Niobium dioxide

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

No data is available for Niobium dioxide (target substance). Thus, available data from Niobium oxide and Niobium pentachloride (source substances) are used to assess in a read-across approach the mutagenicity potential of Niobium dioxide. In a bacterial reverse gene mutation assay the source substance Niobium oxide was tested negative in S. typhimurium (TA 1535, TA 1537, TA 98 and TA 100) and E. coli (WP2uvrA). In addition, the second source substance Niobium pentachloride was tested negative in an in vitro HPRT test according to OECD 476 and in an in vitro Comet assay.

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro DNA damage and/or repair study

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Species / strain:

other: Human Jurkat T-lymphocytes

Metabolic activation:

without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

>65 % at 0.5 mM and higher in comparison to untreated controls

Untreated negative controls validity:

valid

Positive controls validity:

not examined

Table 1: Concentrations of Metals Required to Induce a a Significant Harmful Effect (DNA Damage, Apoptosis, Viability, and Proliferation Inhibition) on T-Helper Jurkat Cells
Metal Concentrations (mM)	DNA Damage	Apoptosis	Viability	Proliferation Inhibition	Average Concentration of Four Parameters
V	0.05	0.05	1.0	0.05	0.29
Ni	0.05	0.1	5.0	0.5	1.41
Co	5.0	5.00	0.5	0.1	2.65
Cu	>5	0.5	5.0	0.1	>2.65
Nb	>5	0.5	0.5	>5	>2.75
Mo	>5	1.0	>5	0.5	>2.87
Zr	5.0	0.5	5.0	>5	>3.875
Be	>5	5.0	1.0	5.0	>4
Cr	>5	>5	>5	>5	>5
Al	>5	5.0	>5	>5	>5
Fe	>5	5.0	>5	>5	>5
Significant effect:
DNA damage: IDD>75.
Apoptosis: >50% caspase 9-positive cells.
Viability: >50% PI-positive cells.
Proliferation inhibition: p< 0.05 significance in metal-treated cells CPMs reduction compared to untreated controls.

Conclusions:

Under the experimental conditions reported, the test item Niobium pentachloride solution is considered to be non-mutagenic.

Executive summary:

In an in vitro Comet assay, human Jurkat T-lymphocyte cells cultured in vitro were exposed to Niobium pentachloride solution at concentrations of 0.05, 0.1, 0.5, 1.0 and 5 mM in the absence of mammalian metabolic activation. For assessment of cytotoxicity apoptosis and cell viability were measured. Niobium pentachloride solution induced >50% caspase-9 positive cells at 0.5 mM concentration or higher (apoptosis) and a reduction of viable cells to <33% at 0.5 mM and higher (cell viability). Niobium pentachloride solution showed no effect on cell proliferation at the concentrations tested. No significant increase of DNA damage, measured by using an index of DNA damage (IDD, average tail length of 50 cells) were observed. Therefore, niobium pentachloride solution is considered to be not genotoxic in the Comet assay.

 

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Reference 2

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Species / strain:

S. typhimurium, other: TA98, TA100, TA 1535 and TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Key result

Species / strain:

E. coli WP2 uvr A

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

For detailed results please see Table 1 in box "Any other information on results".

Table 1: Summarized Results

Bacteria tester strain	Metabolic activation	Exp.	Mean numbers of revertants								Evaluation
			Controls			mg test item per plate
			UTC	VC	PC	5.0	1.0	0.5	0.1	0.05
Salmonella typhimurium
TA1535	no	1^st	19.0	21.0	1269.3	18.3	19.0	19.0	20.7	19.0	-
	no	2^nd	18.0	18.3	1792.0	12.0	17.3	18.7	16.0	16.7	-
	yes	1^st	25.0	27.0	282.7	22.3	22.0	22.7	21.3	24.3	-
	yes	2^nd	18.7	21.0	309.3	21.0	19.0	21.7	19.7	19.7	-
TA1537	no	1^st	8.7	11.7	2560.0	8.3	7.7	7.3	7.0	9.3	-
	no	2^nd	14.7	14.0	1600.0	13.3	13.0	12.7	11.0	10.7	-
	yes	1^st	12.7	13.0	389.3	12.7	11.3	11.0	12.0	13.7	-
	yes	2^nd	14.3	12.7	389.3	11.3	12.7	11.3	12.0	9.3	-
TA 98	no	1^st	24.3	20.0	720.0	18.3	15.3	21.3	17.7	18.3	-
	no	2^nd	19.3	16.3	624.0	15.3	16.7	14.7	13.0	14.0	-
	yes	1^st	25.7	24.7	3349.3	33.3	31.3	36.3	38.7	38.0	-
	yes	2^nd	29.3	27.0	3109.3	30.7	30.3	27.3	30.3	31.7	-
TA 100	no	1^st	201.3	20.0	1786.7	171.3	183.3	207.3	187.3	189.7	-
	no	2^nd	234.3	16.3	1445.3	189.7	188.0	183.0	190.0	206.0	-
	yes	1^st	206.7	24.7	3642.7	198.7	168.0	204.0	195.3	190.0	-
	yes	2^nd	221.0	27.0	3061.3	201.7	199.3	196.0	216.3	214.7	-
Escherichia coli
WP2uvrA	no	1^st	27.3	23.3	282.7	282.7	26.7	26.3	25.7	23.7	-
	no	2^nd	27.7	28.0	378.7	378.7	29.0	28.7	32.7	29.0	-
	yes	1^st	39.7	38.3	261.3	261.3	34.0	45.3	39.3	37.7	-
	yes	2^nd	43.3	40.3	170.7	170.7	36.3	40.7	48.0	43.0	-

Abbreviations:       

Exp.= independent experiment 1 or 2, 1^stexperiment: plate incorporation method, 2^ndexperiment: pre-incubation method

UTC = untreated control

VC = vehicle control

PC = positive control

- = none mutagenic effect

+ = mutagenic effect

Conclusions:

In conclusion, the test item is not genotoxic in the bacterial reverse gene mutation assay in the presence and absence of mammalian metabolic activation.

Executive summary:

In a reverse gene mutation assay in bacteria (EU method B.13/14), strains of S. typhimurium (TA 1535, TA 1537, TA 98 and TA 100) and E. coli strain (WP2uvrA) were exposed to Niobium oxide (>99% purity) suspended in DMSO at concentrations of 5.0, 1.0, 0.5, 0.1 and 0.05 mg/plate in the presence and absence of mammalian metabolic activation. Niobium oxide was tested up to the limit dose (5.0 mg/plate). The positive controls induced the appropriate responses in the corresponding strains. There was no evidence of induced mutant colonies over background.

This study is classified as acceptable and satisfies the requirement for Test Guideline Directive 67/548/EEC, Annex V, B.13/14 for in vitro mutagenicity (bacterial reverse gene mutation) data.

 

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

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:

weight of evidence

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Species / strain:

Chinese hamster lung fibroblasts (V79)

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Remarks:

A biologically relevant growth inhibition (reduction of relative growth below 70%) was observed after the treatment with the test item in experiment I and II without metabolic activation

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: The pH-value detected with the test item was within the physiological range (pH 7.0 ± 0.4).
- Effects of osmolality: not examined
- Precipitation: Precipitation of the test item was noted in experiment I without metabolic activation at concentrations of 0.5 mM and higher and with metabolic activation at concentrations of 0.25 mM and higher. In experiment II precipitation was detected at concentrations of 0.2 mM and higher with metabolic activation.

RANGE-FINDING/SCREENING STUDIES:
A solubility test was performed with different solvents and vehicles. Based on the results of the solubility test EtOH was used as solvent. After pre-dissolving the test item in EtOH (100 mM) a dilution series was prepared in EtOH. First a 9fold volume of phosphate buffer was used adding it to each concentration. After noticing that in the pre-experiment without metabolic activation the buffer reacts with the cells the phosphate buffer was replaced for the main experiments by Aqua ad injectabilia. So the 9fold volume of Aqua ad injectabilia was added to each concentration. After an initial reaction of approx. 10 minutes, this test item solution was added to cell culture medium (MEM without serum) at a ratio of 1 :10, resulting in 1% EtOH and 9% Aqua ad injectabilia in the final treatment medium. The pH-value detected with the test item was within the physiological range (pH 7.0 ± 0.4). The solvent used is a composition of well-established solvents and is compatible with the survival of the cells and the activity of the S9 mix. The toxicity of the test item was determined in pre-experiments. Eight concentrations [0.0025, 0.005, 0.01, 0.050, 0.10, 0.25, 0.50, 1.0 mM] were tested without and with metabolic activation. In the pre-experiment the test item concentrations were dissolved in 1% ethanol and 9% phosphate buffer. The experimental performance for the pre-experiment was the same as described below for the main experiments (excepting the solvent composition)

COMPARISON WITH HISTORICAL CONTROL DATA:
In all experiments the mutant values of the negative controls, the solvent controls and all mutant values of the test item concentrations found were within the historical control data of the test facility (without metabolic activation: 2-43 mutants per 10^6 cells, with metabolic activation: 5-44 mutants per 10^6 cells

Table 1
Experiment I - Mutagenicity, without metabolic activation
Dose Group	Concentration [mM]	Number of mutant colonies per flask^a					Mean	SD	Mutant SD colonies per 10^6 cells^b	Mutation factor
		I	II	III	IV	V
NC1	0	6	6	9	10	6	7.4	1.74	20.11
NC2		4	6	6	*	8	6	1.41	18.29
S1	0	9	10	13	16	10	11.6	2.58	33.72
S2		7	6	9	8	10	8	1.41	23.46
2	0.025	6	6	5	14	9	8	3.29	20.05	0.69
3	0.05	5	3	6	2	8	4.8	2.14	14.08	0.48
4	0.1	4	4	6	5	12	6.2	2.99	18.34	0.63
5	0.25	9	10	10	7	5	8.2	1.94	25.39	0.87
6	0.5	6	11	5	5	7	6.8	2.23	18.28	0.63
7	0.75	15	14	11	15	18	14.6	2.24	40.67	1.4
8	1.0	9	6	6	12	12	9	2.68	25.86	0.89
9	1.5	3	5	5	4	7	4.8	1.33	14.72	0.51
10	2.0	9	13	6	9	6	8.6	2.58	25.83	0.89
EMS	300 µg/mL	84	72	80	89	90	83	6.57	233.15	8.01
NC:	negative control/ medium control
S:	solvent control
a:	number of mutant colonies in flask I to V
b:	mean mutant colonies x 10^6/ (400000 x Cloning Efficiency/100)
EMS:	Ethylmethanesulfonate [300 µg/mL]
*:	Contamination of cell culture in flask

Table 2
Experiment I - Mutagenicity, with metabolic activation
Dose Group	Concentration [mM]	Number of mutant colonies per flask^a					Mean	SD	Mutant SD colonies per 10^6 cells^b	Mutation factor
		I	II	III	IV	V
NC1	0	5	5	6	6	11	6.6	2.24	20.06
NC2		2	5	7	11	11	7.2	3.49	20.11
S1	0	3	5	6	7	10	6.2	2.32	18.62
S2		3	4	9	9	10	7.0	2.90	19.83
2	0.025	4	4	5	6	10	5.8	2.23	14.61	0.76
3	0.05	5	12	8	3	8	7.2	3.06	18.56	0.97
4	0.10	11	10	11	10	11	10.6	0.49	30.64	1.59
5	0.25	5	6	7	10	14	8.4	3.26	20.64	1.07
6	0.50	2	2	4	5	5	3.6	1.36	9.65	0.50
7	0.75	3	7	8	9	9	7.2	2.23	19.15	1.00
8	1.0	4	8	11	12	12	9.4	3.07	25.61	1.33
9	1.5	7	7	8	8	9	7.8	0.75	18.22	0.95
10	2.0	7	7	9	9	11	8.6	1.50	22.34	1.16
DMBA	0.8µg/mL	105	107	133	96	97	107.6	13.41	303.95	15.81
DMBA	1.0µg/mL	111	149	118	122	109	121.8	14.39	369.09	19.20
NC:	negative control/ medium control
S:	solvent control
a:	number of mutant colonies in flask I to V
b:	mean mutant colonies x 10^6/ (400000 x Cloning Efficiency/100)
DMBA:	7, 12-Dimethylbenz(a)anthracene [0.8 and 1.0 µg/mL]

Table 3
Experiment II - Mutagenicity, without metabolic activation
Dose Group	Concentration [mM]	Number of mutant colonies per flask^a					Mean	SD	Mutant SD colonies per 10^6 cells^b	Mutation factor
		I	II	III	IV	V
NC1	0	8	9	10	6	5	7.6	1.85	21.05
NC2		14	8	5	9	12	9.6	3.14	26.89
S1	0	15	7	8	9	12	10.2	2.93	29.74
S2		9	12	9	8	5	8.6	2.24	24.02
2	0.025	16	4	8	5	6	7.8	4.31	25.91	0.96
3	0.010	10	12	12	11	7	10.4	1.85	33.02	1.23
4	0.025	12	5	10	10	5	8.4	2.87	25.23	0.94
5	0.050	15	15	8	13	13	12.8	2.56	36.57	1.36
6	0.10	8	18	12	18	14	14.0	3.79	39.11	1.45
7	0.25	10	10	7	10	10	9.4	1.2	26.26	0.98
8	0.50	16	10	13	8	20	13.4	4.27	37.22	1.38
9	0.75	14	7	18	16	15	14.0	3.74	35.90	1.34
10	1.0	9	12	8	11	8	9.6	1.62	27.12	1.01
EMS	300µg/mL	160	175	179	169	177	172.0	6.87	607.77	22.61
NC:	negative control/ medium control
S:	solvent control
a:	number of mutant colonies in flask I to V
b:	mean mutant colonies x 10^6/ (400000 x Cloning Efficiency/100)
EMS:	Ethylmethanesulfonate [300 µg/mL]

Table 4
Experiment II - Mutagenicity, with metabolic activation
Dose Group	Concentration [mM]	Number of mutant colonies per flask^a					Mean	SD	Mutant SD colonies per 10^6 cells^b	Mutation factor
		I	II	III	IV	V
NC1	0	13	10	8	11	3	9.0	3.41	24.93
NC2		19	12	18	12	16	15.4	2.94	43.38
S1	0	3	8	6	5	3	5.0	1.90	13.7
S2		9	7	12	13	5	9.2	2.99	25.41
2	0.004	13	13	8	13	6	10.6	3.01	26.84	1.37
3	0.01	4	10	8	7	8	7.4	1.96	20.11	1.03
4	0.02	5	12	7	11	7	8.4	2.65	22.22	1.14
5	0.04	9	8	11	12	6	9.2	2.14	23.41	1.20
6	0.07	15	6	10	12	7	10.0	3.29	25.71	1.31
7	0.2	7	8	4	11	14	8.8	3.43	26.19	1.34
8	0.4	9	13	14	17	13	13.2	2.56	35.97	1.84
9	0.7	9	13	12	9	6	9.8	2.48	29.17	1.49
10	1.0	13	10	14	12	13	12.4	1.36	35.63	1.82
DMBA	0.8µg/mL	77	89	71	88	90	83.0	7.62	244.12	12.48
DMBA	1.0µg/mL	109	120	126	106	114	115.0	7.27	357.14	18.26
NC:	negative control/ medium control
S:	solvent control
a:	number of mutant colonies in flask I to V
b:	mean mutant colonies x 10^6/ (400000 x Cloning Efficiency/100)
DMBA:	7, 12-Dimethylbenz(a)anthracene [0.8 and 1.0 µg/mL]

Conclusions:

Under the experimental conditions, the test item Niobium pentachloride (decomposed) is considered to be non-mutagenic in the HPRT locus using V79 cells of the Chinese Hamster.

Executive summary:

In a mammalian cell HPRT gene mutation assay, V79 cells cultured in vitro were exposed to Niobium pentachloride (decomposed) (99.9 %) in 1% ethanol and 9% Aqua ad injectibilia at concentrations of 0.025, 0.05, 0.10, 0.25, 0.50, 0.75, 1.0, 1.5 and 2.0 mM in the presence and absence of mammalian metabolic activation (experiment I) and for experiment II at concentrations of 0.005, 0.010, 0.025, 0.050, 0.10, 0.25, 0.50, 0.75 and 1.0 mM without metabolic activation and 0.004, 0.007, 0.02, 0.04, 0.07, 0.2, 0.4, 0.7 and 1.0 mM with metabolic activation.

In experiment I and II with and without metabolic activation mutant values of the negative controls, the solvent controls and all mutant values of the test item concentrations found were within the historical control data.

For all tested treatment groups no dose-response relationship could be observed. The positive controls did induce the appropriate response. There was no evidence of induced mutant colonies over background. 

This study is classified as acceptable. This study satisfies the requirement for Test Guideline OPPTS 870.5300, OECD 476 for in vitro mutagenicity (mammalian forward gene mutation) data.

 

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No data is available for Niobium dioxide (target substance). Thus, available data from Niobium oxide and Niobium pentachloride (source substances) are used to assess in a read-across approach the genotoxicity of Niobium dioxide. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

The source substance Niobium oxide was not genotoxic in a bacterial reverse gene mutation assay (Ames test). The second source substance Niobium pentachloride was tested negative in an in vitro HPRT test conducted according to OECD 476 and furthermore in an in vitro Comet assay.

Justification for classification or non-classification

Based on available data from suitable read-across partners, the target substance Niobium dioxide does not warrant classification for mutagenicity.