1,2 Benzisothiazolin 3 one ( BIT) Risk Assessment Antimicrobials Division Office of Pesticide Programs U. S. Environmental Protection Agency 1921 Jefferson Davis Highway Arlington, VA 22202 September 8, 2005 TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION . . . . . . . . . . . . 9 2.1 Chemical Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.2 Physical/ Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.0 ENVIRONMENTAL FATE ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 4.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 4.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 4.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4.4 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION . . . . . . . . . . . . . . . . . 18 5.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 5.2 Dietary Exposure/ Risk for Active Ingredient Uses . . . . . . . . . . . . . . . . . . . . . . 18 5.2.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 5.2.2 Acute Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 5.2.3 Chronic Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 5.2.4 Cancer, Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 5.3 Dietary Exposure/ Risk for Inert Ingredient Uses . . . . . . . . . . . . . . . . . . . . . . . . 20 5.4 Drinking Water Exposures and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 5.5 Residential Exposure/ Risks for Active Ingredient Uses . . . . . . . . . . . . . . . . . . . 24 5.5.1 Residential Handler Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 <IP_ADDRESS> Paint Exposures and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 <IP_ADDRESS> Cleaning Product Exposures and Risks . . . . . . . . . . . . . . . . . . . 25 5.5.2 Residential Post application Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 26 5.6 Residential Exposure and Risks From Inert Ingredient Uses . . . . . . . . . . . . . . . 31 6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS . . 36 6.1 Acute and Chronic Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 6.2 Short and Intermediate Term Aggregate Exposures and Risks . . . . . . . . . . . . . 38 7.0 CUMULATIVE RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 8.0 OCCUPATIONAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 8.1 Occupational Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 8.2 Occupational Post application Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 9.0 ECOTOXICOLOGY ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 10.0 DATA NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 11.0 INCIDENT REPORT ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 1 1.0 EXECUTIVE SUMMARY 1,2 benzisothiazolin 3 one ( BIT) is an antimicrobial that is recommended for use as an industrial preservative for the protection of water based adhesives, caulks, sealants, grouts, spackling, ready mixed cements, ready mixed wallboard compounds, aqueous compositions such as emulsion paints, aqueous slurries, home cleaning and car care products, laundry detergents, fabric softeners, stain removers, inks, photographic processing solutions, paints and stains, titanium dioxide slurries, oil in water emulsions, latices, metalworking fluids, casein/ rosin dispersions, textile spin finish solutions, pesticide formulations, tape joint compound, leather processing solutions, preservation of fresh animal hides and skins, and for offshore and terrestrial gas/ oil drilling muds and packer fluids preservation. The specific antimicrobial use categories include the following general use patterns: material preservatives ( indoor food and indoor/ outdoor non food), industrial processes and water systems ( indoor nonfood), and indoor and outdoor residential uses. 1,2 benzisothiazolin 3 one is also used as an inert ingredient in a variety of products as a materials preservative. Residential and occupational exposures and risks from the use of products containing 1,2 benzisothiazolin 3 one as both the active and inert ingredients are assessed in this risk assessment.

Environmental Fate: The environmental fate assessment for 1,2 benzisothiazolin 3 one is based on limited information; data are only available for hydrolysis, aerobic soil metabolism, and adsorption/ desorption. These data indicate that 1,2 benzisothiazolin 3 one is hydrolytically stable ( half life > 30 days), but breaks down fairly quickly in aerobic soils ( half life < 24 hours in sandy loam soil). 1,2 benzisothiazolin 3 one shows moderate binding to soils, with adsorption K d values estimated to be between 1.24 to 9.56. If used outdoors, 1,2 benzisothiazolin 3 one may possibly move with soil during rainfall events and potentially reach surface waters. However, with a K ow value of 20 at 25 o C, 1,2 benzisothiazolin 3 one is unlikely to bioaccumulate in aquatic organisms.

Hazard: Acute toxicity data show that 1,2 benzisothiazolin 3 one is moderately toxic by the oral and dermal routes ( Toxicity Category III for both studies), but also show that this chemical is a severe eye irritant ( Toxicity Category I). Data from acute dermal irritation studies indicate only mild skin irritation ( Toxicity Category IV), but repeated dermal application indicates a more significant skin irritation response. This response could be related to the ability of this chemical to cause a moderate skin sensitization.

Subchronic oral toxicity studies conducted in both rats and dogs show systemic effects after repeated oral administration. In rats, decreased body weight was observed in males at weeks 2, 3, and 13 as well as an increased incidence of forestomach hyperplasia at a dose of 69 mg/ kg/ day. In a second subchronic oral study, in which rats received gavage doses of 1,2 benzisothiazolin 3 one, stomach lesions were observed at doses of 30 mg/ kg and higher. A 90 day dermal toxicity study in rats was conducted; however, although this study was classified as acceptable, a NOAEL was not obtained based on the presence of stomach lesions, suggestive of oral exposure to the compound, at all doses tested ( 100, 300 and 1000 mg/ kg). In dogs, the 2 effects of repeated oral dosing of 1,2 benzisothiazolin 3 one occur at lower doses than in rats, and include alterations in blood chemistry ( decreased plasma albumin, total protein, and alanine aminotransferase) and increased absolute liver weight at a dose of 20 mg/ kg/ day.

Two developmental toxicity studies were conducted in rats with 1,2 benzisothizolin 3 one. One study was conducted with test material of 73.4% purity, and maternal effects included decreased body weight gain during dosing and decreased food consumption at a dose of 100 mg/ kg/ day. The other study was conducted with test material of 100% purity, and maternal effects in this study consisted of clinical toxicity signs ( audible breathing, haircoat staining of the anogenital region, dry brown material around the nasal area) as well as increased mortality at a dose of 30 mg/ kg/ day. In both studies, however, reported developmental effects are similar although occurring at different effect levels, and consist of increases in skeletal abnormalities ( extra sites of ossification of skull bones, unossified sternebra) but not external or visceral abnormalities. Despite the differences in purity of the test material in the two studies, the effect levels at which fetal effects occur are similar in both studies ( 90 and 100 mg/ kg/ day). The maternal effects were however, substantially different ( increased mortality at 30 mg/ kg/ day and body weight changes at 100 mg/ kg/ day).

In a two generation reproduction study in rats, there is no indication of increased sensitivity to offspring, as the observed effects in offspring ( delayed balanopreputial separation, impaired growth and reduced pup survival) occurred at doses that were in excess of the dose of 1,2 benzisothiazolin 3 one associated with parental toxicity.

A dermal penetration study was conducted in rats which demonstrated that when 1,2 benzisothiazolin 3 one is applied dermally, a maximum of 40.6% ( 41%) of the labeled material is absorbed after 72 hours.

Mutagenicity studies assessing point mutations ( Ames test and mouse lymphoma test), micronucleus formation, and unscheduled DNA synthesis were also conducted for 1,2 benzisothiazolin 3 one. All of these studies show a negative mutagenic response for this chemical.

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. The endpoints selected were reviewed by the Antimicrobial Division's Toxicology Endpoint Selection Committee ( ADTC) in 2002 and 2005.

Dietary Endpoints: The acute and chronic RfDs are 0.017 mg/ kg/ day. These endpoints are based on a subchronic toxicity study in dogs with a reported NOAEL of 5 mg/ kg/ day and which indicated increased incidences of emesis and clinical chemistry alterations at the LOAEL of 20 mg/ kg/ day. An uncertainty factor of 300 ( 10x for interspecies extrapolation, 10x for intraspecies variability, and 3x for database uncertainty) was applied to the NOAEL to obtain the 3 acute and chronic RfDs. The data base uncertainty factor of 3x is applied to account for oral data base concerns based on the lack of reliable developmental toxicity data with respect to maternal toxicity.

Oral Endpoints: The short and intermediate term oral endpoint is 5 mg/ kg/ day and is based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day in a subchronic toxicity study in dogs. The target margin of exposure ( MOE) is 300.

Dermal Endpoints: The short, intermediate, and chronic term dermal endpoint is 5 mg/ kg/ day and is based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day in an oral subchronic toxicity study in dogs. The target MOE is 100 for residential and occupational exposure. A 41% dermal absorption value is used for an oral to dermal route extrapolation.

Inhalation Endpoints: The short, intermediate, and chronic term inhalation endpoint is 5 mg/ kg/ day and is based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day in a subchronic toxicity study in dogs. The target MOE is 100 for occupational and residential exposure; however if the resulting MOE is not at least 1000, the Agency can request a repeat dose inhalation study of at least 28 days in duration. ( The MOE of 1000 is based on the application of a 10X uncertainty factor for interspecies extrapolation, a 10X uncertainty for intraspecies variability and a 10X for the lack of an inhalation study).

FQPA Safety Factor: Initially, on August 28, 2002 the ADTC reviewed the available toxicology data for 1,2 benzisothiazolin 3 one and recommended that the special hazard based FQPA safety factor of 10x be retained. This conclusion is based on the lack of a reproduction toxicity study, which is a required study for food contact uses, the lack of a developmental toxicity study in a non rodent species, concerns for the discrepancies in maternal effect levels between the two developmental toxicity studies in rats, the expected daily dietary exposure to this chemical from the indirect food contact uses, and the gastrointestinal irritancy of this chemical as observed in the submitted database. The initial retention of the 10x factor to address FQPA concerns is intended to account for both the database deficiencies as well as potential sensitivity issues, and is consistent with the Antimicrobials Division's interim working policy on indirect food uses of antimicrobial pesticides.

The ADTC revisited their decision on February 9, 2005, after receiving additional data which included a multi generational reproduction study, a dermal penetration study and a 90 oral gavage study. At this meeting the 10x factor was reduced to 1X. While sensitivity issues were addressed by the new data, there were still data base deficiencies relative to the maternal toxicity in the developmental toxicity studies; thus a 3X database uncertainty factor was applied to the oral route of exposure.

Based on Agency policy, a RfD modified by a FQPA safety factor is a population adjusted dose ( PAD). The Agency calculated an acute PAD and a chronic PAD, and used this value to 4 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.

Dietary Exposure: The Agency has conducted a dietary exposure and risk assessment for use of 1,2 benzisothiazolin 3 one as a pulp and paper mill slimicide, and a preservative in paper coatings and paper adhesives, all of which may end in indirect food contact scenarios. For both the acute and chronic dietary exposure, the risk is highest for children ( 21.8% of the acute and chronic PAD). For an adult, the acute and chronic dietary exposure is 9.4% of the acute and chronic PAD. All dietary exposures calculated are below the Agency's level of concern ( 100% of aPAD or cPAD). Furthermore, given the conservative nature of the assumptions used in the inert dietary exposure and risk assessment, risks of concern from food are not likely from the use of 1,2 benzisothiazolin 3 one as inert ingredients in pesticide products.

Water Exposure and Risk: Based on environmental fate data, 1,2 benzisothiazolin 3 one binds moderately with soil and may potentially move with the soil during rainfall events and reach surface waters. Although, 1,2 benzisothiazolin 3 one has been shown to be hydrolytically stable with a half life of > 30 days, it breaks down fairly quickly in aerobic soils. Outdoor use patterns of 1,2 benzisothiazolin 3 one which may lead to contact with soil and/ or surface water include: 1) the application of agricultural pesticides that contain 1,2 benzisothiazolin 3 one as an inert ingredient, and 2) the application of paints that contain 1,2 benzisothiazolin 3 one. Considering 1,2 benzisothiazolin 3 one readily biodegrades and the small amount ( 0.02 lbs. per acre) that may be applied to crops via the inert use and the small amount likely to come into contact with soils/ surface waters via the paint use, 1,2 benzisothiazolin 3 one is not likely to be present in food or drinking water sources at substantial concentrations.

Residential Exposure and Risk: 1,2 benzisothiazolin 3 one may be added to residential household cleaning and paint products to control bacteria and fungi. The residential handler scenarios evaluated, which are considered to be representative of all possible exposure scenarios, include: 1) dermal and inhalation exposure during handling of BIT containing paint through brush/ roller and airless spray application methods, and 2) dermal and inhalation exposure during handling of BIT containing cleaning products through wiping and mopping application methods. The scenarios were evaluated based on the Residential Exposure Assessment Standard Operating Procedures ( SOPs), product label maximum application rates, related used information, Agency standard assumptions, Pesticide Handlers Exposure Database ( PHED) unit exposure data, and Chemical Manufacturing Association ( CMA) unit exposure data. None of the residential handler exposure scenarios exceeded the Agency's level of concern ( i. e., dermal and inhalation MOEs are greater than the target MOE of 100).

Short and intermediate term residential postapplication exposures considered in this assessment include exposure to residues from hard surfaces ( floors) that have been mopped with BIT containing products and exposure to clothing laundered with 1,2 benzisothiazolin 3 one preserved detergents. None of the dermal or incidental oral scenarios exceeded the Agency's level of concern. 5 1,2 benzisothiazolin 3 one is also used as a materials preservative inert ingredient in various types of products including turf insecticides, fungicides and herbicides; garden and ornamental insecticides; flea and tick control products for pets; indoor crack and crevice insecticides; paints; and household cleaners. A representative subset of these products was assessed for the potential exposure to BIT residues when used as an inert ingredient. These exposure scenarios included residential handlers of turf, garden, and pet products as well as, toddler post application exposure to residues from use of turf and pet products. The scenarios were evaluated based on the Residential Exposure Assessment Standard Operating Procedures ( SOPs), product label maximum application rates, related used information, Agency standard assumptions, and the Agency's inert screening level model PiRat. None of the residential handler exposure scenarios exceeded the Agency's level of concern. Although most of the postapplication exposures did not exceed the Agency's level of concern, the toddler post application dermal exposure scenario to residues remaining on pets resulted in a MOE of 33 which is lower than the target MOE of 100. Therefore, this scenario results in risks of concern and requires further refinement and/ or mitigation. The registrant indicated that there is the potential to reduce the amount of BIT in pet products. If the amount of BIT is reduced from 0.1 percent to 0.032 percent there would be no risks of concern.

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. Since 1,2 benzisothiazolin 3 one has one inert ingredient exemption from the requirement of a tolerance for residues under 40 CFR part 180.920 for growing crops and the Agency currently has a petition for BIT as an inert ingredient, exemptions from the requirement of a tolerance for residues under 40CFR part 180.930 for livestock animals, 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 assessments were conducted for acute ( 1 day), short term ( 1 30 days), intermediate term ( 1 6 months) and chronic ( 6 months to lifetime) exposures.

The acute and chronic aggregate risk assessments generally include only dietary and drinking water exposures. Since drinking water exposure is not expected from any of the indoor or outdoor uses of 1,2 benzisothiazolin 3 one, as either an inert or active ingredient, the acute and chronic aggregate assessments only included dietary exposures from the active indirect food uses ( i. e., use in food contact packaging) and inert dietary exposures from agricultural pesticide uses. The acute and chronic aggregate risk estimates associated with 1,2 benzisothiazolin 3 one are well below the Agency's level of concern where, the adult's risks were 17.1% of the aPAD and 12.2% of the cPAD, and the children's risks were 44.1% of the aPAD and 31.8% of the cPAD. 6 The short and intermediate term aggregate assessments were conducted for adults and children. The following representative scenarios were included in the aggregate assessments:

Short term, Adults: ° dietary, inert and active ° handling cleaning products via wiping ° handling cleaning products via mopping ° wearing clothing washed in detergent preserved with BIT Short term, Children: ° dietary, inert and active ° post application exposure to cleaning product residues via mopping ° wearing clothing washed in detergent preserved with BIT Intermediate term, Adults: ° dietary, inert and active ° wearing clothing washed in detergent preserved with BIT Intermediate term, Children: ° dietary, inert and active ° post application exposure to cleaning product residues via mopping ° wearing clothing washed in detergent preserved with BIT Since the toxicity endpoints for all of the routes of exposure ( oral, dermal and inhalation) are based on the same study and same toxic effect, all routes are aggregated together. However, the aggregate risk index ( ARI) method was utilized in the assessment. This method was used because the oral, dermal and inhalation endpoints have different uncertainty factors that need to be applied. For 1,2 benzisothiazolin 3 one, all endpoints for exposure were derived from a subchronic oral study in dogs however, the uncertainty factors ( i. e., target MOEs) for oral, dermal and inhalation routes are 300, 100 and 100, respectively. A risk index $ 1 indicates no risk of concern. The short term ARIs for adults and children were 6.8 and 1.9, respectively, while the intermediate term ARIs for adults and children were 7.5 and 1.9, respectively. These ARIs indicate that there is reasonable certainty of no harm from using 1,2 benzisothiazolin 3 onecontaining products.

Occupational Exposure and Risk: The Agency has determined that there is potential for worker exposure to 1,2 benzisothiazolin 3 one through mixing, loading, application, and handling activities. Dermal and inhalation exposures from contact with 1,2 benzisothiazolin 3 one were assessed for the following scenarios:

Formulated Product Handlers ° Pouring the liquid biocide preservative into industrial process intermediate materials ( dispersions, slurries, emulsions, solutions, etc.) ° Pouring the liquid biocide preservative into industrial process water for leather and photo processing systems 7 ° Pouring the biocide into metalworking fluid ° Pouring the biocide during oil field activities Materials Preservative Handlers ° Handling BIT containing paint through brush/ roller and airless sprayer application methods ° Handling BIT containing cleaning products through low pressure spray, wipe, and mopping application methods ° Handling BIT containing metalworking fluids during machinist activities Materials preservative handler scenarios were not assessed for the application of building materials because based on end use product application methods and use amounts, the Agency assumes that exposures while applying paints will be equal to or greater than exposures while applying building materials.

The inhalation exposures are not of concern for the any of the handler scenarios assessed. However, for handlers using BIT treated paint via an airless sprayer, the dermal MOE of 90 indicates a risk of concern ( i. e., MOEs < 100). However, these risk estimates are based on a number of conservative assumptions. For example, the unit exposure values used in the assessment do not consider the use of personal protection equipment such as gloves or respirators, which are often recommend by paint manufacturers, especially for airless spray equipment applications. Moreover, 100 percent dermal bioavailability was assumed for BIT contained in a paint matrix, which is believed to be an overestimate.

Occupational by stander/ post application dermal and inhalation exposures are limited to mists, steams, or vapors resulting from manufacturing process operations. The dermal exposures are likely to be minimal because of the dilution during processing or compared to the metal working fluid machinist. Inhalation exposures are also expected to be minimal because aerosol generation is not expected and the vapor pressure of 1,2 benzisothiazolin 3 one is very low.

Ecological Hazard and Risk: The available ecological effects data for 1,2 benzisothiazolin 3 one are somewhat limited. Based on acute toxicity information, 1,2 benzisothiazolin 3 one displays low to moderate toxicity to birds and mammals. It is moderately toxic to freshwater fish and invertebrates, slightly toxic to marine/ estuarine fish, and highly toxic to marine/ estuarine invertebrates.

The indoor uses of BIT considered in this RED make it unlikely that any appreciable exposure to terrestrial or aquatic organisms would occur. Facilities using BIT for indoor industrial applications are required to have NPDES permits before discharging effluents into receiving waters. The potential exposure to terrestrial and aquatic species from the oil recovery uses of BIT cannot be estimated at this time, as there is currently no validated model available for such a purpose. The high toxicity of BIT to green algae and invertebrate species suggests that potential adverse acute effects could occur to some species if environmental contamination from BIT treated oil recovery fluids occurs. 8 1,2 benzisothiazolin 3 one is used as an inert ingredient in pesticide products but the allowable amount that can be applied is small ( not more than 0.1% formulation and 0.02 lbs. per acre). Data indicate that 1,2 benzisothiazolin 3 one breaks down quickly in aerobic soils ( half life < 24 hours in sandy loam soil). 1,2 benzisothiazolin 3 one's ready biodegradation in soil and small application amount greatly reduce the exposure potential for terrestrial and aquatic organisms. Run off into surface water from pesticidal uses is likely to be low and it is not likely to be present in water sources at substantial concentrations. Therefore, risk to nontarget organisms is not anticipated from the inert uses of 1,2 benzisothiazolin 3 one.

Listed Species: The indoor uses of BIT addressed in this document are unlikely to result in any appreciable exposure to terrestrial or aquatic organisms, and thus have a low risk potential for Listed Species. The potential exposure to terrestrial and aquatic species from the oil recovery uses of BIT cannot be estimated at this time, as there is currently no validated model available for such a purpose. The high toxicity of BIT to green algae and invertebrate species suggests that potential adverse acute effects could occur to some species if environmental contamination from BIT treated oil recovery fluids occurs. 1,2 benzisothiazolin 3 one is used as an inert ingredient in pesticide products but the allowable amount that can be applied is small ( not more than 0.1% formulation and 0.02 lbs. per acre). Data indicate that 1,2 benzisothiazolin 3 one breaks down quickly in aerobic soils ( half life < 24 hours in sandy loam soil). 1,2 benzisothiazolin 3 one's ready biodegradation in soil and small application amount greatly reduce the exposure potential for terrestrial and aquatic organisms. Run off into surface water from pesticidal uses is likely to be low and it is not likely to be present in water sources at substantial concentrations. Therefore, risk to Federally listed species and critical habitats is not likely to occur from the inert ingredient uses of 1,2 benzisothiazolin 3 one.

Incident Reports: The incident reports for 1,2 benzisothiazolin 3 one do not contain information that would be of concern.

Data Gaps: An acute inhalation study is required for the technical grade active ingredient based on new waiver criteria and advances in inhalation technology which nullified the previous waiver. An additional developmental study may be required to remove the 3X database uncertainty factor applied to oral exposure scenarios.

EPA requires that the registrant submit carcinogenicity data for BIT to support the metal working fluid use. The registrant may claim that a carcinogenicity study would not be required for the metalworking fluid use if the use is for " enclosed metalworking systems". Under this scenario, it has been determined that certain toxicology data requirements including carcinogenicity testing would be held in reserve pending review of worker exposure in such enclosed systems. 9 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION 2.1 Chemical Identification Chemical identification parameters, including chemical and common/ trade names, chemical family, CAS Number, and molecular formula are provided in Table 1.

Table 1. Chemical Identification Parameter Value Chemical Name 1,2 benzisothiazolin 3 one Common/ Trade Names IPX, Proxan, Proxel, XBINX ® , Acticide ® BIT Chemical Family Isothiazolines CAS Number 2634 33 5 Molecular Formula C7H5NOS 2.2 Physical/ Chemical Properties The physical and chemical properties of the Technical Grade Active Ingredient ( TGAI) of 1,2 benzisothiazolin 3 one are shown in Table 2.

Table 2. Physical/ Chemical Properties Parameter Value Molecular Weight 151.9 Color Off white to brown Physical State solid Specific gravity 1.45 at 20oC Dissociation Constant 9.12 x 10 8 pH 4.8 at 23oC Stability Stable with respect to sunlight and normal or elevated temperatures; not stable with respect to copper metal and iron ( III) ions Melting point 159.5 160oC Water Solubility Three separate solubilities provided by different registrants: 1118 ppm at 20oC, 1380 ppm at 24oC, and EPA database ( EPI Suite) lists 2.1 g/ L at 25oC Table 2. Physical/ Chemical Properties Parameter Value 10 Solubility in organic solvents ° methanol: 67,000 ppm at 23oC ° acetone: 42,000 ppm at 24oC ° dichloromethane: 31,000 ppm at 23oC ° toluene: 5,000 ppm at 24oC ° ethyl acetate: 23,000 ppm at 23oC ° n hexane: 100 ppm at 23oC ° acetonitrile: 13,000 ppm at 23oC ° heptane: 135 ppm at 20oC Octanol water Partition Coefficient 20.0 at 25 ° C Vapor Pressurea ° 4.4 x 10 7mm Hg at 20 ° C ° 9.8 x 10 7mm Hg at 25 ° C ° 2.78 x 10 6mm Hg at 25 ° C Henry's Law Constant ° 2.38 x 10 10 atm m3/ mole Persistence in Air Half life: 7.8 hours a Note: a number of registants have reported various values for the vapor pressure. Since these values are within experimental errors, the Agency does not consider them to be different from each other 3.0 ENVIRONMENTAL FATE ASSESSMENT The environmental fate assessment for 1,2 benzisothiazolin 3 one was based on limited information; data were only available for hydrolysis, aerobic soil metabolism, and adsorption/ desorption. These data indicate that 1,2 benzisothiazolin 3 one is hydrolytically stable ( half life > 30 days), but breaks down fairly quickly in aerobic soils ( half life < 24 hours in sandy loam soil). 1,2 benzisothiazolin 3 one shows moderate to strong binding to soils, with adsorption K d values estimated to be between 1.24 to 9.56. If used outdoors, 1,2 benzisothiazolin 3 one may possibly move with soil during rainfall events and potentially reach surface waters. However, it breaks down aerobically on the surface soils. Since it has a moderate binding potential to soils, it is not likely to migrate into the ground and there is low potential for ground water contamination. Furthermore, with a K ow value of 20 at 25 o C, 1,2 benzisothiazolin 3 one is unlikely to bioaccumulate in aquatic organisms.

4.0 HAZARD CHARACTERIZATION 4.1 Hazard Profile A detailed hazard assessment for 1,2 benzisothiazolin 3 one is presented in the attached appendix.

Acute Toxicity. Acute toxicity data show that 1,2 benzisothiazolin 3 one is moderately toxic by the oral and dermal routes ( Toxicity Category III for both studies), but that this chemical is a severe eye irritant ( Toxicity Category I). Irritation to the skin from acute data show only mild 11 skin irritation ( Toxicity Category IV), but repeated dermal application indicated a more significant skin irritation response. Table 3 presents the acute toxicity data for 1,2 benzisothiazolin 3 one and Table 4 highlights the key toxicological studies for 1,2 benzisothiazolin 3 one.

Subchronic Toxicity. Subchronic oral toxicity studies conducted in both rats and dogs showed systemic effects after repeated oral administration. In rats, decreased body weight was observed in males at weeks 2, 3, and 13 at a dose of 69 mg/ kg/ day. An increased incidence of forestomach hyperplasia was also observed at this dose level. In a second oral gavage study in rats, non glandular stomach lesions were reported in both sexes at doses of 30 mg/ kg/ day and higher. In dogs, the effects of repeated oral dosing of 1,2 benzisothiazolin 3 one occurred at lower doses than in rats, and included alterations in blood chemistry ( decreased plasma albumin, total protein, and alanine aminotransferase) and increased absolute liver weight at a dose of 20 mg/ kg/ day. A 90 day dermal toxicity was conducted in rats and although the study was classified as acceptable, a NOAEL was not obtained based on the presence of stomach lesions, suggestive of oral exposure to the compound, at all doses tested ( 100, 300 and 1000 mg/ kg/ day).

Developmental Toxicity. Developmental toxicity studies were conducted in rats with 1,2 benzisothiazolin 3 one. One study was conducted with test material of 73.4% purity, and maternal effects included decreased body weight gain during dosing and decreased food consumption, both occurring at a dose of 100 mg/ kg/ day. The other study was conducted with test material of 100% purity, and maternal effects in this study consisted of clinical toxicity signs ( audible breathing, haircoat staining of the anogenital region, dry brown material around the nasal area) as well as increased mortality at a dose of 30 mg/ kg/ day. In both studies, however, developmental effects were similar although occurring at different effect levels, and consisted of increases in skeletal abnormalities ( extra sites of ossification of skull bones, unossified sternebra) but not external or visceral abnormalities. Despite the differences in purity of the test material in the two studies, the effect levels at which fetal effects occurred were similar in both studies ( 100mg/ kg and 90g/ kg for the first and second studies, respectively).

Reproductive Toxicity. A two generation reproduction study was conducted in which 1,2 benzisothiazolin 3 one was administered in the diet at concentrations of 0, 250, 500 or 1000 ppm. Parental toxicity was observed at 500 ppm and was characterized by lesions in the stomach. In pups, toxic effects were reported at 1000 ppm and consisted of preputial separation in males and impaired growth and survival in both sexes. The reproduction study did not show evidence of increased susceptibility of offspring to the effects of 1,2 benzisothiazolin 3 one.

Dermal Penetration. A dermal penetration study was conducted in rats in which a 10 mg/ kg dermal dose of 1,2 benzisothiazolin 3 one was applied to the skin for durations of 4, 8, 24, 48 or 72 hours. At 72 hours a maximum dermal penetration of 40.6% was achieved.

Mutagenicity. Acceptable mutagenicity studies were conducted with 1,2 benzisothiazolin 3 one which evaluated both point mutations ( mouse lymphoma test), micronucleus formation, and unscheduled DNA synthesis. All acceptable studies conducted showed a negative mutagenic response for this chemical. In an unacceptable Ames test, one strain of bacteria ( TA102) had a positive mutagenic response, with mammalian metabolic activation, in 12 three separate experiments. The test was deemed unacceptable due to failure to report test material purity.

Metabolism. Metabolism studies show that 91% of the test material was excreted in the urine. Accumulation was not reported in the abdominal fat and # 0.22 ppm 1,2 benzisothiazolin 3 one was recovered from the liver tissue samples. There were no metabolites of toxicological concern.

Neurotoxicity. The ADTC concluded that there is not a concern for neurotoxicity resulting from exposure to 1,2 benzisothiazolin 3 one. The neurotoxicity observed in the rat acute oral toxicity study ( piloerection and upward curvature of the spine at 300 mg/ kg and above; decreased activity, prostration, decreased abdominal muscle tone, reduced righting reflex, and decreased rate and depth of breathing at 900 mg/ kg) and the acute dermal toxicity study ( upward curvature of the spine was observed in increased incidence, but this was absent after day 5 postdose at a dose of 2000 mg/ kg) were felt to be at exposures in excess of those expected from the use pattern of this pesticide and that such effects would not be observed at estimated exposure doses.

Table 3. Acute Toxicity of 1,2 benzisothiazolin 3 one Guideline No. Study Type MRID #( s) Results Toxicity Category 870.1100 Acute Oral 41022101; 42858101 LD50 = 670 mg/ kg ( M); 784 mg/ kg ( F) III 870.1200 Acute Dermal 41022102; 42858102 LD50 > 2000 mg/ kg III 870.1300 Acute Inhalation waiver granted 870.2400 Primary Eye Irritation 42905102 severe eye irritant I 870.2500 Primary Skin Irritation 42905101 slight irritant IV 870.2600 Dermal Sensitization 41750001; 42858103 moderate dermal sensitizer Not Applicable Table 4. Toxicity Profile of 1,2 benzisothiazolin 3 one Guideline No./ Study Type MRID No. ( year)/ Classification/ Doses Results 870.3100 90 Day oral toxicity rodents 41910401 ( 1990) satisfies guideline 0, 200, 900, 4000 ppm M: 0, 15.3, 69.0, 322 mg/ kg/ d F: 0, 17.6, 78.3, 356 mg/ kg/ d NOAEL = 15.3 ( male) and 78 mg/ kg/ day ( female) LOAEL = 69 ( male) and 356 mg/ kg/ day ( female) based on decreased body weights in both males and females and increased incidence of gross non neoplastic lesions in females. Table 4. Toxicity Profile of 1,2 benzisothiazolin 3 one Guideline No./ Study Type MRID No. ( year)/ Classification/ Doses Results 13 870.3100 90 Day oral toxicity rodents 46346201 ( 2002) satisfies guideline 0,10,30, 75 mg/ kg/ d NOAEL = 10 mg/ kg/ d LOAEL = 30 mg/ kg/ d based on gross and microscopic lesions in the stomach of both sexes 870.3150 90 Day oral toxicity in nonrodents 42205701 ( 1991) 0, 5, 20, and 50 mg/ kg/ day NOAEL = 5 mg/ kg/ day LOAEL = 20 mg/ kg/ day based on the incidence of emesis and clinical chemistry alterations.

870.3250 90 Day dermal toxicity 45184601 ( 1998) acceptable/ guideline 0, 100, 300, 1000 mg/ kg Systemic NOAEL $ 1000 mg/ kg/ day Non systemic LOAEL < 100 mg/ kg/ day based on stomach pathology, indicative of irritation.

870.3700a Prenatal developmental in rodents 43663008 ( 1994) 0, 10, 30, and 90 mg/ kg/ day 40961201/ 42858104 ( 1988/ 1993) 0, 10, 40, and 100 mg/ kg/ day Maternal NOAEL = 10 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on mortality, clinical signs of toxicity, and gross pathology findings. Developmental NOAEL = 30 mg/ kg/ day LOAEL = 90 mg/ kg/ day based on treatment related increase in litter and fetal incidence of extra sites of ossification of the skull bones and unossified sternebra.

Maternal NOAEL = 40 mg/ kg/ day LOAEL = 100 mg/ kg/ day based on decreased body weight gain and food consumption. Developmental NOAEL = 40 mg/ kg/ day LOAEL = 100 mg/ kg/ day based on decreased fetal body weight and increased incidence of delays in skeletal ossification..

870.3800 Reproductive toxicity Rodents 46097101 ( 2002) 0, 250, 500, 1000 ppm M: 24, 48, 98 mg/ kg/ day ( approximate dose) Parental NOAEL= 250 ppm Parental LOAEL = 500 ppm based on hyperplasia of the limiting ridge of the stomach Offspring NOAEL = 500 ppm Offspring LOAEL = 1000ppm based on preputial separation in F1 males and impaired growth and survival of pups in both sexes.

870.7600 Dermal Penetration Rodents 46237901 ( 1999) dermal dose : 10 mg/ kg acceptable/ non guideline Approximately 41% dermal penetration ( maximum) was reported after 72 hours Table 4. Toxicity Profile of 1,2 benzisothiazolin 3 one Guideline No./ Study Type MRID No. ( year)/ Classification/ Doses Results 14 Gene Mutation 870.5100 Microbial gene mutation assay 870.5300 In vitro mammalian cell gene mutation test 45534603 ( 1996) classification: unacceptable guideline 0.07, 0.33, 1.64, 8.2, and 41 µ g/ plate, ± S9, first test 0.07, 0.33, 1.64, 8.2, and 41 µ g/ plate  S9, and 0.41, 0.82, 4.1, 8.2, 20.5, and 57.4 µ g/ plate + S9, second test 41022103/ 42858105 ( 1988/ 1993) classification: coreacceptable 0.03 to 2.00 µ g/ mL ( S9) 1 to 64 µ g/ mL (+ S9) In strain TA102, there was evidence of a positive mutagenic response, + S9, in three separate experiments. No other strains showed evidence of positive mutagenicity in this assay.

No biologically significant increase in mutation frequency was noted at the thymidine kinase locus either with or without metabolic activation at any of the concentrations tested.

Cytogenetics 870.5393 Mouse micronucleus assay 41022104/ 42858106 ( 1988/ 1993) classification: coreacceptable 245 or 392 mg/ kg ( males), 331 or 529 mg/ kg ( females) No significant increases in the frequency of micronucleated polychromatic erythrocytes were noted in the bone marrow at any of the times tested.

Other Genotoxicity 870.870.5550 unscheduled DNA synthesis assay in primary rat hepatocytes 41022105/ 42858107 ( 1988/ 1993) classification: acceptable 10 8 to 10 5 M The test compound did not induce unscheduled DNA synthesis in primary cultures of rat hepatocytes.

870.7485 Metabolism and pharmacokinetics 45124901 ( 1972) acceptable/ guideline single 20 mg/ kg dose or 2,3, or 4 daily doses of 10 mg/ kg The results reported were based on the analysis of urine and fecal samples collected from the rats in Group 1 and abdominal fat and liver samples from the rats in Group 2. The estimated percentage of radioactivity in the excreta was reported for individual animals every 24 hours for 3 days ( feces) or 5 days ( urine). The authors report that in Group 1, 91% of the radioactivity was excreted in the urine within 5 days post exposure and 5% was excreted in the feces. In the Group 2 rats, accumulation was not reported in the abdominal fat and # 0.22 ppm BIT was recovered from the liver tissue samples. 15 4.2 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."

On August 28, 2002 the Antimicrobials Division's Toxicology Endpoint Selection Committee ( ADTC) reviewed the available toxicology data for 1,2 benzisothiazolin 3 one ( BIT) with regard to the acute and chronic Reference Doses ( RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to 1,2 benzisothiazolin 3 one was also evaluated as required by the Food Quality Protection Act ( FQPA) of 1996. On February 8, 2005, the ADTC met again to consider additional data submitted by the registrant in response to the conclusions reached from the first meeting and as discussed in the September 2002 ADTC memo. The ADTC recommended that the special hazard based FQPA safety factor of 10x be reduced to 1x. The reduction of the safety factor from 10x to 1x is based on submission of the 2 generation reproduction toxicity study which was previously cited as a data gap and the lack of evidence for susceptibility in this study. Taken together with the already reviewed developmental toxicity data that showed no evidence of susceptibility, the ADTC concluded the special FQPA hazard based factor could be reduced to 1x. Also, use of NOAEL values from the subchronic toxicity studies in the dog and rat for the dietary endpoints are protective as these values ( 5 mg/ kg/ day and 8.42 mg/ kg/ day) are lower than the NOAEL values from the developmental studies ( 10 and 40 mg/ kg/ day respectively). However a 3X database uncertainty factor was retained for use in oral exposure scenarios based on uncertainties in the existing developmental toxicity database ( specifically in the maternal toxicity) and the lack of developmental toxicity data in non rodents. 16 4.3 Dose Response Assessment The doses and toxicological endpoints selected by ADTC for various exposure scenarios are summarized in Table 5 below.

Table 5. Summary of Toxicology Endpoints Selected for 1,2 benzisothiazolin 3 one Exposure Scenario Dose Used in Risk Assessment ( mg/ kg/ day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects Acute Dietary General population, including infants and children NOAEL= 5 mg/ kg/ day UF = 100 ( 10x inter species extrapolation, 10x intra species variation) FQPA SF= 1 DB UF = 3 Acute RfD = 0.017 mg/ kg/ day Co Critical studies: Subchronic toxicity , dog , NOAEL = 5 mg/ kg/ day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day. and Subchronic toxicity , rats , NOAEL = 8.42 mg/ kg/ day based on macroscopic and microscopic lesions in the non glandular and glandular regions of the stomach.

Chronic Dietary All populations NOAEL= 5 mg/ kg/ day UF = 100 ( 10x inter species extrapolation, 10x intra species variation) FQPA SF= 1 DB UF = 3 Chronic RfD = 0.017 mg/ kg/ day Co Critical studies: Subchronic toxicity , dog , NOAEL = 5 mg/ kg/ day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day. and Subchronic toxicity , rats , NOAEL = 8.42 mg/ kg/ day based on macroscopic and microscopic lesions in the non glandular and glandular regions of the stomach.

Non Dietary Risk Assessments Incidental Oral ( short and intermediate term NOAEL= 5 mg/ kg/ day MOE = 300 ( 10x interspecies extrapolation, 10x intraspecies variation) FQPA SF= 1 DB UF= 3 Co Critical studies: Subchronic toxicity , dog , NOAEL = 5 mg/ kg/ day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day. and Subchronic toxicity , rats , NOAEL = 8.42 mg/ kg/ day based on macroscopic and microscopic lesions in the non glandular and glandular regions of the stomach. Table 5. Summary of Toxicology Endpoints Selected for 1,2 benzisothiazolin 3 one Exposure Scenario Dose Used in Risk Assessment ( mg/ kg/ day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects 17 Dermal All time periods ( occupational and residential) NOAEL= 5 mg/ kg/ day MOE = 100 ( 10x interspecies extrapolation, 10x intraspecies variation) Co Critical studies: Subchronic toxicity , dog , NOAEL = 5 mg/ kg/ day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day. and Subchronic toxicity , rats , NOAEL = 8.42 mg/ kg/ day based on macroscopic and microscopic lesions in the non glandular and glandular regions of the stomach.

Inhalation All time periods ( occupational and residential) NOAEL= 5 mg/ kg/ day MOE = 100 ( 10x inter species extrapolation, 10x intraspecies variation)

An additional 10x route toroute extrapolation is used to determine if an inhalation toxicity study is warranted. Co Critical studies: Subchronic toxicity , dog , NOAEL = 5 mg/ kg/ day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/ kg/ day. and Subchronic toxicity , rats , NOAEL = 8.42 mg/ kg/ day based on macroscopic and microscopic lesions in the non glandular and glandular regions of the stomach.

Cancer No cancer data available for 1,2 benzisothiazolin 3 one Notes: UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, DB UF = data base uncertainty factor, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, LOC = level of concern, MOE = margin of exposure 4.4 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 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). 18 When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, 1,2 benzisothiazolin 3 one may be subjected to additional screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION 5.1 Summary of Registered Uses 1,2 benzisothiazolin 3 one, a member of the Isothiazoline class, is an industrial preservative that is recommended to inhibit the control the growth of microorganisms in the preserved product. 1,2 benzisothiazolin 3 one is recommended for use as an industrial preservative for the protection of water based adhesives, caulks, sealants, grouts, spackling, ready mixed cements, ready mixed wallboard compounds, aqueous compositions such as emulsion paints, aqueous slurries, home cleaning and car care products, inks, photographic processing solutions, paints and stains, titanium dioxide slurries, oil in water emulsions, latices, metalworking fluids, casein/ rosin dispersions, textile spin finish solutions, laundry detergents, pesticide formulations, tape joint compound, leather processing solutions, preservation of fresh animal hides and skins, and for offshore and terrestrial gas/ oil drilling muds and packer fluids preservation. Furthermore, 1,2 benzisothiazolin 3 one is used as an inert ingredient in over 900 different products primarily as a materials preservative. The specific antimicrobial use categories include the following general use patterns: material preservatives ( indoor food and indoor/ outdoor non food), industrial processes and water systems ( indoor nonfood), and indoor and outdoor residential uses.

5.2 Dietary Exposure for Active Ingredient Uses The Agency has carried out the dietary exposure and risk assessment for use of 1,2 benzisothiazolin 3 one as a pulp and paper slimicide, and a preservative in paper coatings and paper adhesives, all of which may result in indirect food contact exposures. No residue chemistry data were submitted by the registrants, nor were any asked for by the Agency. The Agency has used the US FDA methodology to estimate 1,2 benzisothiazolin 3 one residues on food due to migration of this chemical from food contact paper to food ( US FDA, 2002). The FDA methodology makes the following basic assumptions to calculate the Estimated Daily Intake ( EDI):

° Food contact surface could be a one time use/ day or repeat use material/ day; ° The amount of food that comes into contact with the treated paper is based on an FDA default value; and ° All of the active material present in the paper migrates into the food.

Additionally, based on the Label 67071 24 ( Acticide BW10), the amount of 1,2 benzisothiazolin 3 one used as a slimicide and as a preservative in paper coating and paper adhesive is 5 lbs of product per 1,000 pounds of material being preserved. The concentration of 1,2 benzisothiazolin 3 one in Acticide BW10 is 10%. 19 5.2.1 Residue Profile There are no known residues of concern for 1,2 benzisothiazolin 3 one.

5.2.2 Acute Dietary The acute dietary risks for adults and children are discussed in 5.2.3.

5.2.3 Chronic Dietary The acute and chronic dietary risks for adult and children from exposure to treated paper are shown in Table 6. For adults, the cumulative acute and chronic dietary exposure is 9.4% of the acute PAD and chronic PAD. For children, the cumulative acute and chronic dietary exposure is 21.8% of the acute PAD and chronic PAD. The highest exposure is for the children.

Table 6. Summary of Dietary Exposure and Risk for 1,2 Benzisothiazolin 3 one Population Subgroup EDI (: g/ person/ day) Acute and Chronic Dietary Dietary Exposurea ( mg/ kg/ day) % aPAD and % cPAD b Slimicide Adult 14.1 0.0002 1.2 Child 7.05 0.00047 2.8 Paper Adhesive Preservative Adult 21.0 0.0003 1.8 Child 10.5 0.0007 4.1 Paper Coating Preservative Adult 75.0 0.0011 6.5 Child 37.5 0.0025 14.7 Cumulative Adult 110.1 0.0016 9.4 Child 55.1 0.0037 21.8 a For adults, acute and chronic exposure analysis is based on a body weight of 70 kg. For children, exposure is based on a body weight of 15 kg. b% PAD = dietary exposure ( mg/ kg/ day) * 100 / aPAD or cPAD, where aPAD and cPAD for adults and children = 0.017 mg/ kg/ day 20 5.2.4 Cancer Dietary There are no dietary cancer risks identified for 1,2 benzisothiazolin 3 one.

5.3 Dietary Exposure for Inert Ingredient Uses Included in this RA is the reassessment of 1,2 benzisothiazolin 3 one when used as an inert ingredient in pesticide products. 1,2 benzisothiazolin 3 one is used as a preservative/ stabilizer in a wide variety of residential use and agricultural pesticide products, including outdoor yard, garden, and turf products, and agricultural crop products. 1,2 benzisothiazolin 3 one currently has one inert ingredient exemption from the requirement of a tolerance for residues as required under the Food Quality Protection Act ( FQPA) section 408. The existing exemption is for use on growing crops under 40 CFR part 180.920. In addition, the Agency has received a petition to establish an exemption from the requirement for a tolerance for the use of 1,2 benzisothiazolin 3 one as an inert ingredient in pesticides applied to animals under 40 CFR part 180.930. The existing exemption from the requirement of a tolerance as well as the proposed exemption are summarized in Table 7.

Table 7. Tolerance Exemptions Tolerance Exemption Expression CAS Number 40 CFR § Limits Use 1,2 benzisothiazolin 3 one ( Also known as " BIT") 2634 33 5 180.9201 180.9302 Not more than 0.1% of formulation. Not more than 0.02 lbs. to be applied per acre. preservative/ stabilizer 1. Residues listed in 40 CFR § 180.920 are exempted from the requirement of a tolerance when used as inert ingredients in pesticide formulations when applied to growing crops only.

2. Residues listed in 40 CFR § 180.930 are exempted from the requirement of a tolerance when used as inert ingredients in pesticide formulations when applied to animals only.

Inert Dietary Exposure Assumptions A dietary exposure analysis for the inert ingredient use of 1,2 benzisothiazolin 3 one was conducted using the generic screening model for estimating inert ingredient dietary exposure as a basis for estimating 1,2 benzisothiazolin 3 one dietary exposure. The generic model's output was adjusted to reflect the tolerance exemption limitation given in 40 CFR § 180.920 which states that 1,2 benzisothiazolin 3 one cannot be applied at more than 0.02 lbs per acre. The generic screening model does not specifically include an application rate input, rather it is based on tolerances for pesticide active ingredients with application rates generally ranging from 1 to 5 lb 21 ai/ acre. Therefore, to more accurately estimate residues resulting from the lower application rate limitation of 0.02 lbs/ acre of 1,2 benzisothiazolin 3 one, the results from the generic model were adjusted by a factor of 50 ( using the ratio of 1 lb. per acre ÷ 0.02 lbs per acre) and 250 ( using the ratio of 5 lbs. per acre ÷ 0.02 lbs/ acre) to reflect residue levels resulting from the specified maximum application rate of 1,2 benzisothiazolin 3 one.

The dietary assessment is unrefined and extremely conservative in nature because the screening model assumes that the inert ingredient is used on all commodities, and that 100 percent of crops are treated with the inert ingredient. Further, the model assumes residues will be present for every consumed commodity ( including meat, milk, poultry and eggs) that is included in the Dietary Exposure Evaluation Model ( DEEM   ) . Additionally, in the case of 1,2 benzisothiazolin 3 one, the choice of an adjustment factor based on maximum application rate is conservative in nature, because the use of an adjustment factor based on concentration in formulation results in exposures less than half of the lowest values for the U. S. population and all population subgroups reported in Tables 8 and 9.

Inert Dietary Risk from Food The tables below provide a summary of the results of the acute and chronic dietary risk estimates for 1,2 benzisothiazolin 3 one. Only one population subgroup had an estimated exposure over 100 % of either PADs at the 95th percentile of exposure   " Children ( 1 2 years)" had 112% of the aPAD but this was only at the high end of exposure. Considering the unrefined and extremely conservative nature of this screening level model ( e. g., inclusion of all commodities; 100% of commodities are treated; adjustment factor for application rate), the results for all population subgroups are considered not to be of concern.

It should be noted that while the results from the screening level model do not raise a dietary concern, the modeling results would be even lower if an alternate adjustment factor had been used. As described in the " Exposure Assumptions" section above, 1,2 benzisothiazolin 3 one's maximum application rate of 0.02 lbs/ acre was adjusted by 50 and 250 in the generic model. Instead of adjusting for application rate, the model could have been adjusted for the concentration of 1,2 benzisothiazolin 3 one in the pesticide formulation, which is limited to a maximum of 0.1% under 40 CFR § 180.920 ( the proposed tolerance exemption for use on animals under 180.930 has the same limitation). Adjusting the model for the concentration in the formulation would mean using a factor of 500.

The adjustment factor using formulation concentration is 500, which is calculated using 1,2 benzisothiazolin 3 one's maximum concentration ( 0.1%) and a value used in the screen level model of 50%, which represents a group of active ingredients that are typically found in agricultural food use products at concentrations > 50%. Using the adjustment factor of 500 ( 50% ÷ 0.1%) to account for the effect of the limitation of 0.1% of 1,2 benzisothiazolin 3 one in pesticide formulations on residue levels would certainly lower the model results even further that what are presented in the Tables 8 and 9, below. 22 This dietary assessment includes the existing use of 1,2 benzisothiazolin 3 one as a pesticide inert ingredient used on growing crops under 40 CFR part 180.920. In addition, the Agency has received a petition to establish an exemption from the requirement for a tolerance for the use of 1,2 benzisothiazolin 3 one as an inert ingredient in pesticides applied to animals under 40 CFR part 180.930 with the same limitations as currently exist under 180.920. This dietary assessment also includes animals as a commodity. Therefore, the results of this assessment cover all existing and currently proposed inert ingredient uses of 1,2 benzisothiazolin 3 one. Dietary exposures of concern from food are not likely from the use of 1,2 benzisothiazolin 3 one as inert ingredients in pesticide products.

Table 8. Estimated Acute Dietary ( Food) Risk Estimates for 1,2 benzisothiazolin 3 one Population Subgroup 95th Percentile of Exposure BIT Estimated Exposure, mg/ kg/ day % aPAD1/

U. S. Population ( total) 0.0013  0.007 8%  40%

All infants (< 1 year) 0.0028  0.014 17%  84%

Children ( 1 2 years) 0.0038  0.019 22%  112%

Children ( 3 5 years) 0.0027  0.014 16%  82%

Children ( 6 12 years) 0.0016  0.008 9%  47%

Youth ( 13 19 years) 0.0010  0.005 6%  29%

Adults ( 20 49 years) 0.00080  0.004 5%  24%

Adults ( 50+ years) 0.00076  0.004 5%  23%

Females ( 13 49 years) 0.00079  0.004 5%  24%

1/ aPAD= 0.017 mg/ kg/ day 23 Table 9. Chronic Dietary ( Food) Risk Estimates for 1,2 benzisothiazolin 3 one Population Subgroup BIT Estimated Exposure, mg/ kg/ day % cPAD2/

U. S. Population ( total) 0.00048  0.0024 3%  14%

All infants (< 1 year) 0.0010  0.0049 6%  29%

Children ( 1 2 years) 0.0017  0.0084 10%  51%

Children ( 3 5 years) 0.0012  0.0062 7%  37%

Children ( 6 12 years) 0.00070  0.0035 4%  21%

Youth ( 13 19 years) 0.00040  0.0020 2%  12%

Adults ( 20 49 years) 0.00035  0.0017 2%  10%

Adults ( 50+ years) 0.00034  0.0017 2%  10%

Females ( 13 49 years) 0.00035  0.0017 2%  10%

2/ cPAD= 0.017 mg/ kg/ day 5.4 Drinking Water Exposures and Risks Based on environmental fate data, 1,2 benzisothiazolin 3 one binds moderately with soil and may potentially move with the soil during rainfall events and reach surface waters. Although, 1,2 benzisothiazolin 3 one has been shown to be hydrolytically stable with a half life of > 30 days, it breaks down fairly quickly in aerobic soils. Outdoor use patterns of 1,2 benzisothiazolin 3 one which may lead to contact with soil and/ or surface water include: 1) the application of agricultural pesticides that contain 1,2 benzisothiazolin 3 one as an inert ingredient, and 2) the application of paints that contain 1,2 benzisothiazolin 3 one. Considering 1,2 benzisothiazolin 3 one's ready biodegradation and the small amount of ( 0.02 lbs. per acre) that may be applied to crops via the inert use and the small amount likely to come into contact with soils/ surface waters via the paint use, 1,2 benzisothiazolin 3 one is not likely to be present in food or drinking water sources at substantial concentrations. Therefore a quantitative drinking water assessment was not conducted. 24 5.5 Residential Exposures and Risks for Active Ingredient Uses A detailed human exposure risk assessment for 1,2 benzisothiazolin 3 one is provided in the attached Appendix. The summary of the exposures and risks to the residential population are presented below.

5.5.1 Residential Handler Scenarios 1,2 benzisothiazolin 3 one may be added to residential use products used to control bacteria and fungi, including as a preservative for paint ( e. g., EPA Reg. No. 72674 15) and household cleaning products. The residential handler scenarios evaluated including handling BITcontaining paint through brush/ roller and airless spray application methods and handling BITcontaining cleaning products through low pressure spray, wiping, and mopping application methods. Where the data were available, residential assessment assumed that the handlers would be wearing short pants and short sleeved shirts. For example, the data available in the Pesticide Handlers Exposure Database ( PHED) provides unit exposures for both a short pant/ sleeve scenario as well as a long pant/ sleeve scenario ( explaining the difference between the residential unit exposures and the occupational unit exposures for painters).

<IP_ADDRESS> Paint Exposures and Risks There are no chemical specific exposure data to assess paint applications. Therefore, dermal and inhalation exposures were assessed for brush and airless sprayer applications using surrogate data. Specifically, PHED Version 1.1 values found in the Residential Exposure SOPs ( U. S. EPA, 1997a) were used ( short pants, short sleeved shirts). 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. In addition, product label maximum application rates, related use information, and Agency standard values were used to assess residential handler exposures. Specifically, it was assumed that residential handlers will use 2 gallon/ day ( 20 lbs/ day) of paint for brush applications and 15 gallons/ day ( 150 lbs/ day) of paint for airless sprayer applications. Additionally, based on the label for EPA Registration No. 67071 24, 5 lbs of the formulated material preservative ( 10% a. i.) are used per 1,000 lb of paint. Therefore, the use amount for paint brush applications is 0.01 lb ai/ day ( 20 lbs paint/ day x ( 5 lb product/ 1000 lb paint) x 10% ai) and the use amount for airless sprayer applications is 0.075 lb ai/ day ( 150 lbs paint/ day x ( 5 lb product/ 1000 lb paint) x 10% ai). All homeowner painting scenarios are believed to be best represented by the short term exposure duration.

The non cancer risk estimates are expressed in terms of margin of exposure ( MOE). MOEs greater than 100 for inhalation and dermal exposures do not exceed the Agency's level of concern for residents ( i. e., " target" MOEs). For the paint scenarios, the short term dermal MOE for the paint brush/ roller use is 370 and for the airless sprayer 140. Thus, the dermal MOEs are not of concern for painting. The short term inhalation MOE is 130,000 and 5,600 for the brush/ roller and airless sprayer, respectively. Therefore, the inhalation exposure indicates that the 25 risks do not exceed the Agency's level of concern. The total risk ( inhalation + dermal) is also presented because both toxicological endpoints are from the same study ( and same toxicological effect). The total MOEs for the brush/ roller and airless sprayer are 370 and 140, respectively. The dose and MOEs are summarized in Table 10.

<IP_ADDRESS> Cleaning Product Exposures and Risks The following two scenarios were considered for residential handlers of BIT containing cleaning products:

° Use of cleaner as a wipe on hard non porous surfaces, and ° Use of cleaner for mopping hard non porous surfaces such as floors.

These potential exposures from a general purpose cleaner are expected to be best represented by the short term duration. The short term dermal and inhalation exposures were assessed for wipe and mopping application methods using surrogate data. Specifically, values from the Chemical Manufacturers Association ( CMA) antimicrobial study ( U. S. EPA, 1999) were used. 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. In addition, product label maximum application rates, related use information, and Agency standard values were used to assess residential handler exposures. Specifically, it was assumed that residential handlers will use 0.5 liters of cleaning solution wiping and 1 gallon of cleaning solution for mopping. Additionally, based on the label for EPA Registration No. 67071 22, it is assumed that 0.000033 lb ai are used for wiping ( i. e., 0.13 gal solution x 8.3 lb/ gal density x 0.15 lb/ 1000 lb cleaning solution x 20% ai = 0.000033 lb ai). The amount of 1,2 benzisothiazolin 3 one used for mopping is assumed to be 0.00025 lb ai ( i. e., 8.3 lb cleaning solution/ gal x 0.15 lb/ 1000 lb cleaning solution x 20% ai).

The results of the short term risk assessment for cleaning products are presented in Table 10. Using the assumptions discussed above, the calculated short term dermal MOEs are 9,000 and 48,000 for the wipe and mop scenarios, respectively. The short term inhalation MOEs are 160,000 ( wipe) and 590,000 ( mop). The total risks ( inhalation + dermal) are represented by the total MOE of 8,500 and 44,000 for wiping and mopping, respectively. Therefore, for the cleaning solutions containing 1,2 benzisothiazolin 3 one, the risks do not exceed the Agency's level of concern. 26 Table 10. Estimates of Short term Exposures and Risks to Residential Handlers of 1,2 benzisothiazolin 3 one Product Scenario Absorbed Dermal Dosea ( mg/ kg/ day) Inhalation Dosea ( mg/ kg/ day) Dermal MOEb ( Target MOE= 100) Inhalation MOEc ( Target MOE = 100) Total MOEd ( Target MOE = 100)

Paint Paint brush/ roller 0.013 4E 05 370 130,000 370 Airless sprayer 0.035 0.00089 140 5,600 140 Cleaning Wiping 0.00055 3.2E 05 9,000 160,000 8,500 Mopping 0.00010 8.5E 06 48,000 590,000 44,000 a Inhalation/ Absorbed Dermal Dose ( mg/ kg/ day) = ( Application Rate ( lb ai) * Inhalation/ Dermal Unit Exposure ( mg/ lb ai) )/ Body Weight ( 70 kg), where dermal absorption is 41 percent. b Dermal MOE= Dermal NOAEL ( 5 mg/ kg/ day)/ Absorbed Dermal Dose ( mg/ kg/ day). c Inhalation MOE= Inhalation NOAEL ( 5 mg/ kg/ day)/ Inhalation Dose ( mg/ kg/ day). d Total MOE = NOAEL 5 mg/ kg/ day / ( abs dermal dose mg/ kg/ day + inhalation dose).

5.5.2 Residential Post application Exposure Postapplication exposures refer to those potential exposures which may occur to handlers while involved in postapplication or reentry activities following application of the pesticide concentrate or formulated end use product. Postapplication exposures to individuals can also occur from contact to treated surfaces and while occupying areas where pesticide end use products have recently been applied. The residential post application scenarios considered in this assessment are exposure to residues from hard surfaces ( i. e., floors) that have been mopped with a product containing 1,2 benzisothiazolin 3 one and the use of laundry detergents containing 1,2 benzisothiazolin 3 one where residues could remain on clothing articles after laundering. Although residential floors are believed to be washed/ mopped on an intermittent basis ( perhaps weekly), facilities such as day care centers may clean the floors more often. Therefore, both the short and intermediate term exposure durations have been presented ( for 1,2 benzisothiazolin 3 one, the dermal and incidental oral endpoints and uncertainty factors are the same values for short and intermediate term durations).

Floor Cleaner Dermal Exposure:

There is the potential for dermal exposure to toddlers crawling on the floor. To determine toddler exposure to residues on treated floor, the following equation was used:

PDD FR x SA BW =

where 27 PDD = Potential daily dose FR = Flux rate of chemical from material ( mg/ m2/ day) SA = Surface area of the body which is in contact with floor ( m2) BW = Body weight ( kg)

The following conservative assumptions were made in calculating the exposures/ risks due to limited data:

° Toddlers ( 3 years old) are used to represent the 1 to 6 year old age group and are assumed to weigh 15 kg, the median for male and female toddlers ( USEPA, 2000b). A body surface area of 0.657 m2 has been assumed, which is the median value. ° Based on EPA Reg 67071 22 label, 0.15 lb of preservative that contains 20% 1,2 benzisothiazolin 3 one is added to 1000 lb of cleaner ( weight fraction = 0.15 lb product x 0.2 ai/ 1000 lb cleaner = 0.00003 or 0.003 percent). It was assumed that the density of the cleaner is 8.3 lbs/ gal. Therefore, the use amount for the application of treated cleaning products is 0.00025 lb ai/ gallon ( weight fraction 0.00003 x 8.3 lb/ gal density). It was assumed that the resulting solution is applied at a rate of 1 gallon per 1000 sq. ft. ° No data could be found regarding the quantity of solution residue left on the floor after treatment. It has been assumed that 25% of the cleaner remains after the final mopping. ° No transferable residue data were available that could be used to estimate the skin transfer of 1,2 benzisothiazolin 3 one from the floor. Therefore, Residential SOPs estimate of 10% of the amount on the hard surface is available for dermal transfer.

The calculations of the absorbed dermal dose and the dermal MOE are presented in Table 11. The dermal MOE is estimated to be 9,200 which is above the target MOE of 100, and therefore not of concern.

Table 11. Short and Intermediate term Risks Associated with Postapplication Dermal Exposure on Treated Floors.

Parameter Value Rationale Application Rate 1000 ft2/ gallon of solution USEPA Assumption Cleaning Solution 0.00025 lb ai/ gallon Maximum rate listed on label ( EPA Reg. No. 67071 22)

Transferable Residues ( TR) 0.030 mg/ m2/ day (( 0.00025 lb ai/ gal)/( 1000ft2/ gal)) * ( 25% remaining)* ( 10% transfer) * ( Conversion Factors)

Surface Area of Body in Contact with Hard Surfaces ( floors) 0.657 m2 Median surface area of toddler Body Weight 15 kg Median body weight of toddler Table 11. Short and Intermediate term Risks Associated with Postapplication Dermal Exposure on Treated Floors.

Parameter Value Rationale 28 Absorbed Dermal Dose 0.00055 mg/ kg/ day TR * SA* 41% dermal Abs/ BW Dermal NOAEL 5 mg/ kg/ day Dermal MOE 9,200 ( Dermal NOAEL) / ( Daily Dermal Dose). Target MOE = 100.

TR = [(( 0.00025 lb ai/ gal / 1000ft2/ gal) x ( 454 g/ lb) x ( 1000 mg/ g) x ( 1 ft2 / 0.093 m2)) x ( 0.25 remaining) x ( 0.1 transferable)]

Incidental Ingestion:

In addition to dermal exposure, infants crawling on treated floors will also be exposed to 1,2 benzisothiazolin 3 one via incidental oral exposure. To calculate incidental ingestion exposure to 1,2 benzisothiazolin 3 one due to hand to mouth transfer, the scenarios established in the Standard Operating Procedures ( SOPs) for Residential Exposure Assessments were used. These scenarios use assumptions that are similar to those used in calculating exposures due to dermal contact of 1,2 benzisothiazolin 3 one from toddlers crawling on treated floors. The assumptions above in the dermal assessment ( Table 11) estimates the transferable residues as 0.0030 : g/ cm2 ( equivalent to 0.030 mg/ m2). The estimated potential ingestion dose rate immediately after application would be calculated as follows:

PDR norm = ISR t x SA x FQ x SE x ET x 0.001 mg/: g BW where: PDR norm = Potential dose rate ( mg/ kg/ day); ISR t = Indoor Surface Residue (: g/ cm2) at time 0; SA = Surface area of the hands that contact both the treated area, and the individuals mouth ( cm2/ event); FQ = Frequency of hand to mouth events ( events/ hr); SE = Saliva extraction efficiency of 50%; ET = Exposure Time ( 4 hrs/ day); and BW = Body weight ( 15 kg)

Based on the data provided in EPA's Residential SOPs, the surface area used for each hand to mouth event is 20 cm2. It is assumed that there are 20 hand to mouth exposure events per hour ( 90th percentile) for short term exposure duration and 9.5 events per hour ( mean) for the intermediate term duration. The short and intermediate term incidental oral NOAEL of 5 mg/ kg/ day ( target MOE = 300) should be used as the toxicity endpoint for this scenario because of the intermittent nature of cleaning the floor. The potential dose rate ( PDR) using this equation is 0.00016 mg/ kg/ day for short term and 7.7E 5 mg/ kg/ day for the intermediate term duration resulting in a hand to mouth MOEs for toddlers of 31,000 ( ST) and 65,000 ( IT). The incidental 29 oral exposure is not of concern ( i. e., above the target MOE of 300).

The ARI methodology is used to determine the total risk from children playing on BITtreated floors ( i. e., incidental oral + dermal exposure). The short term dermal MOE reported above is 9,100 ( target MOE is 100) and the short term incidental oral MOE is 31,000 ( target MOE is 300). The ARI is 48, and therefore, not of concern [ ARI = 1/(( target dermal MOE/ dermal MOE) + ( target oral MOE/ oral MOE))]. Note: the intermediate term MOE is greater than the short term MOE because of the frequency of hand to mouth activities is less over time ( 90th percentile used for short term and mean used to represent intermediate term) but the toxicological endpoints are the same for both time periods.

Clothing/ Textile BIT labels also include a microbiocide use in laundry detergents, fabric softeners, and stain removers ( EPA Reg. No. 67071 23). To determine dermal and incidental oral exposure to treated clothing, the guidance provided in Human and Environmental Risk Assessment ( HERA) Guidance Document ( 2003) was used for indirect skin contact from wearing clothes and oral exposure from mouthing or sucking on treated fabric. HERA ( 2003) provides the following basic equations.

Dermal Exposure Dermal Exposure ( mg/ kg/ day) = [(( M x F1 x FD)/ WI) x F1 x S der x F2 x F3 x F4]/ BW where M = amount of undiluted product used ( e. g., laundry detergent), 150,000 mg ( HERA 2003) F1 = water mass left after spin cycle ( kg) / total water mass initially present ( kg), FD = fabric density for mixed cotton and synthetics ( 10 mg/ cm2) ( HERA 2003), WI = total weight of fabric estimate ( 1E+ 6 mg) ( HERA 2003), F1 = weight fraction of ai applied ( EPA Reg 67071 23, 0.15% product by weight x 20% ai = 0.03% or 0.0003), Sder = Surface area of the body which is in contact with clothing ( 5670 cm2 child and 16,900 cm2 adult), F2 = weight fraction transferred from clothing to skin ( 0.01 or 1%) ( HERA 2003), F3 = weight fraction remaining on skin ( 1 or 100%) ( HERA 2003),

F4 = dermal absorption of BIT ( 0.41 or 41%), and BW = Body weight ( kg)

Ingestion/ Mouthing Oral Exposure ( mg/ kg/ day) = [(( M x F1 x FD)/ WI) x F1 x Fm x SE]/ BW where M = amount of undiluted product used ( e. g., laundry detergent), 150,000 mg ( HERA 2003) F1 = water mass left after spin cycle ( kg) / total water mass initially present ( kg), FD = fabric density for mixed cotton and synthetics ( 10 mg/ cm2) ( HERA 2003), WI = total weight of fabric estimate ( 1E+ 6 mg) ( HERA 2003), F1 = weight fraction of ai applied ( EPA Reg 67071 23, 0.15% product by weight x 20% ai = 30 0.03% or 0.0003), Fm = fabric area mouthed ( 100 cm2) ( HERA 2003), SE = saliva extraction efficiency ( 1 or 100%) ( HERA 2003), and BW = Body weight ( 15 kg)

Data on which these calculations could be based were generally unavailable; therefore, a number of conservative assumptions have been made:

( 1) Toddlers ( 3 years old) are used to represent the 1 to 6 year old age group and are assumed to weigh 15 kg, the median for male and female toddlers ( USEPA, 2000b). The median surface area for a 3 year old, minus the head, is 0.567 m2. Median values for body weights and surface areas for adults have been used ( 70 kg and 1.69 m2, not including head surface area). ( 2) No leaching data were available that could be used to estimate a dermal flux rate of the chemical from clothing. Therefore, HERA's assumption of 1% transfer was used. ( 3) No dissipation data were available, therefore, the amount of BIT remaining on the skin is assumed to be 100 percent. ( 4) No information is available to estimate the amount of product remaining after a wash rinse cycle. The HERC document provides an estimate for this variable as " the water mass left after spin cycle ( kg) / total water mass initially present ( kg)". This variable could be estimated using default assumptions if risks were identified in the future. However, at this time, F1 is assumed to be = 1, when in reality a value closer to 0.01 is more probable. Moreover, the registrant indicated in the public comments that "... washing is normally carried out at high pH, around 10, rinsing is usually pH 7 and softening at the end of the wash may be slightly acidic, pH 6   7. Under all these pH conditions, BIT will not have a positive charge. All of the common fibers used for clothing have either a negative charge, or are not charged. These fibers will have no ionic attraction for BIT. There will not be any significant hydrogen bonding and BIT does not have the extended planar aromatic structure required by dyestuffs for substantivity to cotton ( usually 3 or more aromatic rings) thus BIT will not be able to " dye" the anionic or neutral fibers. Under laundry conditions, BIT will not adsorb onto any of these fibres. From the above, BIT remains in the wash water and the vast majority is discharged to drain after draining/ spinning. Only a small amount of BIT will be present in the residual entrained wash water and this will be readily removed in any rinse cycle. Since all textile washing incorporates some element of rinsing, it is likely that the potential for deposited residues of BIT on textiles is very low." Therefore, the estimates provided below are considered to be screening level and an overestimate of the true risks.

The calculation of the short and intermediate term oral and dermal doses and MOEs are presented in Table 12. The incidental oral MOE as a result of mouthing treated fabric is 1,700 and is not of concern. The dermal MOEs calculated for both toddler and adult scenarios are also not of concern ( MOEs = 7,200 and 11,000 for toddlers and adults, respectively).

The ARI methodology is used to determine the total risk to children wearing clothing 31 treated with BIT ( i. e., incidental oral + dermal exposure). The ARI is 5.2, and therefore, not of concern [ i. e., 1/(( target dermal MOE/ dermal MOE) + ( target oral MOE/ oral MOE)), ARI greater than 1 is not of concern].

Table 12. Short and Intermediate term Risks Associated with Postapplication Exposure to Laundered Clothing Parameter 3 yr old Toddler Adult Rationale Body Weight 15 kg 70 kg Median body weight Surface area, minus head 5,670 cm2 16,900 cm2 Median surface area Surface area of cloth mouthed 100 cm2 NA HERA 2003 Concentration on clothing 4.5E 4 mg/ cm2 ( 150,000 mg product x 0.03% ai x 10 mg/ cm2 cloth density)/ 1E+ 6 mg weight of fabric. EPA Reg. No. 67071 23. Note: Some fraction of the chemical is lost due to the rinse cycle in the wash but there are no data at this time to estimate the amount.

Daily Dermal Dose 0.00070 mg/ kg/ day 0.00045 mg/ kg/ day ( concentration on clothing mg/ cm2 x surface area cm2 x transfer efficiency 1% to skin and 100% to mouth) * ( 41% dermal absorption or 100% oral absorption) / Body Weight Incidental Oral Ingestion ( mouthing) 0.003 mg/ kg/ day NA ( Qty. a. i.) / ( Body Weight)

Dermal NOAEL 5 mg/ kg/ day Oral endpoint selected Oral NOAEL 5 mg/ kg/ day Oral endpoint selected Dermal MOE 7,200 11,000 ( NOAEL) / ( Dose). Target MOE = 100.

Incidental Oral MOE ( mouthing) 1,700 NA ( NOAEL) / ( Dose). Target MOE = 300.

5.6 Residential Exposures and Risks from Inert Ingredient Uses 1,2 benzisothiazolin 3 one is an inert ingredient in over 900 different products and is used primarily as a materials preservative. The types of products that contain 1,2 benzisothiazolin 3 one as an inert ingredient include turf insecticides, fungicides and herbicides; garden and ornamental insecticides; flea and tick control products for pets; indoor crack and crevice insecticides; paints; and household cleaners. Since 1,2 benzisothiazolin 3 one is also used as an active ingredient in paints and household cleaners at a higher percent formulation 32 than the inert, the inert exposure assessment did not include an analysis of the paint and cleaning products. The residential exposure assessment ( section 4.3) addresses these exposures and shows that the MOEs are above the Agency's level of concern. Furthermore, the inert assessment did not specifically evaluate indoor crack and crevice uses since it was anticipated the applicator exposures resulting from the outdoor lawn products ( where 1,2 benzisothiazolin 3 one is an inert ingredient) would result in higher exposures based on the amount used per day. Additionally, it was anticipated the post application exposures resulting from the use of indoor residential cleaners ( where 1,2 benzisothiazolin 3 one is an active ingredient) would result in higher exposures when considering the fact that exposure to residues from a floor cleaner are much more accessible than residues applied in cracks/ crevices and along baseboards. An inert exposure assessment was conducted for several representative residential products such as various formulations of turf and garden products as well as, flea and tick pet spray products.

U. S. EPA's Pesticide Inert Risk Assessment Tool ( PiRat) was used to estimate applicator and post application exposure and risk from the use of 1,2 benzisothiazolin 3 one as an inert ingredient in representative residential products. Background information and the downloadable executable file for PiRat can be found at http:// www. epa. gov/ opptintr/ exposure/ docs/ pirat. htm. All of PiRat's default values were used in each run. The percent formulation of 0.1% was used in all of the model simulations. This value was based on the tolerance exemption limitation as specified in 40 CFR 180.920 and a review of several Confidential Statement of Formula ( CSFs) for various types of products. As previously discussed, since 1,2 benzisothiazolin 3 one is used in numerous types of products, only exposures from representative high end scenarios were estimated using PiRat. These scenarios include applicator dermal exposures to RTU, EC, and granular turf products and toddler dermal and incidental ingestion exposures to liquid turf products. Again, it is expected that the indoor crack and crevice applicator exposure scenarios would result in lower exposures and higher MOEs. The applicator exposures and risks are presented in Table 13 while the post application exposures and risks are presented in Table 14.

Table 13. Applicator Short term Exposures and MOEs for 1,2 benzisothiazolin 3 one used as an Inert Ingredient in Outdoor Products Product Use Application Method Dermal Exposure mg/ kg/ day Inhalation Exposure mg/ kg/ day Dermal MOE1 Inhalation MOE1 Total MOE2 Emulsifiable Concentrate Turf3 hose end sprayer; MLAP 5.27 x 10 4 4.07 x 10 7 9,500 12,000,000 9,500 Granular Turf3 push type spreader; LA 5.27 x 10 5 2.70 x 10 7 95,000 19,000,000 94,000 Ready to Use Liquid Turf spot/ gardens pump trigger; APP 1.03 x 10 2 2.74 x 10 4 490 18,000 470 1 MOEs = NOAEL / exposure where dermal and inhalation NOAELs = 5.0 mg/ kg/ day. Target MOEs $ 100 33 2 Total MOEs were estimated since dermal and inhalation toxicological effects are the same. Total MOE = 1 / [( 1/ MOEdermal) + ( 1/ MOEinhalation)] 3 an application rate of 0.00015 lb product/ ft2 was assumed for all scenarios Table 14. Toddler Short term Post Application Exposures and MOEs for 1,2 benzisothiazolin 3 one used as an inert in outdoor products Product Use Route of Exposure Exposure mg/ kg/ day MOE Emulsifiable Concentrate Turf Dermal 7.00 x 10 3 710 Emulsifiable Concentrate Turf Incidental ingestion: hand to mouth 9.81 x 10 5 51,000 ARI 6.9 1 MOEs = NOAEL / exposure where dermal and inhalation NOAELs = 5.0 mg/ kg/ day. Target Dermal MOE $ 100 and Target Oral MOE $ 300 2 Aggregate Risk Index ( ARI) was estimated since dermal and oral toxicological effects are the same but the target MOEs are different. Note: ARI $ 1 are not of concern. ARI = 1 / [( Target MOEdermal/ MOEdermal) + ( Target MOEoral/ MOEoral)]

1,2 benzisothiazolin 3 one is also used in several pet flea and tick products. Therefore, applicator dermal and inhalation exposures as well as toddler incidental oral and dermal postapplication exposures were evaluated. Although PiRat has a module that can estimate exposures to pet products, it was not used since HED's screening level methodologies have changed since the development of PiRat. Therefore, the most recent methodologies were utilized to assess exposure to 1,2 benzisothiazolin 3 one used as an inert ingredient in pet products.

The following equation and assumptions were used to estimate dermal and inhalation residential applicator exposures to pet product residues:

Exposure = UE x AR x N / BW where, AR = Application rate ( lb ai/ can) UE = Unit exposure ( mg/ lb ai) N = Number of cans ( cans/ day) BW = Body weight ( kg)

All of the input parameters are defaults provided in HEDs Residential SOPs ( US EPA, 1997 and 2001). The percent formulation of 0.1% used in this assessment was based on the tolerance exemption limitation as specified in 40 CFR 180.920 and a review of several Confidential Statements of Formula ( CSFs) for the various types of products. Table 15 provides the input parameters and resulting exposures and MOEs. 34 Table 15. Applicator Short term Exposures and MOEs for 1,2 benzisothiazolin 3 one used as an Inert Ingredient in Aerosol Pet Flea and Tick Products Exposure = UE x AR x N / BW Dermal Inhalation Unit Exposure ( mg / lb ai) 1 UE 220 2.4 Application Rate ( lb ai/ can) 2 AR 0.0004 0.0004 Number of cans/ day 1 N 0.5 0.5 Percent Absorption 41% 100% Body weight ( kg) 1 BW 70 70 Daily Dose ( mg/ kg/ day) 2.52E 04 6.70E 06 Oral NOAEL ( mg/ kg/ day) 5 5 Target MOE 100 100 MOE3 20,000 750,000 Total MOE4 19,000 1 US EPA, 1997 and 2001 ( HED's Residential SOPs) 2 6 oz/ can x 0.1% ai x 1gal/ 128oz x 8.34lb/ gal ( assuming density of water) 3 MOEs = NOAEL / exposure 4 Total MOEs were estimated since dermal and inhalation toxicological effects are the same. Total MOE = 1 / [( 1/ MOEdermal) + ( 1/ MOEinhalation)]

The following equation and assumptions were used to estimate toddler dermal residential post application exposure to pet product residues:

Exposure = AR x T x SA x DA / BW where,

AR = Application rate ( mg/ cm2 animal) T = Transfer fraction from treated pet (%) SA = Surface area of a child hug ( cm2/ day) DA = Dermal absorption (%) BW = Body weight ( kg)

All of the input parameters are defaults provided in HEDs Residential SOPs ( US EPA, 1997 and 2001). The percent formulations of 0.033% and 0.1% were used in this assessment. Table 16 provides the input parameters and resulting exposures and MOEs.

Table 16. Toddler Short term Post application Dermal Exposure and MOE for 1,2 benzisothiazolin 3 one used as an Inert Ingredient in Aerosol Pet Flea and Tick Products 35 Exposure = AR x T x SA x DA / BW 0.1% formulation 0.033% formulation Application Rate ( mg/ cm2 of animal) 1 AR 0.015 0.005 Transferable Fraction2 T 20% 20% Surface area of a child hug ( cm2) 2 SA 1,875 1,875 Dermal Absorption DA 41% 41% Body weight ( kg) 2 BW 15 15 Daily Dose ( mg/ kg/ day) 0.15 0.05 Oral NOAEL ( mg/ kg/ day) 5 5 Target MOE 100 100 MOE3 33 100 1 3 oz x % formulation / 6000cm2 x 1gal/ 128oz x 8.34lb/ gal x 1kg/ 2.2lb x 1000g/ kg x 1000mg/ g where it was assumed that ½ of 6 oz spray container is applied to a 30 lb animal having a surface area of 6000cm2 2 US EPA, 1997 and 2001 ( HED's Residential SOPs) 3 MOE = NOAEL / exposure The following equation and assumptions were used to estimate toddler incidental oral residential post application exposure to pet product residues:

Exposure = AR x T x SA x SE x FQ / BW where, AR = Application rate ( mg/ cm2 animal) T = Transfer fraction from treated pet (%) SA = Surface area of a child's hands ( cm2/ event) SE = Saliva extraction (%) FQ = Frequency of contact ( event/ day) BW = Body weight ( kg)

All of the input parameters are defaults provided in HEDs Residential SOPs ( US EPA, 1997 and 2001). The percent formulation of 0.1% was used in this assessment. Table 17 provides the input parameters and resulting exposures and MOEs.

Table 17. Toddler Short term Post application Incidental Oral Exposure and MOE for 1,2 benzisothiazolin 3 one used as an Inert Ingredient in Aerosol Flea and Tick Pet Products Exposure = AR x T x SA x SE x FQ / BW 36 Application Rate ( mg/ cm2 of animal) 1 AR 0.015 Transferable Fraction2 T 20% Surface area of a child's hand ( cm2) 2 SA 20 Dermal Absorption SE 50% Frequency ( events/ day) 3 FQ 1 Body weight ( kg) 2 BW 15 Daily Dose ( mg/ kg/ day) 0.0020 Oral NOAEL ( mg/ kg/ day) 5 Target MOE 300 MOE4 2,500 1 3 oz x 0.1% ai/ 6000cm2 x 1gal/ 128oz x 8.34lb/ gal x 1kg/ 2.2lb x 1000g/ kg x 1000mg/ g where it was assumed that ½ of 6 oz spray container is applied to a 30 lb animal having a surface area of 6000cm2 2 US EPA, 1997 and 2001 ( HED's Residential SOPs) 3 frequency was modified to reflect transferable residue assumptions which is based on a 5 minute heavy rubbing/ petting technique that would lead to significantly higher hand concentrations than would result from a single contact 4 MOE = NOAEL / exposure Because the dermal and oral toxicological effects are the same but the target MOEs differ, an aggregate risk index ( ARI) is assessed for the total toddler exposure to the pet product residues. The resulting total risk ( ARI) for toddlers exposed to 1,2 benzisothiazolin 3 one residues in pet products are of concern at the 0.1% formulation ( 1/(( 100/ 33) + ( 300/ 2500)) = ARI = 32). Reducing the formulation to 0.033%, the ARI is 0.89 ( note: at 0.03% the ARI is 0.97). It should be noted that these exposures are based on very conservative models and default input parameters. The " transferable fraction" parameter is a value that could be further refined with chemical specific data. However at this time, the percent transfer factor from pet fur to skin is considered a data gap and is necessary to appropriately refine this dermal exposure.

The results from the exposure and risk assessment for 1,2 benzisothiazolin 3 one used as an inert ingredient in other residential products ( i. e., turf, garden, indoor crack and crevice, paint, and cleaning products) show that all of the individual MOEs, total MOEs and ARIs are above the Agency's level of concern.

6.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS 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 1,2 benzisothiazolin 3 one 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 37 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.

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 6.1 Acute and Chronic Aggregate Risks The acute and chronic aggregate risk assessments generally include only dietary and drinking water exposures. Drinking water exposure is not expected from any of the indoor or outdoor uses of 1,2 benzisothiazolin 3 one used as either an inert or active ingredient. Cumulative acute and chronic dietary risk estimates from indirect food uses ( i. e., use in foodcontact packaging) were calculated and presented in Section 5.2, while the dietary exposures from the inert uses were presented in Section 5.3. Table 18 presents a summary of these exposures, as well as the aggregate risks. The acute and chronic aggregate risk estimates associated with 1,2 benzisothiazolin 3 one are well below the Agency's level of concern. It should be noted that the acute and chronic dietary exposures from the inert uses were selected from the low range values as presented in Tables 8 and 9. It is reasonable to use the low range values in the aggregate assessment given number of conservative assumptions that were the basis for the inert dietary assessment.

Table 18. Acute and Chronic Aggregate Dietary Exposures and Risks Acute Chronic Dietary Exposure Dietary Exposure ( mg/ kg/ day) ( mg/ kg/ day) 38 Active Inert Aggregate Active Inert Aggregate Adults 1.6E 03 1.3E 03 2.9E 03 1.6E 03 4.8E 04 2.1E 03 Children 3.7E 03 3.8E 03 7.5E 03 3.7E 03 1.7E 03 5.4E 03 Adults % a or cPAD 9.4% 7.6% 17.1% 9.4% 2.8% 12.2% Children % a or cPAD 21.1% 22.4% 44.1% 21.8% 10.0% 31.8%

6.2 Short and Intermediate Term Aggregate Exposures and Risks Short and intermediate term aggregate exposures and risks were assessed for adults and children that could be exposed to 1,2 benzisothiazolin 3 one residues from the use of products in non occupational environments. This includes products that contain 1,2 benzisothiazolin 3 one as either the active or inert ingredient. The following lists summarizes all of the potential sources of 1,2 benzisothiazolin 3 one exposures for adults and children:

Adult 1,2 benzisothiazolin 3 one exposures sources: ° Handling of paint containing BIT as an active or inert ingredient via brush ° Handling of paint containing BIT as an active or inert ingredient via sprayer ° Handling of cleaning products containing BIT as an active or inert ingredient during wiping activities ° Handling of cleaning products containing BIT as an active or inert ingredient during mopping activities ° Wearing BIT treated clothing ° Eating food having BIT residues from indirect food contact via the active ingredient paper packaging use ° Eating food having BIT residues from the inert ingredient pesticide use ° Handling of EC, granular or RTU turf and garden products containing BIT as an inert ingredient ° Handling of pet flea control products containing BIT as an inert ingredient Child 1,2 benzisothiazolin 3 one exposures sources: ° Post application exposures to cleaning product residues containing BIT as an active or inert ingredient used on hard surfaces ( i. e., floors) ° Wearing BIT treated clothing ° Eating food having BIT residues from indirect food contact via the active ingredient paper packaging use ° Eating food having BIT residues from the inert ingredient pesticide use ° Post application exposures to turf residues containing BIT as an active or inert ingredient ° Post application exposures to pet flea control product residues containing BIT as an inert ingredient The use patterns of the products and probability of co occurrence must be considered when selecting scenarios for incorporation in the aggregate assessment. In the case of 1,2 benzisothiazolin 3 one, homeowner painting activities occur only once or twice a year, while the use of turf/ garden and pet products occurs on an intermittent basis. Therefore the probability 39 of co occurrence and the potential for exposure to residues from these products on the same day is highly unlikely. However, it is likely that someone could clean the kitchen ( mopping and wiping activities) as well as, wear clothing treated with 1,2 benzisothiazolin 3 one during the same day. Table 19 summarizes the scenarios included in the short and intermediate term aggregate assessments.

Table 19 Exposure Scenarios Included in the Aggregate Assessments Short term Aggregate Intermediate Term Aggregate Adults ° chronic dietary  inert ° chronic dietary  active ° handling cleaning products  wiping ° handling cleaning products  mopping ° treated clothing ° chronic dietary  inert ° chronic dietary  active ° treated clothing Children ° chronic dietary  inert ° chronic dietary  active ° post app to cleaning product  mopping ° treated clothing ° chronic dietary  inert ° chronic dietary  active ° post app to cleaning product  mopping ° treated clothing The chronic dietary exposures were used in both the short and intermediate term aggregate assessment because chronic dietary exposures occur nearly every day ( as opposed to acute dietary exposures occurring on a one time basis). Therefore, short or intermediate term non dietary exposures have a much higher probability to cooccur with the chronic dietary intake rather than the acute dietary intake.

Cleaning activities in a residential setting occur on a short term basis. However, the BITcontaining cleaning products are also labeled for use in institutional settings such as day care facilities where cleaning activities can occur on an intermediate term basis. Therefore, children could have exposure to cleaning product residues on a more continuous basis in a day care facility thus, these post application scenarios were included in the intermediate term aggregate assessment.

Since the toxicity endpoints for all of the routes of exposure ( oral, dermal and inhalation) are based on the same study and same toxic effect, all routes are aggregated together. However, the aggregate risk index ( ARI) method outlined in OPP guidance for aggregate risk assessment ( September 1, 2000, Standard Operating Procedure ( SOP) for Incorporating Screening Level Estimates of Drinking Water Exposure into Aggregate Risk Assessments) was utilized in the assessment. This method was used because the oral, dermal and inhalation endpoints have different uncertainty factors that need to be applied. For 1,2 benzisothiazolin 3 one, all endpoints for exposure were derived from a subchronic oral study in dogs however, the uncertainty factors 1It should be noted that the inhalation target MOE of 1,000 is used to determine whether an additional inhalation study is warranted. However, the inhalation target MOE used in the aggregate assessment is 100.

40 ( i. e., target MOEs) for oral, dermal and inhalation routes are 300, 100 and 1001, respectively. A risk index $ 1 indicates a risk of no concern. Tables 20 and 21 present the short and intermediate term exposures used in the aggregate assessment, respectively, while Tables 22 and 23 present the resulting ARIs for the short and intermediate term aggregate assessments, respectively.

Table 20. Exposures for Short term Aggregate Assessment Dietary Clothing Hard Surface Cleaning Exposure Routes ( mg/ kg/ day) ( mg/ kg/ day) ( mg/ kg/ day) Active Inert Total Post App Applicator Post App Wipe Mop Mop Adults Oral Ingestion 1.6E 03 4.8E 04 2.1E 03 NA NA NA NA Inhalation NA NA NA NA 3.2E 05 8.5E 06 NA Dermal NA NA NA 4.5E 04 5.5E 04 1.0E 04 NA Toddlers Oral Ingestion 3.7E 03 1.7E 03 5.4E 03 3.0E 03 NA NA 1.6E 04 Inhalation NA NA NA NA NA NA NA Dermal NA NA NA 7.0E 04 NA NA 5.5E 04 Table 21. Exposures for Intermediate term Aggregate Assessment Dietary Clothing Hard Surface Exposure Routes ( mg/ kg/ day) ( mg/ kg/ day) ( mg/ kg/ day) Active Inert Total Post App Post App Mop Adults Oral Ingestion 1.6E 03 4.8E 04 2.1E 03 NA NA Inhalation NA NA NA NA NA Dermal NA NA NA 4.5E 04 NA Toddlers Oral Ingestion 3.7E 03 1.7E 03 5.4E 03 3.0E 03 1.6E 04 Inhalation NA NA NA NA NA Dermal NA NA NA 7.4E 04 5.5E 04 41 Table 22 Short term Aggregate Risks Dietary Clothing Hard Surface Cleaning Exposure Routes Active Inert Total Post App Applicator Post App Total ARI Wipe Mop Adults Oral Ingestion MOEs 3,100 10,000 2,400 NA NA NA NA NA Inhalation MOEs NA NA NA NA 160,000 590,000 NA 120,000 Dermal MOEs NA NA NA 11,000 9,100 50,000 NA 7,700 Total MOE 8,600 46,000 NA 7,200 6.8 Toddlers Oral Ingestion MOEs 1,400 2,900 930 1,700 NA NA 31,000 31,000 Inhalation MOEs NA NA NA NA NA NA NA NA Dermal MOEs NA NA NA 7,100 NA NA 9,100 9,100 ARI 5.2 48.5 48.5 1.9 MOE = NOAEL/ exposure ARI = 1/(( target MOEoral/ MOEoral) + ( target MOEdermal/ MOEdermal) + ( target MOEinhalation/ MOEinhalation)

All NOAELs = 5 mg/ kg/ day Target MOE oral = 300 Target MOE dermal = 100 Target MOE inhalation = 100 42 Table 23 Intermediate term Aggregate Risks Dietary Clothing Hard Surface Cleaning Exposure Routes Active Inert Total Post App Post App ARI Mop Adults Oral Ingestion MOEs 3,100 10,000 2,400 NA NA Inhalation MOEs NA NA NA NA NA Dermal MOEs NA NA NA 11,000 NA 7.5 Toddlers Oral Ingestion MOEs 1,400 2,900 930 1,700 31,000 Inhalation MOEs NA NA NA NA NA Dermal MOEs NA NA NA 7,100 9,100 ARI 5.2 48.5 1.9 MOE = NOAEL/ exposure ARI = 1/(( target MOEoral/ MOEoral) + ( target MOEdermal/ MOEdermal) + ( target MOEinhalation/ MOEinhalation) All NOAELs = 5 mg/ kg/ day Target MOE oral = 300 Target MOE dermal = 100 Target MOE inhalation = 100 The short term ARIs for adults and children were 6.8 and 1.9, respectively, while the intermediate term ARIs for adults and children were 7.5 and 1.9, respectively. These ARIs indicate that there is reasonable certainty of no harm from using BIT containing products. Taking into consideration all available information on the current and proposed use of 1,2 benzisothiazolin 3 one as an inert ingredient in pesticide products, there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure when considering dietary exposure and all other non occupational sources of pesticide exposure for which there is reliable information. Therefore, it is concluded that the exemption from the requirement of a tolerance established for residues of 1,2 benzisothiazolin 3 one in/ on raw agricultural commodities can be considered reassessed as safe under section 408( q) of the FFDCA, and that the proposed exemption for use on animals can be established and considered safe as part of this 408 finding.

7.0 CUMULATIVE RISK 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 43 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. Although 1,2 benzisothiazolin 3 one is classifies as a member of the isothiazoline class of compounds, the Agency does not have, at this time, available data to determine whether 1,2 benzisothiazolin 3 one has a common mechanism of toxicity with other substances.

Guidance for conducting cumulative risk assessments on substances that have a common mechanism of toxicity has recently been finalized. This guidance is available from the OPP website ( http:// www. epa. gov/ pesticides).

8.0 OCCUPATIONAL EXPOSURE A detailed human exposure risk assessment for 1,2 benzisothiazolin 3 one is provided in the attached Appendix. The summary of the exposures and risks to occupational workers are presented below.

8.1 Occupational Handler Formulated Product Handlers:

EPA has assessed the exposure to handlers mixing/ loading/ applying products containing the active ingredient. The following handler exposure scenarios which involve handling the formulated product were assessed for 1,2 benzisothiazolin 3 one to represent the high end of industrial uses of the formulated product.

° Pouring the BIT containing liquid biocide preservative into industrial process intermediate materials ( dispersions, slurries, emulsions, solutions, etc.) ° Pouring the BIT containing liquid biocide preservative into industrial process water for leather and photo processing systems ° Pouring the BIT containing liquid biocide preservative into metalworking fluid ° Pouring the BIT containing liquid biocide preservative during oil field activities There are no chemical specific exposure data to assess primary handler applications. Therefore, dermal and inhalation exposures were assessed using CMA surrogate exposure data. Specifically, the liquid pour for preservative data from CMA were used as surrogate data for the scenarios involving the pouring of liquid preservatives into industrial process intermediate materials, leather and photo processing systems, and oil fields; the liquid pour for metal working fluid data from CMA were used as surrogate data for the liquid pouring of preservatives into metalworking fluid; the liquid pump for preservative data from CMA were used as surrogate data for the liquid pumping of preservatives into oil fields. In addition, product label maximum application rates, related use information, and Agency standard values were used to assess 44 residential handler exposures.

The results of the MOE analysis are presented in Table 24. The calculated short and intermediate term inhalation and dermal MOEs are greater than the target MOEs, and therefore, are not of concern ( Note: the dermal MOE for commercial painting with an airless sprayer is 90). In addition, the total MOEs ( inhalation + dermal) have been presented. The total MOEs are all greater than 100, indicating no risks of concern, except for the commercial painting with an airless sprayer where the total MOE = 85.

Material Preservative Handlers:

EPA has assessed the exposure to handlers mixing/ loading/ applying products containing the active ingredient as a material preservative, not the formulated product ( previously defined as " secondary" handlers). For example, those individuals exposed to the active ingredient as a direct result of its incorporation into an end use product ( e. g., individuals using caulk or paint that in itself is not a registered product). The scenarios assessed have been selected to represent the high end of exposure to these types of products such as application of stains, water based adhesives, caulks, sealants, grouts, spackling, ready mixed cements, and ready mixed wallboard compounds. Based on end use product application methods, it is assumed that exposures while applying paints will be equal to or greater than exposures while applying building materials. ( Note: metal working fluids for machinists are assessed separately below.) The following material uses were assessed to represent the high end of exposure to 1,2 benzisothiazolin 3 one:

° Handling BIT containing paint through brush/ roller and airless sprayer application methods. ° Handling BIT containing cleaning products through wiping and mopping application methods.

These handler exposure scenarios were assessed using surrogate unit exposure data from PHED Version 1.1 for the painting scenarios and using surrogate unit exposure from CMA for the cleaning product scenarios. For the painting scenarios, it was assumed that commercial painters apply 5 gallons ( 50 lbs) of paint through brush/ roller application methods and 50 gallons ( 500 lbs) of paint through airless sprayer application methods. For the cleaning product scenarios, it was assumed that occupational handlers ( i. e., janitors) use 1 liter for wiping and 2 gallons for mopping.

The results of the MOE analysis for the occupational handlers are also presented in Table 24. The calculated short and intermediate term inhalation and dermal MOEs are greater than the target MOE, and therefore, are not of concern. There are no representative unit exposure data for chemical metering into secondary recovery oil operations. Because the volume of water being treated in secondary recovery operations is so large, the available CMA data can not be reliably extrapolated without the potential to overestimate the exposure. However, for BIT, even when the exposures are extrapolated to the large volumes in the secondary recovery oil operation, the inhalation MOE is 830. Because this risk is believed to be an overestimate based on the extrapolation error to large volumes handled, the inhalation MOE of 830 will not trigger a 45 confirmatory inhalation toxicity study. Moreover, in the painting scenarios the dermal absorption factor of 41 percent was not adjusted to account for the potential reduction of the bioavailability of BIT in paint because of a lack of chemical specific data. It is believed that the paint matrix has the potential to reduce the dermal exposure. Therefore, the dermal MOE of 90 for the airless sprayer may be an overestimate of risk.

Table 24. Estimates of Short and Intermediate term Risks to Occupational Handlers of 1,2 benzisothiazolin 3 one Scenarios Use Site Category Inhalation MOEb ( Target MOE = 100) Dermal MOEc ( Target MOE = 100) Total MOE ( Target = 100)

Occupational/ Industrial Handler ( Formulated Products)

Mixing/ loading/ applying BITcontaining biocides using liquid open pour methods for preservation of industrial process intermediate materials. ( Gloves) Material Preservatives 20,000 1,300 1,200 Mixing/ loading/ applying BITcontaining biocides using liquid open pour methods for industrial process and water system use. ( Gloves) Industrial Processes and Water Systems 25,000 1,600 1,500 Mixing/ loading/ applying BITcontaining biocides using liquid open pour methods for preservation of metalworking fluids ( Gloves) Material Preservatives 51,000 5,700 5,100 Mixing/ loading/ applying BITcontaining biocides using liquid open pour methods for preservative products ( Gloves) Oil/ gas Drilling fluids 7E+ 06 4.5E+ 05 4.2E+ 05 Mixing/ loading/ applying BITcontaining biocides using liquid pump methods for preservative products ( Gloves) Oil Secondary Recovery 830 130 110 Occupational Material Preservative Handlers ( In can Preservatives)

Handling BIT containing cleaning solutions through wiping application methods ( No gloves) Material Preservatives 79,000 4,500 4,300 Handling BIT containing cleaning solutions through mopping application methods ( No gloves) Material Preservatives 290,000 24,000 22,000 Handling BIT containing paint through paint brush/ roller application methods ( No gloves) Material Preservatives 50,000 190 190 Handling BIT containing paint through airless sprayer application methods ( No gloves) Material Preservatives 1,700 90 85 a Dermal MOE is based on the short and intermediate term NOAEL of 5 mg/ kg/ day. Target MOE= 100 b Inhalation MOE is based on the ST and IT inhalation NOAEL of 5 mg/ kg/ day. Target MOE= 1000. 46 c Total MOE = NOAEL of 5 mg/ kg/ day / ( abs dermal dose + inhalation dose). Target MOE = 100.

Metal Working Fluids:

Potential inhalation and dermal exposures may exist when using treated metal working fluids. A screening level long term inhalation exposure estimate for treated metal working fluids has been developed using the OSHA PEL for oil mist. The Agency conducted the screening level assessment for metal working fluids using the USEPA/ OPPTS Chemical Engineering Branch ( CEB) model ( U. S. EPA, 1991). The CEB model uses measured and/ or assumed airborne oil mist concentrations for metal working operations. Since no measured concentrations are available for 1,2 benzisothiazolin 3 one, the high end oil mist concentration is based on the OSHA's Permissible Exposure Limit ( PEL) of 5 mg/ m3 ( NIOSH, 1998). EPA Reg. No. 72674 15 indicates that 0.25% ( i. e., 0.0025) of the label product is added to metal working fluids and of that, only 19.3% is the active ingredient ( 1,2 benzisothiazolin 3 one). Therefore, the upper bound air concentration of 1,2 benzisothiazolin 3 one that a worker is exposed to is 5 mg/ m3 x 0.0025 x 0.09 or an air concentration of 0.0011 mg/ m3. Additionally, the following assumption were made in the assessment: the inhalation rate for adults is 1.25 m3 / hr; the exposure duration is 8 hours; and body weight is 70 kg. Using these assumptions, the long term inhalation dose was calculated to be 1.6E 4 mg/ kg/ day, resulting in a long term inhalation MOE of 31,000. Therefore, the calculated MOE indicates that the inhalation risks do not exceed the Agency's level of concern for machinist exposures to metal working fluid ( i. e., MOE $ 1,000).

A screening level long term dermal exposure estimate was derived from the 2 Hand Dermal Immersion in Liquid Model in ChemSTEER ( EPA/ OPPT). The model is available at http:// www. epa. gov/ opptintr/ exposure/ docs/ chemsteer. htm. The weight fraction of 1,2 benzisothiazolin 3 one in metal working fluids is 0.00048 ( 0.0025 formulated product added to oil x 0.193 ai in formulated product = 0.00048), calculated from EPA Reg. No. 72674 15. Based on the model for emersion of hands in metal working fluids, the long term absorbed dermal dose is estimated at 0.025 mg/ kg/ day. The long term dermal MOE is 200 ( i. e., oral NOAEL of 5 mg/ kg/ day / absorbed dermal dose of 0.025 mg/ kg/ day). The dermal MOE is above the target MOE of 100, and therefore, not of concern. The total risk ( NOAEL /( inhalation dose + absorbed dermal dose)) for the machinist is also presented. The total MOE for machinists is 200, and therefore, not of concern.

8.2 Occupational Post application Exposure Postapplication exposures may occur in industrial settings around the water systems via inhalation, and dermal exposures may occur while maintaining industrial equipment. However, occupational postapplication dermal and inhalation exposures to 1,2 benzisothiazolin 3 one are likely to be minimal when compared to handler exposure because of dilution during processing or when compared to machinists using the MWF. No postapplication exposure data have been submitted to the agency to determine the extent of postapplication exposures in the industrial settings. Inhalation exposures are expected to be minimal because aerosol generation is not 47 expected and the vapor pressure of 1,2 benzisothiazolin 3 one is low.

9.0 ECOTOXICOLOGY ASSESSMENT Environmental Modeling/ Exposure Environmental exposure modeling was not conducted for the indoor uses of BIT considered in this RED. Modeling was not conducted for the outdoor oil recovery uses of BIT, as no validated methodology is currently available to estimate environmental exposure from these uses. The potential exposure to terrestrial and aquatic species from the oil recovery uses of BIT cannot be estimated at this time, as there is currently no validated model available for such a purpose. 1,2 benzisothiazolin 3 one is also used as an inert ingredient in agricultural pesticide formulations, which do result in outdoor exposure. However, considering BIT's ready biodegradation, and the small amount ( 0.02 lbs. per acre) that may be applied to crops, BIT is not likely to be present in surface or ground water sources at substantial concentrations as a result of their use as inert ingredients in pesticide products and therefore it was not necessary to conduct any modeling activities for the inert uses.

Ecological Hazard and Risk The available ecological effects data for 1,2 benzisothiazolin 3 one are somewhat limited. Based on acute toxicity information, 1,2 benzisothiazolin 3 one displays low to moderate toxicity to birds and mammals. It is moderately toxic to freshwater fish and invertebrates, slightly toxic to marine/ estuarine fish, and highly toxic to marine/ estuarine invertebrates. A submitted rat developmental study provided a NOAEL of 40 mg/ kg/ day. There was no aquatic organism chronic toxicity information available for 1,2 benzisothiazolin 3 one. Phytotoxicity data were particularly scant, with one algae acute study found in published scientific literature, which indicates that 1,2 benzisothiazolin 3 one is highly toxic to green algae. Acute oral toxicity data for 1,2 benzisothiazolin 3 one are shown in Table 25, acute ecotoxicity data are shown in Table 26, and other ecotoxicity data ( subacute dietary, dermal, and developmental) are shown in Table 27.

Table 25. Acute Oral Toxicity of 1,2 benzisothiazolin 3 one Species LD50/ LC50 ( mg/ kg) NOAEL/ NOAEC Toxicity Category Bird Bobwhite quail ( Colinus virginianus) 453 NA Moderately toxic Mammal Rat 650  males 784  females    48 Table 26. Acute Ecotoxicity of 1,2 benzisothiazolin 3 one Species LD50/ LC50 ( mg/ kg) NOAEL/ NOAEC Toxicity Category Freshwater Fish Rainbow Trout ( Oncorhynchus mykiss) 1.3 0.74 Moderately toxic Rainbow Trout ( Oncorhynchus mykiss) 1.6  Moderately toxic Freshwater Invertebrate Waterflea ( Daphnia magna) 1.5 0.7 Moderately toxic Waterflea ( Daphnia magna) 3.3 1.4 Moderately toxic Estuarine/ Marine Fish Sheepshead minnow ( Cyprinodon variegatus) 12.2 3.3 Slightly toxic Estuarine/ Marine Invertebrates Mysid shrimp ( Mysidopsis bahia) 0.99 0.25 Highly toxic Pacific oyster ( Crassostrea gigas) 0.047 0.024 Very highly toxic Aquatic Algae Green algae, species not indicated 0.15 ( 72 hour EC50)

Table 27. Other Toxicity Studies of 1,2 benzisothiazolin 3 one Species LD50/ LC50 ( mg/ kg) NOAEL/ NOAEC LOAEL/ LOAEL Toxicity Category Subacute Dietary Toxicity of 1,2 benzisothiazolin 3 one to Birds Bobwhite quail ( Colinus virginianus) > 5620   Practically non toxic Acute Dermal Toxicity of 1,2 benzisothiazolin 3 one to Rats Rats > 2000

Developmental Toxicity of 1,2 benzisothiazolin 3 one to Rats Rats  40 100   49 The indoor uses of BIT considered in this RED make it unlikely that any appreciable exposure to terrestrial or aquatic organisms would occur. Facilities using BIT for indoor industrial applications are required to have NPDES permits before discharging effluents into receiving waters. The potential exposure to terrestrial and aquatic species from the oil recovery uses of BIT cannot be estimated at this time, as there is currently no validated model available for such a purpose.

1,2 benzisothiazolin 3 one is used as an inert ingredient in pesticide products but the allowable amount that can be applied is small ( not more than 0.1% formulation and 0.02 lbs. per acre). Data indicate that 1,2 benzisothiazolin 3 one breaks down quickly in aerobic soils ( half life < 24 hours in sandy loam soil). 1,2 benzisothiazolin 3 one's ready biodegradation in soil and small application amount greatly reduce the exposure potential for terrestrial and aquatic organisms. Run off into surface water from pesticidal uses is likely to be low and it is not likely to be present in water sources at substantial concentrations. Therefore, risk to non target organisms is not anticipated from the use of 1,2 benzisothiazolin 3 one.

Listed Species Consideration The Agency has developed the Endangered Species Protection Program to identify pesticides whose use may cause adverse impacts on listed, and to implement mitigation measures that address these impacts. The Endangered Species Act requires federal agencies to ensure that their actions are not likely to jeopardize listed species or adversely modify designated critical habitat. To analyze the potential of registered pesticide uses to affect any particular species, EPA puts basic toxicity and exposure data developed for risk assessments into context for individual listed species and their locations by evaluating important ecological parameters, pesticide use information, the geographic relationship between specific pesticide uses and species locations, and biological requirements and behavioral aspects of the particular species. A determination that there is a likelihood of potential impact to a listed species may result in limitations on use of the pesticide, other measures to mitigate any potential impact, or consultations with the Fish and Wildlife Service and/ or the National Marine Fisheries Service as necessary.

The indoor uses of BIT addressed in this document are unlikely to result in any appreciable exposure to terrestrial or aquatic organisms, and thus have a low risk potential for Listed Species. The potential exposure to terrestrial and aquatic species from the oil recovery uses of BIT cannot be estimated at this time, as there is currently no validated model available for such a purpose. The high toxicity of BIT to green algae and invertebrate species suggests that potential adverse acute effects could occur to some species if environmental contamination from BIT treated oil recovery fluids occurs.