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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information
In vitro: Several studies were conducted to access genetic toxicity according to standard methods and most were in accordance with GLPs. These studies consisted of: Ames test (gene mutation), CHO/HGPRT (gene mutation), CHO (chromosome aberration) and UDS (DNA damage and or repair).
Link to relevant study records
Reference
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:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to a standard method but was non-GLP.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
This study used methods and materials described by Ames et al . in Mutation Research (1975) Vol. 31, pp. 347-364.
GLP compliance:
no
Type of assay:
bacterial reverse mutation assay
Target gene:
TA98- hisD3052, TA100-hisG46, TA1535-hisG46, TA1537-hisC3076
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Details on mammalian cell type (if applicable):
No data
Additional strain / cell type characteristics:
not specified
Metabolic activation:
with and without
Metabolic activation system:
The compound was tested in the presence and absence of a mammalian activation system in both plate incorporation and spot tests.
Test concentrations with justification for top dose:
The sample was tested in plate incorporation assays at concentrations of: 0.05, 0.1, 0.13, 0.4, 1, 2, 10, 17, 33, 43, 100, and 500 ug/plate
Vehicle / solvent:
DMSO
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
yes
Positive controls:
yes
Positive control substance:
other: TA98: w/o S-9 4-nitroquinoline-N-oxide, w S-9 2-acetamidofluorene, TA100: w/o S-9 4-nitroquinollne -N-oxide, w S-9 benzo (a) pyrene; TA1535: w/o S-9 NaNO2, w S-9 tris ( 2, 3-dibromopropyl)phosphate, TA1537: w/o S-9 9-aminoacridine, w S-9 2 aminoanthracene
Details on test system and experimental conditions:
No additional data
Evaluation criteria:
A positive response is indicated if three treatments show a response which is significantly different from the solvent controls at the p less than 0.01 level and if there is a dose response.
Statistics:
Statistical analysis for significance of difference between treatments and controls is performed for each treatment using a t-test. Values of revertants / plate are transformed using log to the base 10. Variance is calculated as within-levels pooled variance for the treatment and solvent control revertants / plate. Values of p are calculated for a one-sided t-test.
Species / strain:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Remarks:
observed at the 33 ug and 100 ug levels with TA1535 and TA1537.
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
MUTAGENICITY TEST RESULTS:
1. Spot Test: The subject compound Diphenyl Oxide was assayed at a maximum concentration of 10 mg per plate using the four test strains TA98, TA100, TA1535, and TA1537. The compound was tested with and without mouse and rat microsomal preparations. No mutagenic activity was observed.
2. Plate Incorporation Test: No significant mutagenic activity was detected towards TA98, TA100, TA1535 or TA1537 in the Salmonella plate incorporation test of Diphenyl Oxide with or without rat S-9 microsomal activation. Maximum concentrations tested were 500 ug per plate in the absence of activation and 500 ug per plate in the presence of microsomal enzymes.

TOXICITY:
The subject compound gave no indication of toxic effects with strains TA98 and TA100 at the 100 ug per plate level. However, toxic damage was observed at the 33 ug and 100 ug levels with TA1535 and TA1537.
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.

None

Conclusions:
Interpretation of results (migrated information):
negative

Diphenyl Oxide was not mutagenic towards any of the Salmonella strains assayed under these test conditions.
Executive summary:

The objective of the study was to determine whether any significant mutagenic activity of' the test material could be detected towards Salmonella strains TA98, TA100, TA1535, and TA1537 either in the presence or absence of a mammalian metabolic activation system in both plate incorporation and spot tests. This study used rnethods and materials described by Ames et al. in Mutation Research (1975) Vol. 31, pp. 347-364, and as described in the standard protocol for Salmonella mutagenicity tests on file in the Monsanto Co. Environrnental Health Laboratory: Standard Protocol for Ames/Salmonella Test (2-10-78). The sample was tested in plate incorporation assays at concentrations of: 0.05, 0.1, 0.13, 0.4, 1, 2, 10, 17, 33, 43, 100, and 500 ug/plate.

Diphenyl Oxide was not mutagenic towards any of the Salmonella strains assayed under these test conditions.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

In vitro: In the standard method 1978 key study (ks) Ames study (Klimisch=2), Diphenyl oxide (DPO) was assessed for mutagenic activity using Salmonella strains TA98, TA100, TA1535, and TA1537 either in the presence or absence of a mammalian metabolic activation system in both plate incorporation and spot tests. Results indicated that DPO was not mutagenic towards any of the Salmonella strains assayed under these test conditions.

In the standard method 1987 ks CHO/HGPRT mammalian cell forward gene mutation assay (Klimisch=2), there were no statistically significant increases in the mutation frequencies of DPO-treated cultures when compared to the negative controls.

In the standard method 1987 ks chromosome aberration study in Chinese Hamster Ovary (CHO) cells (Klimisch=2), treatment with DPO produced no statistically significant increase in the number of aberrations per cell and the proportion of aberrant metaphases at any dose level evaluated with and without S9 metabolic mix.

In the standard method 1987 ks unscheduled DNA synthesis in primary rat hepatocyte cultures (Klimisch=2), results indicate that DPO is not a genotoxic agent in the in vitro rat hepatocyte DNA repair assay.

Justification for classification or non-classification

Not classified - DPO was negative (non-genotoxic) in all of the in vitro genetic toxicity tests performed.