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EC number: 202-163-5 | CAS number: 92-52-4
- 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

Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study noted as being performed according to OECD453 and to GLP principles with a focus on urinary and bladder effects. No information was provided on hematology and clinical chemistry, with limited information on histopathology of other organs.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 002
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- Version / remarks:
- 1981
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Biphenyl
- EC Number:
- 202-163-5
- EC Name:
- Biphenyl
- Cas Number:
- 92-52-4
- Molecular formula:
- C12H10
- IUPAC Name:
- 1,1'-biphenyl
- Details on test material:
- - Name of test material (as cited in study report): biphenyl
- Analytical purity: >98%
- Stability under test conditions: concentrations in the diet were confirmed by gas chromatography and found within the range of 86.2 and 101% of target concentrations.
- Other: test substance obtained from Wako Pure Chemical Industries, Ltd. (Tokyo, Japan)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344/DuCrj
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan Inc. (Kanagawa, Japan)
- Age at study initiation: 6 weeks
- Weight at study initiation: mean body weights read from figure: roughly 95-130 g. The weight variation for each sex did not seem to exceed ± 20 % of the mean weight.
- Fasting period before study: no
- Housing: individually in stainless-steel wire-mesh hanging cages (170 x 294 x 176 mm)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week quarantine followed by 1 week acclimation
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 2
- Humidity (%): 55 +/- 10
- Air changes (per hr): 15-17
- Photoperiod (hrs dark / hrs light): 12 / 12 (fluorescent lighting)
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: no information
DIET PREPARATION
- Rate of preparation of diet (frequency): no information;
the diet containing appropriate concentrations of test substance was prepared by mixing in a spiral mixer for 20 min.
- Mixing appropriate amounts with (Type of food): gamma-irridiation sterilized CRF-1 powdered diet (Oriental Yeast Co., Chiba Japan)
- Storage temperature of food: 4 degC
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations in the diet were confirmed by gas chromatography and found within the range of 86.2 and 101% of target concentrations.
- Duration of treatment / exposure:
- 105 weeks
- Frequency of treatment:
- continuous
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
500 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
1500 ppm
Basis:
nominal in diet
- Remarks:
- Doses / Concentrations:
4500 ppm
Basis:
nominal in diet
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: not indicated
- Rationale for animal assignment (if not random): not indicated
- Section schedule rationale (if not random): not indicated - Positive control:
- no positive control tested
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: clinical signs, behavioral changes and mortality
BODY WEIGHT: Yes
- Time schedule for examinations: once a week for the first 14 weeks, and every 4 weeks thereafter
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): food consumption was measured once a week for the first 14 weeks, and every 4 weeks thereafter.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
OPHTHALMOSCOPIC EXAMINATION: Yes, as anemia-colored eyes were noticed.
- Time schedule for examinations: no data
- Dose groups that were examined: at least the high dose group males (showing hematuria)
HAEMATOLOGY: No data
CLINICAL CHEMISTRY: No data
URINALYSIS: Yes
- Time schedule for collection of urine: final week (week 105)
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: urinary parameters including pH and occult blood using Urolabsix (Diagnostic Diutsior, bayer, Elkhart, Germany)
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- All organs were examined macroscopically, the organs weighed and the tissues for microscopic examination included the ones specified in the OECD 453 test guideline.
- Statistics:
- Chi-square test (incidence non-neoplastic lesions, urinary data) and Fisher's exact test (incidence neoplastic lesions)
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, treatment-related
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
Mortality males: control 13/50; 500 ppm 9/50; 1500 ppm 9/50; 4500 ppm 19/50 (statistically significant)
Mortality females: control 5/50; 500 ppm 12/50; 1500 ppm 5/50; 4500 ppm 13/50
Clinical hematuria was observed from the 40th week onward in 32 males of the 4500 ppm group, of which 14 had anemia-colored skin and/or eyes.
No clinical signs in females.
BODY WEIGHT AND WEIGHT GAIN
Significant body weight decrease in 4500 ppm males. Other dose groups and females were normal.
OPHTHALMOSCOPIC EXAMINATION
Anemia colored eyes in 4500 ppm males (number unknown) with clinical hematuria.
URINALYSIS
4500 ppm males: significant increase in urinary pH (ca. 104%) and incidences of positive occult blood (23/50), compared to controls (1/50).
4500 ppm females: significant increase in incidences of positive occult blood (10/50) compared to controls (1/50).
ORGAN WEIGHTS
Relative kidney weight: statistically significant increase in 1500 and 4500 ppm rats (males and females)
Absolute kidney weight: statistically significant increase in 4500 ppm males.
GROSS PATHOLOGY
Bladder calculi: 43/50 in the 4500 ppm males (40th week onwards), 8/50 in the 4500 ppm females. No calculi were observed in other dose groups.
Male calculi varied in color, shape and sizes. The male calculi were triangular, pyrimidal and cubical in shape, with sizes ranging form 0.3-1.0 cm
Female calculi were white/yellow, spheroidal and of same size.
4/8 in the 4500 ppm females with calculi had thickening of bladder wall.
41/50 in the 4500 ppm males had polyp-like or papillary nodules which protruded from the bladder wall into the lumen. Of these 41, 38 had also bladder calculi.
HISTOPATHOLOGY: NON-NEOPLASTIC
Other organs than bladder: no tumor-related lesions.
500 ppm and 1500 ppm groups: There were no significant lesions of the urinary bladder, ureter or kidney. In the 1500 ppm females there was simple transitional cell hyperplasia of renal pelvis (12/50) and deposit of hemosiderin (22/50).
4500 ppm dose groups:
Significant lesion of the bladder in 4500 ppm males :
- transitional cell hyperplasia: simple (12/50), nodular (40/50), papillary (17/50), total (45/50).
- Squamous metaplasia: (19/50)
- Squamous cell hyperplasia (13/50)
- Inflammatory polyp (10/50).
In 4500 ppm females some bladder lesions identified as significant in the males dosed with 4500 ppm were also found, but they were not statistically significant.
Significant other lesions in 4500 ppm males:
- Ureter transitional cell hyperplasia: simple (8/50)
- Ureter dilatation (14/50)
- Renal pelvis transitional cell hyperplasia: simple (19/50) or nodular (21/50)
- Pelvis desquamation (11/50)
- Pelvis calculi (13/50)
- Mineralization of cortico-medullary junction: (10/50)
- Mineralization of papilla (23/50).
Significant other findings/lesions in 4500 ppm females:
- Renal pelvis transitional cell hyperplasia: simple (25/50) or nodular (12/50)
- Mineralization of pelvis (27/50)
- Mineralization of papilla (12/50)
- Papillary necrosis (23/50) or infarct (8/50)
- deposit of hemosiderin (25/50)
Significant other findings/lesions in 1500 ppm females:
- Renal pelvis transitional cell hyperplasia: simple (12/50)
- deposit of hemosiderin (22/50)
A few other none statisitically significant lesions were also identified in both males and females dosed with 4500 ppm of the test substance.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Other organs than bladder: no tumor or tumor-related lesions.
Urinary bladder, ureter, kidney: no lesions in control, 500 ppm and 1500 ppm groups (m/f).
Significant neoplastic lesions in 4500 ppm males:
- Transitional cell papilloma (10/50)
- Carcinoma (24/50).
- Total bladder tumors (31/50)(3 rats had both transitional cell papilloma and carcinoma). One rat showed squamous cell papilloma and carcinoma (not significant).
In 4500 ppm females no neoplastic lesions were found.
HISTORICAL CONTROL DATA: Neither squamous cell papilloma nor squamous cell carcinoma have been observed in the F344 male rats historically either in the laboratory performing the study nor by NTP.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 4 500 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOAEL
- Effect level:
- 1 500 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- food consumption and compound intake
- other: none
- Dose descriptor:
- LOAEL
- Effect level:
- 1 500 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: A statistically significant (and dose-dependent) increase in simple transitional cell hyperplasia and deposit of hemosiderin was observed at levels at and above 1500 ppm.
- Dose descriptor:
- NOAEL
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Tumors in male rats dosed with 4500 ppm biphenyl were induced in high association with calculus formation and hematuria, together with pre-neoplastic, regenerative lesions in the urinary system.
In the male rat, the transitional cell hyperplasia and the squamous cell hyperplasia were considered to represent a regenerative, pre-neoplastic response to the epithelial damage caused by bladder calculi rather than to administration of biphenyl. The hyperplasia can be therefore categorized as a pre-neoplastic lesion with possible progression into bladder tumors.The sustained mechanical damage caused by the bladder calculi plays an important role in tumorigenesis. The physical characteristics of the bladder calculi such as size and shape can be considered to affect the degree and/or frequency of pre-neoplastic and neoplastic lesions occurring in response to mechanical damage to the bladder epithelium caused by calculi.
The authors indicated that a sex-difference in the metabolic pathways of biphenyl plays an important role in the formation of bladder calculi and the development of bladder tumors.
Applicant's summary and conclusion
- Conclusions:
- Mortality was significantly increased in males dosed with 4500 ppm over two years. In addition to mortality, animals in this dose group also exhibited statistically significant decreases in body weight, increases in urinary pH and presence of occult blood in the urine. Males dosed with 4500 ppm also exhibited significant increases in non-neoplastic and neoplastic lesions of the bladder and urinary system.
In females statistically significant (and dose-dependent) increases of simple transitional cell hyperplasia of renal pelvis and deposit of hemosiderin was observed at levels at and above 1500 ppm.
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