Biphenyl-2-ol

Specific investigations: other studies

Administrative data

Endpoint:

mechanistic studies

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 20, 2009 - February 3, 2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: non GLP study, no applicable guideline, well documented

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

no guideline available

GLP compliance:

no

Type of method:

in vivo

Endpoint addressed:

carcinogenicity

Test material

Test material information

Constituent 1

Reference substance name:

Biphenyl-2-ol

EC Number:

201-993-5

EC Name:

Biphenyl-2-ol

Cas Number:

90-43-7

Molecular formula:

C12H10O

IUPAC Name:

[1,1'-biphenyl]-2-ol

Test material form:

solid

Details on test material:

- Lot/batch No.: CHHYDD0051

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, North Carolina)
- Age at study initiation: 6 Weeks
- Housing: animals were housed one per cage in stainless steel cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C with a tolerance of ± 1°C (and a maximum permissible excursion of ± 3°C)
- Humidity (%): 40-70%
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: January 20, 2009 To: February 3, 2009

Administration / exposure

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

7 or 14 days

Frequency of treatment:

ad libitum

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
500 mg/kg bw/day
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1000 mg/kg bw/day
Basis:
nominal in diet

No. of animals per sex per dose:

3

Control animals:

yes, plain diet

Details on study design:

For this pilot study, male B6C3F1 mice (3/dose /time point) were exposed to 0, 500, or 1000 mg/kg/day OPP in the diet for 7 or 14 days.

Examinations

Examinations:

Following exposure, targeted liver cytochrome P450 (Cyp1a1, Cyp2b10, Cyp3a11, and Cyp4a10) gene expression and Cyp2b enzymatic activity (PROD) were evaluated to address possible aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome-proliferator-activated-receptor-alpha (PPARa) mediated liver enlargement, respectively.

Results and discussion

Details on results:

Of the endpoints examined, only Cyp4a10 gene expression was elevated in both treatment groups at 7 and 14 days (range of 52- to 113-fold). Although Cyp2b10 gene expression was elevated in the top dose 7.26-fold at 7 days, the small degree of gene induction compared to Cyp4a10, combined with the lack of Cyp2b enzyme activity (PROD), suggest only peripheral involvement of CAR.
In addition, histopathologic evaluation of archived liver tissue from male mice exposed to 1000 mg/kg/day OPP for one year revealed centrilobular or panlobular hepatocyte hypertrophy with finely granular to homogenous cytoplasm and increased eosinophilia, which was suggestive of increased amounts of peroxisomes and/or smooth endoplasmic reticulum.

Applicant's summary and conclusion

Conclusions:

The results indicate that OPP may be an agonist ligand for PPARa and this activity might have played a role in the development of liver tumors observed in the 2-year chronic study.