Pyrithione zinc

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

0.41

Additional information

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.

Jeffcoat et al, 1980,investigated the metabolism and disposition of zinc Pyrithione in rabbit, rat, monkey, dog and swine in a non-guideline, non GLP study. The metabolic profiles of orally administered zinc pyrithione in rats, rabbits, dogs and monkeys confirm the presence of the same terminal metabolite, 2-methylsulphonylpyridine, in all the species.

The identification of a common terminal metabolite suggests a common metabolic pathway.

Following oral administration, zinc pyrithione disassociates to liberate Zn and the Pyrithione moiety, which are then absorbed independently. The major route of elimination after oral administration of zinc pyrithione is through kidneys. Excretion of zinc pyrithione was found to be rapid (>95% in 72 h), principally via the urine as metabolites (75-94%) and faecal excretion being a minor route of excretion (2.6-20%). Furthermore, radio assays of tissues showed that zinc pyrithione is rapidly eliminated and is not retained in the body to any significant degree. In rats, males did not achieve as high concentrations of zinc pyrithione in the blood as females. Also, males metabolize zinc pyrithione more rapidly than females.

A further GLP study to US EPA Guideline 85-1 byChadwick et al, 1989,investigated the disposition and metabolism of Sodium omadine in rats after oral and intravenous administration.The results with sodium pyrithione were similar to those obtained with zinc pyrithione by Jeffcoat, et al. (above) supporting the fact that the pyrithione moiety is responsible for the toxicity regardless of the salt.

Based on comparison of urinary and faecal excretion in the i.v. and p.o. dosed groups, it was shown that sodium pyrithione was well absorbed by males and females in all three oral dose groups. Metabolism was extensive. The major urinary metabolite was 2‑pyridinethiol-1-oxide-S-glucuronide (designated metabolite K), which is the glucuronic acid conjugate of free pyrithione. Metabolite K represented 59-67% of the dose in 0-72 hour urine after a single 0.5 mg/Kg oral dose, 41-49% after multiple 0.5 mg/Kg oral doses, 50% after a single 0.5 mg/Kg i.v. dose, and 43-47% after a single 25 mg/Kg oral dose. No unconjugated pyrithione was detected. 

After oral dosing, the concentration of¹⁴C pyrithione equivalents in the blood showed a broad secondary peak after the initial peak following dosing. Evidence of a secondary peak or plateau was also seen after i.v. dosing. Elimination from the blood occurred at several rates, with a slow terminal rate in all of the orally dosed groups. No abnormalities were observed in any of the treatment groups.

Discussion on absorption rate:

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.

Dermal Penetration

An in vitro dermal penetration study was completed by Blackstock, 2010, using human skin. The concentration of zinc pyrithione in the aqueous dispersion was 48%. Zinc [14C]-pyrithione was prepared at an application volume of 10ul/cm sq to human split-thickness skin membranes mounted into flow-through diffusion cells in vitro. Percutaneous absorption was assessed by collecting receptor fluid hourly from 0 to 8 hours post application, and then in 2 hour fractions from 8 to 24 hours post application. At 8 hours exposure was terminated by washing the skin surface. At 24 hours, the underside of the skin was rinsed with receptor fluid. The skin was removed from the flow-through diffusion cells, dried, and then stratum corneum was removed with 20 successive tape strips. The remaining skin was divided into exposed and unexposed skin and the exposed skin was heat separated to give epidermis and dermis. All samples were analysed by liquid scintillation counting.

The majority of the applied dose (8.8%) was removed by washing at 8 hours after application. 24 hours after application 98.85% of the applied dose was dislodged. The stratum corneum retained 0.46% of the applied dose; 0.3% was removed after the first 5 tape strips. 99.31% of the applied dose was not absorbed. The absorbed dose of zinc [14C]-pyrithione was <0.01% (0.16ug/cm sq). The dermal delivery was 0.24% (14.43 ug/cm sq) and the potentially absorbable dose was 0.41% (23.91ug/cmsq).

Dermal Penetration

Small laboratory animals, such as rats, mice and rabbits, lack sweat glands but have more hair follicles than human skin. For example, guinea pig skin contains ~4,000-5,000 follicles/cm²,rat skin ~8,000 follicles/cm²and rabbit skin > 10,000 follicles/cm², whereas human skin contains ~6 follicles/cm²(Scott et al, 1991). Such laboratory animals have been extensively used in percutaneous absorption studies with the rat being the most prevalent species used in comparative studies.

Thein vivoand in vitro data reported on the penetration of several unionised solutes through the skin of a variety of species demonstrate that, in general, the magnitude of difference in skin permeability between the species is ranked in the order rabbit > rat > pig > monkey > man. More importantly, there is sufficient available data to suggest that the skins of the rat and the rabbit do not give reliable estimations of human skin penetration(e.g., Bartek et al, 1972, Feldmann and Maibach, 1974; Bronaugh et al, 1982-1991).

All of the above papers are referenced in theEuropean Commission Guidance Document on Dermal Absorption (2004).

An extensive recent study, using a series of fourteen organic compounds, ranging in molecular weight from 231 to 466 and in aqueous solubility from 0.000057 to 600mg/ml (log P_o/wof 0.7 to 4.5), demonstrated that rat skin was more permeable that human skin in all cases with a mean difference of 10.9-fold(van Ravenzwaay and Leibold, 2004a,b.. Others, using individual chemicals at differing application concentrations, have found that rat skin is 3 – 5-fold more permeable than human skin(Moody et al, 1995; Kenyon et al, 2004).

The overall conclusion is that the systemic exposure of humans may be significantly overestimated if risk assessment is based on the results of anin vivorat study and that the use ofin vitrohuman skin studies is more appropriate for risk assessment.