Pyridine-2-thiol 1-oxide, sodium salt

Endpoint summary

Additional information

Sodium pyrithione has tested negative in the ames assay, the in vitro CHO/HGPRT forward mutation assay, the in vitro rat hepatocyte primary culture/DNA repair test and in the in vivo mouse micronucleus assay [see tables 7.6.1 & 7.6.2]. 

All studies proved negative with the exception of one unscheduled DNA synthesis (UDS) study in the rat and the sodium salt of pyrithione was evaluated in the UDS.  The results from the UDS [reference 7.6.1.005, EZPTF 6067 -001] indicated that pyrithione (tested as sodium pyrithione) failed to induce a mean net nuclear grain count of plus five or greater over the control and vehicle control indicating a clear negative result for inducing DNA synthesis. The two highest concentrations of sodium pyrithione tested induced cytotoxicity demonstrating that sufficient test article was delivered to the test system

 

Based on the wealth of negative mutagenicity and genotoxicity studies in in vitro and in vivo test systems, sodium pyrithione is not genotoxic.

Table 7.6.1     Summary of genotoxicity in vitro

Test system Method Guideline	Organism/ strain(s)	concentrations	Result		Remark	Reference
			+ S9	- S9
EEC Council Directive 2000/32, Annex 4D; OECD 471 (1997); ICH S2A Genotoxicity GLP   Test material Natrium Pyrion 40%	S. typhimurium: TA 1535, TA 1537, TA 98, TA 100, TA 102	Experiment 1: 0; 6.25; 12.5; 25; 50; 100 µg a.s./plate; Experiment 2, strains TA 1535, TA 98, TA 100, TA 102: 0; 3.13; 6.25; 12.5; 25; 50; 100 µg a.s./plate Experiment 2, strain TA1537: 0; 1.56; 3.13; 6.25; 12.5; 25; 50 µg a.s./plate	Negative	Negative	The test substance did not induce two-fold increases in the number of revertant colonies in the plate incorporation or pre-incubation assay, at any dose level, in any tester strain, in the absence or presence of S9 metabolism.	7.6.1.001   ESPTF 6061-001   Scarcella O, Brightwell J (2002). (unpublished).
Non-GLP study   Test Material – Sodium Pyrithione 40% aqueous solution	S. typhimurium: TA 1535, TA 1537, TA 1538, TA 98, TA 100	5 µg/plate 10 µg/plate 15 µg/plate 20 µg/plate 25 µg/plate   0.6 µg/plate 1.2 µg/plate 1.8 µg/plate 2.4 µg/plate 3.0 µg/plate	Negative Negative Negative Negative Negative	Negative Negative Negative Negative Negative	The test substance did not induce two-fold increases in the number of revertant colonies in the plate incorporation or pre-incubation assay, at any dose level, in any tester strain, in the absence or presence of S9 metabolism.	7.6.1.006   ESPTF 6061-002   E.I. du Pont de Nemours and Co. Haskell Laboratory (1976)

EEC Council Directive 2000/32, Annex 4A; OECD 473 (1997); ICH S2A Genotoxicity GLP   Test material Natrium Pyrion 40%	Chinese hamster lung fibroblasts (V79)	Concentrations used: 0; 0.313; 0.625; 1.25; 2.50; 5.00; 10.0; 20.0; 40.0; 80.0 µg a.s./mL Concentrations scored: 0; 20.0; 40.0; 80.0 µg a.s./mL	Yes	Yes	The test substance induces chromosomal aberrations in Chinese hamster V79 cells after in vitro treatment under the reported experimental conditions.	7.6.1.002   ESPTF 6062-001   Iliutti P, Brightwell J (2002). (unpublished).
EEC Council Directive 2000/32, Annex 4E; OECD 476 (1997). GLP   Test material Natrium Pyrion 40%	Chinese hamster V79 cells	1(-) 1250; 938; 625; 313; 156; 78.1 1(+) 313; 234; 156; 78.1; 39.1; 19.5 2(-) 1875; 1250; 833; 556; 370; 247 2(+) 470; 313; 209; 139; 92.8; 61.9   (µg a.s./mL)	No	No	No reproducible five-fold increases in mutant numbers or mutant frequency were observed following treatment with the test substance at any dose level, in the absence or presence of S9 metabolism.	7.6.1.003   ESPTF 6063-001   Cinelli S, Brightwell J (2002). (unpublished).

GLP Study under USEPA Guideline 84-2   Test Material – Sodium pyrithione 40% aqueous solution

CHO-K1-BH4 cells from stock cultures of known stable spontaneous mutant grequency and mycoplasm free cells

0.005 µg/plate 0.010 µg/plate 0.020 µg/plate 0.035 µg/plate 0.050 µg/plate 0.100 µg/plate 0.200 µg/plate 0.350 µg/plate 0.500 µg/plate   0.500 µg/plate 1.00 µg/plate 2.50 µg/plate 5.00 µg/plate 10.00 µg/plate 25.00 µg/plate 75.00 µg/plate 100 µg/plate

Negative Negative Negative Negative Negative Negative Negative Negative Negative

Negative Negative Negative Negative Negative Cytotoxic Cytotoxic Cytotoxic

The average mutant frequency of the negative control cultures ranged from 1.2 to 8.5 TG mutants/10^6clonable cells, while those of the cultures treated with sodium pyrithone ranged from 1.0 to 10.5 TG mutants/10^6clonable cells.   Statistical analysis of the data indicate that there is no dose-dependent increases in the mutant frequencies in the test article treated cultures.   Sodium pyrithione was negative in the CHO/HRPT Mammalian Cell Forward Gene Mutation.

7.6.1.004   ESPTF 6063-002   Stankowski (1987)   (unpublished)

Mammalian rat hepatocyte primary culture/DNA Repair Test GLP   Test material NaPT 40% aqueous solution

Rat hepatocytes from one rat

1x10^-5viable hepatocytes  Two hr incubation at 37ºC, cells serum free medium containing test article and^3H-thymidine was added to each culture.

0.067, 0.050, 0.167, 0.50, 1.67, 5.0, 16.7, 50.0, 166.7 and 500 ng/ml

Negative After 7-days of exposures, autoradiograhs were developed and UDS “repair” synthesis evidenced by a net increase in black silver grains over the nucleus is quantified by determining nuclear and cytoplasmic grain counts.

NaPT even at cytotoxic levels failed to produce a mean net nuclear grain count of plus 5 or greater than vehicle control mean net nuclear grain counts.

7.6.1.005   EZPTF 6067-001   Barfknecht, T.R. (1987)   (unpublished)

Table 7.6.2          Summary of genotoxicity in vivo 

Type of test Method/ Guideline	Species Strain Sex no. per group	frequency of application	sampling times	dose levels [mg/kg bw]	Results	Remarks	Reference
Directive 2000/32/EC, B.12; OECD 47 "Mammalian erythrocyte micronucleus test" (1997).   GLP   Natrium Pyrion solid (92.5%)	Mouse Crl:NMRI BR. Charles River   5m, 5f per dose per sampling time	Once by oral gavage	24 & 48 hours	400, 482, 580 mg/kg bw	No statistically significant increase in the amounts of micronucleated polychromatic erythrocytes was observed at any dose tested compared to the negative controls, neither 24 nor 48 hours after treatment, neither for males nor for females. Bioavailability of the test substance was proven by mortality and by cytotoxicity at the high dose.	The test substance does not produce relevant increases of the numbers of micronuclei in polychromatic erythrocytes after in vivo treatment of mice of either sex of the test strain at doses of 400, 482 and 580 mg/kg bw.	7.6.2.001   ESPTF 6064-001   Bornatowicz N (2002).   (unpublished).
In vivoMouse Micronucleus Test USEPA Guideline 84-2 consistent with OECD 474   Test Article: Sodium Pyrithione 40% aqueous solution	CRL 5 male and 5 female mice per dose	Once by Intraperitoneal injection.	30, 48 and 72 hours post dosing.	TEM (positive control) 0.5 kg/kg  Distilled water 10 ml/kg NaPT  575 mg/kg	No statistically significant increase in the amounts of micronucleated polychromatic erythrocytes was observed at the dose tested compared to the negative controls, neither 30, 48, or 72 hours after treatment, neither for males nor for females..	The test substance does not produce relevant increases of the numbers of micronuclei in polychromatic erythrocytes after in vivo treatment of mice of either sex of the test strain at a dose of 575 mg/kg bw.	7.6.2.002   ESPTF 6064-002     Sorg, R.M. (1987) (unpuglished)

The information contained within this robust summary document comes from studies which are in the ownership of Arch Chemicals Inc. and which are protected in several regions globally. This information may not be used for any purpose other than in support of the Chemical safety Report submitted by Arch Chemicals Inc. under RegulationEC 1907/2006.

 

Endpoint Conclusion: No adverse effect observed (negative)