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EC number: 224-081-9 | CAS number: 4196-89-8
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Principles of method if other than guideline:
- In a study according to OECD guideline 414 twenty-two female rats were administered once daily doses of 100, 300 or 1000 mg/kg bw/day 2-dimethylpropane-1,3-diyl dibenzoate by oral gavage 7 days a week from Day 6 to Day 20 post-coitum. The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, gross necropsy findings, number of corpora lutea, (gravid) uterine weight and uterine contents. In addition, the following parameters were determined for the F1-generation: the number of fetuses, early and late resorptions, total implantations, fetal body weights, sex ratio, external, visceral (including sex) and skeletal malformations and developmental variations.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2,2-dimethylpropane-1,3-diyl dibenzoate
- EC Number:
- 224-081-9
- EC Name:
- 2,2-dimethylpropane-1,3-diyl dibenzoate
- Cas Number:
- 4196-89-8
- Molecular formula:
- C19H20O4
- IUPAC Name:
- 3-(benzoyloxy)-2,2-dimethylpropyl benzoate
- Reference substance name:
- 3-hydroxy-2,2-dimethylpropyl benzoate
- Cas Number:
- 5522-92-9
- Molecular formula:
- C12H16O3
- IUPAC Name:
- 3-hydroxy-2,2-dimethylpropyl benzoate
- Test material form:
- solid: crystalline
- Details on test material:
- Batch No.: GSOH160441
Constituent 1
impurity 1
- Specific details on test material used for the study:
- Additional information:
Test Facility Test Item Number: 05810/B
Purity/Composition correction factor: No correction factor required
Test item handling: No specific handling conditions required
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- Justification for Test System and Number of Animals
The Wistar Han rat was chosen as the animal model for this study as it is an accepted rodent species for developmental toxicity testing by regulatory agencies. Charles River Den Bosch has historical data on the background incidence of fetal malformations and developmental variations in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of developmental toxicants.
The total number of animals used in this study was considered to be the minimum required to properly characterize the effects of the test item. This study has been designed such that it does not require an unnecessary number of animals to accomplish its objectives.
Husbandry
Housing
On arrival and following randomization females were housed individually in Macrolon plastic cages (MIII type, height 18 cm) containing appropriate bedding equipped with water bottles. The room in which the animals were kept was documented in the study records.
Each cage was clearly labeled with a color-coded cage card indicating Test Facility Study No., group, sex and animal number.
Environmental Conditions
Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 20.9 to 21.3°C with an actual daily mean relative humidity of 43.32 to 51.54%. A 12 hour light/12 hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
Food
Pelleted rodent diet was provided ad libitum throughout the study, except during designated procedures.
The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility.
It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
Water
Municipal tap water was freely available to each animal via water bottles.
Periodic analysis of the water was performed, and results of these analyses are on file at the Test Facility.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Polyethylene glycol 400
- Details on exposure:
- Vehicle
Identification: Polyethylene glycol 400
Supplier : Merck, Darmstadt, Germany
Specific gravity: 1.125
• Polyethylene glycol Stability for at least 5 hours at room temperature is confirmed over the concentration range 20 to 200 mg/mL, Test Facility Study No. 506379
Test Item Characterization
The Sponsor provided to the Test Facility documentation of the identity, purity, composition, and stability for the test item. A Certificate of Analysis or equivalent document was provided to the Test Facility.
Reserve Samples
For each batch (lot) of Test Item, a reserve sample (about 0.5 gram) was collected and maintained under the appropriate storage conditions by the Test Facility and destroyed after the expiration date.
Dose Formulation and Analysis
Preparation of Test Item
Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared daily as a solution and dosed within 5 hours after adding the vehicle to the test item. Formulations were heated to a maximum temperature of 45±5°C for a duration of 25-105 minutes to obtain visual homogeneity (see deviation in Appendix 7). Formulations were released for dosing when they obtained a temperature of 40°C or lower.
Test item dosing formulations were kept at room temperature until dosing. The dosing formulations and vehicle were continuously stirred until and during dosing, except when the dosing formulations and vehicle were transferred to the animal room. Adjustment was made for specific gravity of the vehicle. No correction was made for the purity/composition of the test item. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose Formulation and Analysis
Preparation of Test Item
Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared daily as a solution and dosed within 5 hours after adding the vehicle to the test item. Formulations were heated to a maximum temperature of 45±5°C for a duration of 25-105 minutes to obtain visual homogeneity (see deviation in Appendix 7). Formulations were released for dosing when they obtained a temperature of 40°C or lower.
Test item dosing formulations were kept at room temperature until dosing. The dosing formulations and vehicle were continuously stirred until and during dosing, except when the dosing formulations and vehicle were transferred to the animal room. Adjustment was made for specific gravity of the vehicle. No correction was made for the purity/composition of the test item.
Sample Collection and Analysis
Dose formulation samples were collected for analysis.
All samples were stored on dry ice immediately after sampling. The analytical laboratory was notified before shipment of the samples. Upon receipt at the analytical laboratory, the samples were stored in the ultra-low freezer ≤ -70 °C until analysis.
Analytical Method
Analyses were performed by LC-DAD using a validated analytical procedure.
Concentration Analysis
Duplicate sets of samples (approximately 500 mg) for each sampling time point were sent to the analytical laboratory. Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 10% for solutions of target concentration.
Homogeneity Analysis
Duplicate sets of samples (approximately 500 mg) for each sampling time point were sent to the analytical laboratory. Homogeneity results were considered acceptable if coefficient of variation (CV) of concentrations was <= 10% for each group.
Stability Analysis
Stability analyses performed previously in conjunction with the method development and validation study demonstrated that the test item is stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study.
Additional stability analysis was conducted to determine the stability under the conditions of the deviation. Stability of the prepared formulation was determined at 5 hours at room temperature. Duplicate sets of each sample (approximately 500 mg) were sent to the analytical laboratory. Stability results were considered acceptable if the sample analysis results were within or equal to ±10% of the concentration determined by the initial analysis of each formulation. - Details on mating procedure:
- Time-mated female Wistar Han Rats were received from Charles River Laboratories Deutschland, Sulzfeld, Germany. The females arrived on Day 0 or Day 1 post-coitum (Day 0 post-coitum is defined as the day of successful mating) and were 10 - 14 weeks old and weighed between 164 and 233 g.
- Duration of treatment / exposure:
- From Day 6 to 20 post-coitum.
- Frequency of treatment:
- Once daily.
- Duration of test:
- Scheduled necropsy was conducted on the following days:
Females surviving to planned necropsy: Day 21 post-coitum.
Females with abortion or early delivery: Within 24 hours of abortion or early delivery.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Control
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- 2,2-Dimethylpropane-1,3-diyl dibenzoate
- Dose / conc.:
- 300 mg/kg bw/day
- Remarks:
- 2,2-Dimethylpropane-1,3-diyl dibenzoate
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- 2,2-Dimethylpropane-1,3-diyl dibenzoate
- No. of animals per sex per dose:
- 22 animals per sex/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Necropsy – F0-Generation
All animals (including the animal that was found dead) were subjected to an external, thoracic and abdominal examination, with special attention being paid to the reproductive organs. All macroscopic abnormalities were recorded, collected and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution). No tissues (except the uterus) were weighed.
Each ovary and uterine horn of all animals were dissected and examined as quickly as possible to determine:
• The number of corpora lutea.
• The weight of the (gravid) uterus (not for animals found dead).
• The number and distribution of live and dead fetuses.
• The number and distribution of embryo-fetal deaths.
• The sex of each fetus based on the ano-genital distance.
In case no macroscopically visible implantation sites were present, nongravid uteri were stained using the Salewski technique in order to detect any former implantation sites.
For the animal that was found dead before planned necropsy, these findings were reported in the individual data tables only.
Necropsy procedures were performed by qualified personnel with appropriate training and experience in animal anatomy and gross pathology.
Terminal Procedures – F1-Generation
Fetal Examinations – F1-Generation
External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
External Examinations – F1-Generation
Each viable fetus was sexed, examined in detail to detect macroscopic visible abnormalities and their weight (not for fetuses of animals found dead) was determined.
For late resorptions and recognizable fetuses of females that were found dead, a gross external examination was performed (if possible).
Visceral Examinations– F1-Generation
The sex of all fetuses was confirmed by internal examination and approximately one-half of the fetuses (live and dead) in each litter (all groups) were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected using a technique described by Stuckhardt and Poppe1. This examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development as described by Woo and Hoar2.
The heads were removed from this one-half of the fetuses in each litter and placed in Bouin's solution for soft-tissue examination using the Wilson sectioning technique3. After examination, the tissues without variation or malformations were discarded. Tissues with variations or malformations were stored in 10% formalin.
Skeletal Examinations– F1-Generation
All eviscerated fetuses, following fixation in 96% aqueous ethanol, were macerated in potassium hydroxide and stained with Alizarin Red S by a method similar to that described by Dawson4.
Subsequently, skeletal examination was done for one-half of the fetuses (i.e. the fetuses with heads).
All specimens were archived in glycerin with bronopol as preservative.
Examinations
- Maternal examinations:
- Necropsy – F0-Generation
All animals (including the animal that was found dead) were subjected to an external, thoracic and abdominal examination, with special attention being paid to the reproductive organs. All macroscopic abnormalities were recorded, collected and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution). No tissues (except the uterus) were weighed. - Ovaries and uterine content:
- Necropsy – F0-Generation
Each ovary and uterine horn of all animals were dissected and examined as quickly as possible to determine:
• The number of corpora lutea.
• The weight of the (gravid) uterus (not for animals found dead).
• The number and distribution of live and dead fetuses.
• The number and distribution of embryo-fetal deaths.
• The sex of each fetus based on the ano-genital distance.
In case no macroscopically visible implantation sites were present, nongravid uteri were stained using the Salewski technique in order to detect any former implantation sites.
For the animal that was found dead before planned necropsy, these findings were reported in the individual data tables only.
Necropsy procedures were performed by qualified personnel with appropriate training and experience in animal anatomy and gross pathology. - Fetal examinations:
- Terminal Procedures – F1-Generation
Fetal Examinations – F1-Generation
External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
External Examinations – F1-Generation
Each viable fetus was sexed, examined in detail to detect macroscopic visible abnormalities and their weight (not for fetuses of animals found dead) was determined.
For late resorptions and recognizable fetuses of females that were found dead, a gross external examination was performed (if possible).
Visceral Examinations– F1-Generation
The sex of all fetuses was confirmed by internal examination and approximately one-half of the fetuses (live and dead) in each litter (all groups) were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected using a technique described by Stuckhardt and Poppe1. This examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development as described by Woo and Hoar2.
The heads were removed from this one-half of the fetuses in each litter and placed in Bouin's solution for soft-tissue examination using the Wilson sectioning technique3. After examination, the tissues without variation or malformations were discarded. Tissues with variations or malformations were stored in 10% formalin.
Skeletal Examinations– F1-Generation
All eviscerated fetuses, following fixation in 96% aqueous ethanol, were macerated in potassium hydroxide and stained with Alizarin Red S by a method similar to that described by Dawson4.
Subsequently, skeletal examination was done for one-half of the fetuses (i.e. the fetuses with heads).
All specimens were archived in glycerin with bronopol as preservative. - Statistics:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% and 5% levels.
- Indices:
- Maternal Variables
Body Weight Gains: Calculated between at least each scheduled interval.
Corrected Body Weight Gains: Terminal body weight minus the body weight on Day 6 post-coitum and the weight of gravid uterus.
Relative Food Consumption: Calculated against the body weight for scheduled intervals.
Reproduction and Developmental Variables
For each group, the following calculations were performed:
Pre-implantation loss (%): (number of corpora lutea - number of implantation sites) : (number of corpora lutea) x 100
Post-implantation loss (%) (number of implantation sites - number of live fetuses) : (umber of implantation sites) x 100
The fetal developmental findings were summarized by:
1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and
2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis, where:
Viable fetuses affected/litter (%): (number of viable fetuses affected/litter) : (number of viable fetuses/litter) x 100 - Historical control data:
- Historical control data are available.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment related clinical signs were noted.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period that was considered to be related to treatment with the test item.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean body weights, body weight gain and body weight gain corrected for the weight of the gravid uterus of treated animals remained in the same range as controls over the study period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption before or after correction for body weight was similar between treated and control animals over the study period.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- At necropsy, no test item related macroscopic findings were noted in any of the groups.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Remarks on result:
- other: No treatment-related changes were noted in any of the maternal parameters investigated in this study (e.g. clinical appearance, body weight, food consumption and macroscopic examination).
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): There was no treatment related effect on mean fetal body weights. - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The male:female ratio was unaffected by treatment up to 1000 mg/kg.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects on litter size for any group.
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- External malformations and variations were not seen in any group.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects on skeletal morphology following treatment up to 1000 mg/kg.
Two malformations were revealed at skeletal examination in fetuses of which the dams received test item. Due to single occurrence and/or occurrence in control fetuses only, these malformations were considered to be chance findings. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects on visceral morphology following treatment up to 1000 mg/kg bw/day.
- Other effects:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: No treatment-related changes were noted in any of the developmental parameters investigated in this study (e.g. fetal body weights, external, visceral (including sex) and skeletal malformations and developmental variations).
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
No maternal toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups.
No developmental toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups.
In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for 2,2-Dimethylpropane-1,3-diyl dibenzoate was established as being at least 1000 mg/kg bw/day (limit dose; highest dose tested).
SUMMARY OF MATERNAL SURVIVAL AND PREGNANCY STATUS
Dose group | 1 | 2 | 3 | 3 | ||||
No. | % | No. | % | No. | % | No. | % | |
Females on study | 22 | 22 | 22 | 22 | ||||
Females that aborted or delivered |
0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Females that died | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 4.5 |
Females that aborted | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Nongravid | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Gravid | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 100.0 |
Females that were euthanized | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Nongravid | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Gravid | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Females examined at scheduled necropsy-@ |
22 | 100.0 | 22 | 100.0 | 22 | 100.0 | 21 | 95 .5 |
Nongravid | 0 | 0.0 | 2 | 9.1 | 0 | 0.0 | 0 | 0.0 |
Gravid | 22 | 100.0 | 20 | 90.9 | 22 | 100.0 | 21 | 100.0 |
with resorptions only | 0 | 0 | 1 | 5.0 | 0 | 0.0 | 0 | 0 |
with viable fetuses | 22 | 100.0 | 19 | 95.0 | 22 | 100.0 | 21 | 100.0 |
Total females gravid | 22 | 100.0 | 20 | 90.9 | 22 | 100.0 | 22 | 100.0 |
1- 0 MG/KG 2- 100 MG/KG 3- 300 MG/KG 4- 1000 MG/KG
SUMMARY OF FETAL DATA AT SCHEDULED NECROPSY
Group | Sex M |
Sex F |
Viable fetuses |
Dead fetuses |
Resorptions Early |
Resorptions Late |
Post implantation loss |
Implantation sites |
Corpora lutea |
Pre implantation loss |
Fetal weights in grams |
No. of gravid females |
|
1 | Total | 111 | 129 | 240 | 0 | 9 | 0 | 9 | 249 | 264 | 15 | NA | 22 |
Mean | 5.0 | 5.9 | 10.9 | 0.0 | 0.4 | 0.0 | 0.4 | 11.3 | 12.0 | 0.7 | 5.2 | ||
S.D. | 1.70 | 1.86 | 1.48 | 0.00 | 1.14 | 0.00 | 1.14 | 1.52 | 1.45 | 1.21 | 0.27 | ||
2 | Total | 106 | 104 | 210 | 1 | 6 | 0 | 7 | 217 | 231 | 14 | NA | 20 |
Mean | 5.3 | 5.2 | 10.5 | 0.1 | 0.3 | 0.0 | 0.4 | 10.9 | 11.6 | 0.7 | 5.2 | ||
S.D. | 2.23 | 2.12 | 2.84 | 0.22 | 0.66 | 0.00 | 0.67 | 2.80 | 2.42 | 0.86 | 0.38 | ||
3 | Total | 120 | 126 | 246 | 0 | 7 | 0 | 7 | 253 | 261 | 8 | NA | 22 |
Mean | 5.5 | 5.7 | 11.2 | 0.0 | 0.3 | 0.0 | 0.3 | 11.5 | 11.9 | 0.4 | 5.3 | ||
S.D. | 2.30 | 2.31 | 2.32 | 0.00 | 0.57 | 0.00 | 0.57 | 2.13 | 1.61 | 0.95 | 0.18 | ||
4 | Total | 96 | 130 | 226 | 0 | 8 | 0 | 8 | 234 | 241 | 7 | NA | 21 |
Mean | 4.6 | 6.2 | 10.8 | 0.0 | 0.4 | 0.0 | 0.4 | 11.1 | 11.5 | 0.3 | 5.3 | ||
S.D. | 1.89 | 1.78 | 1.45 | 0.00 | 0.97 | 0.00 | 0.97 | 1.65 | 1.81 | 0.48 | 0.36 |
None significantly different from control group
NA = NOT APPLICABLE
MEAN NUMBER OF VIABLE FETUSES, MEAN NUMBER OF IMPLANTATION SITES, MEAN NUMBER OF CORPORA LUTEA,
FETAL WEIGHTS COMPARED USING DUNNETT'S TEST
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1- 0 MG/KG 2- 100 MG/KG 3- 300 MG/KG 4- 1000 MG/KG
SUMMARY OF FETAL DATA AT SCHEDULED NECROPSY [% PER LITTER]
Group | 0 MG/KG |
100 MG/KG |
300 MG/KG |
1000 MG/KG |
Corpora lutea |
|
|
|
|
Mean |
12.0 |
11.6 |
11.9 |
11.5 |
S.D. |
1.45 |
2.42 |
1.61 |
1.81 |
N |
22 |
20 |
22 |
21 |
Implantation sites |
|
|
|
|
Mean |
11.3 |
10.9 |
11.5 |
11.1 |
S.D. |
1.52 |
2.80 |
2.13 |
1.65 |
N |
22 |
20 |
22 |
21 |
Viable fetuses (%) |
|
|
||
Mean |
96.8 |
92.7 |
96.7 |
97.1 |
S.D. |
8.45 |
22.4 |
6.29 |
7.17 |
N |
22 |
20 |
22 |
21 |
Dead fetuses (%) |
|
|
|
|
Mean |
0.0 |
5.0 |
0.0 |
0.0 |
S.D. |
0.00 |
22.36 |
0.00 |
0.00 |
N |
22 |
20 |
22 |
21 |
Early resorptions (%) |
|
|
|
|
Mean |
3.2 |
2.4 |
3.3 |
2.9 |
S.D. |
8.45 |
5.14 |
6.29 |
7.17 |
N |
22 |
20 |
22 |
21 |
Late resorptions (%) |
|
|
|
|
Mean |
0.0 |
0 |
0 |
0 |
S.D. |
0.00 |
0.00 |
0.00 |
0.00 |
N |
22 |
20 |
22 |
21 |
Total resorptions (%) |
|
|
|
|
Mean |
3.2 |
2.4 |
3.3 |
2.9 |
S.D. |
8.45 |
5.14 |
6.29 |
7.17 |
N |
22 |
20 |
22 |
21 |
Pre-implantation loss (%) |
|
|
|
|
Mean |
5.3 |
8.2 |
3.6 |
2.7 |
S.D. |
9.31 |
16.64 |
10.00 |
3.90 |
N | 22 | 20 | 22 | 21 |
Post-implantation loss (%) | ||||
Mean | 3.2 | 7.4 | 3.3 | 2.9 |
S.D. | 8.45 | 22.40 | 6.29 | 7.17 |
N | 22 | 20 | 22 | 21 |
Males (%) | ||||
Mean | 46.4 | 50.3 | 48.4 | 42.3 |
S.D. | 14.66 | 16.25 | 17.74 | 15.19 |
N | 22 | 19 | 22 | 21 |
Females (%) | ||||
Mean | 53.6 | 49.7 | 51.6 | 57.7 |
S.D. | 14.66 | 16.25 | 17.74 | 15.19 |
N | 22 | 19 | 22 | 21 |
Male fetal weights (g) | ||||
Mean | 5.4 | 5.4 | 5.5 | 5.4 |
S.D. | 0.32 | 0.39 | 0.17 | 0.43 |
N | 22 | 19 | 22 | 21 |
Female fetal weights (g) | ||||
Mean | 5.1 | 5.0 | 5.2 | 5.1 |
S.D. | 0.28 | 0.42 | 0.21 | 0.31 |
N | 22 | 19 | 22 | 21 |
Combined fetal weights (g) | ||||
Mean | 5.2 | 5.2 | 5.3 | 5.3 |
S.D. | 0.27 | 0.38 | 0.18 | 0.36 |
N | 22 | 19 | 22 | 21 |
PROPORTIONAL (%) DATA COMPARED USING THE MANN-WHITNEY TEST
CORPORA LUTEA AND IMPLANTATION SITES COMPARED USING DUNNETT'S TEST
None significantly different from control group
SUMMARY OF FETUSES AND LITTERS WITH MALFORMATIONS [ABSOLUTE NO.]
Fetuses | Litters | |||||||
Dose group: | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number examined externally | 240 | 210 | 246 | 226 | 22 | 19 | 22 | 21 |
Number with findings | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Number examined viscerally | 121 | 108 | 124 | 114 | 22 | 19 | 22 | 21 |
Lung abnormal lobation | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Situs inversus | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Number examined skeletally | 120 | 102 | 122 | 112 | 22 | 19 | 22 | 21 |
Bent limb bone(s) | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Rib anomaly | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Vertebral centra anomaly | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
Vertebral anomaly with or without associated rib anomaly | 1 | 0 | 0 | 1 | 1 | 0 | 0 | 1 |
Total number with malformations | ||||||||
External: | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Soft tissue: | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Skeletal: | 3 | 1 | 0 | 1 | 3 | 1 | 0 | 1 |
Combined: | 3 | 1 | 0 | 1 | 3 | 1 | 0 | 1 |
1- 0 MG/KG 2- 100 MG/KG 3- 300 MG/KG 4- 1000 MG/KG
SUMMARY OF LITTER PROPORTIONS OF MALFORMATIONS % PER LITTER
Dose group: | 1 | 2 | 3 | 4 | |
Number of litters examined externally | 22 | 19 | 22 | 21 | |
Number of litters with findings | 0 | 0 | 0 | 0 | |
Number of litters examined viscerally | 22 | 19 | 22 | 21 | |
Lung-abnormal lobation | Mean | 0.8 | 0.0 | 0.0 | 0.0 |
S.D. | 3.55 | 0.00 | 0.00 | 0.00 | |
Situs inversus | Mean | 0.8 | 0.0 | 0.0 | 0.0 |
S.D. | 3.55 | 0.00 | 0.00 | 0.00 | |
Number of litters examined skeletally | 22 | 19 | 22 | 21 | |
Bent limb bone(s) | Mean | 0.9 | 0.0 | 0.0 | 0.0 |
S.D. | 4.26 | 0.00 | 0.00 | 0.00 | |
Rib anomaly | Mean | 0.8 | 0.0 | 0.0 | 0.0 |
S.D. | 3.55 | 0.00 | 0.00 | 0.00 | |
Vertebral centra anomaly | Mean | 0.0 | 1.1 | 0.0 | 0.0 |
S.D. | 0.00 | 4.59 | 0.00 | 0.00 | |
Vertebral anomaly with or without associated rib anomaly | Mean | 0.9 | 0.0 | 0.0 | 1.0 |
S.D. | 4.26 | 0.00 | 0.00 | 4.36 | |
Number of litters examined | 22 | 19 | 22 | 21 | |
Total malformations | |||||
Percent per litter with external malformations | Mean | 0.0 | 0.0 | 0.0 | 0.0 |
S.D. | 0.00 | 0.00 | 0.00 | 0.00 | |
Percent per litter with soft tissue malformations | Mean | 0.8 | 0.0 | 0.0 | 0.0 |
S.D. | 3.55 | 0.00 | 0.00 | 0.00 | |
Percent per litter with skeletal malformations | Mean | 2.6 | 1.1 | 0.0 | 1.0 |
S.D. | 6.66 | 4.59 | 0.00 | 4.36 | |
Total percent per litter with malformations | Mean | 2.4 | 1.1 | 0.0 | 1.0 |
S.D. | 6.27 | 4.59 | 0.00 | 4.36 |
1- 0 MG/KG 2- 100 MG/KG 3- 300 MG/KG 4- 1000 MG/KG
SUMMARY OF FETUSES AND LITTERS WITH VARIATIONS [ABSOLUTE NO.]
Fetuses | Litters | |||||||
Dose group: | 1 | 2 | 3 | 4 | 1 | 2 | 3 | 4 |
Number examined externally | 240 | 210 | 246 | 226 | 22 | 19 | 22 | 21 |
Number with findings | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Number examined viscerally | 121 | 108 | 124 | 114 | 22 | 19 | 22 | 21 |
Liver - small supernumerary lobe(s) | 3 | 5 | 5 | 1 | 3 | 5 | 3 | 1 |
Number examined skeletally | 120 | 102 | 122 | 112 | 22 | 19 | 22 | 21 |
14th rudimentary rib(s) | 53 | 55 | 66 | 76 | 19 | 18 | 20 | 21 |
14th full rib(s) | 5 | 6 | 13 | 10 | 5 | 4 | 9 | 8 |
Pelvic gridle- caudal shift | 6 | 5 | 13 | 9 | 5 | 4 | 9 | 8 |
Bent rib(s) | 9 | 8 | 12 | 7 | 8 | 6 | 8 | 4 |
Sternebra(e) malaligned (slight or moderate) | 12 | 19 | 16 | 9 | 9 | 13 | 11 | 7 |
reduced ossification of the skull | 7 | 13 | 15 | 11 | 5 | 9 | 8 | 7 |
7th cervical ossification site(s) | 10 | 6 | 6 | 9 | 6 | 5 | 5 | 5 |
Metacarpal(s) and/or metatarsal(s) unossified | 4 | 4 | 0 | 1 | 3 | 1 | 0 | 1 |
7th cervical full rib(s) | 0 | 2 | 0 | 0 | 0 | 2 | 0 | 0 |
Sternebra(e) #5 and/or #6 unossified | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 0 |
1- 0 MG/KG 2- 100 MG/KG 3- 300 MG/KG 4- 1000 MG/KG
Applicant's summary and conclusion
- Conclusions:
- No maternal toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups.
No developmental toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups.
In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for 2,2-Dimethylpropane-1,3-diyl dibenzoate was established as being at least 1000 mg/kg bw/day (limit dose; highest dose tested). - Executive summary:
In a study according to OECD guideline 414 twenty-two female rats were administered once daily doses of 100, 300 or 1000 mg/kg bw/day 2-dimethylpropane-1,3-diyl dibenzoate by oral gavage 7 days a week from Day 6 to Day 20 post-coitum. The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, gross necropsy findings, number of corpora lutea, (gravid) uterine weight and uterine contents. In addition, the following parameters were determined for the F1-generation: the number of fetuses, early and late resorptions, total implantations, fetal body weights, sex ratio, external, visceral (including sex) and skeletal malformations and developmental variations.
In addition, the No Observed Adverse Effect Levels (NOAELs) for maternal toxicity and developmental toxicity were evaluated.
The dose levels were selected based on the results of the repeated dose 28 day oral toxicity study with 2,2-Dimethylpropane-1,3-diyl dibenzoate by daily gavage in the rat (Test Facility Study No. 506379), and in an attempt to produce graded responses to the test item. Treatment up to 1000 mg/kg bw/day was well tolerated. No toxicologically significant changes were noted in any of the parameters investigated in the study.
Chemical analyses of formulations were conducted once during the study to assess accuracy and homogeneity.
The following parameters and end points were evaluated in this study for the F0-generation: mortality/moribundity, clinical signs, body weights, food consumption, gross necropsy findings, number of corpora lutea, (gravid) uterine weight and uterine contents. In addition, the following parameters were determined for the F1-generation: the number of fetuses, early and late resorptions, total implantations, fetal body weights, sex ratio, external, visceral (including sex) and skeletal malformations and developmental variations.
Formulation analyses confirmed that formulations of test item in Polyethylene glycol 400 were prepared accurately and homogenously.
No maternal toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups.
No developmental toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups.
In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for 2,2-Dimethylpropane-1,3-diyl dibenzoate was established as being at least 1000 mg/kg bw/day (limit dose; highest dose tested).
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