Pyridine-2-thiol 1-oxide, sodium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Pyridine-2-thiol 1-oxide, sodium salt

EC Number:

223-296-5

EC Name:

Pyridine-2-thiol 1-oxide, sodium salt

Cas Number:

3811-73-2

Molecular formula:

C5H5NOS.Na

IUPAC Name:

sodium (1-oxo-1λ⁵-pyridin-2-yl)sulfanide

Details on test material:

- Analytical purity: 41.41%
- Lot/batch No.: radiolabelled = 2332-038 non-radiolabelled = S08708
- Radiochemical purity (if radiolabelling): 99%
- Specific activity (if radiolabelling): 12.6mCi.mmole

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Source: Taconic Farms
-Age: 7-10 weeks
-Weight: male = 242-323g female = 176-232g

Administration / exposure

Route of administration:

other: oral and intravenous

Vehicle:

other: see below

Doses / concentrations

Remarks:

Doses / Concentrations:
-Vehicle: oral = water 0.2 mg/ml, intraveous = 0.9% saline 10.8 mg/ml
-Dosing regime: group A: single intraveous 0.5 mg/kg
group B: single oral 0.5 mg/kg
group C: rpt oral 0.5mg/kg (days 1-14 non-radiolabelled day 15 radiolabelled)
group D: single oral 25 mg/kg

No. of animals per sex per dose / concentration:

10 male and 10 female (5 males and 5 females used for serial blood collection and 5 males and 5 females used for urine and feces collection)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Comparison of the 0-96 hour urinary radioactivity from the orally-dosed rats and the i.v.-dosed rats indicated that the pyrithione was well absorbed by the oral route. The estimated percentage of the dose absorbed was calculated as the fraction of the oral dose excreted in the urine between day-0 and day-4 divided by the fraction of the i.v. dose excreted in the urine over the same time period. The absorption values ranged from 88% to 105%.

Details on distribution in tissues:

The highest dose was in the liver for all groups, see table below

Details on excretion:

Urine was the main route of excretion in all four dose groups, with the urine and cage wash combined accounting for average values ranging from 74.2% to 86.0% of the dose for males and 75.8% to 85.0% of the dose for females after 96 hours. Within 24 hours, 55.5% - 75.6% of the dose was excreted in the urine for the males and 51.1% - 74.0% for the females. Feces accounted for 3.2% of the dose for both males and females in the i.v. group and in oral groups ranged from 5.3 to 12.3% of the dose in males and 6.0% to 11.4% of the dose in females (0-96 hours). In the oral groups, the tissues accounted for 0.4% - 0.8% of the dose and the carcass contained 1.3% - 2.1%. The tissues and carcass were not measured in the i.v. groups. Average total recovery (oral dose groups) ranged from 85.1% to 95.1%.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The main mechanism for metabolism of sodium pyrithione was the formation of S-linked conjugates of 2-pyridinethiol-1-oxide (pyrithione) and 2-pyridinethiol. No free pyrithione was detected in the urine. Twelve urinary metabolites (designated A-L) were separated by HPLC, all but two of which (metabolites A and K) accounted for <10% of the dose. The most prominent metabolite by far was 2-pyridinethiol-1-oxide-S-glucuronide (metabolite K, 41.4% - 67.2%). Metabolite A (7.7% - 21.3% of the dose) was not identified. The primary metabolic pathway involved glucuronic acid conjugation with the thiol group of pyrithione (2 pyridinethiol-1-oxide). 2-Pyridinethiol-S-glucuronide (metabolite H, 1.0% -8.0 %) was also identified, indicating that reduction of the N oxide group also occurred

Any other information on results incl. tables

	Mean percentage of the dose 96 hours after dosing
	0.5 mg/kg p.o. single dose		0.5 mg/kg p.o. multiple dose		25 mg/kg p.o. single dose
Tissue	M	F	M	F	M	F
Plasma^a	0.02	0.01	0.02	0.01	0.03	0.02
Blood cells^a	0.07	0.08	0.06	0.07	0.07	0.07
Liver	0.23	0.14	0.27	0.16	0.29	0.19
Kidney	0.04	0.03	0.06	0.04	0.08	0.03
Heart	0.01	0.01	0.01	0.01	0.01	0.01
Lung	0.01	0.01	0.02	0.01	0.02	0.01
Brain	0.01	0.00	0.01	0.01	0.02	0.01
Fat^a	0.00	<0.01	0.01	0.00	0.00	<0.01
Skeletal muscle^a	0.01	0.01	0.01	0.01	0.01	0.01
Spleen	0.01	0.01	0.01	0.01	0.01	0.01
Reproductive organ	0.02	0.00	0.02	0.00	0.03	0.00
Bone Marrow^a	<0.01	<0.01	<0.01	<0.01	<0.01	<0.01
Sciatic nerve^a	<0.01	<0.01	<0.01	<0.01	<0.01	<0.01
Spinal cord^a	<0.01	<0.01	<0.01	<0.01	<0.01	<0.01
Intestines	0.07	0.03	0.09	0.06	0.09	0.07
Intestine contents	0.08	0.05	0.11	<0.01	0.14	0.13
Urinary bladder	0.01	0.01	<0.01	<0.01	<0.01	<0.01
Total	0.60	0.39	0.70	0.39	0.90	0.55

Applicant's summary and conclusion

Conclusions:

Sodium pyrithione was extensively absorbed after an oral dose of 0.5 or 25 mg/Kg. Metabolism was extensive, with the S-glucuronide of pyrithione as the major metabolite in all dose groups. Excretion of the dose was rapid and occurred primarily via the urine. Residual radioactivity in tissues was low, ranging from 2% to 3% of the dose 96 hours after dosing, and was most concentrated in blood cells, liver, and kidneys. 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 Regulation EC 1907/2006.