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EC number: 204-029-1 | CAS number: 113-48-4
- 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:
- 1986-1987
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 987
- Report date:
- 1987
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide
- EC Number:
- 204-029-1
- EC Name:
- N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide
- Cas Number:
- 113-48-4
- Molecular formula:
- C17H25NO2
- IUPAC Name:
- N-(2-ethylhexyl)-8,9,10-trinorborn-5-ene-2,3-dicarboximide
- Reference substance name:
- (E)-1,4-Bis(2-ethylhexylamino)-2-butene-1,4-dione
- Molecular formula:
- C20H38N2O2
- IUPAC Name:
- (E)-1,4-Bis(2-ethylhexylamino)-2-butene-1,4-dione
- Reference substance name:
- 1-(2-ethylhexyl)-1H-pyrrole-2,5-dione
- Molecular formula:
- C12H19NO2
- IUPAC Name:
- 1-(2-ethylhexyl)-1H-pyrrole-2,5-dione
- Test material form:
- liquid
- Details on test material:
- Purity and characterisation analysis conducted on the following sample; Supplier: McLaughlin Gormley King ; Batch Number: AB9500
Constituent 1
impurity 1
impurity 2
- Specific details on test material used for the study:
- MGK 264
LOT 3843
Active Ingredients: N - Octybicycloheptene dicarboximide 98.00%
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- Eighty-five untreated, sexually mature 4 month old, virgin female New Zealand White SPF rabbits were received from Hazleton Research Animals, Denver, Pennsylvania on August 13, 1986. During the 142-day acclimation period, the animals were carefully observed for
changes in appearance and behavior. each animal was provided with basal Rabbit Chow® #5322 and tap water ad libitum.
The temp/humidity recording was monitored and maintenance was notified if protocol-designated ranges (temperature 15 to 19°C, humidity 30 to 70%) were exceeded. Fluorescent lighting provided illumination 12 hours per day. The females were housed individually in suspended stainless steel cages from receipt until sacrifice. Nesting material was not provided since the females were sacrificed prior to delivery. Each female was identified by cage,"group and individually by a Monel® metal ear tag bearing its animal number. The individual animal number plus the IRDC study number comprised a unique identification number for each animal. The females were approximately 8-1/2 months old at the time of insemination and weighed between 3672 and 5452 g on gestation day 0.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% methylcellulose
- Details on exposure:
- The test article was prepared at concentrations to permit the administration of dose levels of 10, 30 and 100 mg/kg/day at a dosage volume of 3 ml/kg. The test article was administered as a single daily dose on days 7 through 19 of gestation. Test article administration was accomplished by intragastric intubation using 20 cc disposable plastic syringes and 12 gauge, 15 cm long curved stainless steel dosing needles. Dosing began approximately 6 to 10 1/4 hours after initiation of the illuminated phase of the photoperiod.
The control group received the vehicle only on a comparable regimen at a volume of 3 ml/kg. Individual dosages were determined from the most recently recorded individual body weights. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- During the study, the 24-hour stability of test suspensions was assessed. In addition, the first daily preparation of each dosing week was analyzed for concentration.
Gas Chromatograph with FID detector used:
Gas Chromatograph Parameters (may be changed as necessary to optimize analyte chromatography) .
1. Instrument; Tracor 560 fitted with flame ionization detector (FID)
2. Column; 6' x 4 mm glass column packed with 5% OV-101 on chromosorb W/HP
3. Temperatures; Oven 157°C, Detector 283°C Injector 242°C
4. Flow rate; Carrier; (Nz) 27 ml/min, Air; 1. 45 SCFH, Hz; 30 mg/min
5. Injection volume; about 6 mcl.
Inject equal volumes of standard and sample in the order; standard, sample, sample, standard, sample, etc ...
Measure peak heights of the internal standard and the first component of the 2 component test article. - Details on mating procedure:
- Eight proven male rabbits of the same breed and source were selected to serve as donors. Semen was collected using an artificial vagina and the gelatinous plug was removed from the ejaculate. The semen was immediately evaluated for motility and was used for insemination only if the motility was 60% or greater. The ejaculate was diluted with 3.0 ml of 0.9% Sodium Chloride for Injection U.S.P. at 33-37°C and 0.3 ml of this dilute semen was introduced into the anterior vagina of the female using an insemination pipette. A minimum of 0.5 million sperm/doe was provided at insemination. Immediately after insemination, ovulation was induced by an injection of 100 U.S.P. units of human chorionic gonadotropin into a marginal ear vein. Semen from one male was used to inseminate an equal number of females in each group. Insemination procedures were performed on three consecutive days and an equal number of females were inseminated in each group per day. The day of insemination was designated as day 0 of gestation.
- Frequency of treatment:
- single daily dose on days 7 through 19 of gestation.
- Duration of test:
- 29 days of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Vehicle control group
- No. of animals per sex per dose:
- 16 female rabbits per dose group
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- Survival, Appearance and Behavior
Throughout the study the females were observed twice daily for mortality and overt changes in appearance and behavior. The presence and duration of clinical signs of toxicity were recorded once daily on days 0 through 29 of gestation. Females not surviving to the scheduled sacrifice were necropsied in an attempt to determine the cause of death. Any female showing signs of abortion or premature delivery was sacrificed and necropsied on the day such evidence was observed. Fetuses from does that died, aborted, delivered or were sacrificed within a day of scheduled Cesarean section were processed and evaluated as for the scheduled termination animals. Fetuses from does dying or aborting prior to this time were preserved in neutral buffered 10% formalin for possible future ewaluations. Maternal tissues were preserved in neutral buffered 10% formalin for microscopic examination as deemed necessary by the gross findings. - Ovaries and uterine content:
- Immediately following sacrifice, the uterus and ovaries were exposed by an abdominal incision. The number and location of viable and nonviable fetuses, early and late resorptions and the number of total implantations and corpora lutea were recorded. The uterus was then excised and the fetuses removed. The abdominal and thoracic cavities and organs of the does were examined for grossly evident morphological changes and the carcasses discarded. Maternal tissues were preserved in neutral buffered 10% formalin for histopathological examination as deemed necessary by the gross findings. Uteri from females that appeared nongravid were opened and placed in 10% ammonium sulfide solution for detection of implantations.
- Fetal examinations:
- All fetuses were individually weighed, tagged and examined for external malformations and variations. Each fetus was dissected, internally sexed and examined for visceral malformations and variations, including the brain by a mid-coronal slice. The heart was dissected by a modification of the method described by Staples. The eviscerated skinned fetuses were fixed in alcohol, macerated in potassium hydroxide, stained with Alizarin Red S and cleared with glycerin by a method similar to that described by Dawson for subsequent skeletal examination.
- Statistics:
- A.ll statistical analyses compared the treatment groups with the control group, with the levels of significance ac p<0.05 and p<0.01. All
means were accompanied by standard deviations. Male to female fecal sex ratios were compared using the Chi-square test criterion with Yates' correction for 2 x 2 contingency tables and the proportions of litters with malformations were compared using Fisher's exact probability test as described by Siegel to determine the significance of differences.
The proportions of resorbed and dead fetuses and post-implantation losses were compared by the Mann-Whitney U-test as described by Siegel and Weil to determine the significance of differences.
Numbers of corpora lutea, total implantations and live fetuses, mean maternal and fecal body weights and maternal body weight changes were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variance and the appropriate t-test (for equal or unequal variance) as described by Steel and Torrie using Dunnett's multiple comparison tables to determine the significance of differences. - Historical control data:
- The rabbit is an acceptable model for teratology studies. This laboratory has historical control data on the incidence of fetal malformations and variations in this strain from this source. This strain is susceptible to known teratogenic agents.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- There was an increased incidence of post-dose excessive salivation at the high-dose level compared to the control group. This finding was considered treatment related. This was also seen in one mid-dose animal.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Control - 1 aborted
10mg/kg - 1 died and 1 aborted
30mg/kg - 3 died and 1 aborted
100mg/kg - 1 aborted
Given the lack of a dose-relationship, the deaths and abortions seen in this study were not considered treatment related - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no biologically relevant differences between the mean maternal body weight changes of the treated groups and those of the
control group during the treatment (gestation days 7 through 19), overall gestation (gestation days 0 to 29) or adjusted gestation (gestation days 0 to 29 less the weight of uterus and contents) intervals. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- not examined
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Control - 1 aborted
10mg/kg - 1 died and 1 aborted
30mg/kg - 3 died and 1 aborted
100mg/kg - 1 aborted
Given the lack of a dose-relationship, the deaths and abortions seen in this study were not considered treatment related - Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Only 1 loss seen in study at 100mg/kg therefore considered not treatment related.
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- no effects observed
- Other effects:
- not examined
- Details on maternal toxic effects:
- MGK 264 was considered to be responsible for an increase in the incidence of excessive salivation in the high dose females (100 mg/kg bw/day). The high dose in this study was selected based on the findings of a dose range finding study in which there was excessive toxicity at 300 mg/kg bw/day (lowest dose tested).
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- clinical signs
Results (fetuses)
- 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:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All malformations of fetuses observed were noted exclusively among the treated groups. However, no relationship to treatment was assumed as the anomalies seen in each group occurred in single incidence. See attached table Fetal Malfunctions (background information)
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All malformations of fetuses observed were noted exclusively among the treated groups. However, no relationship to treatment was assumed as the
anomalies seen in each group occurred in single incidence. See attached table Fetal Malfunctions (background information) - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All malformations of fetuses observed were noted exclusively among the treated groups. However, no relationship to treatment was assumed as the anomalies seen in each group occurred in single incidence. See attached table Fetal Malfunctions (background information)
- Other effects:
- not examined
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no significant changes observed were caused by test material at 100 mg/kg/day (highest dose level tested)
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Lowest effective dose / conc.:
- 100 mg/kg bw/day (nominal)
Applicant's summary and conclusion
- Conclusions:
- Treatment of pregnant New Zealand White SPF rabbits with MGK 264 did not elicit fetotoxic effects at any dosage level tested. The test article was considered responsible for an increase in the incidence of excessive salivation in the maternal high- dose group animals. In conclusion, the no observable effect level of MGK 264 with respect to fetotoxicity was 100 mg/kg/day (high-dose) when administered orally to pregnant New Zealand White SPF rabbits.
- Executive summary:
Mated female New Zealand White Rabbits, randomly assigned to one control and three treatment groups of 16 animals each, were used to determine the developmental toxicity potential of MGK® 264. Dosage levels of 10, 30 and 100 mg/kg/day were administered orally by gavage as a single daily dose on days 7 through 19 of gestation at a volume of 3 ml/kg. The control group received the vehicle only, 0.5% methylcellulose, on a comparable regimen. Cesarean sections were performed on all surviving females on gestation day 29 and the fetuses were removed for teratologic evaluation.
Treatment of New Zealand White rabbits with MGK® 264 elicited maternally toxic effects (increased incidence of excessive salivation) in the high-dose group. The test article did not induce developmentally toxic effects at any dosage level.
In summation, the no observable effect level of MGK® 264 with respect to developmental toxicity was 100 mg/kg/day when administered orally by gavage to New Zealand White Rabbits.
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