Manganese antimony titanium buff rutile

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Bacteria:

According to OECD 471; non-GLP; TA1535, TA1537, TA98, TA100; concentrations 20, 100, 500, 2500 and 5000 ug/ plate; not mutagenic (unpublished data, 1985)

Gene mutation:

RA: OECD 476; GLP; L5178Y cells; 3.13, 6.25, 12.5, 25, 50, 100 µg/ml; not mutagenic (1996)

Chromosome aberration:

RA: OECD 487; GLP; CHL V79 cells; range 0.078 to 25 µg/ml; not clastogenic or aneugenic (2001)

Link to relevant study records

Reference

Reference 1

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

Remarks:

(missing tester strain to detect crosslinking/oxidising agents, non-GLP)

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Deviations:

no

Remarks:

missing tester strain to detect crosslinking/oxidising agents according to latest OECD 471 guideline

Principles of method if other than guideline:

Standard plate test (repeated with identical concentrations)

GLP compliance:

no

Type of assay:

bacterial reverse mutation assay

Target gene:

his-

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Metabolic activation:

with and without

Metabolic activation system:

induced rat liver S-9 mix

Test concentrations with justification for top dose:

0, 20, 100, 500, 2500 and 5000 ug/ plate

Vehicle / solvent:

DMSO

Negative solvent / vehicle controls:

yes

Positive controls:

yes

Positive control substance:

other: with S-9 mix: 10 ug 2-aminoanthracene (all strains); without S-9 mix: 5 ug N-methyl-N'-nitro-N-nitroso-guanidine for the strains TA 100 and TA 1535; 10 ug 4-nitro-o-phenylenediamine for the strain TA 98; 100 ug 9-aminoacridine chloride monohydrate for t

Details on test system and experimental conditions:

METHOD OF APPLICATION: in agar (plate incorporation)


NUMBER OF REPLICATIONS: 3

Evaluation criteria:

In general, a substance to be characterized as positive in the Ames test has to fulfill the following requirements:
- doubling of the spontaneous mutation rate (control)
- dose-response relationship
- reproducibility of the results.

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity nor precipitates, but tested up to recommended limit concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Additional information on results:

Complete solubility of the test substance in DMSO.

1st Standard Plate Test
Solvent: DMSO
Strain	Metabolic activation system	Replicates	maximum revertant factor	dose dependency	Assessment
TA 1535	no	3	1.2	yes	negative
	yes	3	1.3	no	negative
TA 100	no	3	1.1	no	negative
	yes	3	1.1	no	negative
TA 1537	no	3	1.3	no	negative
	yes	3	1.4	no	negative
TA 98	no	3	1.1	no	negative
	yes	3	1.0	no	negative
2nd Standard Plate Test
Solvent: DMSO
Strain	Metabolic activation system	Replicates	maximum revertant factor	dose dependency	Assessment
TA 1535	no	3	1.0	no	negative
	yes	3	1.3	no	negative
TA 100	no	3	1.1	no	negative
	yes	3	1.0	no	negative
TA 1537	no	3	0.9	no	negative
	yes	3	1.1	no	negative
TA 98	no	3	1.1	no	negative
	yes	3	1.1	no	negative

Conclusions:

Not mutagenic under the conditions of the test.

Reference 2

Endpoint:

genetic toxicity in vitro, other

Remarks:

cytogenicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See read-across justification

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Guideline:

OECD Guideline 487 (In vitro Mammalian Cell Micronucleus Test)

Guideline:

OECD Guideline 473 (In Vitro Mammalian Chromosomal Aberration Test)

Species / strain:

Chinese hamster lung fibroblasts (V79)

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Reference 3

Endpoint:

in vitro gene mutation study in mammalian cells

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

See read-across justification attached to IUCLID section 13.2

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Species / strain:

mouse lymphoma L5178Y cells

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

not examined

True negative controls validity:

not examined

Positive controls validity:

valid

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In vitro

For the gene mutagenicity in bacteria, two valid studies were available, which were both performed according to OECD TG 471 but did not follow GLP requirements (unpublished data, 1985a, 1985b). Both studies were performed as repeated standard plate tests with S. typhimurium strains TA1535, TA1537, TA98 and TA100 with or without metabolic activation up to 5000 µg/plate; a strain to detect crosslinking/ oxidising agents was not included in the studies. In one study, TA1535 produced equivocal results without metabolic activation. In the test repeat and the complete other study, TA1535 produced negative results. All other strains were negative, too. Since not all evaluation criteria (maximum revertant factor >2, repeatable result) were fulfilled, the substance was assessed to be negative under the conditions of the test.

Additionally, in vitro gene mutation and chromosome aberration studies were conducted with two analogue substances, namely Pigment Yellow 53 (CAS 8007-18-9) and Pigment Brown 24 (CAS 68186-90-3). Detailed information are presented subsequently.

Pigment Yellow 53 (CAS 8007-18-9) was used in a study performed as plate incorporation tests with S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537, TA 1538 and E. coli WP2 uvrA with or without metabolic activation up to 5000 µg/plate. All strains gave negative results, thus giving no indication for a mutagenic potential of the test substance (unpublished data 1995a, OECD 471, GLP). In addition, Pigment Yellow 53 was used to expose L5178Y cells to concentrations of 3.13, 6.25, 12.5, 25, 50 and 100 µg/mL (suspension with DMSO) in the presence and absence of mammalian metabolic activation (Aroclor-induce rat liver (S9)). None of the six analyzed treatments with or without metabolic activation induced a mutant frequency that exceeded the minimum criterion for a positive response. Thus, the test substance was concluded to have no mutagenic potential under the conditions chosen (unpublished data, 1996, OECD 476, GLP).

Chinese hamster lung cells (CHL/IU) were exposed to Pigment Yellow 53 at concentrations ranging from 9.79 to 78.1 μg/mL with and without metabolic activation. No increase in chromosomal aberrations was observed in the test neither with the short-term treatment (-S9 mix and +S9 mix) nor the continuous treatment. Thus, the test substance was concluded to not be clastogenic (unpublished data, 2001a, OECD 473, GLP).

Pigment Brown 24 (CAS 68186-90-3) was tested in an Ames assay. The tester strains used were S. typhimurium strains TA98, TA100, TA1535, TA1537, TA 1538 and the E. coli tester strain WP2 uvrA. The strains were exposed to concentrations of 100, 250, 500, 1000, 2500 and 5000 µg/plate in the presence and absence of S9 mix. The test substance did not cause a positive increase in the number of revertants per plate of any of the tester strains either in the presence or absence of S9 mix (unpublished data, 1995b, OECD 471, GLP). In addition, Pigment Brown 24 was tested with mouse lymphoma cells using concentrations (suspension in DMSO) of 3.13, 6.25, 12.5, 25.0, 50.0 and 100 µg/mL in the presence and absence of rat liver S9 metabolic activation. None of the six analyzed treatments with or without metabolic activation included a mutation frequency that exceeded the minimum criterion for a positive response. Thus, the test substance was negative (unpublished data, 1996, OECD 476, GLP).

CHL V79 cells were exposed to concentrations of Pigment Brown 24 in the range of 0.078 and 25 µg/ml. Strong test substance precipitation in the vehicle was observed at all test doses. In culture the test substance was obviously soluble up to 6.25 µg/mL. The test substance did not cause any increase in the number of cells containing micronuclei either without S-9 mix or after adding a metabolizing system. Thus, the test substance is neither clastogenic nor aneugenic under the conditions chosen (unpublished data, 2001, OECD 487, GLP).

 

Taking all information together, the target substance is not expected to be mutagenic in bacteria or mammalian cells and is not assumed to be clastogenic or aneugenic.

In vivo

There is no positive result from any in vitro study performed. An in vivo study is therefore not considered to be appropriate according to Regulation (EC) No 1907/2006, Annex IX, 8.4.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result, the substance is not considered to be classified for genotoxicity under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) 2018/1480 of 4 October 2018.