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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(unpublished).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/106clonable cells, while those of the cultures treated with sodium pyrithone ranged from 1.0 to 10.5 TG mutants/106clonable 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 and3H-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)

Justification for classification or non-classification