Registration Dossier

Toxicological information

Specific investigations: other studies

Currently viewing:

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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: >99%
- Lot/batch No.: CHHYDD0051
- Stability under test conditions: confirmed

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male
Details on test animals 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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500 mg/kg bw/day
Basis:
nominal in diet
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.