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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information

In vitro genotoxicity of 4,4'-thiobis(6-tert-butyl-m-cresol) was tested in various cell systems. In two key studies the experimental results of 4,4'-thiobis(6-tert-butyl-m-cresol) in a chromosomal aberration assay and in cultured E. Coli and S. Typhimurium cells (Ames test) are described.

In vivo genotoxicity was studied by administration of 4,4'-thiobis(6-tert-butyl-m-cresol) to male and female rats and subsequent analysis of bone marrow cells for chromosomal events.

In none of the tests the substance was found to induce genotoxicity.

Link to relevant study records
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 1, 1987 - March 21, 1988
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is performed according to the applicable OECD and EPA guidelines under GLP conditions. No deviations were reported.
according to guideline
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
according to guideline
EPA OPPTS 870.5385 (In Vivo Mammalian Cytogenetics Tests: Bone Marrow Chromosomal Analysis)
GLP compliance:
Type of assay:
chromosome aberration assay
Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories
- Age at study initiation: 61 days
- Weight at study initiation: males: 139 - 158 g; females: 104 - 122 g.
- Assigned to test groups randomly: yes
- Fasting period before study: 18 hr.
- Housing: individually in stainless, steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days
Route of administration:
oral: gavage
- Vehicle(s)/solvent(s) used: corn oil
Duration of treatment / exposure:
6, 18, 30 hours
Frequency of treatment:
single dose
Doses / Concentrations:
0, 700, 1400 mg/kg bw
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Positive control(s):
- Route of administration: oral gavage
- Doses / concentrations: 20 mg/kg bw
Tissues and cell types examined:
bone marrow
Details of tissue and slide preparation:
Cells were resuspended in a small amount of freshly prepared fixative. Slides were prepared by dropping the cell suspension on precleaned methanol-wet glass slides followed by flaming. Slides were stained in 3% Giemsa in distilled water for 10 minutes, rinsed in distilled water and air dried. Slides were cleared in xylene and coverslips mounted with Permount.
Evaluation criteria:
Cytogenetic abnormalities were classified on a standard scoring sheet according to chromosome or chromatid aberrations and further according to type of aberration. Aberrations were classified according to the nomenclature of Buckton and Evans, 1973 and Savage, 1975.
Mean number of aberrations per cell per rat (50 cells per rat) were analyzed for statistically significant increases in chromosome aberration by a one-way analysis of variance (ANOVA). Each sampling time was analyzed separately as compared to its concurrent vehicle control group. The CP group was not included in the ANOVA.
Data from this group were analyzed separately by a one-tailed t test comparing CP with the 18 hour vehicle control. The mean and standard deviation of aberrations/cell were also determined for each group of rats (500 cells; 50 cells per rat). The number of aberrant metaphases was analyzed by Chi-square analysis for statistically significant increases. Statistical significance was determined at the p<= 0.05 probability level.
Vehicle controls validity:
Negative controls validity:
Positive controls validity:
Additional information on results:
- Dose range: 1500 and 2075 mg/kg bw
- Clinical signs of toxicity in test animals: severe toxicity signs at 1500 mg/kg bw and mortality at 2075 mg/kg bw

- Types of structural aberrations for significant dose levels (for Cytogenetic or SCE assay): no structural chromosomal aberrations induced by testing substance
- Appropriateness of dose levels and route: all rats dosed with 1400 mg/kg exhibited mild to severe toxicity signs at all times evaluated. Thus, the tested substance was dosed near the maximum tolerated dose.


Interpretation of results (migrated information): negative
Male and female Fisher 344 rats received 0, 700, 1400 mg/kg Santowhite R by oral gavage. The hemopoietic cells of the bone marrow were analyzed after 6, 18, and 30 hours. No statistically significant increases in the incidence of aberrations or in the number of cells with one or more aberrations were observed in animals treated with Santowhite crystals at 700 or 1400 mg/kg at any of the three sampling times evaluated. Therefore, under the conditions of this assay, Santowhite crystals was not clastogenic to the hemopoietic cells of the rat bone marrow.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

4,4'-Thiobis(6-tert-butyl-m-cresol) did not increase the number of revertant colonies in a gene reverse mutation test performed with TA 98, 100, 1535, 1537 and with E. Coli uvrA in one key study. These results were confirmed in two supportive studies describing an Ames test as well. In addition 4,4'-thiobis(6-tert-butyl-m-cresol) did not induce chromosomal aberrations in a test performed with cultured hamster cells (CHL/IU) in one key study. Overall, 4,4'-thiobis(6-tert-butyl-m-cresol) does not express mutagenic potential in vitro in the studies as described above.

In vivo, the mutagenicity of 4,4'-thiobis(6-tert-butyl-m-cresol) was studied in male and female rats. Upon oral gavage of sublethal doses, bone marrow cells were analysed after 6, 18, and 30 hours. No statistically significant increases in the incidence of aberrations or in the number of cells with one or more aberrations were observed. Thus, 4,4'-thiobis(6-tert-butyl-m-cresol) was not clastogenic under the circumstances as described above.

Justification for selection of genetic toxicity endpoint

In vivo study

Justification for classification or non-classification

Based on the available results, 4,4'-thiobis(6-tert-butyl-m-cresol) does not need to be classified for genotoxicity according to the CLP Regulation (EC) 1272/2008 and the Dangerous Substance Directive 67/548/EC.