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EC number: 482-400-9 | CAS number: 138776-88-2
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Study period:
- 2010
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD guidenline and GLP study.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Remarks:
- Not specified in report
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- Remarks:
- Not specified in report
- Qualifier:
- according to guideline
- Guideline:
- other: EPA 712-C-00-366
- Deviations:
- no
- Remarks:
- Not specified in report
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 482-400-9
- EC Name:
- -
- Cas Number:
- 138776-88-2
- Molecular formula:
- C52H56O6P2
- IUPAC Name:
- 9-[(3,3',5,5'-tetra-tert-butyl-2'-{8,10-dioxa-9-phosphatricyclo[9.4.0.0²,⁷]pentadeca-1(11),2(7),3,5,12,14-hexaen-9-yloxy}-[1,1'-biphenyl]-2-yl)oxy]-8,10-dioxa-9-phosphatricyclo[9.4.0.0²,⁷]pentadeca-1(11),2,4,6,12,14-hexaene
- Details on test material:
- Test material information section indicated that the purity of the test material was 93.6% ± 0.27% RSD by high performance liquid chromatography, 0.1% wt. ethyl acetate by gas chromatography, with identification by nuclear magnetic resonance and high performance liquid chromatography mass spectrometry. The test material was supplied by 'The Dow Chemical Company, South Charleston, West Virginia' with the lot number VD1255T809.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The animals were 6-8 weeks old at the start of the study. The animals were housed two-three per cage in stainless steel cages, in rooms designed to maintain adequate conditions (temperature, humidity, and photocycle), and acclimated to the laboratory for at least one week prior to the start of the study. Before administration of test material, animals were stratified by body weight and then randomly assigned to treatment groups using a computer program designed to increase the probability of uniform group mean weights and standard deviations at the start of the study. Animals placed on study were uniquely identified via subcutaneously implanted transponders. Animals were provided LabDiet Certified Diet in meal form. After assignment, animals were housed one per cage in stainless steel cages. The temperature and humidity maintained were 22°C with a tolerance of ± 1°C (and a maximum permissible excursion of ± 3°C) and 40-70%, respectively. 12-hour light/dark cycle was maintained throughout the study period with air changes of 12-15 times/hour.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- All dosing suspensions were prepared by mixing the test material in corn oil at concentrations of 0, 25, 75, or 250 mg/ml and administered at a dose volume of 4 ml/kg body weight to achieve the targeted dose levels. Dose suspensions were not adjusted for purity. Dose volumes were adjusted at least weekly based on individual body weights.
The control rats were dosed with corn oil at 4 ml/kg body weight. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose confirmation analysis of all dose suspensions from the first mix was determined pre-exposure. The homogeneity of the low-dose and the
high-dose test suspensions was determined concurrent with dose confirmation. The method used for analyzing the test material in corn oil was
high performance liquid chromatography with ultraviolet detection. Stability of the test material in the vehicle was initiated prior to the start of the study at concentrations of 0.25, 2.5, 25 and 250 mg/mL. The test material was found to be stable for at least 14 days at concentrations of 25 and 250 mg/mL . Test suspensions were prepared and used within these stability limits. - Duration of treatment / exposure:
- Animals were dosed once daily, seven days/week for 29 days.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100 mg/kg/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
300 mg/kg/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1000 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Test material was administered to groups of five male and five female F344/DuCrl rats by gavage at targeted dose levels of 0, 100, 300, or 1000 mg/kg body weight/day in corn oil. for at least 28 days to evaluate the potential for systemic toxicity. Daily cage-side observations, daily clinical observations, weekly detailed clinical observations, ophthalmic examinations, functional tests, body weights, feed consumption, hematology,
prothrombin time , urinalysis, clinical chemistry, and selected organ weights were evaluated (4Table 1). In addition, a gross necropsy was
conducted with extensive histopathology examination of tissues.
Examinations
- Observations and examinations performed and frequency:
- - Cage-side examination: At least once a day, generally at the same time each day (usually in the morning).
- Clinical observations: All animals pre-exposure and weekly throughout the study.
- Detailed clinical observations (DCO): Pre-exposure and once per week throughout the study.
- The functional tests (sensory evaluation, rectal temperature, grip performance and motor activity): Pre-exposure and during the last week of the
treatment period.
- Ophthalmological examination: Pre-exposure and prior to the scheduled necropsy using indirect ophthalmoscopy.
- Body weight: Pre-exposure, twice during the first week and at least weekly during the dosing period.
- Food consumption: Twice during the first week and at least weekly
- Clinical pathology: At scheduled necropsy
- Hematology: Hematocrit (HCT), Hemoglobin (HGB) concentration, Red blood cell (RBC) count, Total white blood cell (WBC) count, Differential WBC count, Platelet (PLT) count, Reticulocyte (RET) count, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC)
- Coagulation: Prothrombin time (PT)
- Clinical chemistry: Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST),
Gamma-glutamyl transpeptidase (GGT), Albumin (ALB), Albumin/Globulin Ratio (A/G) (calculated), Cholesterol (CHOL), Creatinine (CREA), Electrolytes (NA, K, PHOS, CL and CA), Globulin (GLOB)(calculated), Glucose (GLU), Total Bile Acids (TBA), Total bilirubin (TBIL), Total protein (TP), Triglycerides (TRIG), Urea nitrogen (UN)
- Urinalysis: Color, appearance, specific gravity (refractometer) and urine volume, pH, Bilirubin, Glucose, Protein, Ketones, Blood, Urobilinogen, Microscopic examination
- Anatomic pathology: At scheduled necropsy
- Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY
- Organ weights: Brain, liver, kidneys, heart, adrenals, testes, epididymides, prostate + seminal vesicles with coagulating glands (and fluids), prostate, thymus and spleen.
- Macroscopic: Major organs, all gross lesions
- Microscopic: all the organs - Other examinations:
- None
- Statistics:
- All parameters examined statistically (feed consumption is addressed below) were first tested for equality of variance using Bartlett's test (alpha = 0.01; Winer, 1971). If the results from Bartlett's test were significant, then the data for the parameter may be subjected to a transformation to obtain equality of the variances. The transformations that were examined are the common log, the inverse, and the square root, in that order. In-life body weights were evaluated using a repeated measures (RM) analysis of variance (ANOVA), the multivariate approach, for time (the repeated factor), sex, and dose (Winer, 1971). In the RM-ANOVA, differences between the groups were primarily detected by the time-dose interaction. Terminal body weight, organ weight (absolute and relative, excluding epididymides and testes), urine volume, urine specific gravity, hematologic parameters (excluding RBC indices and differential WBC), coagulation and clinical chemistry parameters (excluding globulin and albumin/globulin ratio) were evaluated using a two-way ANOVA (Steel and Torrie, 1960) with the factors of sex and dose. Results for epididymides, testes, prostate + seminal vesicles with coagulating glands (and fluids), and prostate weights (absolute and relative) were analyzed using a one-way ANOVA. Feed consumption data were evaluated by Bartlett's test for equality of variances. DCO and sensory evaluation incidence data (scored observations only) were qualitatively analyzed. Means and standard deviations were calculated for rectal temperature, grip performance and motor activity counts. Motor activity counts were reported as their square roots to minimize problems of heterogeneity of variance and departure from normality that commonly occur from treatment
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- 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:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- liver weight increases
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- vacuolization of hepatocytes consistent with fatty change
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: No clinical signs or deaths
DETAILED CLINICAL SIGNS AND CAGE SIDE OBSERVATIONS: No effects
FUNCTIONAL TESTS: No effects
OPHTHALMOLOGY: No effects
BODY WEIGHT AND WEIGHT GAIN: No effects
FOOD CONSUMPTION: No effects
HEAEMATOLOGY: No effects
PROTHROMBIN TIME: No effects
CLINICAL CHEMISTRY: No effects
URINALYSIS: No effects
ORGAN WEIGHTS:
LIVER: Limited to statistically significant higher absolute and relative liver weights of males and females in the 1000 mg/kg/day group, and a statistically-significant higher relative liver weight of males in the 300 mg/kg/day group.
KIDNEY: Males and females in the 1000 mg/kg/day group had statistically-identified higher mean relative kidney weight, which was interpreted to be unrelated to treatment because it was within the historical control range.
TESTES: Males in the 300 mg/kg/day group also had a statistically identified lower mean relative testes weight. This finding was interpreted to be unrelated to treatment as it lacked a dose-response relationship, was within the historical control range, and was reflective of the higher body weights of males at this dose level, relative to the controls. Furthermore, histopathology of testes did not detect any alterations.
GROSS PATHOLOGY: No effects
HISTOPATHOLOGY: NON-NEOPLASTIC: Treatment-related histopathologic changes were limited to the liver and consisted of vacuolization of hepatocytes consistent with fatty change in males and females in the 300 or 1000 mg/kg/day groups.
Effect levels
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
None
Applicant's summary and conclusion
- Conclusions:
- The no-observed-effect level (NOEL) for F344/DuCrl Rats of either sex was the targeted dose of 100 mg/kg/day test material. .
- Executive summary:
Five male and five female F344/DuCrl rats per group were administered 0, 100, 300, or 1000 milligrams 6,6'-[[3,3',5,5'-tetrakis(1,1-dimethylethyl)-[1,1'- biphenyl]-2,2'-diyl] bis(oxy)]bis-dibenzo[d,f][1,3,2]-dioxaphosphepin per kilogram body weight per day (mg/kg/day) in corn oil via oral gavage for 28 days to evaluate the potential for systemic toxicity. Parameters evaluated were daily cage-side observations, daily clinical observations, weekly detailed clinical observations, ophthalmic examinations, functional tests, body weights, feed consumption, hematology, prothrombin time, urinalysis, clinical chemistry, selected organ weights, and gross and histopathologic examinations. There were no treatment-related effects in clinical signs, body weights, feed consumption, ophthalmic examinations, functional tests, hematology, prothrombin time, clinical chemistry, urinalysis parameters or gross pathologic observations. Treatment-related effects on organ weights were limited to statistically-identified higher absolute and relative liver weights of males and females in the 1000 mg/kg/day group, and a statisticallyidentified higher relative liver weight of males in the 300 mg/kg/day group. These organ weight findings corresponded to hepatocellular vacuolization (consistent with fatty change) of various regions of the liver lobules in males and females at these dose levels. All males in the 1000 mg/kg/day group had vacuolization of centrilobular/midzonal or panlobular hepatocytes consistent with a very slight or slight fatty change. Very slight fatty change in centrilobular hepatocytes was present in 2 of 5 males in the 300 mg/kg/day group. The majority of females in the 300 mg/kg/day (4 of 5 animals) and all of the females in the 1000 mg/kg/day group had periportal hepatocyte vacuolization consistent with a slight or moderate fatty change, respectively. The no-observed-effect level (NOEL) for F344/DuCrl rats of either sex was the targeted concentration of 100 mg/kg/day test material.
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