2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

Genetic toxicity: in vivo

Administrative data

Endpoint:

genetic toxicity in vivo

Remarks:

Type of genotoxicity: other: Hepatic cRNA array,

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Published

Data source

Reference

Reference Type:

publication

Title:

Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver

Author:

Ellinger-Ziegelbauer, H., Stuart, B., Wahle, B., Bomann, W., Ahr, H.J.

Year:

2005

Bibliographic source:

Mutation Research 575, 61-84

Materials and methods

Principles of method if other than guideline:

Groups of male Wistar rats was treated with 1200 mg/kg bw/day for 1, 3 or 7 days; liver were taken for histopathological evaluation and gene expression profiles analysed using Affimetriy RG_U34A arrays

GLP compliance:

not specified

Type of assay:

other: In vivo repeated dosing, enzyme induction/inhibition array

Test material

Test material information

Constituent 1

Reference substance name:

Piperonyl butoxide

IUPAC Name:

Piperonyl butoxide

Constituent 2

Reference substance name:

2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

EC Number:

200-076-7

EC Name:

2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

Cas Number:

51-03-6

Molecular formula:

C19H30O5

IUPAC Name:

2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

Details on test material:

Purity 88.5%
Source Sigma, St Louis, MO, USA

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

Carboxymethyl cellulose

Details on exposure:

no data

Duration of treatment / exposure:

1, 3, 7 days

Frequency of treatment:

daily

Post exposure period:

none

Doses / concentrations

Remarks:

Doses / Concentrations:
1200 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Positive control(s):

Dimethylnitrosamine, 2-nitrofluorene, aflatoxin B1, 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK)

Examinations

Tissues and cell types examined:

Liver

Details of tissue and slide preparation:

Livers were excised and processed for histopathological examination and RNA extraction
RNA isolation with Qiagen RNAeasy 96 well kits and quality control using RNA 6000 Nanaochips on Agilent 2001 Bioanalyzer (Agilent Technologies GmbH, Germany)
biotin labelled cRNA samples were prepared and hybridizatuion on Affymetrix Genechip RG_U34A arrays according to published procedures.

Evaluation criteria:

Data evaluation using Gene-Data Expression analyst software as published

Statistics:

Significantly deregulated genes (compared to time-matched controls) significances using twosample t-test with cut-off p-value 0.001.
Genes generally differntiating were obtsined by applying Welch's test

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

not specified

Positive controls validity:

valid

Additional information on results:

The profile of up-or down-regulated genes was clearly different for PBO as compared to genotoxic positive control treatments.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): negative
The profile of up-or down-regulated genes was clearly different for PBO as compared to genotoxic positive control treatments.
Thus Piperony butoxide was not genotoxic in the liver.

Executive summary:

Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RG_U34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be sufficient to discriminate the two classes of carcinogens, it became evident that combinations of pathway-associated gene expression profiles may be used to predict a genotoxic or nongenotoxic carcinogenic potential of a compound in short-term studies.