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Diss Factsheets

Toxicological information

Genetic toxicity: in vitro

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Administrative data

Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-08-25 to 2011-11-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Version / remarks:
adopted 21 July 1997
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of assay:
bacterial reverse mutation assay

Test material

Constituent 1
Chemical structure
Reference substance name:
R,R-1-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Molecular formula:
C20H26O3
IUPAC Name:
R,R-1-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Constituent 2
Chemical structure
Reference substance name:
R,S-1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Molecular formula:
C20H26O3
IUPAC Name:
R,S-1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Constituent 3
Chemical structure
Reference substance name:
S,S-1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Molecular formula:
C20H26O3
IUPAC Name:
S,S-1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Constituent 4
Chemical structure
Reference substance name:
S,R-1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Molecular formula:
C20H26O3
IUPAC Name:
S,R-1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
Test material form:
solid
Details on test material:
Minimum purity 95% w/w
Specific details on test material used for the study:
Designation: Art. 132720
Synonym: Avodiol
Chem. Name: 1-(4-tert-Butyl-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-diol
CAS-No.: 955359-35-0
Batch: 11/LE/016 K1
Purity: 95.1% (w/w)
Appearance: White, solid
Released until: May 18, 2012
Storage: Tightly closed, dark at room temperature (15 to 25°C)

Method

Target gene:
HIS operon (S. thyphimurium), TRP operon (E. coli)
Species / strainopen allclose all
Species / strain / cell type:
S. typhimurium TA 1535
Species / strain / cell type:
S. typhimurium TA 1537
Species / strain / cell type:
S. typhimurium TA 98
Species / strain / cell type:
S. typhimurium TA 100
Species / strain / cell type:
S. typhimurium TA 102
Species / strain / cell type:
E. coli WP2 uvr A
Metabolic activation:
with and without
Metabolic activation system:
liver S9 mix from Aroclor 1254-pretreated rats with standard co-factors
Test concentrations with justification for top dose:
The test material concentrations were used selected according to the EC and OECD guidelines for this test system:
1st series: 5.00, 15.8, 50.0, 158, 500, 1580 and 5000 µg per plate
2nd series: 5.00, 15.8, 158, 500, 889 and 1580 µg per plate
3rd series: 250, 500, 750, 1000, 1250, 1500, 2000, and 2500 µg/plate
Vehicle / solvent:
DMSO
Controls
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
4-nitroquinoline-N-oxide
9-aminoacridine
sodium azide
benzo(a)pyrene
cumene hydroperoxide
other: Daunomycin, 2-Aminoanthracene
Details on test system and experimental conditions:
according to guideline
Rationale for test conditions:
The test conditions were chosen as described in OECD 471.
Evaluation criteria:
Definitions:
The assessment of test material-induced effects is dependent on the number of spontaneous revertants of each bacterial strain (solvent controls) and the in-crease in the number of revertants at the test material concentration which shows the highest number of colonies. The following criteria, based upon the historical controls of the laboratory and statistical considerations, are established:


Mean Number of Colonies Maximal Mean Number of Colonies over the Actual
(Solvent Control) Solvent Control
(Test Material)
<=10 <=9 >=30
<=30 <=19 >= 40
<=80 <=29 >=80
<=200 <=49 >=120
<=500 <=79 >=200

Assessment: "No Increase" "Clear Increase"

All further results, ranging between "no" and "clear", are assessed as "weak in-creases".
Interpretations:
A test material is defined as non-mutagenic in this assay if
• "no" or "weak increases" occur in the first and second series of the main ex¬periment. ("Weak increases" randomly occur due to experimental variation.)

A test material is defined as mutagenic in this assay if
• a dose-related (over at least two test material concentrations) increase in the number of revertants is induced, the maximal effect is a "clear increase", and the effects are reproduced at similar concentration levels in the same test system;
• "clear increases" occur at least at one test material concentration, higher concentrations show strong precipitation or cytotoxicity, and the effects are reproduced at the same concentration level in the same test system.

In all further cases, a third test series with the bacterial strain in question should be performed. If the criteria for a positive test result are not fulfilled in at least two out of the three series, the test material is defined as being non-mutagenic in this test system.

Statistics:
Dunnett's test

Results and discussion

Test resultsopen allclose all
Species / strain:
S. typhimurium TA 98
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 100
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 102
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1537
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with
Genotoxicity:
positive
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 102
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with
Genotoxicity:
positive
Cytotoxicity / choice of top concentrations:
no cytotoxicity, but tested up to precipitating concentrations
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1537
Metabolic activation:
with
Genotoxicity:
positive
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with
Genotoxicity:
positive
Cytotoxicity / choice of top concentrations:
no cytotoxicity, but tested up to precipitating concentrations
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Remarks on result:
other: 10% S9: negative; 30% S9: positive

Any other information on results incl. tables

The investigations for the mutagenic potential of the test item were performed using Salmonella typhimurium tester strains TA 98, TA 100, TA 102, TA 1535 and TA 1537, and Escherichia coli WP2 uvrA. The plate incorporation test with and without addition of liver S9 mix from Aroclor 1254-pretreated rats was used. Thwo independent series were performed without metabolic activation. Three independent experimental series were performed with S9 mix as the metabolic activation system. In the three series with S9 mix, 10 % S9 in the S9 mix were used in the 1st and 30 % in the 2nd and 3rd series, respectively.

The test item was dissolved in dimethyl sulfoxide (DMSO) and tested at concentrations ranging from 5.00 to 5000 µg/plate. Precipitation of the test material on the agar plates occurred at con-centrations ≥ 500 µg/plate. Toxicity to the bacteria was observed at concentrations ≥ 889 µg/plate.

Daunomycin, sodium azide, 9-aminoacridine, 4-nitroquinolin-N-oxide and cumene hydroperoxide served as strain specific positive control test materials in the absence of S9 mix. 2-Aminoanthracene and benzo[a]pyrene were used for testing the bacteria and the activity of the S9 mix. Each treatment with the test materials used as positive controls led to a clear increase in revertant colonies, thus, showing the expected reversion properties of all strains and good meta-bolic activity of the S9 mix used.

Without addition of S9 mix and with addition of S9 mix containing 10% S9 as the external metabolizing system,the test item was not mutagenic under the conditions described. After addition of S9 mix containing 30% S9 in the 2nd and 3rd series as the external metabolizing system, Art. 132720 induced an increase in the number of revertants at concentrations ≥ 1500 µg per plate, i.e. in the precipitated concentration range only.

It can be concluded that after metabolic activation, the test item was mutagenic to bacteria under the experimental conditions described. These effects, however, occurred in the precipitated concentration range only.

Applicant's summary and conclusion

Conclusions:
Based on all this data, the test item was positive in this bacterial mutagenicity assay.
The test item was negative in the Ames test without metabolic activation and with metabolic activation when S9 mix containing 10% S9 was used as the metabolic activation system. However, the test item was mutagenic to bacteria in case S9 mix containing 30% S9 was used as the metabolic activation system.
Executive summary:

The test item was negative in the Ames test without metabolic activation and with metabolic activation when S9 mix containing 10% S9 was used as the metabolic activation system. However, the test item was mutagenic to bacteria in case S9 mix containing 30% S9 was used as the metabolic activation system.

Taking together, the test item was positive in this bacterial mutagenicity assay.