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Specific investigations: other studies

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mechanistic studies
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The set-up of this study was similar to a chronic guideline study (104 weeks dietary exposure), but no examinations were done, except for analysis of calculi in the urinary bladder. Only one concentration was tested.

Data source

Reference Type:

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
50 rats per sex and per dose were fed for 104 weeks with a diet containing 0.45% biphenyl. After the administration period, calculi from the urinary bladder were collected and analysed.
GLP compliance:
not specified
Other chronic studies from the same lab are performed according to GLP principles.
Type of method:
in vivo
Endpoint addressed:
not applicable

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): biphenyl
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Lot/batch No.: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other: obtained from Wako Pure Chemical Ind. (Osaka, Japan)

Test animals

Fischer 344/DuCrj

Administration / exposure

Route of administration:
oral: feed
unchanged (no vehicle)
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
Post exposure period:
not applicable
Doses / concentrations
Doses / Concentrations:
0.45% (w/w) i.e. 4500 ppm
nominal in diet
No. of animals per sex per dose:
Control animals:
yes, plain diet

Results and discussion

Details on results:
43/50 (86%) of the biphenyl-treated male rats had calculi in the urinary bladder, whereas only 8/50 (16%) of similarly treated female rats developed such calculi. The shapes of calculi in males varied, whereas the majority of the calculi in females were spheroid. Urinary calculi in male rats were composed mainly of potassium 4-hydroxybiphenyl-o-sulfate (4-HBPOSK), whereas calculi in female rats were composed mainly of 4-hydroxybiphenyl (4-HBP) and KHSO4 produced by the hydrolysis of 4-HBPOSK. Calculi in males had a multilayer structure consisting of alternating layers of 4-HBPOSK and calcium phosphate, whereas the calculi in females had no multilayer structure, but open holes in which needle-shaped crystals are present in some places. Calculus formation in males may involve a series of successive and irreversible reactions, whereas calculus formation in females may result from a series of reversible reactions, including hydrolysis of 4-HBPOSK.

Any other information on results incl. tables

Comparison of urinary calculi in male and female rats.

Calculi in males:

Shape Spheroid, triangular pyramidal, cubical

Size 0.3-1.0 cm

Color White, yellow, brown, gray, black

Main constituent potassium 4-hydroxybiphenyl-o-sulfate (4-HBPOSK)

Principal elements S, K, P, Ca

Structure Multilayer composed of inside alternating layers (S-K layer and P-Ca layer) and an outside thick layer

Components Inner layer (4-HBPOSK) Outer layer (Ca3(PO4)2)

Distribution of principal elements Inside alternating layers (S-K and P-Ca layers) Outside thick layer (P-Ca)

Calculi in females:

Shape Spheroid

Size 0.3-1.0 cm

Color White, yellow

Main constituent 4-hydroxybiphenyl (4-HBP)and potassium sulfate

Principal elements S, K, P, Ca

Structure Stone-like lump with the center hole, where the needle crystal exists, and outside thin layer

Components Open hole needle (4-HBP) Open hole surrounding area (KHSO4)

Distribution of principal elements Inside layer (S-K) Outside thin layer (P-Ca)

Applicant's summary and conclusion

It appears that calculus formation in male rats may involve a series of successive and irreversible reactions, whereas calculus formation in females may result from a series of reversible reactions, including the hydrolysis of 4-HBPOSK. The series of irreversible reactions involved in calculus formation in male rats seems to be relatively more stable than that in the case of female rats. Thus, a sex difference in the reaction features may be responsible for the observed difference in the incidence of calculus formation.