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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
mechanistic studies
Remarks:
enzyme induction
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Benzotriazole Ultraviolet Stabilizers Show Potent Activities as Human Aryl Hydrocarbon Receptor Ligands
Author:
Nagayoshi H, Kakimoto K, Takagi S, Konishi Y, Kajimura K and T Matsuda
Year:
2015
Bibliographic source:
Environmental Science & Technology, (2015) Vol. 49, No. 1, pp. 578-587

Materials and methods

Principles of method if other than guideline:
Yeast reporter gene assay for activation of Arylhydrocarbon receptor; including an assay for inactivation by human CYP1A1
GLP compliance:
no
Type of method:
in vitro
Endpoint addressed:
other: Arylhydrocarbon receptor binding

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Specific details on test material used for the study:
purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan)
qualitatively described as being of the highest available purity

Test animals

Details on test animals and environmental conditions:
Saccharomyces cerevisiae strain YCM3, which expresses human AhR and AhR nuclear translocator (Arnt; the protein partner of AhR in the functional heterodimeric receptor) complex, was obtained from Dr. C. A. Miller III (Tulane University)

Human cytochrome P450 1A1 (CYP1A1) clone (GenBank accession no. BC023019) was purchased from the American Type Culture Collection through Summit Pharmaceuticals International Corp. (Tokyo, Japan).

Administration / exposure

Route of administration:
other: in yeast culture medium
Vehicle:
DMSO
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
18h
Frequency of treatment:
single treatment
Doses / concentrationsopen allclose all
Dose / conc.:
0.01 other: mM
Dose / conc.:
0.001 other: mM
Dose / conc.:
0 other: mM
Dose / conc.:
0 other: mM
Dose / conc.:
0 other: mM
Dose / conc.:
0 other: mM
Dose / conc.:
0 other: mM
Dose / conc.:
0 other: mM
No. of animals per sex per dose:
Each assay was conducted three times.
Details on study design:
AhR, Arnt cDNA are under the control of the bidirectional GAL1, 10 promoter; therefore, these receptors are expressed when galactose is used
as the carbon source.

Examinations

Positive control:
TCDD for AhR induction
indirubin was used as a working standard for CYP1A1

Results and discussion

Details on results:
The EC50 for AhR activity in yeast cells was 130 nM (95% confidence interval 82 - 210 nM).
Activity of AhR binding is not diminished by overexpression of human CYP1A1 from which the authors conclude that the substance is not a substate for CYP1A1.

The authors also conclude that based on the absence of metabolism by CYP 1A1, the substance has a potential for biaccumulation. This is however considered to be far-fetched since the phenolic hydroxy group does not require phase-I metabolism and instead can be directly be metabolized by phase-II enzymes. In addition, CYP1A1 is one of many phase-I enzymes in the liver and not the only one that is upregulated upon AhR-activation.

Applicant's summary and conclusion