UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: September 30, 2004 SUBJECT: Zinc Pyrithione ( Zinc Omadine ® ) : AD Risk Assessment for the Reregistration Eligibility Decision ( RED) Document. Chemical No. 088002. Case No. 2480. DP Barcode: D308704 FROM: Deborah Smegal, MPH, Toxicologist/ Risk Assessor Timothy F. McMahon, Ph. D., Senior Toxicologist Doreen Aviado, Biologist Kathryn Montague, M. S. Biologist Najm Shamim, Ph. D. Chemist Siroos Mostaghimi, Ph. D. Environmental Engineer Antimicrobials Division ( 7510C)

THRU: Norm Cook, Chief Risk Assessment and Science Support Branch Antimicrobials Division ( 7510C)

TO: Tony Kish Regulatory Management Branch I/ Team 33 Antimicrobials Division ( 7510C)

Attached is RASSB's Risk Assessment for Zinc Pyrithione ( Zinc Omadine ® ) for the purpose of issuing a Reregistration Eligibility Decision ( RED). The disciplinary science chapters and other supporting documents for the zinc omadine RED are also included as attachments as follows: Zinc Omadine: Revised Toxicology Endpoint Selection Report from the Antimicrobials Divisions's Toxicology Endpoint Selection Committee ( ADTC), September 2004 Toxicology Science Chapter for the Reregistration Eligibility Decision Document, From T. McMahon to D. Smegal, April 2004 D301369 Occupational and Residential Exposure Assessment for the RED Document. From D. Aviado/ D. Smegal to B. Chambliss. September 2004, D308705 Residue Chemistry Science Chapter for Zinc 2 pyridinethiol 1 oxide. From A. N. Shamim to J. Fairfax. D251938 Environmental Fate Science Chapter for Zinc Omadine for Reregistration Eligibility Document ( RED). From A. N. Shamim to D. Smegal. April 2004, D301372 Predicted Environmental Concentration ( PEC) for Zinc Omadine and Tributyl Tin ( TBT). From S. Mostaghimi to D. Smegal. April 2004, D301373 Ecological Hazard and Environmental Risk Assessment for Zinc Omadine. From K. Montague. September 2004, D309561 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0. PHYSICAL AND CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 3.4 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION . . . . . . . . . . . . . . . . . . . 20 4.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2 Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.3 Drinking Water Exposure and Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.4 Residential Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.4.1 Residential Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.4.2. Anti Dandruff Shampoo Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.4.3. Postapplication Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 27 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION . . . . . . . 29 5.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 5.2 Short and Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . 32 5.3 Chronic ( non cancer) Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 6.0 CUMULATIVE EXPOSURE AND RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 7.0 OCCUPATIONAL EXPOSURE AND RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 8.0 INCIDENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.0 ENVIRONMENTAL RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 10.0 DEFICIENCIES/ DATA NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 11.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 1 1.0 EXECUTIVE SUMMARY Zinc pyrithione ( zinc omadine ® ) is used as an industrial preservative to prevent microbial deterioration and to maintain the integrity of manufacturing precursor materials and finished manufactured articles. It is a bacteriostat, fungicide, and microbiocide/ microbiostat registered for incorporation into food packaging adhesives ( indoor food), incorporation into articles made from or coated with FDA approved food contact polymers such as food processing equipment, conveyor belts, utensils, and storage containers ( indoor food), paint preservation ( indoor/ outdoor nonfood), control of bacterial growth on laundered products ( indoor nonfood), and preservation of adhesives, caulks, patching compounds, sealants, grouts, latex paints, coatings, dry wall, gypsum, pearlite, plaster ( indoor nonfood) and ductwork ( HVAC use). Zinc pyrithione is also used for the control of mildew in nonfood contact polymers and control of mildew and bacteria in styrene butadiene rubber and thermoplastic resins ( e. g. carpets and other floor coverings, textiles, home furnishings, housewares, sports equipment, automotive/ public transport systems, mattress liners, air ducts, etc). In addition, it is conditionally registered as an antifouling agent for boat paints to control the growth of slime, algae, and marine fouling organism ( eg., barnacles, tubeworms, etc.) below the water line of recreational and commercial boat hulls in fresh, salt, or brackish water. The registrant, Arch Chemicals, is conducting a study to assess exposures of workers performing painting of commercial vessels with antifoulant paints containing zinc pyrithione. This study is expected to be completed and submitted in 2006, and will be used to assess the conditional registrations for the antifoulant paint use. Ecological risks associated with antifoulant paint use are not included in this risk assessment because of pending data, and will be assessed upon submission of the requested ecotoxicity studies. Residential exposures, however, for handlers that could use zinc pyrithione containing paint on recreational boats or other locations are assessed, and are also incorporated into the aggregate assessment.

In addition to its pesticidal uses, zinc pyrithione is approved by the Food and Drug Administration ( FDA) for use in anti dandruff shampoos. It is considered to be safe and effective ( considered generally recognized as safe ( GRAS) and generally recognized as effective ( GRAE) by the FDA as an over the counter drug) for the treatment of dandruff and seborrheic dermatitis with a history of over 40 years of human use.

Hazard: The toxicology database for zinc pyrithione is adequate for the registered uses, but uncertainty factors were applied for lack of adequate characterization of neurotoxicity of zinc pyrithione. Neurotoxicity studies are requested as confirmatory data to properly characterize the dose response relationship that exists for this aspect of zinc pyrithione toxicity.

The toxicology database for zinc pyrithione indicates that by the oral route, zinc pyrithione is moderately toxic ( LD 50 is 267 mg/ kg; Toxicity Category II) but that acute toxicity by the dermal route is not as significant ( LD 50 > 2000 mg/ kg; Toxicity Category III). Acute toxicity by the inhalation route is also relatively low ( LC 50> 0.61 mg/ L; Toxicity Category III). Zinc pyrithione is a severe eye irritant ( Toxicity category I) but does not appear to demonstrate significant dermal irritation ( Toxicity category IV). Zinc pyrithione does not demonstrate dermal sensitization 2 potential.

Repeated dose ( 13 weeks) toxicity studies indicate that by the dermal route, zinc pyrithione is relatively non toxic ( decreased food consumption, decreased body weight gain, decreased food efficiency at the limit dose of 1000 mg/ kg/ day), but by the oral route, toxicity is significantly greater ( increased relative organ weights, clinical toxicity, and hindlimb weakness at 3.75 mg/ kg/ day). In both oral developmental studies in rats and rabbits, there was no quantitative evidence of increased susceptibility [ i. e., maternal and developmental no observed adverse effect levels ( NOAELs) were the same]. There was however, qualitative evidence of increased susceptibility ( i. e., fetal effects were considered to be more severe in the presence of minimal maternal toxicity). Significant nervous system deficits following either acute or subchronic oral administration are observed with zinc pyrithione. Intravenous administration of 5 mg/ kg zinc pyrithione to female Yorkshire pigs produced symptoms similar to cholinergic effects lasting for 30 60 minutes post dose ( HED document 003933). Increased salivation was reported immediately after dosing in the rat developmental toxicity study at a dose of 3 mg/ kg/ day ( MRID # 42827904). Subchronic administration of zinc pyrithione at 3.75 mg/ kg/ day has been shown to produce hindlimb weakness ( HED document no. 003933). Peripheral neuropathy in the form of axonal degeneration has been observed. Neurotoxicity studies are thus triggered ` for cause' in order to properly characterize the effects of zinc pyrithione on nervous system structure and function as well as a more adequate identification of the neurotoxic dose response in adults.

Toxicity Endpoints: The toxicity endpoints used in this document to assess potential risks include acute and chronic dietary reference doses ( RfDs), and short, intermediate and/ or long term incidental oral, dermal and inhalation doses. Health Effects Division's ( HED) Hazard Identification Assessment Review Committee ( HIARC) selected these toxicity endpoints in 1999, which were upheld by the Antimicrobials Division's endpoint selection committee ( ADTC) in September 2003.

Acute and Chronic RfDs: Because zinc pyrithione causes adverse developmental effects, the HIARC identified two acute dietary acute RfDs, one for females of child bearing age ( 13 50 years) and one for the general population. The acute RfDs are 0.0016 mg/ kg/ day and 0.0025 mg/ kg/ day for females ( 13 50 years) and the general population, respectively. The female ( 13 50 year) aRfD is based on adverse developmental effects ( increased post implantation loss and decreased viable fetuses) at 1.5 mg/ kg/ day in a rabbit developmental study, while the aRfD for the general population is based on increased salivation in maternal rats at 3 mg/ kg/ day in a rat developmental study. The chronic RfD is 0.0016 mg/ kg/ day based on adverse developmental effects in the rabbit developmental study. An uncertainty factor of 300 ( 10X for interspecies extrapolation, 10X for intraspecies variability, and 3X for database uncertainties) was applied to the NOAEL to obtain the acute and chronic RfDs. A database uncertainty factor of 3x is applied to non occupational risk assessments for zinc pyrithione, due to the lack of characterization of neurotoxic dose response relationships for zinc pyrithione, and the need for additional neurotoxicity testing. A 3x factor for lack of neurotoxicity data ( as opposed to a higher factor of 10x) is adequate because neurotoxicity observed in the available data occurs at similar 1 PAD = Population Adjusted Dose = Acute or Chronic RfD FQPA Safety Factor 3 effect levels as other adverse responses, the doses and endpoints selected for dietary and nondietary assessments encompass the doses at which neurotoxicity is observed, there is no quantitative evidence of susceptibility to the toxic effects of zinc pyrithione, and traditional uncertainty factors afford a degree of protection that is considered conservative.

Incidental oral endpoints: The short term, and intermediate term incidental oral endpoint of 0.75 mg/ kg/ day is based on increased salivation in maternal rats at 3 mg/ kg/ day in a rat developmental study.

Dermal endpoints: Because zinc pyrithione causes adverse developmental effects, there are two dermal endpoints, one for females of child bearing age ( 13 50 years) and one for the children. The short term, intermediate term, and long term dermal endpoints are identical for these two population subgroups. The dermal endpoint for females ( 13 50 years) is 0.5 mg/ kg/ day ( NOAEL) based on adverse developmental effects ( increased post implantation loss and decreased viable fetuses) at 1.5 mg/ kg/ day in a rabbit developmental study, while the dermal endpoint for children is based on body weight decrements observed at 1000 mg/ kg/ day in a subchronic dermal toxicity study. The dermal no observed adverse effect level ( NOAEL) is 100 mg/ kg/ day. A 3% dermal absorption factor is used for the dermal endpoint for females of child bearing age.

Inhalation endpoints: The short, intermediate and long term inhalation endpoint of 0.13 mg/ kg/ day ( 0.0005 mg/ L, the NOAEL) is based on labored breathing, rales, increased salivation, decreased activity, dry red brown material around the nose, increased absolute and relative lung weights, and death of undetermined cause at 0.0025 mg/ L ( 0.65 mg/ kg/ day) in a whole body subchronic rat inhalation study.

FQPA Safety Factor. The ADTC committee concluded that the hazard based FQPA safety factor can be reduced to 1x since the degree of concern is low ( i. e. a complete developmental and reproductive database is available with clear NOAELs/ LOAELs for parental and offspring toxicity) and there are no residual uncertainties for prenatal toxicity. The developmental toxicity database shows effects in offspring at similar dose levels as effects in adults, while a reproductive toxicity study for sodium pyrithione ( a structurally related chemical) shows effects in offspring at doses above those occurring in parental animals. Effects observed in offspring from developmental toxicity studies have been selected for use in dietary risk assessments, thus being protective of infants and children.

Based on Agency policy, a RfD modified by a FQPA safety factor is a population adjusted dose ( PAD) 1. The Agency calculated an acute PAD and a chronic PAD, and uses this value to estimate acute and chronic dietary risk. The acute PAD is the acute RfD divided by the FQPA safety factor. The chronic PAD is the chronic RfD divided by the FQPA safety factor. 4 Dietary Exposure and Risk: AD considered potential dietary exposure to zinc pyrithione residues in food and water. When assessing acute and chronic ( non cancer) dietary risk, AD considered potential dietary exposure to the U. S. population including infants and children as well as to females 13 50 years, based on the developmental toxicity potential of this active ingredient. AD expresses dietary risk estimates as a percentage of the aPAD or chronic PAD. Dietary exposures that are less than 100% of the aPAD or cPAD are below the Agency's level of concern.

Acute Dietary Risk. Acute dietary risks were calculated from use of zinc pyrithione as an antimicrobial pesticide in food packaging materials and repeat use of polymeric food contact materials. Dietary exposure to zinc pyrithione can result from migration of the active ingredient from the treated article. AD has determined that, based on the assumptions and models used, the acute dietary risk from exposure to zinc pyrithione does not exceed the Agency's level of concern for all subpopulations examined. The highest dietary risk estimate is 2.7% of the acute PAD, for infants and children.

Chronic Dietary Risk. In the present submission, without further data, screening level estimates used for the acute dietary risk analysis are used to assess potential chronic dietary exposure. The risk analysis assumes daily exposure from contact with polymeric treated articles that come into contact with food. The chronic non cancer dietary analysis indicates all risk estimates are below the Agency's level of concern for all population subgroups. The highest dietary risk estimate is 4.2% of the chronic PAD, for infants and children.

Water Exposure and Risk: AD has considered the conditionally registered use of zinc pyrithione in antifoulant paints and chemical specific information on degradation, mobility and leaching rates from antifoulant paint. Uses in antifouling paints for recreational boats are expected to impact surface water resources ( i. e., rivers, lakes and marinas). To assess drinking water impact, the Agency estimated predicted environmental concentrations ( PEC) that range from 0.0144 to 0.101 ppb zinc pyrithione, using conservative assumptions and the Marine Antifoulant Model Predicted Environmental Concentration ( MAM PEC) model ( 100% market share and default marina values). Because of lack of data for fresh water, the PECs estimated by MAMPEC were used to assess potential drinking water exposures the could result from antifoulant paint on boats in fresh water such as lakes and rivers. The PECs were used to assess both acute and chronic drinking water exposures. Based on current Agency policy, drinking water level of comparison ( DWLOCs) are compared to the PEC. When the PEC is greater than the DWLOC, AD considers the estimate of aggregate risk to exceed the Agency's level of concern.

Residential ( Non Occupational) Exposure and Risk: Zinc pyrithione is incorporated into many substrates that can result in non dietary exposure, such as footwear, shower curtains, plastic objects, rubber gloves, carpet fibers, synthetic floor coverings, plastic furniture, mattress liners/ ticking/ covers, paints, sealants and caulks. The Agency evaluated exposures to residential handlers that could use zinc pyrithione containing antifoulant paints on recreational boats, or other paints or consumer products that contain zinc pyrithione as a material preservative. The Agency also evaluated potential postapplication exposures to consumer products that contain zinc 5 pyrithione. Scenarios evaluated, which were considered to be representative of all possible exposure scenarios, included: dermal and inhalation exposure to residential handlers during painting activities, dermal contact with treated shoe sole liners, incidental ingestion of residues on treated plastic objects ( i. e., object to mouth), and incidental ingestion of residues on hands ( i. e., hand to mouth) from contact with treated plastic/ objects. Duration of exposure is short term ( 1 30 days) for residential handler dermal and inhalation exposure, and short, and intermediate term ( 1  6 months) for incidental oral postapplication exposures to children. Dermal exposures from postapplication contact were considered to represent a long term scenario (> 6 months). The scenarios were evaluated based on the Residential Exposure Assessment Standard Operating Procedures ( SOPs), product label maximum application rates, related use information, Agency standard assumptions, and Pesticide Handlers Exposure Database ( PHED) unit exposure data ( for residential handlers).

Residential postapplication exposures show that short, intermediate, and long term dermal risks are not of concern ( i. e. MOEs > 300) for adult/ child contact with zinc pyrithionetreated rubber/ plastic articles, and short and intermediate term incidental oral exposure scenarios for infants/ children that could contact zinc pyrithione treated plastic objects via object to mouth, and hand to mouth exposures. Residential handler exposure scenarios with risk estimates that exceed the Agency's level of concern ( i. e., MOEs < 300) are:

° residential handlers that paint using an airless sprayer: ( antifoulant paint use: dermal MOEs= 15 78, inhalation MOEs= 6 33; material preservative use in paints: dermal MOE= 117, and inhalation MOE= 15; ° residential handlers that paint using a brush: ( antifoulant paint use for all boat sizes: dermal MOE= 3.2 117; inhalation MOE= 18 97 using PHED and inhalation MOE= 5 140 using Health and Safety Executive ( HSE) data ( Garrod et al. 2000); material preservative use in paints ( Dermal MOE= 44); and ° residential handlers that paint using an aerosol spray can ( inhalation MOE= 271).

These risk estimates are based on a number of conservative assumptions. For example, the inhalation endpoint is based on a whole body rat 90 day inhalation study, while the dermal risks are based on an oral developmental study and a 3% dermal absorption factor. There is likely reduced bioavailability of zinc pyrithione from dermal contact as a result of entrapment in a paint matrix.

The Agency also assessed residential dermal exposure from use of zinc pyrithionecontaining shampoo. Although not a registered use under the EPA's authority, non dietary nonpesticidal use of zinc pyrithione in anti dandruff shampoo was considered in the aggregate risk assessment. The Agency evaluated a conservative screening level scenario involving once daily use of zinc pyrithione containing shampoo. The estimated long term dermal MOE is 500, based on conservative assumptions, and the results of a study that measured radioactivity associated with metabolized zinc pyrithione ( zinc pyrithione) in the urine for 5 days following a single 6 shampoo application containing radiolabeled zinc pyrithione.

Aggregate Exposure and Risk: In order for a pesticide registration to continue, it must be shown that the use does not result in " unreasonable adverse effects on the environment". Section 2 ( bb) of FIFRA defines this term to include " a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with standard under section 408..." of FFDCA. Consequently, even though no pesticide tolerances have been established for zinc pyrithione, the standards of FQPA must still be met. As mandated by the FQPA amendments to FIFRA and the Federal Food, Drug and Cosmetic Act ( FFDCA), the Agency must consider total aggregate exposure from food, drinking water and residential sources of exposure to zinc pyrithione.

Acute. The acute aggregate food ( from indirect food contact) and drinking water exposure ( from antifoulant paint use) do not exceed the Agency's level of concern for adults or children. Percentages of the acute PAD occupied from food sources were highest for infants and children ( 2.7%), and were less for adult males and females 13 50 years. All of the acute DWLOCs ( 24 86 ppb) are greater than the PECs of 0.0144 to 0.101 ppb, indicating that aggregate exposures are not of concern.

Short and Intermediate Term. Short and intermediate term aggregate risks are considered together since the exposure and toxicity endpoints are identical for incidental oral residential exposures for both durations. The short and intermediate term aggregate assessment includes average dietary exposure ( food and water) and estimated incidental oral exposures from residential uses such as plastic objects for children. For adult females, the aggregate assessment includes dietary ( oral) and residential dermal exposures during painting since there is concern for potential developmental effects for zinc pyrithione. Inhalation residential exposures ( i. e., residential handler during painting activities) were not aggregated with the oral exposures due to different toxicological endpoints for oral ( increased salivation/ developmental), and inhalation ( clinical signs of toxicity and lung effects).

The adult aggregate assessment assumed that a resident would apply paint containing zinc pyrithione ( as a material preservative) via an aerosol can ( dermal exposure), in addition to receiving potential oral exposures via dietary and drinking water exposure. As noted previously, dermal risks are already of concern for residents that could apply antifoulant paint to their boats ( dermal MOEs range from 3.2 17 for a paintbrush, and 15 78 for an airless sprayer), or use a paintbrush or an airless sprayer to apply products when zinc pyrithione is used as a material preservative ( dermal MOEs are 44 and 17, respectively). Thus, these scenarios were not considered in the aggregate risk assessment, because inclusion of this use in the aggregate would also contribute to dermal aggregate risks of concern. 7 INHALATION. The only uses which pose inhalation exposure are from the residential handler uses of paint, which have MOEs that exceed the Agency's level of concern ( inhalation MOEs range from 5 140 for antifoulant paint use and 15 271 for paint containing zinc pyrithione as a materials preservative). However, these risk estimates are conservative because they are based on a whole body rat 90 day inhalation study.

Chronic. Chronic aggregate risk determines the combined risk from average daily exposure in the diet ( food + water) with those exposures arising as a result of residential uses ( if applicable). For adult females, this assessment includes chronic food and drinking water exposures, in addition to long term residential exposures through the dermal route of exposure ( i. e., anti dandruff shampoo use, or shoe liner exposure), to be protective of potential developmental effects of zinc pyrithione. However, for children, only chronic dietary and drinking water exposures were aggregated because the developmental effects are not appropriate for assessing children's risk, and the oral and dermal endpoints for this population are different. As noted previously, chronic dietary exposures do not exceed the Agency's level of concern ( highest exposure represents 4.2% of the cPAD for infants and children). The chronic DWLOCs are greater than the PEC for adults and infants/ children, indicating that aggregate food, drinking water and residential ( as appropriate) exposure do not exceed the Agency's level of concern. These results are based upon a number of conservative assumptions regarding dietary and water exposure and do not necessarily represent the most refined drinking water assessment.

Occupational Exposure and Risk. The Agency has determined that there is potential for worker exposure to zinc pyrithione through mixing, loading, application, and handling activities associated with zinc pyrithione pesticide products. There are potential exposures from use in commercial, and industrial settings via the dermal and inhalation routes. Based on the EPAregistered use patterns, appropriate primary and secondary handler exposure scenarios were identified for zinc pyrithione. An exposure/ risk assessment for occupational antifoulant boat paint use, which is a time limited registration, was not included in this assessment but will be evaluated later, following the submission of relevant worker exposure data for this use. In general terms, EPA defines " primary" handler exposure as direct exposure to the pesticide formulation during mixing/ loading/ applying operations. " Secondary" handler exposure is defined as exposure to a pesticide active ingredient as a direct result of its incorporation into an end product. Examples of secondary handler exposure include the application of treated paints and coatings, and building materials such as caulks, adhesives, spackling, groutings, sealants, stucco and joint cements. Based on end use product application methods and use amounts, it is assumed that exposures while applying paints will be equal to or greater than exposures while applying building materials. Therefore, occupational handler exposures were assessed for the application of paint, as this scenario represents maximum possible exposure to the chemical. Under this scenario, dermal and inhalation exposures were assessed for brush, airless sprayer, and aerosol application methods.

The exposure and risk assessment for primary and secondary occupational handlers was conducted using product label maximum application rates, related use information from the registrant ( Arch Chemicals, Inc), Agency standard values for industrial practices, and unit 8 exposure data from the Chemical Manufacturers Association ( CMA) the Pesticide Handlers Exposure Database ( PHED), and the relevant scientific literature. For mixing/ loading liquids and powders in closed systems ( i. e., using a metered pump, or automatic dispensing techniques), the margin of exposure ( MOE) calculations indicate risks ( i. e., target MOEs

100) below the Agency's level of concern for the dermal and inhalation exposure scenarios assessed. The " dermal" exposure risks are not of concern ( i. e., MOE

100) for potential short term, intermediate term, and long term exposures during open mixing/ loading of powders and liquids for all the scenarios assessed. Also, the dermal and inhalation MOEs for the laundered fabrics scenarios were not of concern.

However, the following short, intermediate, and long term exposure scenarios have MOEs of concern ( i. e., MOEs < 100):

° mixing/ loading/ applying powders and liquids for general preservative use patterns using open pour methods ( inhalation MOE= 53 for liquid formulations; inhalation MOE= 15 for powder formulation; dermal MOE= 42 for powder formulation); ° mixing/ loading/ applying powders and liquids for paint preservation using open pour methods ( inhalation MOE= 53 for liquid formulations; inhalation MOE= 15 for powder formulation; dermal MOE= 42 for powder formulation); ° handling zinc pyrithione containing paint products ( as a material preservative) using an airless sprayer application method ( inhalation MOEs= 4.4 without PPE, and 44 with the use of an organic vapor respirator as PPE, and dermal MOE= 11 without the use of gloves as PPE, and MOE= 29 with gloves), and ° handling zinc pyrithione containing paint products ( as a material preservative) using a paintbrush ( dermal MOE= 22 without gloves).

It is assumed that in real use situations for airless sprayer applications, the occupational handlers will have adequate respiratory protection by wearing either a dust/ mist or organic vapor respirator as PPE recommended by paint manufacturers for spray equipment applications. The Agency may consider requiring risk mitigation steps, such as closed delivery systems or use of a respirator during open pouring. Although the dermal MOE for a paintbrush scenario is of concern ( MOE= 22) without gloves, the MOE is not of concern ( MOE= 167) when gloves are worn as protective equipment. It is assumed that in real use situations the occupational handlers will have adequate dermal protection by wearing gloves as may be recommended by paint manufacturers. Dermal and inhalation MOEs obtained for the painting scenario involving use of an aerosol spray can application method is not of risk concern.

Primary occupational post application dermal and inhalation exposures are limited to mists, steams, or vapors resulting from manufacturing process operations. These exposures are likely to be minimal because of the dilution of the pesticide during processing and the low vapor pressure of the active ingredient, and thus were not quantitatively evaluated in this report.

Other Food Quality Protection Act ( FQPA) Considerations 9 Cumulative Effects. Section 408 of the FFDCA stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe. EPA does not have, at this time, available data to determine whether zinc pyrithione has a common mechanism of toxicity with other substances including sodium pyrithione.

Endocrine Disruption. Zinc pyrithione caused impacts on growth and reproduction to several species of aquatic organisms in laboratory studies, at levels slightly below the LC 50. These types of effects suggest that zinc pyrithione may possibly have endocrine disruption potential. The Food Quality Protection Act ( FQPA; 1996) requires that EPA develop a screening program to determine whether certain substances ( including all pesticides and inerts) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect...." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed and validated, zinc pyrithione may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

Environmental Risk Environmental Fate. Zinc pyrithione is a complex ( coordination) compound formed through a chemical reaction between the inorganic zinc ion and organic moiety pyrithione. Hydrolytically the chemical is stable in water under abiotic and buffered conditions ( pH 5, 7 and 9), as well as in simulated sea water. The extrapolated hydrolytic half lives were 99, 120 and 123 days at pHs 5, 7 and 9, respectively. In simulated sea water, the extrapolated half life was 96 days. Photolytic measurements showed that zinc pyrithione rapidly degrades with a half life of 13 minutes in buffered medium and in about 17 minutes in simulated sea water. In a study on aerobic 10 aquatic system, zinc pyrithione degradation follows a biphasic process and in the first phase it degrades rapidly with a half life of 0.065 hours in salt water and in 1.3 hours in fresh water samples. In a second phase, the half lives of zinc pyrithione were 12.3 and 15 days for fresh water and sea water respectively. It may not pose a concern for surface water run off.

There are multiple degradation pathways for zinc pyrithione. Under aerobic conditions, zinc pyrithione degradation half life is 0.6 hours in aqueous system and 0.89 days in sediment. Similarly zinc pyrithione shows a tendency of degrading anaerobically in water within 0.5 hours and in about 19 hours in sediments. It may not be a concern for ground water contamination.

Zinc pyrithione shows a moderately strong tendency to bind with soils and sediments: With salt water soil and sediment its K d s are 50 and 99, respectively. Tendency to bind with freshwater soils and sediments are less strong and observed K d s are 11 and 48, respectively. There may be a short lived water/ sediment partitioning issue. There could be an acute adverse impact on benthic aquatic organisms. However, since it degrades fairly quickly in freshwater and saltwater soils and sediments ( half lives 0.89 days to 19 hours), the acute adverse impact may be very shortlived It is not likely to persist in water and microbial soils and sediments. Sediment toxicity studies with both freshwater and marine organisms are currently in progress by the registrant. The results of these studies will provide additional clarification as to the chemical behavior and toxicity of zinc pyrithione in water/ sediment systems.

The reported Octanol/ Water Partition coefficient K OW is < 10 ( Log Kow is 0.97), and therefore zinc pyrithione is not likely to bioaccumulate in aquatic organisms ( fish etc.), although because of moderately high K d s with salt water sediments it may partition in water and become available to benthic organisms.

Ecological Hazard and Risk. The ecological effects database for zinc pyrithione is adequate to support the indoor uses considered in this report. As noted previously, the antifoulant paint use is a time limited registration, which is not considered in this document for ecological risks, but will be re evaluated upon review of recently submitted ecotoxicity studies. Zinc pyrithione is moderately toxic to birds via acute oral exposure, and slightly toxic to practically non toxic to birds via dietary exposure. It is also acutely toxic to mammals via oral ingestion ( Toxicity Category II). Zinc pyrithione is very highly toxic on an acute basis to freshwater and marine fish and invertebrates, as well as to some aquatic plant species. It also caused impacts on growth and reproduction to several species of aquatic organisms in laboratory studies, at levels slightly below the LC 50. These types of effects suggest that zinc pyrithione may possibly have endocrine disruption potential Due to the high toxicity of the parent compound to aquatic organisms, coupled with the parent compound's tendency to break down fairly rapidly into more persistent degradates in aquatic systems, aquatic organism acute toxicity tests with two major degradates of zinc pyrithione were submitted. These data indicate that both pyridine sulfonic acid and pyrithione sulfonic acid are only slightly toxic to practically non toxic to freshwater and marine/ estuarine fish 11 N+ O S N+ S O Zn 2 and invertebrates and aquatic plants.

Exposure to terrestrial and aquatic organisms and plants is expected to be minimal from the registered indoor uses of zinc pyrithione. Risk to birds, mammals, fish, aquatic invertebrates, and plants, including Endangered species, is not anticipated from the indoor uses of zinc pyrithione. The ecological risks from the time limited antifoulant paint use will be evaluated later, following a review of the recently submitted ecotoxicity studies.

2.0. PHYSICAL AND CHEMICAL PROPERTIES Identification of Active Ingredients Chemical Name: Zinc pyrithione Chemical Name: zinc 2 pyridinethiol 1 oxide Common Name: Zinc Omadine ® P. C. Code: 088002 CAS Registry Number: 13463 41 7 Empirical Formula: C 10 H 8 N 2 O 2 S 2 Zn Molecular Weight: 317.68 Vapor Pressure: 1.87x10 9 mmHg Log Kow 0.97 at 25o C Log Koc 2.9 4 Solubility 6 mg/ L Structural Formula:

Zinc Pyrithione appears hydrolytically stable in abiotic, buffered and simulated water systems with an extrapolated half life between 99 and 123 days in buffered medium and 96 days ( extrapolated) in simulated sea water. Photolytically, however, it rapidly degrades with a half life of 13 minutes in buffered aqueous medium and 17 minutes in simulated sea water. It may not pose a concern for surface water runoff

There are multiple degradation pathways for zinc pyrithione. Under aerobic conditions, zinc pyrithione degradation half life is 0.6 hours in aqueous system and 0.89 days in sediment. 12 Similarly zinc pyrithione shows a tendency of degrading anaerobically in water within 0.5 hours and in about 19 hours in sediments. It may not be a concern for ground water contamination.

Zinc pyrithione shows a strong tendency ( large K d) to bind with fresh water and salt water sediments. It is, therefore, not a mobile pesticide in soils and sediments. The octanol/ water partition coefficient is less than 10 ( Log Kow is 0.97), which makes it unlikely to bioaccumulate.

3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile A detailed hazard assessment for zinc pyrithione is presented in the attached memorandum ( memo from T. McMahon to N. Cook, April 2004). The acute toxicity of zinc pyrithione is low for dermal toxicity ( Toxicity Category III), inhalation toxicity ( Toxicity Category III) and primary dermal irritation ( Toxicity Category IV), but shows higher toxicity for acute oral toxicity ( Toxicity Category II) and primary eye irritation ( Toxicity Category I). No dermal sensitization was observed with the technical test material. Table 1 presents the acute toxicity data for zinc pyrithione. Table 2 highlights key toxicological studies for zinc pyrithione and sodium pyrithione.

Subchronic Toxicity. Subchronic toxicity studies indicate that by the dermal route, zinc pyrithione is relatively non toxic ( decreased food consumption, decreased body weight gain, decreased food efficiency at the limit dose of 1000 mg/ kg/ day), but by the oral route, toxicity is significantly greater ( increased relative organ weights, clinical toxicity, and hindlimb weakness at 3.75 mg/ kg/ day). In a 90 day whole body inhalation study, rats exhibited clinical signs ( labored breathing, rales, increased salivation, decreased activity), dry red brown stain around the nose, increased absolute and relative lung weights and death of undetermined cause at 0.0025 mg/ L ( 0.65 mg/ kg/ day). The no observed adverse effect level ( NOAEL) was 0.0005 mg/ L ( 0.13 mg/ kg/ day).

Developmental Toxicity. In both oral developmental studies in rats and rabbits, there was no quantitative evidence of increased susceptibility [ i. e., maternal and developmental noobserved adverse effect levels ( NOAELs) were the same]. There was however, qualitative evidence of increased susceptibility ( i. e., fetal effects were considered to be more severe in the presence of minimal maternal toxicity). Neurotoxicity in maternal animals is also manifest in the rat developmental study. Data on neurotoxicity in developing animals are lacking.

In a rat developmental study ( MRID 42827904), maternal toxicity was evident as increased salivation at 3 mg/ kg/ day, and significant decreases in body weight gains and food consumption, and dilated pupils at higher doses. Developmental toxicity was characterized by a dose related increase in postimplantation loss at the mid and high doses, which was statistically significant at 15 mg/ kg/ day. This correlated with an increase in early resorptions with whole litter 13 resorption occurring in 3 high dose dams. There was also a significant reduction in the number of live fetuses per litter, mean fetal weights, and gravid uterine weights in the 15 mg/ kg/ day group. A significantly greater number of litters in the 15 mg/ kg/ day group contained fetuses with external, visceral, or skeletal malformations/ variations. The most common were digit anomalies, dilated renal pelvis, which is considered indicative of hydronephrosis, a vertebral/ rib anomaly and sternal, rib, and limb ( radius or ulna absent) malformations. Dose related fused ribs were observed in the mid and high dose groups with a statistically significant linear trend and exceedance of the historical control values. The maternal and developmental toxicity NOAEL is 0.75 mg/ kg/ day, and the maternal and developmental toxicity LOAEL is 3.0 mg/ kg/ day, based upon excessive salivation in dams during the dosing period and increased incidences of fused ribs.

In a developmental toxicity study in rabbits ( MRID # 42827905) one doe had total litter resorption at 1.5 mg/ kg/ day, while at 3 mg/ kg/ day one high dose doe aborted on gestation day ( GD) 27, and five others had total resorptions. Dose related early resorptions were seen in the mid and high dose does. These findings corresponded with a dose related increase in postimplantation loss ( early resorption) and a decrease in viable fetuses. It is not clear whether the resorptions were due to maternal or developmental toxicity. No statistically significant differences were seen in the incidence of external, visceral, or skeletal anomalies in the treated groups as compared to controls. Three fetuses from two high dose litters contained multiple cephalic and limb malformations. The Maternal/ Developmental NOAEL is 0.5 mg/ kg/ day. The LOAEL is 1.5 mg/ kg/ day, based on increased postimplantation loss and decreased number of viable fetuses ( it is not clear whether the resorptions were due to maternal or developmental toxicity).

Reproductive Toxicity. Data are available for sodium pyrithione that will satisfy the data requirement for zinc pyrithione. In a two generation reproduction study ( MRID # 41097201) conducted with 40% sodium pyrithione, parental/ systemic toxicity was evidenced as skeletal muscle atrophy, and excessive salivation in both sexes and generations of parental rats at the 1.5 and 3.5 mg/ kg/ day dose levels and decreased body weight at 3.5 mg/ kg/ day. Reproductive toxicity was observed at the 3.5 mg/ kg/ day dose level in the F0 parents and the F1 offspring, characterized as significantly reduced mating and fertility index in males, and increased number of estrous cycles per mating in F0 females at 3.5 mg/ kg/ day. Mean pup body weight was decreased slightly on post natal day 1 but this decrease was not significant. There was delayed pup development at 3.5 mg/ kg/ day as indicated by decreases in developmental landmarks ( percentage of pups with ears open on lactation day 3 and percentage of pups with eyes open on lactation day 15). Mean percentage of pups with startle response on lactation day 15 was decreased significantly by 10%. In the F1 parents and the F2 offspring, mating and fertility indices were reduced at all dose levels relative to control, but it is likely that atrophy of hindlimb muscles in males could impact mating success and therefore would explain the decrease in mating and fertility indices. Mean percentage of pups with startle response on lactation day 15 and mean percentage of pups with eyes open on lactation day 15 was decreased by 13% and 14% respectively, but this was not statistically significant. 14 Based on the results of this study, the systemic NOAEL and LOAEL are 0.5 mg/ kg/ day, and 1.5 mg/ kg/ day, respectively based on increased incidence of histological alterations of the hindlimb skeletal muscle in F0 males and F1 males and females. The reproductive toxicity NOAEL and LOAEL are 1.5 mg/ kg/ day, and 3.5 mg/ kg/ day, respectively based on slightly decreased number of pups per litter in both generations, delayed development in pups from both generations, and decreased pup body weight in both generations.

Chronic Toxicity and Carcinogenicity. Studies with zinc pyrithione were not available to satisfy the data requirements for chronic toxicity and carcinogenicity for this chemical. One two year rat study is available from the 1950' s for zinc pyrithione, however, this study had several deficiencies including: small sample size ( n= 10/ sex/ dose), inadequate histopathological evaluation, no dietary analyses of dose levels administered, no clinical chemistry analysis, no food consumption data, clinical signs were not recorded and only 3 out of 10 male control rats survived ( Tox Record 003933, Larson 1958). Two chronic toxicity and carcinogenicity studies are available for sodium pyrithione: one oral rat gavage study and a mouse dermal study. These two cancer studies for sodium pyrithione showed no evidence of carcinogenicity, but the dermal study did not achieve the maximum tolerated dose. Therefore, sodium pyrithione was classified as a Group D ( not classifiable as to carcinogenicity) carcinogen by the Health Effects Division Carcinogenicity Peer Review Committee.

Genotoxicity. The available evidence for gene mutations using the Ames Salmonella test system suggests that zinc pyrithione is negative for mutations in this system. In a Chinese hamster ovary forward gene mutation assay, zinc pyrithione failed to induce a mutagenic response at doses which included cytotoxicity. In an in vivo micronucleus assay in mice, there was no evidence of a positive effect. Therefore, the data indicate that zinc pyrithione is negative for mutagenic effects.

Metabolism. Disposition and metabolism of zinc pyrithione has been examined in older studies which provide incomplete data. Studies from the published literature were summarized, but not reviewed by the Agency. In Yorkshire pigs administered an intravenous 5 mg/ kg dose of zinc pyrithione, plasma elimination was described as biphasic, with a t ½ alpha of 2.0 2.9 hr, and a t ½ beta of 26.6 36.3 hr ( Adams et al. 1976). There were apparent differences in urinary elimination of 14C derived radioactivity from administration of sodium pyrithione ( 95%) vs. Zinc pyrithione ( 45 65%). In rabbits administered a 40 mg/ kg oral dose of zinc pyrithione, 75% of the administered radioactivity ( 14C) was eliminated in urine by 6 hours post dose, but only 0.05% of zinc was eliminated in urine ( Klaassen 1976). Pharmacokinetic studies in rats showed 74 84% of administered oral doses of 0.5, 1.25, and 12.5 mg/ kg eliminated in urine by 96 hours post dose ( Wedig 1978). There were apparent sex differences in pharmacokinetics. Klaasan ( 1976) utilized 14C zinc pyrithione and isotopic65 zinc pyrithione to study zinc pyrithione. The author's conclusion indicate that zinc and pyrithione go to different locations in the body and are eliminated at different rates and different routes. The data do suggest less in vivo dissociation of zinc pyrithione vs. sodium pyrithione and greater retention of zinc in tissues vs. the pyrithione moiety. 15 Table 1. Acute Toxicity of Zinc Pyrithione Technical Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral Rats 42827901 LD50 = 267 mg/ kg II 870.1200 Acute Dermal Rats 42146701 LD50 > 2000 mg/ kg III 870.1300 Acute Inhalation Rats 42146703 LC50 > 0.61 mg/ L III 870.2400 Primary Eye Irritation Rabbits 42146702 severe irritant I 870.2500 Primary Skin Irritation Rabbits 42146704 slight erythema and edema IV 870.2600 Dermal Sensitization Guinea pigs 43950201 no sensitization observed using Buehler method N/ A 870.6200 Neurotoxicity screening battery non guideline study available  progressive hindlimb weakness and muscle atrophy at 12.5 mg/ kg/ day NA Table 2. Toxicity Profile of Zinc Pyrithione Technical Guideline No./ Study Type Results 870.3250 90 Day dermal toxicity   rat Acceptable Guideline NOAEL = 100 mg/ kg/ day in females and 1000 mg/ kg/ day in males LOAEL = 1000 mg/ kg/ day in females based on decreased body weight gain, food consumption and food efficiency.

870.3465 90 Day inhalation toxicity   rat Acceptable Guideline NOAEL = 0.13 mg/ kg/ day ( 0.0005 mg/ L/ day) LOAEL = 0.65 mg/ kg/ day ( 0.0025 mg/ L/ day) based on labored breathing, rales, increased salivation, decreased activity, dry red brown material around the nose, increased absolute and relative lung weights, and death of undetermined cause.

870.3700a Prenatal developmental in rodents   rat Acceptable Guideline Maternal NOAEL = 0.75 mg/ kg/ day LOAEL = 3 mg/ kg/ day based on excessive salivation during the dosing period. Developmental NOAEL = 0.75 mg/ kg/ day LOAEL = 3 mg/ kg/ day based on increased incidences of fused ribs. Table 2. Toxicity Profile of Zinc Pyrithione Technical Guideline No./ Study Type Results 16 870.3700b Prenatal developmental in nonrodents   rabbit Acceptable Guideline Maternal NOAEL = 0.5 mg/ kg/ day LOAEL = 1.5 mg/ kg/ day based on increased postimplantation loss and decreased number of viable fetuses ( it is unclear whether resorptions were due to maternal or developmental toxicity) Developmental NOAEL = 0.5 mg/ kg/ day LOAEL = 1.5 mg/ kg/ day based on increased postimplantation loss and decreased number of viable fetuses.

870.3800 2 Generation Reproduction and fertility effects   rat Sodium Pyrithione Acceptable Guideline Parental/ Systemic NOAEL = 0.5 mg/ kg/ day LOAEL = 1.5 mg/ kg/ day based on increased incidence of histological alterations of hindlimb skeletal muscle in F0 males and F1 males and females. Reproductive NOAEL = 1.5 mg/ kg/ day LOAEL = 3.5 mg/ kg/ day based on slightly decreased number of pups per litter in both generations Offspring NOAEL = 1.5 mg/ kg/ day LOAEL = 3.5 mg/ kg/ day based on delayed development and decreased pup body weight in both generations.

870.4300 Combined Chronic Toxicity/ Carcinogenicity   rat ( gavage) Sodium Pyrithione Acceptable Guideline NOAEL = 0.5 mg/ kg/ day LOAEL = 1.5 mg/ kg/ day based on increased incidence of degeneration of skeletal muscle of hindlimb of both sexes.

Neurotoxicity. No recent guideline studies have been submitted to the Agency with respect to the neurotoxicity of zinc pyrithione. In a non guideline toxicity study, CD male rats, 150 250g, were divided into 63 pairs. Technical grade zinc pyrithione ( 97.0%) was administered to one rat of each pair at a dose of 250 ppm for either 9 or 14 days. Gastrocnemius and soleus muscles were examined in five treated and five pair fed controls. Eighteen treated and 18 pair fed controls were used for ultrastructural evaluation of nervous tissue. Nerve conduction velocity of the sural nerve was determined in a total of 74 treated and pair fed controls. In vitro recording of nerve conduction velocity was also made using the sciatic nerve. Histologic morphology of all examined muscles was normal. Sciatic, sural, and spinal nerve roots were not altered after 14 days of treatment. Myelinated sural nerve axons in rats recovered for 2 weeks showed accumulation of dense granular axoplasmic deposits. The most prominent changes were observed in intramuscular lumbrical fibers, where axons were enlarged and contained abundant mitochondria and electron dense granules. Sensory nerve conduction velocities measured in vivo showed no significant difference between treated and control rats. However, peak to peak sensory potential amplitudes were significantly different between treated and control rats. At 2 and 4 weeks after treatment, clinical signs were absent in treated rats, but sensory nerve evoked potential amplitudes remained significantly different after 2 weeks recovery. The results of this study suggest a primary toxic 17 effect of zinc pyrithione on muscle fibers, and a toxic effect on nerve fibers consistent with random axonal loss by Wallerian degeneration or inactivation. i. e. approximately 5 mg/ kg and above.

Several studies published in the open scientific literature have also noted neurotoxic effects from exposure to zinc pyrithione. Ross and Lawhorn ( 1990) observed reduction in forelimb and hindlimb grip strength and electrophysiological changes after administration of zinc pyrithione in the diet at 50 ppm ( 2.5 mg/ kg/ day) indicative of neurotoxicity at the neuromuscular junction. Snyder et al. ( 1979) observed progressive hind limb weakness, motor incoordination, and reduced sensory and mixed sensory/ motor nerve evoked potential amplitude ( but no reduction in conduction velocity) in male rats administered 250 ppm ( 12.5 mg/ kg/ day) zinc pyrithione in the diet for 9 or 14 days with a 4 week recovery period. Although clinical signs abated during the recovery period, decreases in nerve evoked potential amplitude remained decreased. Administration of zinc pyrithione to dogs has produced blindness and retinal detachment ( Grant, 1993).

3.2 FQPA Considerations Under the Food Quality Protection Act ( FQPA), P. L. 104 170, which was promulgated in 1996 as an amendment to the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) and the Federal Food, Drug and Cosmetic Act ( FFDCA), the Agency was directed to " ensure that there is a reasonable certainty that no harm will result to infants and children" from aggregate exposure to a pesticide chemical residue. The law further states that in the case of threshold effects, for purposes of providing this reasonable certainty of no harm, " an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children to take into account potential pre and post natal toxicity and completeness of the data with respect to exposure and toxicity to infants and children. Notwithstanding such requirement for an additional margin of safety, the Administrator may use a different margin of safety for the pesticide residue only if, on the basis of reliable data, such margin will be safe for infants and children."

The HIARC in 1999 recommended retention of the 10x safety factor for the protection of infants and children based on qualitative evidence of increased susceptibility in the rat and rabbit prenatal developmental toxicity studies, the lack of reproductive toxicity study for zinc pyrithione and evidence of neurotoxicity from submitted data in experimental animals. Since that time, updated guidance on interpretation of the FQPA safety factor http:// www. epa. gov/ oppfead1/ trac/ science/ determ. pdf ) has been published. Based on this updated guidance and the Antimicrobials Division's Toxicology Endpoint ( ADTC) Selection Committee, reduced the special hazard based FQPA safety factor to 1x. This reduction was based on the following:

( 1) the developmental toxicity database for zinc pyrithione shows effects in offspring at similar dose levels as effects in adults, while the reproductive toxicity database 18 for sodium pyrithione ( a structurally related chemical) shows effects in offspring at doses above those occurring in parental animals. ( 2) effects observed in offspring from developmental toxicity studies have been selected for use in dietary risk assessments, thus being protective of infants and children.

Therefore the hazard based FQPA safety factor can be reduced to 1x since the degree of concern is low ( i. e. a complete developmental and reproductive database is available with clear NOAELs/ LOAELs for parental and offspring toxicity) and there are no residual uncertainties for prenatal toxicity.

3.3 Dose Response Assessment The doses and toxicological endpoints selected for various exposure scenarios are summarized below.

Table 3. Toxicological Endpoints Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary ( Females 13  50 years) NOAEL = 0.5 mg/ kg/ day UF = 100 DB= 3x Acute RfD= 0.0016 mg/ kg/ day FQPA SF = 1x aPAD= acute RfD FQPA SF = 0.0016 mg/ kg/ day Developmental Toxicity Study in Rabbits LOAEL = 1.5 mg/ kg/ day, based on increased post implantation loss and decreased viable fetuses Acute Dietary ( General population, including infants/ children) NOAEL = 0.75 mg/ kg/ day UF = 100 DB= 3x Acute RfD= 0.0025 mg/ kg/ day FQPA SF = 1x aPAD= acute RfD FQPA SF = 0.0025 mg/ kg/ day Developmental Toxicity Study in Rats LOAEL = 3.0 mg/ kg/ day based on increased salivation in maternal rats.

Chronic Dietary ( all populations) NOAEL = 0.5 mg/ kg/ day UF = 100 DB= 3x Chronic RfD= 0.0016 mg/ kg/ day FQPA SF = 1x cPAD= chronic RfD FQPA SF = 0.0016 mg/ kg/ day Developmental Toxicity Study in Rabbits LOAEL = 1.5 mg/ kg/ day, based on increased post implantation loss and decreased viable fetuses 19 Incidental Oral, Short and Intermediate Term Maternal NOAEL= 0.75 mg/ kg/ day Target MOE = 300 ( residential) Developmental Toxicity Study in Rats LOAEL = 3.0 mg/ kg/ day, Based on increased salivation in maternal rats.

Short, Intermediateand Long Term Dermal Adults ( including Females 13  50 years) NOAEL = 0.5 mg/ kg/ day 3% dermal absorption Target MOE = 300 ( residential) 100 ( occupational) Developmental Toxicity Study in Rabbits LOAEL = 1.5 mg/ kg/ day, based on increased post implantation loss and decreased viable fetuses Children ( 1 6 yrs) Dermal NOAEL = 100 mg/ kg/ day dermal absorption factor not required Target MOE = 300 ( residential) 90 Day Subchronic Dermal Toxicity in Rats LOAEL = 1000 mg/ kg/ day, based on decreased body weight gain, food consumption, and food efficiency in female rats.

Short, Intermediate , and Long Term Inhalation Inhalation NOAEL = 0.0005 mg/ L ( 0.13 mg/ kg/ day) Target MOE = 300 ( residential) 100 ( occupational) 90 Day Subchronic Inhalation Toxicity Study in Rats LOAEL = 0.0025 mg/ L ( 0.65 mg/ kg/ day) based on clinical signs of toxicity, decreased activity, and increased lung weights.

Database Uncertainty Factor. Based on the need for additional neurotoxicity testing and evidence of neurotoxicity in the open scientific literature ( Ross and Lawhorn, 1990; Snyder et al., 1979; Grant, 1993), a database uncertainty factor of 3x is applied to non occupational risk assessments for zinc pyrithione, due to the lack of characterization of neurotoxic dose response relationships for zinc pyrithione. A 3x factor for lack of neurotoxicity data ( as opposed to a higher factor of 10x) is adequate because neurotoxicity observed in the available data occurs at similar effect levels as other adverse responses, the doses and endpoints selected for dietary and non dietary assessments encompass the doses at which neurotoxicity is observed, there is no quantitative evidence of susceptibility to the toxic effects of zinc pyrithione, and traditional uncertainty factors afford a degree of protection that is considered conservative.

3.4 Endocrine Disruption The Food Quality Protection Act ( FQPA; 1996) requires that EPA develop a screening program to determine whether certain substances ( including all pesticides and inerts) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such 20 other endocrine effect...." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, zinc pyrithione may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION Dietary exposure to zinc pyrithione can occur from use in food packaging adhesives, food packaging materials, conveyor belts, and repeat use polymeric food contact materials. Residential exposure to zinc pyrithione can occur from zinc pyrithione containing products, such as paint ( as a materials preservative), or caulk, or from the conditionally registered antifoulant paint use on recreational boats. Postapplication exposure can occur in adults and children from dermal contact with zinc pyrithione treated rubber/ plastic articles, as well as in children from object to mouth, and hand to mouth incidental oral exposure. Occupational exposure to zinc pyrithione can occur from mixing/ loading/ application activities in the industrial setting, including manufacturing antifoulant paints or other paint products and from subsequent use of treated paints, coatings, and building materials.

4.1 Summary of Registered Uses Zinc pyrithione ( Zinc Omadine ® , or Zinc 2 pyridinethiol 1 oxide) is used as an industrial preservative to prevent microbial deterioration and to maintain the integrity of manufacturing precursor materials and finished manufactured articles. It is a bacteriostat, fungicide, and microbiocide/ microbiostat registered for incorporation into food packaging adhesives ( indoor food), incorporation into articles made from or coated with FDA approved food contact polymers such as food processing equipment, conveyor belts, utensils, and storage containers ( indoor food), paint preservation ( indoor/ outdoor nonfood), control of bacterial growth on laundered products ( indoor nonfood), and preservation of adhesives, caulks, patching compounds, sealants, grouts, latex paints, coatings, dry wall, gypsum, pearlite, plaster ( indoor nonfood) and ductwork ( HVAC use). Zinc pyrithione is also used for the control of mildew in nonfood contact polymers and control of mildew and bacteria in styrene butadiene rubber and thermoplastic resins ( e. g. carpets and other floor coverings, textiles, home furnishings, housewares, sports equipment, 21 automotive/ public transport systems, mattress liners, air ducts, etc.). In addition, it is conditionally registered as an antifouling agent for boat paints to control the growth of slime, algae, and marine fouling organism ( eg., barnacles, tubeworms, etc.) growth below the water line of recreational and commercial boat hulls in fresh, salt, or brackish water.

In addition to its pesticidal uses, zinc pyrithione is approved by the Food and Drug Administration ( FDA) for use in anti dandruff shampoos. It is considered to be safe and effective ( considered generally recognized as safe ( GRAS) and generally recognized as effective ( GRAE) by the FDA as an over the counter drug) for the treatment of dandruff and seborrheic dermatitis, with a history of over 40 years of human use.

4.2 Dietary Exposure and Risk Estimates of dietary risk are based upon the detailed analysis in the residue chemistry chapter ( memo from N. Shamim to J. Fairfax, D251938) and are summarized here for completeness. FDA has approved the use of zinc pyrithione as an indirect food additive, for use in food packaging adhesives. AD used the FDA recommended migration study for zinc pyrithione ( MRID#: 441086 02) to determine the residues in food and to calculate acute and chronic dietary exposure estimates.

The label provided lists the following repeat use polymeric food contact materials for zinc pyrithione: food processing equipment, conveyer belts, utensils, storage containers to which zinc pyrithione is applied to control the growth of fungus. AD evaluated conveyer belts as representing the ` worst case scenario', based on repeatability of use, high frequency of use and a short life at the use level. Zinc pyrithione is permitted to be used up to 1000 ppm in food packaging and polymeric contact surfaces ( such as a conveyor belt). The Agency has estimated that approximately 0.7 ppm zinc pyrithione migrates in food simulating solvents ( 50% alcohol/ water), and that 0.6733 ppb/ day migrates from the conveyor belt to food. This represents the maximum leaching observed in a study, and was considered to be a good representative of all food packing/ containers. Using these assumptions, and food ingestion rates of 3000 g/ day for adults and 1000 g/ day for children, AD estimated daily intakes of 0.002 mg/ person/ day, and 0.000673 mg/ person/ day for adults and children, respectively. These daily estimates were conservatively used to assess both acute and chronic dietary risks, which are shown below in Table 4 The risk analysis assumes exposure from contact with polymeric treated articles that come into contact with food. Food storage containers are not included in the chronic dietary exposure analysis as migration data have shown that maximum migration from food storage containers occurs only in the first 5 days, which constitutes an acute but not chronic dietary exposure scenario. 22 Table 4. Summary of Dietary Exposure and Risk for Zinc Pyrithione Population Subgroup** Acute Dietary Chronic Dietary Dietary Exposure ( mg/ kg/ day) a % aPAD b Dietary Exposure ( mg/ kg/ day) a % cPAD b adult male 2.8x10 5 1.1 2.8x10 5 1.8 females ( 13 50 years) 3.3x10 5 2.1 3.3x10 5 2.1 infants/ children 6.7x10 5 2.7 6.7x10 5 4.2 a acute and chronic exposure analysis based on daily consumption of 0.002 mg/ person/ day for adults and body weights of 70 kg and 60 kg for males and females, respectively. For infants/ children, exposure based on daily consumption of 0.00067 mg/ person/ day; and a 10 kg body weight. b % PAD = dietary exposure ( mg/ kg/ day) / aPAD or cPAD, where aPAD= 0.0025 mg/ kg/ day for general population; aPAD= 0.0016 for females of child bearing age; and cPAD= 0.0016 mg/ kg/ day 4.3 Drinking Water Exposure and Risk AD has considered the conditionally registered use of zinc pyrithione in antifoulant paints and chemical specific information on degradation, mobility and leaching rates from antifoulant paint. The Agency currently lacks sufficient water related exposure data from monitoring to complete a quantitative drinking water exposure analysis and risk assessment for zinc pyrithione. Therefore, the Agency is presently relying on computer modeled predicted environmental concentrations ( PECs) of pesticides in water to estimate drinking water exposures to zinc pyrithione. Details of the water exposure estimates are present in the attached memorandum ( memo from S. Mostaghimi to D. Smegal, April 2004), while details on chemical specific inputs into the models are presented in the Environmental Fate Chapter ( memo from N. Shamim to D. Smegal, April 2004).

Uses in antifouling boat paints for recreational use are expected to impact surface water resources ( i. e., lakes, and rivers) that could serve as drinking water sources. The Agency estimated PECs that range from 0.0144 to 0.101 ppb zinc pyrithione, using conservative assumptions and the Marine Antifoulant Model Predicted Environmental Concentration ( MAMPEC model ( 100% market share and default marina values). MAM PEC has been adopted by OECD, and predicts total concentrations as maximum, 95%, average, median and minimum in a harbor. A range of average PECs were estimated based on three different leaching rates [ 1.2 ( low), 4.8 ( average) and 8.4 ( high)  g/ cm2/ day]. Because of the lack of real data for fresh water, the PECs estimated by MAM PEC were used to assess potential drinking water exposures from antifoulant paint on boats in fresh water, such as lakes and rivers. The PECs were used to assess both acute and chronic drinking water exposures. The primary use of this model by the Agency at 23 this stage is to provide a coarse screen for assessing whether a pesticide is likely to be present in drinking water at concentrations that would exceed the human health levels of concern.

A drinking water level of comparison ( DWLOC) is the concentration of a pesticide in drinking water that would result in risk estimates below AD's level of concern, when considering total aggregate exposure to that pesticide from food, water, and residential uses. AD uses DWLOCs in the risk assessment process as a surrogate measure of potential exposure associated with pesticide exposure through drinking water. DWLOC values are not regulatory standards for drinking water, however, they do have an indirect regulatory impact through aggregate exposure and risk assessment. In the absences of monitoring data for a pesticide, the DWLOC is used as a point of comparison against the conservative PEC provided by computer modeling. A DWLOC may vary with drinking water consumption patterns and body weight for specific subpopulations.

AD back calculates DWLOCs by a two step process: exposure [ food + ( if applicable) residential exposure] is subtracted from the PAD to obtain the maximum exposure allowed in drinking water; DWLOCs are then calculated using that value and default body weight and drinking water consumption figures. In assessing human health risk, DWLOCs are compared to the PEC. When the PEC is greater than the DWLOCs, AD considers the aggregate risk [ from food + water ( if applicable) residential exposure] to exceed the Agency's level of concern.

4.4 Residential Exposure/ Risk Pathway Details of the residential exposure assessment can be found within the companion memorandum ( memorandum from D. Aviado/ D. Smegal, April 2004). A summary of the residential assessment is presented below.

4.4.1 Residential Handler Exposure Scenarios Zinc Pyrithione is an antifouling agent used to control slime and algae growth below the water line of recreational and commercial boat hulls in fresh, salt, or brackish water. Recreational boat owners have several techniques they can use to paint their hulls including paint brush, roller, and airless sprayer. Residential handler exposures could also occur through the application of treated paints and coatings, and building materials such as caulks, adhesives, spackling, groutings, sealants, stucco and joint cements. The following residential handler scenarios were evaluated:

Antifoulant Use: ( 1) handling zinc pyrithione containing antifoulant paints using a paint brush. ( 2) handling zinc pyrithione containing antifoulant paints using an airless sprayer. Materials Preservative Use: ( 3,4,5) handling zinc pyrithione containing end products using paint brush, airless sprayer, and aerosol spray can application methods. 24 Based on end use product application methods and use amounts, it is assumed that exposures while applying paints will be equal to or greater than exposures while applying building materials, caulk or sealants. Therefore, residential handler exposures were assessed for the application of paint, as this scenario represents maximum possible exposure to the chemical.

Exposure Data and Assumptions There are no chemical specific exposure data to assess paint applications with a brush, roller, airless sprayer or aerosol can. However, surrogate data are available for painting with a brush, an airless sprayer and aerosol can. Dermal and inhalation exposures were assessed for brush, airless sprayer, and aerosol application methods using PHED Version 1.1 values found in the Residential Exposure SOPs ( U. S. EPA, 1997a, 2001). The surrogate exposure data in PHED are based on test subjects painting a bathroom with a paint brush and staining the outside of a house with an airless sprayer. The dermal and inhalation exposures from these techniques have been normalized by the amount of active ingredient handled and reported as unit exposures ( UE) expressed as mg/ lb ai handled. Although the exposures while painting a boat hull may differ slightly, the data are judged to be representative of painting and are used in this assessment. The data from Garrod et al. ( 2000), which evaluated amateur ( consumer) applicators applying antifoulant paint using a paint brush and roller to boat hulls of recreational craft stored on sling/ cradle/ trailers, were also used as a comparison to PHED. The Garrod ( 2000) study design is more representative of the use ( i. e., painting boat hulls using an antifoulant paint). The air concentration data from Garrod et al. ( 2000) are used to present the inhalation route specific risks in normalized units of mg/ m3. The dermal portion of the study monitored mostly exposure on the outside of clothing and only one patch was used underneath clothing, and thus these data are not of sufficient quality for a dermal risk assessment. In addition, product label maximum application rates, related use information, and Agency standard values were used to assess residential handler exposures.

Risk Characterization A summary of the residential handler exposures and risk are presented on Table 5. The non cancer risk estimates are expressed in terms of the MOE. MOEs

300 do not exceed the Agency's level of concern for residents. MOEs from residential use of zinc pyrithione containing antifoulant boat paint on recreational boats showed that dermal and inhalation MOEs were of concern ( i. e. < 300) for all boat sizes when using a paint brush and airless sprayer. It is important to note that the inhalation risk estimates are conservative because the toxicity endpoint is based on a whole body rat 90 day inhalation study.

For residential handlers that handle products containing zinc pyrithione as a materials preservative, short term, intermediate term, and long term MOEs exceed the Agency's level of concern ( MOEs < 300) for the following scenarios:

° handling zinc pyrithione containing paint products using an airless sprayer 25 application method ( Dermal MOE= 17 and inhalation MOE= 15); ° handling zinc pyrithione containing paint products using a paintbrush ( Dermal MOE= 44); and ° handling zinc pyrithione containing paint products using an aerosol spray can application method ( inhalation MOE= 271).

Dermal MOEs were not of concern for the painting scenarios involving use of an aerosol spray can for the materials preservative use of zinc pyrithione.

Table 5 Estimates of Exposures and Risks to Residential Handlers of Zinc Pyrithione Scenarioa Dermal Dose ( mg/ kg/ day) b Inhalation Dose ( mg/ kg/ day) c Dermal MOEd Acceptable MOE

300 Inhalation MOEe Acceptable MOE

300 Residential Handlers: Do it Yourself Boat Hull Painters ( Antifoulant Use) [ EPA Reg Nos. 64684 4 ( 4.8% ai) and 2693 194 ( 47% ai assuming dilution to 5.8% ai)] All Estimates Based on 3 Coats of Paint in One Day ( 1a) Brush f ( PHED) 0.03 0.16 0.0071 0.0013 3.2 17 18 97 ( 1b) Brush f ( Garrod et al. 2000) Not evaluated ( exposure data of insufficient quality) 2 6 hours of painting Not evaluated 5 140 ( 2) Airless Sprayer f 0.033 0.0063 0.021 0.004 15 78 6 33 Residential Handlers: Paints Containing Zinc Pyrithione ( Materials Preservative Use)

( 3) Handling zinc pyrithione containing paint end products using a paint brush application method 0.0115 4.0E 4 44 325 ( 4) Handling zinc pyrithione containing paint end products using an airless sprayer application method 0.0296 8.89E 3 17 15 ( 5) Handling zinc pyrithione containing paint end products using an aerosol spray can application method 0.0015 4.80E 4 325 271 Footnotes: a Scenarios based on use patterns described on labels and LUIS report. Residential handlers include homeowners who apply products containing zinc pyrithione incorporated as a general preservative ( e. g., floor tile adhesives, caulks/ sealants, grout/ patching materials, and rubber/ thermoplastic resin/ polymericbased products), and homeowners who apply latex paint, architectural coating, and dry wall and building materials that contain zinc pyrithione. 26 b Dermal Dose ( mg/ kg/ day) = [ Unit Dermal Exposure ( mg/ lb ai) * Use Rate ( lb ai/ lb product or lb ai/ gal product) * Amount Handled per Day ( lb product/ day)* 0.03 ( dermal absorption factor)] / Body Weight ( kg). * Use of gloves as PPE assumes a 90% protection factor. c Inhalation Dose ( mg/ kg/ day) = [ Unit Inhalation Exposure ( mg/ lb ai) * Use Rate ( lb ai/ lb product or lb ai/ gal product) * Amount Handled per Day ( lb product/ day)] / Body Weight ( kg).** Use of organic vapor respirator as PPE assumes a 90% protection factor. d Dermal MOE = Dermal NOAEL ( mg/ kg/ day) / Dermal Dose ( mg/ kg/ day). Where the NOAEL is 0.5 mg/ kg/ day from the rabbit developmental study. e Inhalation MOE = Inhalation NOAEL ( mg/ kg/ day) / Inhalation Dose ( mg/ kg/ day). Where the inhalation NOAEL of 0.0005 mg/ L/ day is converted to 0.13 mg/ kg/ day, or the route specific inhalation MOE = ( 0.5 mg/ m3 x 6 hrs/ day animal) / [( paint air conc mg/ 3/% ai x % ai in paint x hrs painting) x ( 1 m3 work breathing rate / 0.4 m3 resting breathing rate)]. Note: The route specific inhalation MOEs do not coincide with the route extrapolation inhalation MOEs because of the differences in methodologies ( e. g., UE, dose vs air conc, estimates of hours painting versus amount of ai handled]. f Dermal and Inhalation doses and MOEs vary depending on boat size. Boat sizes assessed are 14ftx5ft, 20 ftx8 ft, and 30ftx10ft.

4.4.2. Anti Dandruff Shampoo Exposure Zinc pyrithione is approved by the Food and Drug Administration ( FDA) for use in antidandruff shampoos. It is considered to be safe and effective [ considered generally recognized as safe ( GRAS) and generally recognized as effective ( GRAE) by the FDA as an over the counter drug] for the treatment of dandruff and seborrheic dermatitis with a history of over 40 years of human use. It can be purchased as an over the counter product that does not require a prescription. It is present at concentrations ranging from 0.3 to 2 percent when formulated to be applied and then washed off after brief exposures, and from 0.1 to 0.25 percent when formulated to be applied and then left on the skin or scalp ( 21 CFR § 358.710).

Percutaneous absorption of zinc pyrithione was assessed for anti dandruff shampoo use for adults. It was assumed that infants and small children do not use anti dandruff shampoo on a regular basis. Information on the absorption of zinc pyrithione from the use of anti dandruff shampoos was obtained from the FDA's docket supporting formal rulemaking leading to a monograph establishing conditions under which over the counter drug products for the control of dandruff, seborrheic dermatitis and psoriasis are generally recognized as safe and effective. In a study involving 30 human subjects, a shampoo containing radio labeled zinc pyrithione ( 14C in the 2 and 6 positions) was applied in both a sink shampoo procedure ( head exposure only) and a shower shampoo ( total body exposure) ( Barker and Winrow 1979). All wash water and towels, etc. were retained and biological samples of skin, hair, blood and urine collected for a period of ten days following application. Recovery of radio label was essentially 100%. In this study, the maximum amount of zinc pyrithione in the urine was 50  g, which is equivalent to an average upper systemic load ( absorbed dose) of 0.001 mg/ kg/ day zinc pyrithione. In this study, absorption was greatest for subjects with seborrheic dermatitis, and the absorbed material was derived from solid zinc pyrithione deposited on the head.

In this assessment, is was conservatively assumed that a 50 kg person, has chronic 27 seborrheic dermatitis and uses an anti dandruff shampoo every day, absorbing the maximum dose of the active ingredient. Table 6 presents a summary of the exposure and risks ( MOEs) for the anti dandruff shampoo.

Table 6: Summary of Long Term Exposure and Risk for Anti Dandruff Shampoo Scenario Receptor Use Potential Absorbed Dosea ( mg/ kg/ day) Dermal MOEb Target MOE

300 Dermal Contact ( percutaneous absorption) Adult Treatment of dandruff and seborrheic dermatitis 0.001 500 a An absorbed dose of 0.001 mg/ kg/ day. b MOE= NOAEL ( mg/ kg/ day) / PDR ( mg/ kg/ day). NOAEL is 0.5 mg/ kg/ day for developmental effects from an oral developmental toxicity study. The dermal absorption of zinc pyrithione is approximately 3%, however, no adjustment for dermal absorption is necessary because the exposure estimate is an " absorbed dose" based on urinary excretion of zinc pyrithione.

4.4.3. Postapplication Residential Exposure Residential postapplication exposures result when bystanders ( adults and children) come in contact with zinc pyrithione in areas where pesticide treated end use products have recently been applied ( e. g., freshly painted walls or boat hulls of recreational craft), or when children incidentally ingest the pesticide residues through mouthing the treated end products/ treated articles ( i. e., handto mouth or object to mouth contact).

Zinc pyrithione is used as a microbiostat and mildewcide to control bacterial and mildew growth in articles used as components of heating ventilation and air conditioning ( HVAC) systems. Zinc pyrithione is impregnated into thermoplastic resins at concentrations up to 4000 ppm. These thermoplastic resins can be incorporated into air filters, air filtration components, air filtration media, and duct work. These end use products are intended for industrial, hospital, residential and commercial HVAC systems.

Although EPA registered zinc pyrithione pesticide product concentrates are not used in residential areas, the manufactured consumer end products containing zinc pyrithione are used extensively in and around the home. Based on the use patterns, EPA has identified exposure scenarios for assessing residential postapplication exposures including:

° Dermal exposures to consumers from products made of polymeric materials containing zinc pyrithione, such as shoe sole liners; 28 ° Non dietary ingestion exposures to children associated with object to mouth contact with zinc pyrithione treated polymeric products ( i. e., plastic objects); and ° Non dietary ingestion exposures to children associated with hand to mouth contact with zinc pyrithione treated polymeric products ( i. e., plastic objects).

A summary of the residential postapplication exposures and risk are presented on Table 7. The non cancer risk estimates are expressed in terms of the MOE. MOEs

300 do not exceed the Agency's level of concern for residents. Dermal exposures to plastic treated with zinc pyrithione, such as shoe liners, were evaluated and determined not to be of concern ( MOEs range from 4,500 7,700). In addition, non dietary incidental ingestion exposures of children via objectto mouth and hand to mouth activities did not exceed the Agency's level of concern ( MOE > 300). Aggregate postapplication residential exposures for a young child were also greater than the target MOE of 300, and are not of concern. As noted previously, dermal and incidental oral exposures and risks are not aggregated because the toxicological endpoints are different for dermal ( decreased body weight gain, food consumption and food efficiency) and oral ( increased salivation) exposures.

Postapplication residential dermal exposures are expected to be of minimal concern for treated articles used in HVAC systems since these components are not readily available for dermal contact. Dermal contact with wet paint was not assessed because the paint is expected to dry within a day, so any potential exposure is expected to be negligible. The potential postapplication inhalation exposure from zinc pyrithione treated articles, such as air duct surfaces in HVAC systems, is expected to be minimal based on bounding estimates of saturation concentrations and/ or dry aerosols from particles degraded from air duct surfaces. Zinc pyrithione has a low vapor pressure ( i. e., 1.87x10 9 mmHg @ 25  C) and is, therefore, not likely to generate sufficient vapor to cause an inhalation concern to residential populations performing postapplication tasks, or occupying recently treated areas, or from bystander contact with treated articles. Thus, there are no risk concerns and inhalation postapplication exposures were not quantitatively evaluated.

Table 7. Summary of Short, and Intermediate Term Residential Postapplication Exposure and Risks ( c)

Scenario Receptor Use Potential Dosea ( mg/ kg/ day) Dermal MOEb Target MOE

300 Oral MOEb Target MOE

300 Dermal Contact to Rubber/ Plastic Incorporated with Preservative Adult Rubber/ Plastic ( Shoe Liner) 4.06E 4 1,231 NA Toddlers 2.2E 2 4,500 NA Non Dietary Ingestion Object to Mouth Infants Rubber/ Plastic 0.0004 NA 2,000 Table 7. Summary of Short, and Intermediate Term Residential Postapplication Exposure and Risks ( c)

Scenario Receptor Use Potential Dosea ( mg/ kg/ day) Dermal MOEb Target MOE

300 Oral MOEb Target MOE

300 29 Non Dietary Ingestion Hand to Mouth Infants Rubber/ Plastic 0.0003 NA 2,500 Total Exposure and Risk Infant Rubber/ Plastic 0.0007 ( total oral) NA 1,100 Toddler 2.2E 2 ( dermal) 4,500 NA Adult 4.06E 4 ( dermal) 1,231 NA NA = Not applicable. a Potential dose calculations for each scenario above are outlined in the attached Occupational/ Residential Assessment ( memo from D. Aviado/ D. Smegal, September 2004). b MOE= NOAEL ( mg/ kg/ day) / PDR ( mg/ kg/ day). Dermal NOAEL is 100 mg/ kg/ day for children and 0.5 mg/ kg/ day for adults to be protective of potential developmental effects; oral NOAEL is 0.75 mg/ kg/ day for children. c Dermal risks are also for long term exposures.

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION In order for a pesticide registration to continue, it must be shown that the use does not result in " unreasonable adverse effects on the environment". Section 2 ( bb) of FIFRA defines this term to include " a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with standard under section 408..." of FFDCA. Consequently, even though no pesticide tolerances have been established for zinc pyrithione, the standards of FQPA must still be met, including " that there is reasonable certainty that no harm will result from aggregate exposure to pesticide chemical residue, including all anticipated dietary exposures and other exposures for which there are reliable information." Aggregate exposure is the total exposure to a single chemical ( or its residues) that may occur from dietary ( i. e., food and drinking water), residential, and other non occupational sources, and from all known or plausible exposure routes ( oral, dermal, and inhalation). Aggregate risk assessment were conducted for acute ( 1 day), short term ( 1 30 days), intermediate term ( 1 6 months) and chronic ( several months to lifetime) exposures. As noted previously, dermal and oral exposures were only combined in the aggregate assessment for adult females to be protective of potential developmental effects of zinc pyrithione. However, for children, oral and dermal exposures were not combined because of different 30 toxicological endpoints for children.

In performing aggregate exposure and risk assessments, the Office of Pesticide Programs has published guidance outlining the necessary steps to perform such assessments ( General Principles for Performing Aggregate Exposure and Risk Assessments, November 28, 2001; available at http:// www. epa. gov/ pesticides/ trac/ science/ aggregate. pdf ). Steps for deciding whether to perform aggregate exposure and risk assessments are listed, which include: identification of toxicological endpoints for each exposure route and duration; identification of potential exposures for each pathway ( food, water, and/ or residential); reconciliation of durations and pathways of exposure with durations and pathways of health effects; determination of which possible residential exposure scenarios are likely to occur together within a given time frame; determination of magnitude and duration of exposure for all exposure combinations; determination of the appropriate technique ( deterministic or probabilistic) for exposure assessment; and determination of the appropriate risk metric to estimate aggregate risk. Aggregate short and intermediate term risk assessments are designed to provide estimates of risk likely to result from exposures to the pesticide or pesticide residues in food, water, and from residential ( or other non occupational) pesticide uses. Short and intermediate term aggregate risks are considered together because the same exposure data are used for short and intermediate term exposures, and the endpoint of concern is the same for short as for intermediate term nondietary exposures.

5.1 Acute Aggregate Risk 5.1.1 Acute Aggregate Risk Assessment The acute aggregate assessment includes both dietary and drinking water exposures. The acute dietary risk estimates from indirect food uses ( i. e. use in food contact packaging and treated articles) range from 1.1 2.7% of the aPAD, with infants/ children being the highest exposed population subgroup. Thus, the acute dietary ( food) risk estimate associated with zinc pyrithione is below the Agency's level of concern. Drinking water exposure is not expected from the indoor uses of zinc pyrithione, but could occur from the conditionally registered antifoulant paint use. Drinking water monitoring data are not available, therefore, AD calculated drinking water level of comparisons ( DWLOCs), which are discussed below to account for potential drinking water exposures.

5.1.2 Acute DWLOC Calculations A drinking water level of comparison ( DWLOC) is the concentration of a pesticide in drinking water that would result in risk estimates below AD's level of concern, when considering total aggregate exposure to that pesticide from food, drinking water, and residential uses. AD uses the DWLOCs in the risk assessment process as a surrogate measure of potential exposure associated with pesticide exposure through drinking water. In the absence of monitoring data for a pesticide, the DWLOC is used as a point of comparison against the conservative predicted 31 environmental concentrations ( PECs) provided by computer modeling.

AD back calculates the acute DWLOCs by a two step process: exposure [ food+ ( if applicable) residential exposure] is subtracted from the acute PAD to obtain the maximum exposure allowed in drinking water; DWLOCs are then calculated using that value and default body weight and drinking water consumption values. A DWLOC may vary depending on the toxic endpoint, drinking water consumption patterns, and body weights for specific subpopulations. In assessing human health risk, the acute DWLOCs are compared to the ( maximum) PECs. When PECs are greater than DWLOCs AD considers the aggregate risk estimates [ from food + water + ( if applicable) residential exposures] to exceed the Agency's level of concern ( HED SOP 99.5 " Standard Operating Procedures for Incorporating Estimates of Drinking Water Exposure into Aggregate Risk Assessment, August 1, 1999).

Table 8 presents the total acute dietary exposure estimate for zinc pyrithione, and the acute DWLOCs. For each population subgroup listed, the acute PAD and the acute dietary ( food) exposure ( from Table 4) for that subgroup were used to calculate the acute DWLOC, using the formulas in the footnotes of Table 8.

Using a conservative screening level model, the range of average PECs for zinc pyrithione in a marina is 0.0144 to 0.101 ppb. As shown on Table 8, the acute DWLOCs are greater than the range of PECs, indicating that aggregate food and drinking water exposure do not exceed the Agency's level of concern.

Table 8. DWLOCs for Acute Aggregate Dietary Exposure Population Subgroup Acute Scenario aPAD mg/ kg/ day Acute Food Exp mg/ kg/ day Max Acute Water Exp mg/ kg/ day1 Surface Water PEC (  g/ L) 2 Acute DWLOC (  g/ L) 3 Potential Risk Concern 4 Males 0.0025 0.000028 0.00247 0.0144 0.101 86 No Females 13 50 years 0.0016 0.000033 0.001567 47 No Infants/ Children 0.0025 0.000067 0.00243 24 No 1 Maximum acute water exposure ( mg/ kg/ day) = [( acute PAD ( mg/ kg/ day)  acute food exposure ( mg/ kg/ day)] 2 Based on sea water for antifoulant use on recreational boats. 3 Acute DWLOC(

g/ L) = [ maximum acute water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L/ day) x 10 3 mg/

g] where body weight is 70 kg, 60 kg and 10 kg for adult males, females and children, respectively and drinking water intake rates are 2 L/ day and 1L/ day for adults and children, respectively. 4 Does the surface water PEC exceed the acute DWLOC? 32 5.2 Short and Intermediate Term Aggregate Risk Short and intermediate term aggregate risks are considered together since the exposure and toxicity endpoints are identical for incidental oral residential exposures for both durations. The short and intermediate term aggregate assessment includes average dietary exposure ( food and water) and estimated incidental oral exposures from residential uses such as plastic objects for children. For adult females, the aggregate assessment includes dietary ( oral) and residential dermal exposures during painting since there is concern for potential developmental effects for zinc pyrithione. Inhalation residential exposures ( i. e., residential handler during painting activities) were not aggregated with the oral exposures due to different toxicological endpoints for oral ( increased salivation/ developmental), and inhalation ( clinical signs of toxicity and lung effects).

Aggregate risks were calculated using the total MOE approach outlined in OPP guidance for aggregate risk assessment ( August 1, 1999, Updated " Interim Guidance for Incorporating Drinking Water Exposure into Aggregate Risk Assessments"). The assumptions and equations are presented in the footnotes on Table 9.

Table 9 presents a summary of the short and intermediate term aggregate risk and DWLOCs. The DWLOCs are greater than the PECs for adult females and children, indicating that aggregate risks do not exceed the Agency's level of concern for these subpopulation groups. It should be noted that several conservative assumptions were used in this assessment.

The adult aggregate assessment assumed that a resident would apply paint containing zinc pyrithione ( as a material preservative) via an aerosol can ( dermal exposure), in addition to receiving potential oral exposures via dietary and drinking water exposure. As noted previously ( and shown on Table 5), dermal risks are already of concern for residents that could apply antifoulant paint to their boats ( dermal MOEs range from 3.2 17 for a paintbrush, and 15 78 for an airless sprayer), or use a paintbrush or an airless sprayer to apply products when zinc pyrithione is used as a material preservative ( dermal MOEs are 44 and 17, respectively). Thus, these scenarios were not considered in the aggregate risk assessment, because inclusion of this use in the aggregate would also contribute to dermal aggregate risks of concern.

Inhalation Aggregate Risk Results. An inhalation aggregate assessment was not conducted. However, as shown previously on Table 5, short and intermediate inhalation MOEs for residential handlers that could apply antifoulant paint to their boats, or apply products containing zinc pyrithione as a material preservative using an airless sprayer and aerosol can exceed the Agency's level of concern ( inhalation MOEs range from 6 271 for a paintbrush, airless sprayer, and aerosol can). However, it is important to note that these risk estimates are conservative because the toxicity endpoint is based on a whole body rat 90 day inhalation study. 33 Table 9 Summary of Short and Intermediate Term ( ST/ IT) Aggregate Exposure and DWLOC Calculations Population Subgroup ST/ IT NOAEL ( mg/ kg/ day)/

Target MOE Chronic Food Exp mg/ kg/ day/

( MOE) ST/ IT Residential Exposure ( mg/ kg/ day)/

( MOE) 5 MOE Water Exp1 Allowable ST/ IT Water Exp ( mg/ kg/ day) 6 Surface Water PEC (

g/ L) 2 ST/ IT DWLOC (

g/ L) 3 Potential Risk Concern4 Adults ( Females 13 50 years) 0.75/ 300 0.000033/

( 22727) 0.0015 /( 500)

( dermal) 775 0.00096 0.0144 0.101 29 No Infants/ Children 0.000067/

( 11195) 0.0007/

( 1100) ( oral) 428 0.0017 17 No ST= short term; IT= intermediate term 1 MOE water = 1 / [ 1/ MOE target aggregate  ( 1/ MOE food + 1/ MOE oral res)]

2 Based on sea water for antifoulant use on recreational boats.

3 ST/ IT DWLOC(

g/ L) = [ maximum ST/ IT water exposure ( mg/ kg/ day) x body weight ( kg)]

[ water consumption ( L/ day) x 10 3 mg/

g]

where body weight is 60 kg and 10 kg for adult females and children, respectively and drinking water intake rates are 2 L/ day and 1L/ day for adults and children, respectively.

4 Does the surface water PEC exceed the DWLOC?

5 Residential exposure based on total oral exposure for infants/ children on Table 7 for zinc pyrithione treated objects. Adult exposure based on dermal exposure from painting using an aerosol can on Table 5.

6 Short term oral NOAEL ( 0.75 mg/ kg/ day) / MOE water. 34 5.3 Chronic ( non cancer) Aggregate Risk 5.3.1 Aggregate Chronic ( non cancer) Risk Assessment The chronic aggregate assessment for adult females includes dietary, residential and drinking water exposures. The chronic dietary risk estimates from indirect food uses ( i. e. use in food contact packaging and treated articles) range from 1.8 4.2% of the cPAD, with infants/ children being the highest exposed population subgroup. Thus, the chronic dietary ( food) risk estimate associated with zinc pyrithione is below the Agency's level of concern. Drinking water exposure is not expected from the indoor uses of zinc pyrithione, but could occur from the antifoulant paint use. Drinking water monitoring data are not available, therefore, AD calculated DWLOCs, which are discussed below to account for potential drinking water exposures.

The chronic aggregate risk estimate for adult females considers the long term dermal residential exposures ( i. e., contact with shoe liners, and anti dandruff shampoo), in order to be protective of potential developmental effects that could occur via oral and dermal exposures. However, for children, it is not appropriate to aggregate dermal exposures from a shoe liner with oral exposures because of different toxicological endpoints via the dermal and oral routes of exposure for children. The developmental effects used to assess aggregate risks for adult females are not appropriate for children.

5.3.2 Chronic ( non cancer) DWLOC Calculations As noted previously, a DWLOC is the concentration of a pesticide in drinking water that would result in risk estimates below AD's level of concern, when considering total aggregate exposure to that pesticide from food, drinking water, and residential uses. AD uses the DWLOCs in the risk assessment process as a surrogate measure of potential exposure associated with pesticide exposure through drinking water. In the absence of monitoring data for a pesticide, the DWLOC is used as a point of comparison against the conservative PECs provided by computer modeling.

AD back calculates the chronic DWLOCs by a two step process: exposure [ food+ ( if applicable) residential exposure] is subtracted from the chronic PAD to obtain the maximum exposure allowed in drinking water; DWLOCs are then calculated using that value and default body weight and drinking water consumption values. In assessing human health risk, the chronic DWLOCs are compared to the PECs. When PECs are greater than DWLOCs AD considers the aggregate risk estimates [ from food + water + ( if applicable) residential exposures] to exceed the Agency's level of concern ( HED SOP 99.5 " Standard Operating Procedures for Incorporating Estimates of Drinking Water Exposure into Aggregate Risk Assessment, August 1, 1999).

Table 10 presents the total chronic dietary and residential exposure estimates for zinc pyrithione, and the chronic DWLOCs. For each population subgroup listed, the chronic PAD and 35 the chronic dietary ( food) exposure ( from Table 4) for that subgroup were used to calculate the chronic DWLOC, using the formulas in the footnotes of Table 10.

Using a conservative screening level model, the range of PECs for zinc pyrithione in a marina is 0.0144 to 0.101 ppb, which in the absence of additional data was also used to assess chronic exposures. As shown on Table 10, the chronic DWLOCs are greater than the PEC for adults and children, indicating that aggregate food, residential and drinking water exposure do not exceed the Agency's level of concern. The results are based upon a number of conservative assumptions regarding dietary and water exposure and do not necessarily represent the most refined drinking water assessment.

Table 10 DWLOCs for Chronic Aggregate Exposure Population Subgroup Chronic Scenario cPAD mg/ kg/ day Chronic Food Exp mg/ kg/ day Chronic Residential Exposure mg/ kg/ day5 Max Chronic Water Exp mg/ kg/ day1 Surface Water PEC ( ppb) 2 Chronic DWLOC (

g/ L) 3 Potential Risk Concern4 Adults ( Females 13 50 years) 0.0016 0.000033 0.0014 0.00156 0.0144 0.101 5 No Infants/ Children 0.000067 NA 0.00153 15 No NA= Not applicable. For children, it is not appropriate to aggregate potential chronic dermal exposures from a shoe liner exposure with oral exposures because of different toxicological endpoints via the dermal and oral routes of exposure for children. The developmental effects used to assess aggregate risks for adult females are not appropriate for children. 1 Maximum chronic water exposure ( mg/ kg/ day) = [( chronic PAD ( mg/ kg/ day)  ( chronic food exposure+ chronic residential exposure ( mg/ kg/ day)] 2 Based on sea water for antifoulant use on recreational boats. 3 Chronic DWLOC(

g/ L) = [ maximum chronic water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L/ day) x 10 3 mg/

g] where body weight is 60 kg and 10 kg for adult females and children, respectively and drinking water intake rates are 2 L/ day and 1L/ day for adults and children, respectively. 4 Does the surface water PEC exceed the chronic DWLOC? 5 Chronic residential exposure consists of shampoo exposure ( 0.001 mg/ kg/ day based on absorbed dermal dose estimate) and dermal exposure to a plastic shoe liner ( 4.06E 4 mg/ kg/ day absorbed dose estimate). Dermal exposures are aggregated with oral exposure for adult females to be protective of potential developmental effects.

6.0 CUMULATIVE EXPOSURE AND RISK Another standard of section 408 of the FFDCA which must be considered in making an unreasonable adverse effects determination is that the Agency consider " available information" 36 concerning the cumulative effects of a particular pesticide's residues and " other substances that have a common mechanism of toxicity."

Zinc and sodium pyrithione are two pesticide active ingredients that might be considered together in a common mechanism of toxicity assessment. It is apparent that there is structural similarity between these two chemicals ( Step 1). However, the zinc pyrithione pesticide contains two pyrithione moieties whereas the sodium pyrithione pesticide contains only one pyrithione moiety. It is apparent also that both cause neurotoxic effects at similar dose levels ( Step 2). It is not known with certainty, however, that both cause this effect by a common toxic mechanism ( Step 3). In addition, the hazard data suggest pharmacokinetic differences in the behavior of the two pesticides. There are also differences with respect to use sites. Sodium pyrithione is primarily used in metalworking and cutting fluids. Zinc pyrithione is not registered for this use. The sodium omadine ® ( sodium pyrithione) Reregistration Eligibility Document ( RED) also states that " the amount of sodium omadine ® in products that may enter the home or occupational setting such as laundry rinse additives, detergents, carpet cleaners, emulsions and jet printer inks would be very low due to dilution." According to the cumulative risk guidance, " a particular pathway for a specific chemical ... should be removed if it is likely to contribute only a very small percentage of the total exposure..." Therefore, it is unlikely that exposures to sodium omadine ® ( sodium pyrithione) will occur concomitant with any exposures to zinc pyrithione, and, for those that may occur together, the contribution of sodium pyrithione to the total exposure would be very low and would not be included in a cumulative risk assessment at this time.

For the purposes of this tolerance action, therefore, EPA has not assumed that zinc pyrithione has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

7.0 OCCUPATIONAL EXPOSURE AND RISK AD has assessed the exposures and risks to occupational workers that handle zinc pyrithione ( memorandum from D. Aviado/ D. Smegal, September 2004). This section will summarize the results of the occupational exposure assessment.

Occupational Handlers. The Agency has determined that there is potential for worker exposure to zinc pyrithione through mixing, loading, application, and handling activities associated with zinc pyrithione pesticide products. There are potential exposures from use in commercial and industrial settings via the dermal and inhalation routes. An exposure/ risk assessment for occupational antifoulant boat paint use is not included in this document. The occupational antifoulant paint use, which is a conditional, time limited registration, will be assessed in the future, pending the submission and review of a study that will assess exposure of workers performing painting of commercial vessels with antifoulant paints containing zinc 37 pyrithione. This study is expected to be completed in 2006. The occupational exposure scenarios, and estimated risks are presented on Table 11.

Based on the EPA registered use patterns, appropriate primary and secondary handler exposure scenarios were identified for zinc pyrithione. In general terms, EPA defines " primary" handler exposure as direct exposure to the pesticide formulation during mixing/ loading/ applying operations. " Secondary" handler exposure is defined as exposure to a pesticide active ingredient as a direct result of its incorporation into an end product.

Primary Occupational Handlers. The exposure and risk assessment for primary occupational handlers was conducted using product label maximum application rates, related use information from Arch Chemicals, Inc., Agency standard values for industrial practices, and CMA unit exposure data. For mixing/ loading liquids and powders in closed systems ( i. e., using a metered pump, or automatic dispensing techniques), the margin of exposure ( MOE) calculations indicate risks ( i. e., target MOEs

100) not exceeding the Agency's level of concern for the dermal and inhalation exposure scenarios assessed. The " dermal" exposure risks are not of concern ( i. e., MOE

100) for potential short term, intermediate term, and long term exposures during open mixing/ loading of liquids for all the scenarios assessed. Also, the dermal and inhalation MOEs for the laundered fabrics scenarios were not of concern. However, MOEs from exposures exceed the Agency's level of concern ( i. e., MOEs < 100) for short term, intermediate term, and long term exposure scenarios during:

° mixing/ loading/ applying powders and liquids for general preservative use patterns using open pour methods ( inhalation MOE= 53 for liquid formulations; inhalation MOE= 15 for powder formulation, dermal MOE= 42 for powder formulation); and ° mixing/ loading/ applying powders and liquids for paint preservation using open pour methods ( inhalation MOE= 53 for liquid formulations; inhalation MOE= 15 for powder formulation, dermal MOE= 42 for powder formulation).

The Agency may consider requiring risk mitigation steps, such as closed delivery systems or use of a respirator during open pouring.

Secondary Occupational Handlers. Secondary occupational handler exposures could occur through the application of treated paints and coatings, and building materials such as caulks, adhesives, spackling, groutings, sealants, stucco and joint cements. Based on end use product application methods and use amounts, it is assumed that exposures while applying paints will be equal to or greater than exposures while applying building materials. Therefore, occupational handler exposures were assessed for the application of paint, as this scenario represents maximum possible exposure to the chemical. Under this scenario, dermal and inhalation exposures were assessed for brush, airless sprayer, and aerosol application methods using PHED Version 1.1 data.

Using product label maximum application rates, related use information, Agency standard 38 values, and PHED unit exposure data, the secondary handler potential short term, intermediateterm and long term MOEs exceed the Agency's level of concern ( MOEs < 100) for:

° handling zinc pyrithione containing paint products using an airless sprayer application method ( inhalation MOEs= 4.4 without PPE and 44 with the use of a respirator as PPE, and dermal MOE= 11 without PPE and MOE= 29 with the use of gloves as PPE), and ° handling zinc pyrithione containing paint products using a paintbrush ( Dermal MOE= 22 without gloves, but risks are not of concern with gloves).

It is assumed that in real use situations for airless sprayer applications, the occupational handlers will have adequate respiratory protection by wearing either a dust/ mist or organic vapor respirator as PPE recommended by paint manufacturers for spray equipment applications. Although the dermal MOE for a paintbrush scenario is of concern ( MOE= 22) without gloves, the MOE is not of concern ( MOE= 167) when gloves are worn as protective equipment. It is assumed that in real use situations the occupational handlers will have adequate dermal protection by wearing gloves as may be recommended by paint manufacturers. Dermal and inhalation MOEs obtained for the painting scenario involving use of an aerosol spray can application method is not of risk concern.

Postapplication Exposure and Risk. Primary occupational post application dermal and inhalation exposures are limited to mists, steams, or vapors resulting from manufacturing process operations. These exposures are likely to be minimal because of the dilution of the pesticide during processing and the low vapor pressure of the active ingredient. Thus, postapplication occupational exposures were not quantitatively evaluated in this report.

Table 11. Estimates of Exposures and Risks to Occupational Handlers of Zinc Pyrithione Application Scenario( a) Use Rate ( lb ai/ 1000 lb, or lb ai/ 100 gal)( b) Amount Handled ( lb/ day or gal/ day)( c) Dermal MOE( d) Target MOE

100 Inhalation MOE( e) Target MOE

100 Primary Occupational Handler: General Preservatives Uses: Dry Film, In Can, and Material Preservation ( 1a) Mixing/ loading/ applying liquid pesticide concentrates using open pour methods 5 lb ai/ 1,000 lb 10,000 lb/ day 147 53 ( 1b) Mixing/ loading/ applying liquid pesticide concentrates using metering equipment ( pump liquid) 5 lb ai/ 1,000 lb 10,000 lb/ day 3,125 452 ( 1c) Mixing/ loading/ applying powder pesticide concentrates using open pour methods 5 lb ai/ 1,000 lb 10,000 lb/ day 42 15 Table 11. Estimates of Exposures and Risks to Occupational Handlers of Zinc Pyrithione Application Scenario( a) Use Rate ( lb ai/ 1000 lb, or lb ai/ 100 gal)( b) Amount Handled ( lb/ day or gal/ day)( c) Dermal MOE( d) Target MOE

100 Inhalation MOE( e) Target MOE

100 39 ( 1d) Mixing/ loading/ applying powder pesticide concentrates using metering equipment ( automatic dispensing techniques) 5 lb ai/ 1,000 lb 10,000 lb/ day 3,125 452 Primary Occupational Handler: Paints: Dry Film Preservation ( 2a) Mixing/ loading/ applying liquid pesticide concentrates using open pour methods 5 lb ai/ 100 gal 1,000 gal 147 53 ( 2b) Mixing/ loading/ applying liquid pesticide concentrates using metering equipment ( pump liquid) 3,125 452 ( 2c) Mixing/ loading/ applying powder pesticide concentrates using open pour methods 42 15 ( 2d) Mixing/ loading/ applying powder pesticide concentrates using metering equipment ( automatic dispensing techniques) 3,125 452 Primary Occupational Handler: Fabrics/ Textiles: Laundering Treatment for Material Preservation ( 3a) Mixing/ loading/ applying liquid pesticide concentrates using open pour methods 0.54 lb ai/ 1,000 lb 10,000 lb 1,370 487 ( 3b) Mixing/ loading/ applying liquid pesticide concentrates using metering equipment ( pump liquid) 29,412 4,180 ( 3c) Mixing/ loading/ applying powder pesticide concentrates using open pour methods 397 142 ( 3d) Mixing/ loading/ applying powder pesticide concentrates using metering equipment ( automatic dispensing techniques) 29,412 4,180 Secondary Occupational Handler: Paints Containing Zinc Pyrithione ( Materials Preservative)

( 4a) Handling zinc pyrithionecontaining paint end products using a paint brush application method 5 lb ai/ 100 gal 5 gal/ day 22 130 167 ( PPE) ( f) not necessary ( 4b) Handling zinc pyrithionecontaining paint end products using an airless sprayer application method 5 lb ai/ 100 gal 50 gal/ day 11 4.4 29 ( PPE) ( f) 44 ( PPE)( f) Table 11. Estimates of Exposures and Risks to Occupational Handlers of Zinc Pyrithione Application Scenario( a) Use Rate ( lb ai/ 1000 lb, or lb ai/ 100 gal)( b) Amount Handled ( lb/ day or gal/ day)( c) Dermal MOE( d) Target MOE

100 Inhalation MOE( e) Target MOE

100 40 ( 4c) Handling zinc pyrithionecontaining paint end products using an aerosol spray can application method 5 lb ai/ 100 gal 0.28 gal/ day ( 3 12 oz cans) 376 500 Footnotes: ( a) Scenarios based on use patterns described on labels and LUIS report. Primary occupational handlers include people who add zinc pyrithione as a general preservative to products such as food/ non food contact adhesives; floor tile adhesives; caulks and sealants; grout and patching compounds; food/ non food contact polymeric materials; rubber and thermoplastic resins; preservatives in latex paint; architectural coatings; dry film preservative in products such as dry wall and building materials; and laundered fabrics. ( b) Represents the maximum use rates on the registered zinc pyrithione product labels; EPA Registration Nos.: 1258 840 and 1258 841. ( C) Standard EPA default assumptions: 10,000 for caulk; 1,000 for paint; and 1,000 for laundered fabric. ( d) Dermal MOE = Dermal NOAEL ( mg/ kg/ day) / Dermal Dose ( mg/ kg/ day). Where the NOAEL is 0.5 mg/ kg/ day from the rabbit developmental study. A 3% dermal absorption factor was used. ( e) Inhalation MOE = Inhalation NOAEL ( mg/ kg/ day) / Inhalation Dose ( mg/ kg/ day). Where the inhalation NOAEL of 0.0005 mg/ L/ day is converted to 0.13 mg/ kg/ day. ( f) PPE for inhalation is organic vapor respirator, which provides approximately 90% protection. Use of gloves as PPE assumes 90% protection factor on hands.

8.0 INCIDENTS There are no reported epidemiological data or incident information for zinc pyrithione.

9.0 ENVIRONMENTAL RISK A detailed ecological hazard and environmental risk assessment for zinc pyrithione is presented in the attached memorandum ( memo from K. Montague 2004), while the detailed information on environmental fate is presented in the attached memo from N. Shamim ( 2004). A brief summary is presented below.

Environmental Fate. Zinc pyrithione is a complex ( coordination) compound formed through a chemical reaction between the inorganic zinc ion and organic moiety pyrithione.

A. Abiotic:

Hydrolytically the chemical is stable in water under abiotic and buffered conditions ( pH 5, 7 and 9), as well as in simulated sea water. The extrapolated hydrolytic half lives were 99, 120 and 123 days at pHs 5, 7 and 9, respectively. In simulated sea water, the extrapolated half life was 96 41 days. Photolytic measurements showed that zinc pyrithione rapidly degrades with a half life of 13 minutes in buffered medium and in about 17 minutes in simulated sea water.

B. Biotic:

In a study on aerobic aquatic system, zinc pyrithione degradation follows a biphasic process and in the first phase it degrades rapidly with a half life of 0.065 hours in salt water and in 1.3 hours in fresh water samples. In a second phase, the half lives of zinc pyrithione were 12.3 and 15 days for fresh water and sea water respectively. It may not pose a concern for surface water runoff

A second aerobic aquatic degradation study was conducted on a salt water harbor used as a boat maintenance site. Degradation data were obtained on zinc and copper pyrithiones. In water samples, and in the presence of pyrithione thiosulfate ( OTS, which may be formed as a degradate or may be present in the sample), the half life was 0.60 hours. Degradation half life in the sediment samples, in the presence of OTS, was 0.89 days, ( OTS may be initially present or may be formed due to degradation process). Kinetic pathway in the sediment samples was non linear. In the absence of OTS, and through non linear pathway, the degradation half life decreased to 0.03 days. The sediment in this study was characterized as sand (% sand = 90, silt: 4% and clay: 6%)

In anaerobic aquatic samples from fresh and salt water, zinc pyrithione degraded through biphasic process. Anaerobically fresh water and salt water samples of zinc pyrithione degraded rapidly in the first phase with a half life of about 2 hours. In the second phase, the degradation half life in fresh and salt water samples increased to 25.5 hours. Fresh water and salt sediment samples, zinc pyrithione degradation half was measured at 13.1 hours.

In a second study, water and sediment samples were collected from a salt marina ( Little Harbor, MarbleHead, MA). A two compartment model was used to analyze the kinetic data: zinc pyrithione degraded in 0.50 hours in water sample and in 18.9 hours in the sediment sample. The sediment of this marina was characterized as sand ( % sand = 86, silt: 6%, and clay: 8%). pH of the sediment was basic ( 7.9) and % organic C = 2.3.

A soil column leaching study conducted on four soil samples: sand, sandy loam, loam and clay ( unaged) and on sandy loam ( aged) indicated that zinc pyrithione is immobile in these systems.

An absorption/ desorption study conducted on Marblehead salt water soil, Marblehead salt water sediment, Portland freshwater soil and Portland freshwater sediment ( all from MA), showed that zinc pyrithione binds moderately strongly with Marble saltwater soil and sediment ( K d= 50 and 99 respectively) and less strongly with Portland freshwater soil and sediment ( K d = 11 and 48). Marblehead salt water soil and sediment were characterized as sandy loam and Portland freshwater soil and sediment as loamy or silt loam. 42 For use of zinc pyrithione as an antifoulant paint on small boat and ship bottoms a special study called Aqueous Availability study which measures the rate of leaching when boats and ships painted with the antifoulant paint navigate in fresh or salt water bodies ( marinas, or lakes or sea) , a number of aqueous availability studies were conducted on a number formulations containing zinc pyrithione and in some cases zinc pyrithione and another biocide. The percent of zinc pyrithione in the formulations varied from 2.0 to 4.7 and the average leach rate/ day ranged from 1.2 µ g/ cm2/ day to 8.4 µ g/ cm2/ day. These were non guideline studies and aqueous availability studies were carried by using the EPA approved ASTM Method D 5108 90.

The Octanol/ Water Partition Coefficient ( K OW) of zinc pyrithione is reported to be less than 10 ( Log Kow is 0.97) which makes it less likely to bioaccummulate in aquatic organisms, although because of moderately high K d s with salt water sediments it may and partition in water and become available to benthic organisms.

Coordination or complex substances like zinc pyrithione have a tendency to transmetallate with other metals present in aquatic media ( copper, mercury, cadmium and other metal ions). Copper pyrithione is shown to be more stable than zinc pyrithione. However, it also degrades with comparable rates as zinc pyrithione in the aerobic and environmental media of water and sediments.

The registrant recently submitted as outdoor microcosm study ( MRID 45876501), which is not required by environmental fate requirements. This study was found deficient in many ways. However, the Agency considers this data to be supplemental. The study indicates that zinc pyrithione degrades under simulated seawater conditions, under dark or in the presence of light. The half lives under all conditions were less than 24 hours. The study also indicates that zinc pyrithione shows little tendency to accumulate in sediment, particularly if light is present. These results provide additional support to the findings of laboratory studies conducted to evaluate the various degradation pathways for zinc pyrithione.

Environmental Modeling/ Exposure. The limited environmental exposure resulting from indoor uses of zinc pyrithione is not anticipated to cause adverse effects to terrestrial or aquatic organisms.

Ecological Hazard and Risk. The ecological effects database for zinc pyrithione is adequate to support the indoor uses considered in this risk assessment. The ecological risks associated with the outdoor antifoulant boat use, which is conditionally registered until June 2005, are not included in this report, but will be evaluated upon review of recently submitted ecotoxicity studies. Zinc pyrithione is moderately toxic to birds via acute oral exposure, and slightly toxic to practically non toxic to birds via dietary exposure. It is also moderately toxic to mammals via oral ingestion ( Toxicity Category II). Zinc pyrithione is very highly toxic on an acute basis to freshwater and marine fish and invertebrates, as well as to aquatic plant species. Zinc pyrithione caused impacts on growth and reproduction to several species of aquatic organisms in laboratory studies, at levels slightly below the LC50. These types of effects suggest that zinc pyrithione may 43 possibly have endocrine disruption potential. The acute toxicity data for zinc pyrithione are summarized on Table 12. Plant toxicity data are presented on Table 13, while chronic ecotoxicity data are presented on Table 14.