/v) in corn oil. Fresh formulations containing 25, 50, 100, and 200 mg/mL of the test substance were prepared daily. The formulations were stirred at ambient temperature until a visually homogeneous mixture was achieved.
VEHICLE
- Justification for use and choice of vehicle: Solubility properties
- Concentration in vehicle: 0, 25, 50, 100 and 200 mg/mL
- Amount of vehicle: 5 mL/kg bw/day - Analytical verification of doses or concentrations:
- yes
- Remarks:
- Homogeneity and concentration of the test substance in the vehicle, as administered to the test system, was determined as part of this study.
- Details on analytical verification of doses or concentrations:
- The neat test substance and selected prepared mixtures (at each concentration), were sampled in duplicate. At the initial and final preparation, a sample of the test substance (neat) was retained for stability. Prior to dosing, samples to verify the homogeneity of the test substance in the dosing mixtures were collected from the initial preparation. Samples from these preparations were collected from the top, middle, and bottom of each concentration of test substance in vehicle. The dose preparations (test and control) were sampled at the beginning as part of the homogeneity assessment, and near the end of the study for the verification of concentration.
The test substance was determined to be stable under the conditions of storage at the laboratory over the course of this study. Based on the overall neat test substance stability, and dose preparation homogeneity and concentration verification analyses, animals were considered to have received at least the target concentrations of the test. - Details on mating procedure:
- - Impregnation procedure: Purchased timed pregnant (animals were received on GD1, 2, or 3, following confirmed mating by the supplier)
- Duration of treatment / exposure:
- 9 days
- Frequency of treatment:
- Daily
- Duration of test:
- From gestation day 5 to gestation day 19
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 125 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control (corn oil)
- No. of animals per sex per dose:
- 20 female animals per dose and control group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on a developmental range-finding/toxicity study (see supporting study in IUCLID section 7.8), selected target dose levels were 125, 250, 500, and 1000 mg/kg/day. The high dose was chosen based on the absence of toxicity in the range finding study and was selected as the maximum guideline-recommended dose. A NOAEL was achieved for this study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily for viability. Cage-side observations of all animals were performed daily during the study.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Prior to the first treatment with the test substance, and approximately weekly thereafter
- Parameters examined: Potential signs noted included, but were not limited to changes in skin, fur, eyes, and mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Likewise, changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypes (e.g., excessive grooming, repetitive circling), or bizarre behavior (e.g., self-mutilation, walking backwards) were also recorded.
BODY WEIGHT: Yes
- Time schedule for examinations: On gestation day 3, 5, 8, 11, 14, 17, and 20
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- 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: No
WATER CONSUMPTION AND COMPOUND INTAKE: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Examination of the external surface of the body, all orifices, as well as the thoracic, abdominal, and cranial cavities, and their contents. Internal examination included but was not limited to, the examination of mammary tissue. Special attention was paid to the organs of the reproductive system. - 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 - Blood sampling:
- - Plasma: No
- Serum: No - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
- Anogenital distance of all live rodent pups: Yes
- Fetal weights: Yes
- Determination of fetal sex: Yes - Statistics:
- Analytical methods for this study were based on regulatory guideline requirements. The laboratory performed statistical analysis of all quantitative data collected during the in-life phase of the study as well as post-mortem phases of the study. Inferential comparisons, between control and test groups were made with regards to homogeneity of variance, normality, and analysis of variance where appropriate. The use of the word “significant” or “significantly” indicates a statistically significant difference between control and the test groups. Significance was judged at p < 0.05. Statistical analyses were conducted using one or more of the following software applications: Provantis® version 9, Tables and Statistics, Instem LSS, Staffordshire UK; INSTAT.
- Historical control data:
- Not included
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Incidental clinical signs noted in females included: slight alopecia on the abdomen, head, or right flank of 1/20 animals in the 125 mg/kg bw/day group and in 3/20 animals in the 500 mg/kg bw/day group; and a lesion on the nose/snout in 1/10 animals of the 250 mg/kg bw/day group. One 125 mg/kg bw/day group and three 1000 mg/kg bw/day group females exhibited corresponding detailed observations of hair loss; these findings were also interpreted to be incidental.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- 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:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Some skeletal variations occured which were non-significant and/or not dose-dependent und were thus considered to be incidental.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Incidental variations of the pelvis included: bilateral, moderately dilated ureters in one 125 mg/kg bw/day group and two 500 mg/kg bw/day group fetuses and left/right, moderately dilated ureters in two 125 mg/kg bw/day group and one 250 mg/kg bw/day group fetuses. There were no other visceral observations.
- Other effects:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In a Prenatal Developmental Toxicity Study according to OECD guideline 414, the no-adverse-effect level (NOAEL) for administration of the test item by oral gavage was determined to be ≥1000 mg/kg/day under the conditions of the study and based on the maternal and fetal developmental toxicity endpoints evaluated.
- Executive summary:
A prenatal developmental toxicity study according to OECD guideline 414 and GLP was conducted in timed-pregnant CRL Sprague-Dawley CD® IGS rats to determine the potential of the test item to produce pre-natal developmental toxicity, when administered orally throughout pregnancy, from implantation to one day prior to term delivery. One hundred (100) timed pregnant female rats were selected for the test and equally distributed into five groups (twenty females per group). Dose levels of 125, 250, 500, and 1000 mg/kg/day of the test item, respectively, as well as vehicle control, were selected for the test. The test substance was determined to be stable under the conditions of storage at the laboratory over the course of this study. Based on the overall neat test substance stability and dose preparation homogeneity and concentration verification analyses, animals were considered to have received at least the target concentrations of the test item. The test substance or vehicle control (corn oil) were administered daily (7 days/week) via oral intubation to each rat during gestation days (GD) 5-19 of a 21-day pregnancy. The test substance was administered as a 25 mg/mL (2.5%), 50 mg/mL (5.0%), 100 (10.0%) or 200 mg/mL (20.0%) w/v mixture in corn oil. Animals were observed daily during pregnancy for clinical signs and mortality. Individual body weights and food consumption for all pregnant females are reported on GD3, 5, 8, 11, 14, 17, and 20. Gross necropsies and caesarean sections were performed on all pregnant rats, where the pregnancy status and uterine contents were evaluated. The conceptuses were assessed for viability, external observations, and then for visceral and skeletal variations. All animals survived administration of the test item. There were no clinical signs or changes in body weight, mean body weight gain, mean food consumption and mean food efficiency considered to be attributed to the administration of the test item.There were no test substance-related changes in pregnancy rate, maternal or placental gross abnormalities, abortions, or premature deliveries. Mean number of corpora lutea, implantations and resorptions as well as pre-implantation and post-implantation loss were comparable for all females. Gravid uterine and adjusted body weights were comparable for all females. A total of 20 litters in Group 1 (240 fetuses), 20 litters in Group 2 (244 fetuses), 20 litters in Group 3 (216 fetuses), 20 litters in Group 4 (240 fetuses), and 20 litters in Group 5 (231 fetuses) were examined at caesarean section for external fetal malformations on GD20. The number of live fetuses per litter was comparable between treatment Groups for animals that survived to scheduled sacrifice and was 12.0, 12.2, 10.8, 12.0, and 11.6 respectively for Groups 1-5. Fetal sex ratios were also comparable across treatment groups. The administration of the test item resulted in no treatment-related external, visceral or skeletal teratogenic effects. Under the conditions of the study and based on the maternal and fetal developmental toxicity endpoints evaluated, the no-adverse-effect level (NOAEL) for administration of the test item by oral gavage was determined to be 1000 mg/kg/day.
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