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Genetic toxicity in vitro

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Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Read across valid as the substnace tested is also titanate complex with glycol and alkylamine, degrading in water to similar degradation products.
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
EU Method B.10 (Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
in vitro mammalian cell transformation assay
Test material information:
Composition 1
Species / strain:
other: Chinese hamster ovary cells
Metabolic activation:
with and without
Test concentrations with justification for top dose:
Concentration range in the main test (with metabolic activation): 50 ... 5000 µg/ml
Concentration range in the main test (without metabolic activation): 50 ... 5000 µg/ml
Vehicle:
DMSO (dimethylsulfoxide)
Details on test system and conditions:
Fixation time:
24 hours. In one experiment, cells were treated continuously
without S9 for 46 hours and harvested at 48 hours.
Key result
Species / strain:
Chinese hamster Ovary (CHO)
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
yes
Remarks:
5000 µg/ml
Vehicle controls valid:
not specified
Negative controls valid:
not specified
Positive controls valid:
not specified
Additional information on results:
Observations:
No toxicity was observed, although precipitation above 250
micrograms per plate without S9 made evaluation impossible.


No increase in the frequency of aberrant metaphase was
observed.
Conclusions:
The test substance was negative with and without metabolic activiation. There was no evidence that the substance induced chromosomal aberrations in the presence or absence of S9 mix.
The visible precipitation at higher concentrations may be a result of titanium dioxide forming during abiotic degradation
Executive summary:

The target substance was negative in genetic toxicity, read-across from study of structural analogue.

Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
EU Method B.10 (Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
in vitro mammalian cell transformation assay
Test material information:
Composition 1
Species / strain:
other: Chinese hamster ovary cells
Metabolic activation:
with and without
Test concentrations with justification for top dose:
Concentration range in the main test (with metabolic activation): 50 ... 5000 µg/ml
Concentration range in the main test (without metabolic activation): 50 ... 5000 µg/ml
Vehicle:
DMSO (dimethylsulfoxide)
Details on test system and conditions:
Fixation time:
24 hours. In one experiment, cells were treated continuously
without S9 for 46 hours and harvested at 48 hours.
Key result
Species / strain:
Chinese hamster Ovary (CHO)
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
yes
Remarks:
5000 µg/ml
Vehicle controls valid:
not specified
Negative controls valid:
not specified
Positive controls valid:
not specified
Additional information on results:
Observations:
No toxicity was observed, although precipitation above 250
micrograms per plate without S9 made evaluation impossible.


No increase in the frequency of aberrant metaphase was
observed.
Conclusions:
The test substance was negative with and without metabolic activiation. There was no evidence that the substance induced chromosomal aberrations in the presence or absence of S9 mix.
The visible precipitation at higher concentrations may be a result of titanium dioxide forming during abiotic degradation
Endpoint:
in vitro gene mutation study in mammalian cells
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
EU Method B.17 (Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
in vitro mammalian cell transformation assay
Test material information:
Composition 1
Species / strain:
mouse lymphoma L5178Y cells
Metabolic activation:
with and without
Metabolic activation system:
Aroclor-induced rat liver S9 mix.
Test concentrations with justification for top dose:
Concentration range in the main test (with metabolic activation): 78.1 ... 1875 μg/ml
Concentration range in the main test (without metabolic activation): 78.1 ... 1875
Vehicle:
ethanol
Details on test system and conditions:
Exposure period (with metabolic activation): 3 hours
Exposure period (without metabolic activation): 24 hours

Expression time:
2 days

Selection time:
10-14 days
Species / strain:
mouse lymphoma L5178Y cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
yes
Remarks:
( 2500 µg/ml)
Vehicle controls valid:
not specified
Negative controls valid:
not specified
Positive controls valid:
not specified
Additional information on results:
No increase in the mutation frequency was seen under any treatment conditions used.
Conclusions:
The test substance was negative with and without metabolic activation. The test material did not induce any toxicologically significant increases at the TK +/- locus in L5178Y cells
A precipitate was observed, possibly from titanium dioxide formed during hydrolysis
Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
Deviations:
no
GLP compliance:
yes
Type of assay:
bacterial reverse mutation assay
Test material information:
Composition 1
Species / strain:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Additional strain characteristics:
not specified
Metabolic activation:
with and without
Metabolic activation system:
Aroclor 1254-induced rat liver S9
Test concentrations with justification for top dose:
Concentration range in the main test (with metabolic activation): 33 ... 10000 µg/plate
Concentration range in the main test (without metabolic activation): 33 ... 10000 µg/plate
Vehicle:
Sterile, ultra-pure water
Key result
Species / strain:
other: S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
yes
Remarks:
10000 µg/plate
Vehicle controls valid:
not specified
Negative controls valid:
not specified
Positive controls valid:
not specified
Additional information on results:
Observations:
No toxicity was observed
Precipitation was observed at concentrations > 333 mg/plate- this is considered to be titanium dioxide and it is likely that precipitation at lower level was not possible to observe.


An increase in revertants was observed only in strain TA
1535 with metabolic activation at 333 and 1000 micrograms
per plate. Two repeat experiments were unable to confirm
this observation.

A concomitant reverse mutation test in Escherichia coli strain WP2 uvrA was also negative. Precipitation of the substance was observed at 333 and 10,000 micrograms per plate with S9 only.

Conclusions:
It was concluded that the substnace is not mutagenic in Salmonella typhimurium.
E Coli strains were also tested and shown to be negative
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Extensive testing and reviews have been conducted on titanium dioxide, triethanolamine and propylene glycol, demonstrating that there is no mutagenic potential. 

 

An IARC monograph on triethanolamine suggests that there is no evidence for mutagenicity, and this is cited in the IUCLID file. WORLD HEALTH ORGANIZATION

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 77

Some Industrial Chemicalshttp://monographs.iarc.fr/ENG/Monographs/vol77/volume77.pdf

 

Titanium dioxide has been extensively investigated, especially in nano-form for use in cosmetics and several review documents suggest low risk. One citation is in Drug Chemistry and Toxicology, 2011 July 34(3):277-84.Cytotoxicity and genotoxicity of titanium dioxide nanoparticles in UVA-irradiated normal peripheral blood lymphocytes: Kang, Lee et al.

Propylene glycol has also been extensively evaluated and review documents suggest low risk of mutagenic potential. A review by the US EPA (Prevention Pesticides and Toxic Substances, EPA-739-R-06-002, September 2006) http://www.epa.gov/oppsrrd1/REDs/propylene_glycol_red.pdf

 

Propylene glycol and dipropylene glycol were tested for mutagenic or genotoxic potential and found to be negative in a battery of studies: a bacterial gene mutation assay using Salmonella typhimurium, and in vitro Chinese hamster ovary (CHO) mutation assay, an in vitro Chinese hamster ovary (CHO) chromosomal aberration assay and an in vitro sister chromatid exchange assay.

 

Propan-2-ol is reported in a review by the EU Scientific Committee on Health and Environmental Risks conclude low toxic risk (25th plenary on 9 September 2008), but suggests that data is limited with regard to in-vitro mutagenicity evaluation.

Justification for classification or non-classification

Negative results in all testing performed and from review of metabolites