Halohydantoins Office of Pesticide Programs Antimicrobials Division U. S. Environmental Protection Agency 1801 South Bell Street Arlington, VA 22202 September 8, 2004 TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.0. PHYSICAL AND CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.1 Chemical Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.2 Physical/ Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 3.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 3.4 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . 24 4.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.2 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 4.3 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.4 Residential Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.4.1 Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.4.2. Postapplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 <IP_ADDRESS> Carpet Shampoo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 <IP_ADDRESS> Clothing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 <IP_ADDRESS> Swimming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION . . . . . . . . . . . 34 5.1 Acute Aggregate Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.2 Short, Intermediate and Long term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . 36 6.0 OCCUPATIONAL EXPOSURE AND RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.1 Industrial Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.2 Material Preservatives & Commercial/ Institutional/ Industrial Premises and Equipment & Swimming Pools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.3 Agricultural Premises and Aquatic Area Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 6.4 Postapplication Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 7.0 ENVIRONMENTAL FATE ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 7.1 Environmental Fate Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 7.2 Environmental Fate and Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 8.0 ECOTOXICITY AND ENVIRONMENTAL RISK ASSESSMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . .44 8.1 Ecotoxicity Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 8.2 Environmental Exposure Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 8.3 Environmental Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 8.4 Endangered Species Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 9.0 INCIDENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 9.1 Incident Report Data Associated with Health Effects of Dihalodialkylhydantoin . . . . . 48 9.2 Epidemiological Data Associated with Chronic Health Effects of Halohydantoin Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 10.0 DATA GAPS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51 11.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Page 3 of 57 EXECUTIVE SUMMARY The halohydantoins are a group of chemicals comprised of several halogenated compounds. This group of chemicals includes the following: 1 Bromo 3 chloro 5,5 dimethylhydantoin, 1.3 Dibromo 5,5 dimethylhydantoin, 1,3 Dichloro 5,5 dimethylhydantoin, 1,3 Dichloro 5 ethyl 5 methylhydantoin, and non halogenated hydantoins 1,3 bis( hydroxymethyl) 5,5 dimethylhydantoin, and 1 hydroxymethyl 5,5 dimethylhydantoin. In addition to these six hydantoins, the Agency determined that the 5,5 Dimethylhydantoin and 5 Ethyl 5 methylhydantoin metabolites of the halogenated hydantoins are appropriate test substances for assessing the toxicity of this group. However, since the hydroxymethylhydantoins as listed above have the potential for release of formaldehyde, the risks associated with this release need to be assessed. The Agency has determined that the risks from exposure to formaldehyde via the hydroxymethylhydantoins will be addressed when the active ingredient formaldehyde is assessed for reregistration eligibility. Therefore, this reregistration eligibility decision ( RED) document assesses the eligibility of the Halohydantoins and their metabolites for reregistration.

These antimicrobial chemicals are registered for use in indoor food, indoor non food, indoor residential, aquatic non food residential, aquatic food, aquatic non food, and aquatic nonfood industrial sites for control of bacteria, fungi, and algal slimes.

Hazard: The acute toxicity of Halohydantoin is low by the oral and dermal routes of exposure ( Toxicity categories III and IV, respectively). Acute lethality by the inhalation route is more significant ( Toxicity category II). The Halohydantoins are significant eye and skin irritants ( Toxicity category I and II, respectively). Positive dermal sensitization has also been observed for some of the Halohydantions.

Non acute toxicity testing of hydantoins ( DMH/ EMH) ( including subchronic, developmental, reproductive, and chronic toxicity testing) all show the presence of non specific toxicity only at relatively high doses of the test chemical. Developmental and reproductive toxicity data demonstrate no increase in susceptibility to the toxic effects of 5,5 dimethylhydantoin with the exception of one study, where fetal and litter effects ( increased incidence of 27th presacral vertebrae) in rabbits were observed at a lower dose level than that which resulted in maternal toxicity ( decreased body weight and food consumption during the dosing period) following treatment. In a prenatal developmental toxicity study conducted in rabbits with 5 ethyl 5 methylhydantoin, there was no increased susceptibility of the fetuses observed.

Chronic toxicity testing of dimethylhydantoins in rats showed a decrement in body weight and body weight gain in females and increased mortality, particularly in females. Males showed increased incidences of hyperplasia of submandibular lymph nodes and testicular fibrinoid vascular degeneration in early decedents. Both sexes showed increased mammary galactoceles in early decedents and enlarged pituitary glands. In chronic toxicity studies conducted in dogs, 5,5 dimethylhydantoin produced slight ( hypertrophy in the adrenal cortex of male dogs upon microscopic examination) to no toxicity at or above the limit dose of 1000 mg/ kg/ day.

Cancer studies in rats and mice indicated no systemic effects other than decreased body Page 4 of 57 weight and body weight gains in females ( rats) and males ( mice) and increased hyperplasia of submandibular lymph nodes in males ( rats). No evidence of carcinogenicity of the test material was reported. 5,5 dimethylhydantoin is classified as ` not likely' to be a carcinogen based upon the negative evidence for carcinogenicity in both the rat and mouse studies as well as the negative evidence of mutagenicity.

The data on mutagenicity of dimethylhydantoins shows, in large part, negative responses in the studies conducted. Literature reports indicate a positive effect for 2 in vitro mammalian cytogenetic assays in Chinese Hamster Ovary cells.

Available metabolism data indicate that the dimethylhydantoins are excreted unchanged in the rat. However, it is known that hydroxymethylhydantoins are formaldehyde releasers. Therefore, any risk assessment involving dietary or non dietary exposure to the hydroxymethylhydantoins will also involve calculating risk from formaldehyde exposure. This assessment will be addressed in the reregistration eligibility decision document for formaldehyde.

Toxicity Endpoints: On July 25, 2000 , the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reviewed the recommendations of the toxicology reviewer for 5,5 dimethylhydantoin ( a chemical representative of hydantoin toxicity) 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 this hydantoin was also evaluated as required by the Food Quality Protection Act ( FQPA) of 1996. Endpoints were established for the hydantoins and a report issued. A summary of the endpoints selected is provided at the end of this chapter.

Dietary Endpoints: Acute and chronic dietary endpoints were selected to be 100 mg/ kg/ day for females 13 50 based on a developmental toxicity study on rabbits, in which skeletal variations were seen at 500 mg/ kg/ day. The Acute and Chronic RfD for this population is 1 mg/ kg. A chronic dietary endpoint of 300 mg/ kg/ day was selected for the general population based on a chronic toxicity study on rats, in which decreased body weight, weight gain, and lymph node hyperplasia were observed. The Chronic RfD for the general population is 3 mg/ kg/ day.

Oral Endpoints: The incidental short term oral endpoint was selected to be 500 mg/ kg/ day, based a developmental toxicity study on rabbits, in which decreased body weight gain in maternal rabbits at 1000 mg/ kg/ day. The intermediate term oral endpoint was selected to be 300 mg/ kg/ day, based on a subchronic oral toxicity study in which decreased body weight and liver weight were observed at 1000 mg/ kg/ day.

Dermal Endpoints: The short, intermediate, and long term dermal endpoints were selected to be 390 mg/ kg/ day. No systemic toxicity was found at the highest dose tested in a subchronic toxicity study on rats. Page 5 of 57 Inhalation Endpoints: The short term inhalation endpoint was selected to be the same as the oral endpoint of 100, due to skeletal effects in offspring at 500 mg/ kg/ day in a developmental toxicity study in rabbits.

FQPA Safety Factor: Although there is quantitative evidence of increased sensitivity of neonatal rabbits, the HIARC considered this effect not indicative of susceptibility, based upon the very high dose level at which the effect occurred, the minimal nature of the effect, and the likelihood that the effect was due to a greater dose received by pups from ingestion of both milk and feed during the lactational period. Therefore, the HIARC recommended that the special hazard based FQPA safety factor could be removed for the hydantoins and that the use of a standard uncertainty factor of 100 would be sufficient.

Dietary Exposure: The Agency has carried out the dietary exposure and risk assessment for use of Halohydantoins as a slimicide in food contact paper and paperboard, and for use as a preservative in inorganic slurries which are used as fillers for food contact paper and paperboard. The acute dietary exposure for an adult female is 0.046% of the acute Population Adjusted Dose ( PAD). The highest chronic exposure occurred in adult females ( 0.0153% of the chronic PAD). All dietary exposures calculated were well below the Agency's level of concern ( 100% of aPAD or cPAD).

Water Exposure and Risk: AD has considered the registered uses of Halohydantoins and the available data on persistence and mobility. The Agency is presently relying on predicted environmental concentrations ( PECs) of pesticides in surface water to estimate drinking water exposures to Halohydantoins. Out of all the uses of the pesticide, the once through cooling water system can be expected to have the greatest impact on the water, since the scenario has the greatest quantity of effluent being produced and has the greatest chance of bacterial fouling and need for pesticide. Using the PDM4 model, the short term EEC in surface water uses estimated to be 36 ug/ L. The chronic maximum EEC using this model was determined to be 313 ug/ L. Based on current Agency policy, drinking water level of comparison ( DWLOCs) are compared to the EEC. When the EEC is greater than the DWLOC, AD considers the estimate of aggregate risk to exceed the Agency's level of concern.

Residential Exposure and Risk: Halohydantoins may be added to residential use products used to control bacteria and fungicide. A number of such products have been identified, including household cleaning products, paint, adhesives, and deodorizers. For the purposes of this screening level assessment, handler scenarios have been developed that encompass multiple products but still represent a worst case scenario for all products represented. Table 12 shows the handler scenarios considered in this assessment. Detergents, soaps, household cleaning products, and carpet shampoo have been grouped together. Of these products, household cleaning products, which should yield the greatest amount of handler exposure to the chemical, was selected for analysis. In tank toilet tablets, which are placed into toilet tanks, differ from the other household cleaning products in that they are not liquid. These tablets were evaluated in a separate scenario. Adhesives, caulks, and paints have been grouped together for evaluation. There are no risks of concern of any of the handler or post application residential exposure scenarios assessed. Page 6 of 57 Aggregate Exposure and Risk: In order for a pesticide registration to continue, it must be shown that the use does not result in " unreasonable adverse effects on the environment". Section 2 ( bb) of FIFRA defines this term to include " a human dietary risk from residues that result from a use of a pesticide in or on any food inconsistent with standard under section 408..." of FFDCA. Consequently, even though no pesticide tolerances have been established for Halohydantoins, the standards of FQPA must still be met, including " that there is reasonable certainty that no harm will result from aggregate exposure to pesticide chemical residue, including all anticipated dietary exposures and other exposures for which there are reliable information." Aggregate exposure is the total exposure to a single chemical ( or its residues) that may occur from dietary ( i. e., food and drinking water), residential, and other non occupational sources, and from all known or plausible exposure routes ( oral, dermal, and inhalation). Aggregate risk assessment were conducted for acute ( 1 day), short term ( 1 30 days), intermediate term ( 1 6 months) and chronic ( several months to lifetime) exposures as needed.

Dermal Aggregate Exposure: Short, intermediate, and long term aggregate dermal risks are considered together since the exposure and toxicity endpoints are identical for dermal exposures for all three durations. It was assumed that a resident would apply paint using either a paintbrush or an aerosol can. The total dermal MOE for an adult resident that could simultaneously contact clothing, cleaning products, toilet cleaners, swimming pools, and paint treated with the pesticide is 132 and 132 for competitive and non competitive swimmers, which is greater than the target MOE of 100, and thus does not exceed the Agency's level of concern.

For children, the aggregate dermal MOE of 107 was greater than the target of 100, indicating no aggregate risk of concern for dermal exposure.

In addition to dermal exposure of children on carpet, infants crawling on treated carpets will also pose a risk of exposure to Halohydantoins via incidental oral exposure. The calculated Margin of Exposure ( 4200) is above the Agency's level of concern. This is not aggregated with other scenarios as there is only one scenario, and the endpoint defining effects by this route is not similar to the dermal or inhalation routes.

Inhalation Aggregate Exposure: As only a short term inhalation endpoint was selected, only short term aggregate exposures were considered. It was assumed that a resident would apply paint using either a paintbrush or an aerosol. The total inhalation MOE for an adult resident that could simultaneously contact toilet cleaners, paint treated with the pesticide, and swimming pools is 9940 for competitive swimmers and 11976 for non competitive swimmers, which is greater than the target MOE of 100, and thus does not exceed the Agency's level of concern.

Occupational Exposure and Risk: Several different sources of handler exposure data were used to assess occupational and residential Halohydantoins risks. Data from the both proprietary Chemical Manufacturers Association ( CMA) antimicrobial exposure study and the Pesticide Handlers Exposure Database ( PHED) were used. Page 7 of 57 Out of all occupational scenarios considered, an MOE lower than the target MOE was found for only two scenarios   placing tablets into public swimming pools wearing baseline protection ( Dermal MOE= 46 but mitigated with the use of gloves MOE= 7500), that have not been mitigated at this time, and greenhouse and nursery irrigation systems ( MOE = 14 for use of tablets with gloves, MOE = 2 for use of granules without gloves). However, the greenhouse use may be overestimates of the true risk associated with use of these products. The product labels state that gloves should be worn when placing tablets into swimming pools, and the PPE calculations should be more applicable to public swimming pool scenarios. And the calculations to determine exposure for irrigation systems were based on very conservative estimates, for lack of better data. There are a number of uncertainties associated with this assessment. In general, conservative values were used in cases where data were lacking. Assessments for these scenarios should be considered as screening assessments, and additional use information for greenhouse irrigations should be submitted.

Environmental Fate: The Agency does not have a complete database for environmental fate studies on Halohydantoins. However, hydrolysis appears to be the major route for dissipation. The rapid hydrolysis, under abiotic conditions, show half lives of less than 30 days in pH 5, pH 7, and pH 9 ( in buffered solutions), which indicated that hydrolysis is an early step in the degradation process. However, the major degradate, dimethylhydantoin ( DMH), was hydrolytically stable at pH 5, pH 7, and pH 9 and may possibly leach in the soil profile or move with surface water runoff and may pose environmental concerns. The Agency lacks any data on Halohydantoins as far as mobility ( soil column leaching) is concerned, as well as binding constants to soils to indicate if Halohydantoinss will be persistent in soils. Because of lack of data, the Agency cannot assess if Halohydantoinss are bioaccumulative and if these can be a source of concern for the aquatic organisms. There is environmental concern for soil or surface water contamination from the major degradate DMH, as DMH is hydrolytically and photolytically stable. No additional fate data on dimethylhydantoins are available to further assess fate of this chemical.

Ecological Hazard: DMH was considered to be the moiety of concern for environmental and ecotoxicology. DMH shows low toxicity to birds, mammals, and freshwater and marine/ estaurine fish and invertebrates. No toxicity data were available to assess the phytotoxicity of DMH or other hydantoin compounds; these data are required to support the once through cooling uses of hydantoin products ( see Data Gaps section of this document).

Environmental Exposure and Modeling: The PDM4 Model was used to estimate exposure from once through cooling tower uses. The details of this model are found in the Environmental Modeling Chapter of this document. A low flow power plant ( 100 + 10 million gallons per day) was used as the scenario providing the maximum concentrations of DMH in the receiving water, e. g., the " worst case" scenario. Peak EECs ranged from 36.0 ppb over 4 days to 313 ppb over 60 days. Actual concentrations in receiving waters are likely lower, and will likely not show the increasing trend indicated by these results, due to higher flow rates and possible degradation/ dissipation of DMH by mechanisms other than hydrolysis.

Environmental Risk Assessment: Terrestrial exposure modeling was not conducted, but Page 8 of 57 exposure from the registered uses of hydantoin products is expected to be low, and risk to birds and mammals is not anticipated. Risk to terrestrial/ semi aquatic plants could not be assessed due to a lack of phytotoxicity data.

Using the very conservative EECs provide by modeling the low flow power plant, no LOCs are exceeded. Other uses of hydantoin products are indoor or contained ( e. g., swimming pool) uses, and should not result in appreciable environmental exposure when products are used as labeled. Risk to freshwater fish and aquatic invertebrates is not anticipated from the use of hydantoins in once through cooking systems. Marine/ estuarine fish are generally less sensitive that freshwater fish to hydantoins, and marine/ estuarine invertebrates are comparably as sensitive to DMH as freshwater invertebrates, so the freshwater RQ are presumed to be protective of marine/ estuarine species. Risk to aquatic plants cannot be assessed due to the lack of phytotoxicity data.

Endangered Species: Risk to endangered birds and mammals is not anticipated from the use of hydantoin products due to low exposure and low toxicity. Calculated RQs for fish and aquatic invertebrates from the once through cooling use are well below LOCs for endangered species; other use of hydantoin products are indoor or contained ( e. g., swimming pool) uses, and should not result in appreciable environmental exposure when products are used as labeled. Therefore, risk to endangered fish and aquatic invertebrate species is not anticipated from the use of hydantoin products. Risk to endangered plants cannot be addressed due to the lack of phytotoxicity data.

Incident Reports: There are many incidences that have been reported associated with exposure to end use products containing Halohydantoins. Dermal, ocular and inhalation are the primary routes of exposure. Most of the incidences are related to irritation and/ or allergic type reaction. The most common symptoms reported for cases of dermal exposure were skin irritation/ burning, rash, itching, skin discoloration/ redness, blistering, allergic type reactions including hives, welts, allergic contact dermatitis, and bleeding also have been reported. The most common symptoms reported for cases of ocular exposure were eye irritation/ burning. Eye pain and swelling of eyes also has been reported in some incidences. The most common symptoms reported for cases of inhalation exposure were respiratory irritation/ burning, irritation to mouth/. throat/ nose, coughing/ choking, shortness of breath, dizziness, flu like symptoms, headache. Seizure and heart palpitation also have been reported. Although oral exposure is considered a minor route of exposure for Halohydantoins use, irritation to mouth/ throat/ nose, vomiting/ nausea/ abdominal pain have been reported in cases of ingestion.

Data Gaps: The following ecological effects data are required to support the oncethrough cooling system uses of hydantoin products:

72 4b/ 850.1400 Invertebrate life cycle testing freshwater TGAI1 123 1/ 850.4225 Seedling emergence dose   response in rice TEP2 Page 9 of 57 123 1/ 850.4250 Vegetative vigor dose response in rice TEP 123 2/ 850.4400 Aquatic vascular plant dose response toxicity Lemna sp. TGAI or TEP 123 2/ 850.5400 Acute algal dose response toxicity  4 species TGAI or TEP 1TGAI= technical grade active ingredient 2TEP= typical end use product Toxicology data gap: 82 4/ 870.3465 90 Day Inhalation 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION The halohydantoins are a group of chemicals composed of several halogenated compounds ( i. e. a central organic hydantoin ring moiety ( either dimethylhydantoin or ethylmethylhydantoin) to which halogen atoms ( bromine and/ or chlorine) can be attached at both the 1 and 3 positions on the hydantoin ring), as well as hydroxymethylhydantoin compounds ( 1,3 bis( hydroxymethyl) 5,5 dimethylhydantoin and 1 hydroxymethyl) 5,5 dimethylhydantoin).

2.1 Chemical Identification The common names, chemical names, empirical formulas, and CAS numbers of the halohydantoins are presented in Table 1.

Table 1. Common Names, Chemical Names, Empirical Formulas, and CAS Numbers Common Name Chemical Name Empirical Formula CAS No.

Dichlorodimethylhydantoin 1,3 dichloro 5,5 dimethylhydantoin C5H6Cl2N2O 2 118 52 5 Bromochlorodimethylhydantoin 1 Bromo 3 chloro 5,5 dimethylhydantoin C5H6BrClN2 O2 16079 88 2 Dichloroethylmethylhydantoin 1,3 dichloro 5 ethyl 5 methylhydantoin C6H8Cl2N2O 2 89415 87 2 In addition to the products listed in Table 1, two additional formulations are also registered: Dantogard ( EPA Reg# 6836 119) and Glycoserve ( EPA Reg#: 6836 112). Their chemical names, PC Codes are listed as follows:

1. Ingredients of Dantogard are: 1,3 bis( hydroxymethyl) 5,5 dimethylhydantoin ( PC Code: 115501) And Hydroxy 5,5 dimethylhydantoin ( PC Code: 115502) September 1988 label of this product states: " The product contains 1.5% formaldehyde"

2. Ingredients of Glycoserve are the same as the Dantogard. The two ingredients vary in percentages in the two formulations.

The label of this product states: " The product contains at a maximum concentration of 2% formaldehyde". Page 10 of 57 NH HN O O Hydantoin NH HN O O CH3 CH3 5,5 Dimethylhydantoin N N Cl Cl O O CH3 CH3 1,3 Dichloro 5,5 Dimethylhydantoin N N Cl Br O O CH3 CH3 1 Chloro, 3 Bromo 5,5 Dimethylhydantoin N N Cl Cl O O CH3 C2H5 1,3 Dichloro 5 Methyl, 5 Ethylhydantoin The information about these chemicals are included here as not only the formulations contain formaldehyde as impurity as stated on the labels but these are also formaldehyde releasers. However, these two chemicals are not assessed here along with other dimethylhydantoins derivatives but will be assessed in the upcoming RED on formaldehyde.

Structures of hydantoin and its derivatives considered in this document are below: Page 11 of 57 N N CH2OH CH2OH O O H3C CH3 1,3 bis( hydroxymethyl) 5,5Dimethylhydantoin NH N CH2OH O O H3C H3C Hydroxymethyl 5,5 Dimethylhydantoin Page 12 of 57 2.2 Physical and Chemical Properties Physical and chemical properties of DantobromTM S are shown in Table 2. Dantobrom   S is one of a number of pesticides containing halohydantoins.

Table 2. Physical and Chemical properties of DantobromTM S Parameter Value Color Off white Physical State Powder Odor Slight chlorine odor Stability Dantobrom   S is stable in the dry state. It decomposes exothermally at 180

C. It is attacked by strong alkalies, acids, and moisture.

Oxidation/ Reduction Oxidizer pH of water solution, 1% slurry at 25oC 3.6 Melting point between 120 and 148oC Kow unknown Water solubility at 25oC 0.54 g / 100 g Vapor Pressure NA The impurities formed during the production of DantobromTM S include sodium chloride and water ( gaseous form). Preliminary analysis of Glychlor and Dantochlor revealed quantities of DMH radical, MEH radical, active chlorine, chloroform insolubles, and volatiles.

3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile A detailed hazard assessment for Halohydantoins is presented in the attached appendix. The acute toxicity of the hydantoins shown in Table 3a is low by the oral and dermal routes of exposure ( Toxicity categories III and IV, respectively). Acute lethality by the inhalation route is more significant ( Toxicity category II). The dimethylhydantoins are significant eye and skin irritants ( Toxicity category I and II, respectively). Positive dermal sensitization has also been observed. Page 13 of 57 Table 3a. Acute Toxicity of Halohydantoins Guideline No./ Study Type MRID No. ( TRID No.) Results Toxicity Categor y 5,5 Dimethylhydantoin 870.1100 Acute oral ( gastric intubation) toxicity ( limit test) Mouse 45738401 LD50 ( combined) > 5,000 mg/ kg IV 1 Bromo 3 chloro 5,5 dimethylhydantoin 870.1100 Acute oral toxicity Rat 93074006, 00128244 ( 4226 010 01) LD50( males) = 1,350 mg/ kg LD50( females) = 1,520 mg/ kg LD50( combined) = 1,390 mg/ kg III 870.1100 Acute oral toxicity Rat 93077008, 00147325 ( 4600 950 21) LD50( males) = 1,037 mg/ kg LD50( females) = 860 mg/ kg LD50( combined) = 929 mg/ kg III 870.1300 Acute inhalation toxicity Rat 43654101 LC50( males) = 0.157 mg/ L LC50( females) = 0.213 mg/ L LC50( combined) = 0.168 mg/ L II 870.2500 Acute dermal irritation Rabbit 93074011, 93075014, 00128242 ( 4225 014 10) severe skin irritant I 870.2500 Acute dermal irritation Rabbit 93077009, 00147326 ( 4600 950 22) severe skin irritant I 870.2600 Skin sensitization Guinea pig 41670001 positive sensitizer N/ A 1,3 Dibromo 5,5 dimethylhydantoin 870.1100 Acute oral toxicity Rat 93076011, 00137105 ( 4334 012 01) LD50 = 760 mg/ kg III 870.1200 Acute dermal toxicity Rabbit 93076025, 00137110 ( 4334 012 07) LD50 cannot be ascertained ( study is classified as Unacceptable/ non guideline

870.2500 Acute dermal irritation Rabbit 93076017, 00137109 ( 4334 012 05) severe skin irritant I 1,3 Dichloro 5,5 dimethylhydantoin 870.1200 Acute dermal toxicity Rabbit 93076013, 00084176 ( 2402 448 05) LD50 > 20,000 mg/ kg IV Page 14 of 57 870.2500 Acute dermal irritation Rabbit 93076017, 00137109 ( 2402 448 01) severe skin irritant I Non acute toxicity testing of hydantoins ( including subchronic, developmental, reproductive, and chronic toxicity testing) all show the presence of non specific toxicity only at relatively high doses of the test chemical ( Table 3b). Developmental and reproductive toxicity data demonstrate no increase in susceptibility to the toxic effects of dimethylhydantoin with the exception of one study, where fetal and litter effects ( increased incidence of 27th presacral vertebrae) in rabbits were observed at a lower dose level than that which resulted in maternal toxicity ( decreased body weight and food consumption during the dosing period) following treatment. In a prenatal developmental toxicity study conducted in rabbits with ethylmethylhydantoin, there was no increased susceptibility of the fetuses observed.

Chronic toxicity testing of dimethylhydantoins in rats showed a decrement in body weight and body weight gain in females and increased mortality, particularly in females. Males showed increased incidences of hyperplasia of submandibular lymph nodes and testicular fibrinoid vascular degeneration in early decedents. Both sexes showed increased mammary galactoceles in early decedents and enlarged pituitary glands. In two chronic toxicity studies conducted in dogs, dimethylhydantoin produced slight ( enlarged pituitary glands) to no toxicity at or above the limit dose of 1000 mg/ kg/ day.

Cancer studies in rats and mice indicated no systemic effects other than decreased body weight and body weight gains in females ( rats) and males ( mice) and increased hyperplasia of submandibular lymph nodes in males ( rats). No evidence of tumorigenicity of the test material was reported. 5,5 dimethylhydantoin is classified as ` not likely' to be a carcinogen based upon the negative evidence for carcinogenicity in both the rat and mouse studies as well as the negative evidence of mutagenicity.

The data on mutagenicity of dimethylhydantoins shows, in large part, negative responses in the studies conducted. A literature report indicates a positive effect for induction of lethal mutations in Drosophila melanogaster.

Available metabolism data indicate that the dimethylhydantoins are excreted unchanged in the rat. However, it is known that methylhydantoins are formaldehyde releasers. Therefore, any risk assessment involving dietary or non dietary exposure to the methylhydantoins will also involve calculating risk from formaldehyde exposure ( This risk assessment will be addressed in the reregistration eligibility decision document for formaldehyde). Page 15 of 57 Table 3b. Subchronic, Chronic and Other Toxicity Tables Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results Subchronic Toxicity 870.3100 90 Day oral toxicity rodents  Rat 1DMH purity > 99.5% 42009201 ( 1991) Acceptable/ guideline0, 100, 300, 1000 mg/ kg/ day NOAEL = greater than or equal to 1000 mg/ kg/ day ( highest dose tested) LOAEL = greater than 1000 mg/ kg/ day ( not established).

28 Day oral toxicity  Mouse DMH purity 100% 45738402 NOAEL = greater than or equal to 50,000 ppm [ males: 10,057, females: 14,972 mg/ kg/ day] ( highest dose tested) LOAEL = greater than 50,000 ppm [ males: 10,057, females: 14,972 mg/ kg/ day] ( not established).

870.3150 90 Day oral toxicity in nonrodents No study available.

870.3200 21/ 28 Day dermal toxicity No study available.

870.3250 90 Day dermal toxicity DMH purity 99.8% 43173901 ( 1994) core/ guideline 0, 39, 130, 390 mg/ kg/ day This study is classified as Acceptable Guideline and it satisfies the guideline requirements for a subchronic toxicity study [ OPPTS 870.3250 ( § 82 1b)] in rats. Higher doses of DMH were not possible in this study; thus, although a limit dose was not tested, the study is considered acceptable. NOAEL = greater than or equal to 390 mg/ kg/ day ( highest dose tested) LOAEL = greater than 390 mg/ kg/ day ( not established) Page 16 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results 870.3465 90 Day inhalation toxicity No study available. Page 17 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results Developmental/ Reproductive Toxicity 870.3700 Prenatal developmental in rats DMH purity 99.8% 42432701 ( 1992) Core Minimum/ Guideline 0, 100, 300, 1000 mg/ kg/ day Maternal Toxicity NOAEL = 300 mg/ kg/ day Maternal Toxicity LOAEL = 1000 mg/ kg/ day based on the transient decrease in body weight gain during gestation days 9 12.

Developmental Toxicity NOAEL = greater than or equal to1000 mg/ kg/ day ( highest dose tested) Developmental Toxicity LOAEL = greater than 1000 mg/ kg/ day ( not established)

870.3700 Prenatal developmental in nonrodents  Rabbits DMH purity 96 98.7% 42413101 ( 1992) core/ guideline 0, 100, 500, 1000 mg/ kg/ day Maternal Toxicity NOAEL = 500 mg/ kg/ day Maternal Toxicity LOAEL = 1000 mg/ kg/ day based on decreased body weight gain and food consumption during the dosing period.

Developmental Toxicity NOAEL = 100 mg/ kg/ day Developmental Toxicity LOAEL = 500 mg/ kg/ day based on the increased incidence of the 27th presacral vertebrae.

870.3700 Prenatal developmental in nonrodents  Rabbits 2EMH purity > 99.5% 42205401 ( 1992) acceptable Phase I: 0, 50, 125, or 375 mg/ kg/ day Phase II: 0 or 1000 mg/ kg/ day Maternal Toxicity NOAEL = 375 mg/ kg/ day Maternal Toxicity LOAEL = 1000 mg/ kg/ day, based on mortality, reduced body weights gains and reduced food consumption.

Developmental Toxicity NOAEL = 375 mg/ kg/ day Developmental Toxicity LOAEL = 1000 mg/ kg/ day, based on decreased fetal body weights.

870.3800 Reproduction and fertility effects DMH purity 96 98.7% 42462502 ( 1992) Core/ Guideline 0, 250, 500, 1000 mg/ kg/ day ( 20,000 ppm)

20,000 ppm ( 1322 and 1602 mg/ kg/ day, respectively) for male and female rats Parental/ Systemic NOAEL = greater than or equal to1000 mg/ kg/ day ( highest dose tested) Parental/ Systemic LOAEL = greater than 1000 mg/ kg/ day ( not established).

Offspring Toxicity NOAEL = greater than or equal to1000 mg/ kg/ day ( highest dose tested) Offspring Toxicity LOAEL = greater than 1000 mg/ kg/ day ( not established). Page 18 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results Chronic Toxicity/ Carcinogenicity 870.4100 Chronic toxicity rodents DMH purity 99.8% 43397702 ( 1994) core/ guideline [ 870.4300 ( § 83 5)] 0, 100, 300, 1000 mg/ kg/ day Systemic Toxicity NOAEL = 300 mg/ kg/ day Systemic Toxicity LOAEL = 1000 mg/ kg/ day, based on decreases in body weight and body weight gain in females and hyperplasia of submandibular lymph nodes in males.

No evidence of carcinogenicity 870.4100 Chronic toxicity rodents DMH purity 97.3%, 97.1%, and 93.5% 44095901 ( 1996) acceptable/ guideline 0, 100, 320, 1000 mg/ kg/ day Systemic Toxicity NOAEL = 320 mg/ kg/ day Systemic Toxicity LOAEL = 1000 mg/ kg/ day, based on enlarged pituitary glands in decedents of both sexes, increased mortality occurring early in ( especially) females, increased mammary galactoceles in early decedents of both sexes and testicular fibroid vascular degeneration in early decedent males.

At the doses tested, there was not a treatment related increase in tumor incidence after 105 weeks of treatment with DMH. No evidence of carcinogenicity 870.4100 Chronic toxicity dogs DMH purity 97.4% 43813301 ( 1996) NOAEL = greater than 1000 mg/ kg/ day ( highest dose tested LOAEL = greater than 1000 mg/ kg/ day ( not established)

870.4100 Chronic toxicity dogs DMH purity 98.9% 43553101 ( 1995) acceptable Males: 0, 120, 342, or 1506 mg/ kg/ day Females: 0, 121, 414, or 1352 mg/ kg/ day NOAEL = 12000 ppm ( 342 mg/ kg/ day) LOAEL = 40000 ppm ( 1506 mg/ kg/ day), based on enlarged adrenal glands in male dogs, shown by microscopic examination to exhibit hypertrophy in the adrenal cortex.

870.4200 Carcinogenicity rats DMH purity 99.8% 43397702 ( 1994) core/ guideline 0, 100, 300, 1000 mg/ kg/ day See Chronic Toxicity in Rodents  Rats No evidence of carcinogenicity There were no increases in tumor incidences for the DMH treated groups when compared to the control group. This study is classified as Page 19 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results 870.4200 Carcinogenicity rats DMH purity 97.3%, 97.1%, and 93.5% 44095901 ( 1996) acceptable/ guideline 0, 100, 320, 1000 mg/ kg/ day See Chronic Toxicity in Rodents  Rats No evidence of carcinogenicity 870.4300 Carcinogenicity mice DMH purity 99.8% 43397701 ( 1994) Acceptable guideline [ 870.4200 ( § 83 2)] 0, 400, 1850, 8500 ppm ( 0, 100, 300, 1000 mg/ kg/ day) Systemic Toxicity NOAEL = 300 mg/ kg/ day Systemic Toxicity LOAEL = 1000 mg/ kg/ day based on decreases in body weight and body weight gain in males.

No evidence of carcinogenicity 870.4300 Carcinogenicity mice DMH purity 94.9 97.1% 44063901 ( 1996) Acceptable/ guideline [ 870.4200 ( § 83 2b)] 0, 100, 320, 1000 mg/ kg/ day Systemic Toxicity NOAEL = greater than or equal to 1000 mg/ kg/ day ( highest dose tested). Systemic Toxicity LOAEL = greater than 1000 mg/ kg/ day ( not established).

Under the conditions of this study, there was no evidence of carcinogenic potential in mice following treatment with DMH and the dosing was considered adequate because the highest dose of 1000 mg/ kg/ day represents a " limit dose."

No evidence of carcinogenicity Mutagenicity Gene Mutation 870.5100 Ames Salomella Assay DMH purity 97.0% 164036 ( 265457) ( 1986) acceptable 100, 500, 2500, 5000, 10000

g/ plate No evidence of a mutagenic response Gene Mutation 870.5100 Ames Salomella Assay EMH purity not reported 137095 ( 1982) acceptable 67, 333, 1667, 3333 or 6666 µ g/ plate No evidence of a mutagenic response Gene Mutation 870.5100 Ames Salomella Assay DMH purity not reported 137100 ( 1982) acceptable No evidence of a mutagenic response Page 20 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results Gene Mutation 870.5300 In vitro Mammalian Cell Assay EMH purity not reported 137089 ( 1982) acceptable S9: 751, 1001, 1335, 1780, 2373, 3164, 4219, 5000, 5625, 7500 µ g/ mL S9+: 563, 751, 1001, 1780, 2373, 3164, 4219, 5625, 7500, 10,000 µ g/ mL No evidence of genotoxic effects Gene Mutation 870.5300 In vitro Mammalian Cell Assay DMH purity not reported 132165 ( 1983) acceptable S9: 563, 1001, 1335, 1780, 2373, 3164, 4219, 5625, 7500, or 10,000

g/ mL. S9+: 751, 1001, 1335, 1780, 2373, 3164, 4219, 5625, 7500, or 10,000

g/ mL. No evidence of a genotoxic response Cytogenetics 870.5375 In vitro Chromosome Aberration Assay DMH purity 97.0% 164037 ( 265457) ( 1986) acceptable 200, 500, 1000, 2000

g/ mL No cytotoxic or clastogenic effects observed Cytogenetics 870.5375 In vitro Chromosome Aberration Assay 3DEMH purity not reported 40348201 ( 1987) acceptable S9: 8, 15, 30, or 60 µ g/ ml S9+: 15, 30, 60, or 120 µ g/ ml No evidence of structural chromosomal aberration Cytogenetics 870.5375 In vitro Chromosome Aberration Assay EMH purity not reported 137096 ( 1982) acceptable 5739.80, 7653.06, or 10204.08 µ g/ ml A 2 fold or greater increase in the percentage of cells with structural chromosomal aberrations, excluding gaps, was seen at two non consecutive doses after treatment in the presence of S9 mix. No dose response was evident. Results from the treatments in the absence of S9 mix were negative at all doses. No increase in polyploid cells was observed in treated or in positive control cultures. Page 21 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results Cytogenetics 870.5375 In vitro Chromosome Aberration Assay DMH purity not reported 137101 ( 1982) acceptable S9: 11250, 15000, or 20,000 µ g/ ml S9+: 8457.5, 11250, or 15000 µ g/ ml. No evidence of structural chromosomal aberration Cytogenetics 870.5375 In vitro Chromosome Aberration Assay DMH purity not reported MRID: N/ A TRID: 470264004 ( 1986) acceptable 80, 400, or 800 µ g/ ml No evidence of structural chromosomal aberration Cytogenetics 870.5375 In vitro Chromosome Aberration Assay DMH purity 100% MRID: N/ A TRID: 470264005 ( 1986) acceptable 10, 20, 40, 80, 160, 320, 640, 1280, 2560, 5120, 10240, or 20480 µ g/ ml No evidence of structural chromosomal aberration Other Effects 870.5550 Unscheduled DNA Synthesis Assay in Rat Hepatocytes DMH purity 97.0% 164038 ( 265457) ( 1986) acceptable 100, 300, 600, 1000, 3000, 6000, 10000

g/ mL No evidence of a genotoxic response Other Effects 870.5550 Unscheduled DNA Synthesis Assay in Rat Hepatocytes EMH purity not reported 137097 ( 1982) acceptable 0.1, 0.5, 1, 5, 10, or 15 mg/ mL No evidence of a genotoxic response Other Effects 870.5550Unscheduled DNA Synthesis Assay in Rat Hepatocytes DMH purity not reported 132166 ( 1982) acceptable 0.001, 0.01, 0.1, 1, 10, or 20 mg/ ml No evidence of a genotoxic response Page 22 of 57 Guideline No./ Study Type/ Substance Purity MRID No. ( year)/ Classification/ Doses Results Neurotoxicity 870.6300 Developmental neurotoxicity Not required Metabolism/ Pharmacokinetics 870.7485 Metabolism and pharmacokinetics DMH purity radiolabeled 98.8% nonradiolabeled 99.5% 42173901/ 42123802 ( 1991) acceptable 100, 1000 mg/ kg DMH was rapidly absorbed and excreted, primarily in the urine (> 89%). There was little accumulation in the tissues.

1 DMH= dimethylhydantoin 2 EMH= ethylmethylhydantoin 3 DEMH= dichloroethylmethylhydantoin Page 23 of 57 3.2 FQPA Considerations Under the Food Quality Protection Act ( FQPA), P. L. 104 170, which was promulgated in 1996 as an amendment to the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) and the Federal Food, Drug and Cosmetic Act ( FFDCA), the Agency was directed to " ensure that there is a reasonable certainty that no harm will result to infants and children" from aggregate exposure to a pesticide chemical residue. The law further states that in the case of threshold effects, for purposes of providing this reasonable certainty of no harm, " an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children to take into account potential pre and post natal toxicity and completeness of the data with respect to exposure and toxicity to infants and children. Notwithstanding such requirement for an additional margin of safety, the Administrator may use a different margin of safety for the pesticide residue only if, on the basis of reliable data, such margin will be safe for infants and children."

There are no data gaps for reproductive or developmental toxicity testing of 5,5 dimethylhydantoin. Evidence of increased sensitivity was observed in a developmental toxicity study in rabbits ( MRID # 42413101). In this study, treatment related anomalies ( increased incidence of adactyly at 1000 mg/ kg/ day; increased litter and fetal incidence of 27th presacral vertebrae at 500 and 1000 mg/ kg/ day) were observed in fetal rabbits in the absence of maternal toxicity. It has been stated recently that the presence of 27th presacral vertebrae in rabbits may not be considered an effect with an adverse developmental outcome (" Additional Comments on the Revised Report of the Hazard Identification Assessment Review Committee for 5,5 Dimethylhydantoin," Toxicology/ Regulatory Services, June 6, 2003). The available data from the rabbit study, however, do indicate a clear effect level for offspring and a clear no effect level, and these effects occur in the absence of maternal toxicity.

In the reproductive toxicity study in rats ( MRID 43290601), pup effects ( decreased body weight and weight gain) were observed during days 7 21 of lactation in the absence of any parental toxicity. However, the HIARC considered this effect not indicative of susceptibility, based upon the very high dose level at which the effect occurred ( 1322 mg/ kg/ day), the minimal nature of the effect, and the likelihood that the effect was due to a greater dose received by pups from ingestion of both milk and feed during the lactational period. Overall, from examination of the effects of DMH in the standard developmental and reproductive toxicity testing data submitted to the Agency, the HIARC concluded that there was some evidence for increased susceptibility, but based on the selection of a developmental endpoint for dietary risk assessment, an additional safety factor to address FQPA concerns is not necessary, as the developmental endpoint is sufficiently protective of effects that may occur in infants and children from exposure to dimethylhydantoin.

3.3 Dose Response Assessment On July 25, 2000 , the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reviewed the recommendations of the toxicology reviewer for 5,5 dimethylhydantoin with regard to the acute and chronic Reference Doses ( RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk Page 24 of 57 assessments. The potential for increased susceptibility of infants and children from exposure to 5,5 dimethylhydantoin ( a chemical representative of hydantoin toxicity) was also evaluated as required by the Food Quality Protection Act ( FQPA) of 1996. Endpoints were established for the dihalodialklhydantoins and a report issued. Table 4 summarizes the findings of the studies reviewed.

Table 4. Summary of Toxicological Dose and Endpoints for the hydantoins for Use in Human Risk Assessment1 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary females 13 50 years of age NOAEL = 100 mg/ kg/ day UF = 100 Acute RfD = 1 mg/ kg FQPA SF = 1 aPAD = acute RfD FQPA SF = 1 mg/ kg/ day developmental toxicity  rabbit developmental LOAEL = 500 mg/ kg/ day based on skeletal variations. ( MRID 42413101)

Chronic Dietarya all populations NOAEL= 300 mg/ kg/ day UF = 100 Chronic RfD ( gen Pop.) = 3 mg/ kg/ day FQPA SF = 1 cPAD = chr RfD FQPA SF = 3 mg/ kg/ day chronic toxicity/ carcinogenicity  rats LOAEL = 1000 mg/ kg/ day based on decreased body weight/ weight gain and lymph node hyperplasia. ( MRID 43397702)

Chronic Dietarya females 13 50 NOAEL= 100 mg/ kg/ day UF = 100 Chronic RfD ( females 13 50) = 1 mg/ kg/ day FQPA SF = 1 cPAD = chr RfD FQPA SF = 1 mg/ kg/ day developmental toxicity  rabbit developmental LOAEL = 500 mg/ kg/ day based on skeletal variations. ( MRID 42413101)

Short Term Oral ( 1 30 days)

( Incidental) oral study NOAEL= 500 mg/ kg/ day UF = 100 Residential, includes the 1x FQPA SF developmental toxicity  rabbit maternal LOAEL = 1000 mg/ kg/ day based on decreased body weight gain in maternal rabbits. ( MRID 42413101)

Intermediate Term Oral ( 1 to 6 months)

( Incidental) oral study NOAEL= 300 mg/ kg/ day UF = 100 Residential, includes the 1x FQPA SF subchronic oral toxicity  rat LOAEL = 1000 mg/ kg/ day based on decreased body weight and liver weight. ( MRID 42009201) Page 25 of 57 Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Dermal all time periods Short,( 1 30 days), Intermediate, ( 1 to 6 months), Long term (> 6 months) ( Occupational/ Residential) dermal study NOAEL= 390 mg/ kg/ day ( HDT) UF = 100 for all populations MOE = 100 ( Occupational)

Residential, includes the 1x FQPA SF subchronic dermal toxicity  rats No systemic toxicity at the highest dose tested ( MRID 43173901)

Short Term Inhalation ( 1 7 days)

( Occupational/ Residential) Oral NOAEL= 100b mg/ kg/ day ( inhalation absorption rate = 100%) UF = 100 for all populations Residential, includes the 1x FQPA SF developmental toxicity  rabbit developmental LOAEL = 500 mg/ kg/ day based on skeletal effects in offspring. ( MRID 42413101)

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure AThe HIARC selected separate chronic RfDs for females, ages 13 50, and the general population. A separate endpoint for the general population was selected because this was an unusual case where the developmental toxicity NOAEL was lower than the NOAEL from the chronic toxicity studies. The chronic RfD for the general population provides a more appropriate endpoint for individuals other than females Page 26 of 57 3.4 Endocrine Disruption The Agency is required under the Federal Food, Drug and Cosmetic Act ( FFDCA), as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was scientific bases 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).

4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION 4.1 Summary of Registered Uses Halohydantoin is an antimicrobial used to control slime formation in water systems. Registered use sites include cooling water systems, paper and paperboard process water, wastewater treatment, use as an in tank toilet bowl sanitizer, and use in swimming pools. Maximum application rates range from 0.000098 lb ai/ gallon for transportation cleaning water systems and up to 0.00122 lb ai/ gallon for spas. Dihalodialkylhydantoin is formulated in the following forms: tablet, pellet, briquette, granular, ready to use solution, wettable powder, soluble concentrate, and gel. Based on examination of the labels, all formulations are solid formulations ( as opposed to liquid formulations). Despite the large variety of uses, the application of dihalodialkylhydantoin is limited, in general, to two methods: placement of tablets/ ready to use solutions, and pouring of powders/ granules. The application rates used in the assessment are based on the maximum stated application rates on labels. The scenarios considered in the risk assessment are shown in Table 5. These scenarios were selected based on examination of product labels describing uses for the product. Most of the scenarios fall under the " industrial premises and water systems" category. Page 27 of 57 Table 5. Dihalodialkylhydantoins Scenarios Use Site Category Scenario ( Representing high end exposures, but not inclusive of all uses)

Material Preservative ° Household cleaning products ° Paints Industrial Premises and Water Systems ( Industrial) ° Placing the dihalodialkylhydantoin tablets/ pellets into cooling and process water systems ° Pouring dihalodialkylhydantoin granules/ powders into a feeder for cooling and process water systems ° Process water systems includes: recirculating cooling water, oncethrough cooling water, sewage systems, pulp and paper process water, photo processing water, air washers, evaporative coolers, and cannery water Commercial, Institutional and Industrial Premises and Equipment ( Commercial/ Institutiona l Premises) ° Placing dihalodialkylhydantoin tablets into air conditioner/ humidifier drip pans ° Placing dihalodialkylhydantoin tablets in ornamental fountains ° Placing dihalodialkylhydantoin tablets in transportation cleaning water systems Swimming Pools ° Placing or pouring dihalodialkylhydantoin tablets/ granules in swimming pools and hot tubs Residential and Public Access Premises ( Residential) ° Handling of liquid general purpose cleaner ° Placing dihalodialkylhydantoin tablets into toilet tank ° Using brush/ roller/ airless sprayer to apply paint to house ° Toddler exposure to residues of carpet shampoo ° Toddler and adult exposure to treated clothing Agricultural Premises and Equipment ° Pouring dihalodialkylhydantoin granules vehicle and foot baths at the entrances to greenhouses Aquatic Areas ° Placing/ pouring dihalodialkylhydantoin tablets/ granules chemigation/ irrigation systems 4.2 Dietary Exposure/ Risk Pathway 4.2.1 Residue Profile The Agency has carried out the dietary exposure and risk assessment for use of Halohydantoins as a slimicide in food contact paper and paperboard, and for use as a preservative in inorganic slurries which are used as fillers for food contact paper and paperboard. No residue chemistry data were submitted by the registrants, nor were any asked for by the Agency. The Agency has used available methods to estimate dihalodialkylhydantoin residues on food due to Page 28 of 57 migration of these chemicals or their breakdown products, when these substances come into contact with food contact paper and paperboard. In this regard, the Food and Drug Administration has developed guidelines to estimate the residues of pesticides used as slimicides on food contact paper and paperboard. The Agency has decided to use FDA methodology to estimate the residues of such chemicals and/ or their breakdown products on food items and also to determine the Estimated Daily Intake ( EDI) of these pesticides.

4.2.2 Dietary Exposure and Risk EPA used two methods to calculate Dietary exposure to adult populations. In the first method, the following assumptions were made:

° 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; ° All of the active material present in the paper migrates into the food.

In the second ( alternative) method, additional consideration is made as to the type of food that is being contained in the treated paper, and factors such as the quantity of active ingredient in the paper are not considered.

The concentration of halohydantoins in the paper slurry was calculated assuming that the chemical was used both as a slimicide and as a preservative in paper. Although two types of use involve different moities ( dimethylhydantoin for slimicide, methylol dimethylhydantoin for preservative), the concentrations were summed together to determine a total concentration of halohydantoins in the slurry. The EDI was then calculated based on this concentration for both adults and children. The results of the calculations are shown in Tables 6 and 7. Acute dietary exposures were calculated only for the adult female population, as the acute dietary endpoint selected was for females between 13 50 years. The acute dietary exposure for an adult female is 0.046% of the acute PAD. The highest chronic exposure occurred in adult females ( 0.0153% of the chronic PAD).

Table 6. Summary of Dietary Exposure and Risk for Halohydantoins ( 1st Method)

Population Subgroup EDI mg/ day Acute Dietary Chronic Dietary Dietary Exposurea ( mg/ kg/ day) % aPAD b Dietary Exposure ( mg/ kg/ day) a % cPAD b Adult Male 0.0276   3.94x10 4 0.0131 Adult Female 0.0276 4.60x10 4 0.046 4.60x10 4 0.0153 Children 0.0138   1.38x10 3 0.046 a acute and chronic exposure analysis based on daily consumption of 0.00276 mg/ person/ day for adults and body weights of 70 kg and 60 kg for males and females, respectively. For infants/ children, exposure based on daily consumption of 0.0138 mg/ person/ day; and a 10 kg body weight. b% PAD = dietary exposure ( mg/ kg/ day) * 100 / aPAD or cPAD, where aPAD for females between 13 50 years of age = 1.0 Page 29 of 57 mg/ kg/ day and cPAD for the general population = 3.0 mg/ kg/ day Table 7. Summary of Dietary Exposure and Risk for Halohydantoins ( 2nd Method)

Population Subgroup EDI mg/ day Acute Dietary Chronic Dietary Dietary Exposurea ( mg/ kg/ day) % aPAD b Dietary Exposure ( mg/ kg/ day) a % cPAD b Adult Male 0.96   0.0137 0.457 Adult Female 0.96 0.016 1.6 0.016 0.533 Children 0.48   0.048 1.6 a acute and chronic exposure analysis based on daily consumption of 0.96 mg/ person/ day for adults and body weights of 70 kg and 60 kg for males and females, respectively. For infants/ children, exposure based on daily consumption of 0.48 mg/ person/ day; and a 10 kg body weight. b% PAD = dietary exposure ( mg/ kg/ day) * 100 / aPAD or cPAD, where aPAD for females between 13 50 years of age = 1.0 mg/ kg/ day and cPAD for the general population = 3.0 mg/ kg/ day 4.3 Water Exposure/ Risk Pathway AD has considered the registered uses of dihalodialkylhydantoin and the available data on persistence and mobility. The Agency currently lacks sufficient water related exposure data from monitoring to complete a quantitative drinking water exposure analysis and risk assessment for dihalodialkylhydantoin. Therefore, the Agency is presently relying on predicted environmental concentrations ( PECs) of pesticides in surface water to estimate drinking water exposures to dihalodialkylhydantoin.

Use of the pesticide in industrial water systems is expected to impact surface and ground water resources. Out of all the industrial water systems for which the pesticide is used, the oncethrough cooling water system can be expected to have the greatest impact on the water, since the scenario has the greatest quantity of effluent being produced and has the greatest chance of bacterial fouling and need for pesticide. The PDM4 Model was used to estimate exposure from once through cooling tower uses. The details of this model are found in the Environmental Modeling Chapter of this document. A low flow power plant ( 100 + 10 million gallons per day) was used as the scenario providing the maximum concentrations of DMH in the receiving water, e. g., the " worst case" scenario. Actual concentrations in receiving waters are likely lower, and will likely not show an increasing trend as indicated by the model, due to higher flow rates and possible degradation/ dissipation of DMH by mechanisms other than hydrolysis.

A drinking water level of comparison ( DWLOC) is the concentration of a pesticide in drinking water that would result in risk estimates below AD's level of concern, when considering total aggregate exposure to that pesticide from food, water, and residential uses. AD uses DWLOCs in the risk assessment process as a surrogate measure of potential exposure associated with pesticide exposure through drinking water. DWLOC values are not regulatory standards for drinking water; however, they do have an indirect regulatory impact through aggregate exposure and risk assessment. In the absences of monitoring data for a pesticide, the DWLOC is used as a point of comparison against the conservative PEC provided by computer modeling. A DWLOC Page 30 of 57 may vary with drinking water consumption patterns and body weight for specific subpopulations.

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

4.4 Residential Exposure/ Risk Pathway Details of the residential exposure and risk assessment can be found in the Occupational and Residential Exposure ( ORE) Chapter. A summary of the residential assessment is presented below.

4.4.1 Residential Handler Scenarios Dihalodialkylhydantoin may be added as a material preservative to control bacteria and fungi in residential use products. A number of such products have been identified, including household cleaning products, paints, adhesives, and deodorizers. It is also used in pools and spas. For the purposes of this screening level assessment, handler scenarios have been assessed for residential uses that represent high end exposures for the wide variety of products. Therefore, not all products are assessed individually. Table 8 presents the handler scenarios considered to represent the high end of exposure for the residential assessment. Household cleaning products and carpet shampoo have been grouped together. Of these products, household cleaning products, which should yield the greatest amount of handler exposure to the chemical, was selected for analysis. In tank toilet tablets, which are placed into toilet tanks, differ from the other household cleaning products in that they are not liquid. These tablets were evaluated in a separate scenario. Adhesives, caulks, and paints have also been grouped together for evaluation. Of these types of uses, the painting scenario, which should yield the greatest amount of handler exposure to the chemical, was selected for analysis. Finally, the pool/ spa and air conditioner drip pan uses are represented by the application to residential ( i. e., backyard) swimming pools and spas.

Table 8. Residential Handler Scenarios Handler Scenario Typical Products Represented ( but not limited to)

Handling of liquid general purpose cleaner Household cleaning products, carpet shampoo, deodorizer Solid placement of in tank toilet cleaner In tank toilet tablet Painting of a house using brush, roller, or airless sprayer Paint, adhesives, caulk Page 31 of 57 Solid placement into swimming pools & spas Pools/ spas and air conditioner drip pans <IP_ADDRESS> General Purpose Cleaner EPA has estimated dermal and inhalation exposure while wiping and mopping to represent the material preservative use for household cleaning products. The following two scenarios were considered for residential handlers of household cleaning products preserved with halohydantoins:

° Use of household cleaning products by wiping on hard non porous surfaces, and ° Use of household cleaning products by mopping on floors.

An application rate could not be determined from the labels. Therefore, the maximum concentration listed on the label ( i. e., EPA Reg. No. 6836 271) is used along with assumptions on the amount of cleaning product diluted in water. EPA Reg. No. 6836 271 indicates that the product, Dantogard Plus Liquid, can be added to household cleaning products as a preservative at a rate of 0.2 to 2.0 percent by weight. Given that EPA Reg. No. 6836 271 contains 52.4 percent active ingredient associated with this RED case ( i. e., 26.9% 1,3 Bis( hydroxymethyl) 5,5 dimethylhydantoin plus 25.5% 1( Hydroxymethyl) 5,5 dimethylhydantoin) and an assumption that the product has the density of water, yields an estimate of 0.084 lb ai/ gallon of a generic household cleaning product ( i. e., 8 lb/ gal cleaner x 0.02 Dantogard x 0.524 ai). Additionally, it is assumed that 4 ounces of a generic household cleaning product is mixed per gallon of water or 0.0026 lb ai/ gallon of diluted cleaning solution for both mopping and wiping ( i. e., 0.084 lb ai/ gal cleaning product x ( 1/ 128 ounce per gallon conversion) x 4 ounces cleaning product per gallon water).

CMA data were used to determine the unit dermal and inhalation exposures. The no gloved CMA unit exposure data for wiping and mopping were used to determine the dermal and inhalation exposure. It was assumed that 0.5 liter ( 0.132 gallons) is used for wiping and 1 gallon is used for mopping.

The results of the MOE analysis for these scenarios are presented in Table 9. Although the dermal endpoint represents short, intermediate, and long term durations, the exposure duration of most homeowner applications of cleaning products is believed to be best represented by the short term duration. The inhalation endpoint used in the assessment represents only the short term duration. The calculated dermal and inhalation MOEs are not of concern for any of the scenarios ( MOE greater than 10,000 for all scenarios). However, as formaldehyde is a metabolite of halohydantoins, there may be risk associated with this exposure, particularly for use of products that produce a greater chance of inhalation exposure to formaldehyde, such as air fresheners. Risks associated with formaldehyde will be assessed at a later date. Page 32 of 57 Table 9. Calculation of Short term Dermal and Inhalation MOE for Residential Handlers of Cleaning Products a Exposure Scenario Method of Applicati on Dermal Unit Exposure ( mg/ lb ai) b Inhalatio n Unit Exposure ( mg/ lb ai) c Appl. Rate d ( lb a. i./ gal) Amount Treated Dermal Dose ( mg/ kg/ day) f Dermal MOE g Inhalation Dose ( mg/ kg/ day ) h Inhalatio n MOE i Household Cleaning Products Wipes 2870 ( CMA no glove) 67.3 ( CMA) 0.0026 0.5 liter of product ( 0.13 gal) 0.014 28,000 0.00033 300,000 Mopping 71.6 2.38 0.0026 1 gallon 0.0053 73,000 0.00018 570,000 aMOEs rounded to 2 significant figures. bDermal unit exposures are from CMA. cInhalation unit exposures are from CMA. dApplication rates are based on EPA Reg. No. 6836 271. fDermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Appl. rate ( lb ai/ gallon) * gallons handled / Body weight ( 70 kg). gDermal MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ Where short term dermal NOAEL = 390 mg/ kg/ day]. Target MOE is 100. hInhalation dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * max appl rate ( lb ai/ gal) * gallons handled * 1 inhalation absorption] / Body weight ( 70 kg). i Inhalation MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ where short term inhalation NOAEL is 100 mg/ kg/ day]. Target MOE is 100.

<IP_ADDRESS> In Tank Toilet Cleaner All products available for use of dihalodialkylhydantoin as a toilet cleaner are in tablet form. It has been estimated, based on packaging size and the number of tablets per package, that the size of a single tablet is 0.08 pounds ( 98 percent ai). It has been assumed that a single individual maintains a house containing three toilets. In general, the clothing attire worn by homeowners during application is assumed to be short pants and short sleeved shirt. The unit exposure values, which are the same as those used for previous solid place scenarios, are taken from CMA data. However, the " ungloved" scenario solid place unit exposure value from the CMA data is for workers wearing long sleeved shirts and long pants. Lacking better data for this scenario, this value has been used. The estimated short term dermal and inhalation MOEs for this task are 11,000 and 110,000 respectively. Therefore, the risks are not of concern ( i. e., MOEs are greater than the target MOE value of 100). See ORE Chapter for a more detailed review.

<IP_ADDRESS> Painting Two painting scenarios have been analyzed in this assessment: a homeowner using a brush to paint walls in a house, and a homeowner using an airless sprayer to paint a house. The exposures associated with both of these painting scenarios were determined using procedures described in the Residential SOPs ( USEPA, 2000b). In following these procedures, a number of assumptions have been made.

° For paints used with a brush, the amount of paint used is 2 gallons per day. This is based on a 90th percentile value of 8 gallons of latex paint used per year divided by the mean frequency of 4 painting events per year ( USEPA, 1997). Page 33 of 57 ° For painting with an airless sprayer, a homeowner is assumed to use three 5 gallon cans of ready to use product ( i. e., 15 gallons). This is based on a coverage rate of 200 ft2/ gallon and a house size of 40x30x20 ft ( surface area of 2,800 ft2) ( USEPA, 2000b). ° Maximum weight fraction of ai in product is 0.01048. ° Surrogate data from PHED were used for the dermal and inhalation unit exposures. ° The density of the paint was assumed to be 1.24 g/ mL.

The short term dermal and inhalation MOEs calculated for use of a brush were 570 and 120,000, respectively. The short term dermal and inhalation MOEs calculated for use of an airless sprayer were 220 and 5,400, respectively. All MOEs calculated for painting scenarios are greater than the target MOE of 100 and are not of concern. See ORE Chapter for a more detailed review.

<IP_ADDRESS> Swimming Pool and Spa Products available for use of dihalodialkylhydantoin in pools and spas are formulated as solids ( assessment of solids include " place" and " pour" as defined by the CMA exposure data). It has been estimated that a large residential swimming pool has a volume of 20,000 gallons and a large spa contains ~ 1,000 gallons. Application rates for pools and spas are 180 grams/ 10,000 gallons and 85 grams/ 150 gallons, respectively. In general, the clothing attire worn by homeowners during application is assumed to be short pants and short sleeved shirt. The unit exposure values, which are the same as those used for previous solid place scenarios, are taken from CMA data. However, the " ungloved" scenario from the CMA data is for workers wearing long sleeved shirts and long pants. Lacking better data for this scenario, this value has been used. The estimated short term dermal and inhalation MOEs for application to swimming pools are 460 to 3,200 ( solid pour and solid place) and 220,000 to 6,500,000 ( solid pour and solid place) respectively. The short term dermal and inhalation MOEs for application to spas are 140 to 980 ( solid pour and solid place) and 67,000 to 2,000,000 ( solid pour and solid place) respectively. All of the estimated MOEs are greater than the target MOE value of 100, indicating no risks of concern. The results of the residential handlers for swimming pools and spas are included in the occupational section ( see Table 15). See ORE Chapter for a more detailed review.

4.4.2 Residential Postapplication Exposure For the purposes of this screening level assessment, postapplication scenarios have been developed that encompass multiple products representing the high end exposure scenario for all products represented. Table 16 presents the postapplication scenarios considered in this assessment. Three scenarios have been considered: ( 1) exposure to residue from hard floors that have been cleaned/ moped with a general cleaner containing dihalodialkylhydantoin, ( 2) exposure to residue on clothing that has been treated with dihalodialkylhydantoin during textile processing, and ( 3) exposure to swimmers in treated pools. For this screening level assessment, fabric softeners have been grouped with textile processing chemicals for calculating exposure. Page 34 of 57 <IP_ADDRESS> Hard Floor Cleaner There is the potential for toddlers playing on treated floors to be exposed to dihalodialkylhydantoin. Due to limited data, the following assumptions have been made to determine toddler exposure playing on treated hard floors:

° Toddlers ( 3 years old) are used to represent the 1 to 6 year old age group. ° As a conservative estimate, it has been assumed that one gallon of mopping solution can treat 1000 ft2 of floor surface. ° No data could be found regarding the quantity of treatment solution residue left on the floor after treatment. It has been assumed that 25% of the solution remains after the final mop. ° No leaching data were available that could be used to estimate the residue transfer from the hard surface ( i. e., floor). Therefore, the Residential SOP estimate of 10 percent of the amount on the floor is available for dermal transfer.

The short and intermediate term dermal MOE calculated is 700, which is above the target MOE of 100. See ORE Chapter for a more detailed review.

In addition to the dermal exposure from toddlers playing on treated floors, there is the potential for incidental oral exposure via hand to mouth activities. Although residential floors are believed to be washed/ moped on an intermittent basis, facilities such as day care centers may clean the floors more often. Therefore, both the short and intermediate term incidental oral endpoints are provided to assess the potential risks. Due to limited data, the following assumptions from the Residential SOPs ( in addition to the assumptions listed above) have been made to estimate handto mouth exposures for toddlers playing on treated carpets:

° The surface area of the portion of the hand to mouth per event is 20 cm2; ° The number of hand to mouth events per hour is 20; ° Exposure time is 4 hours/ day; ° Saliva extraction efficiency is 50 percent Based on these assumptio ns, the potential dose rate using these assumptions is 0.07 mg/ kg/ day resulting in a hand to mouth MOE for toddlers of 7100 ( short term) and 4300 ( intermediate term).

<IP_ADDRESS> Clothing Although dihalodialkylhydantoin has been listed for use in textile processing, it is unclear in what capacity the chemical is to be used. It has been assumed, for this risk assessment, that the chemical is impregnated into the material in the same manner as a dye would impregnated. Data on which these calculations could be based were generally unavailable; therefore, a number of conservative assumptions have been made: Page 35 of 57 ° 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 0.657 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). ° Based on rough estimates provided by the American Association of Textile Chemists and Colorists ( AATCC), dyes are used on fabric at a rate of about 4% by weight ( AATCC, 2003). A medium sized polo cotton shirt of regular knit construction weighs about 250 g. Assuming that the shirt covers 0.659 m2 of the body's surface area ( based on the mean adult surface area for the torso, including the neck ( USEPA, 1997)), the cloth weight to surface area ratio is 379 g/ m2. If an adult wears clothing of a similar weight over all parts of the body, minus the head ( 1.69 m2 ( USEPA, 1997)), then the weight of clothing worn by an adult is 641 g. Using the same cloth weight to surface area ratio, the weight of clothing worn by a toddler is 214 g. Area mouthed, for lack of data, is assumed to be equivalent to the area of fingers used in the hand to mouth exposure estimates ( i. e., 20 cm2 or 20 cm2 / 10,000 = 0.002 m2). ° No leaching data were available that could be used to estimate a flux rate of the chemical from clothing. It has been conservatively assumed that, over the course of a day, the amount of chemical transferred is the full quantity of chemical present in the clothing. This is a conservative assumption and should not be considered as representative of the true rate at which the chemical would be transferred. However, as a screening level assessment the risks are not of concern.

The dermal MOEs calculated for both toddler and adult scenarios are not of concern ( MOEs = 119 and 185 for toddlers and adults, respectively). The short term incidental oral MOE, as a result of mouthing treated fabric, is not of concern ( MOE = 45,000). The short term NOAELs were used instead of the intermediate term NOAELs because all of the residues were assumed to be available for exposure in one day ( for lack of any residue data). See ORE Chapter for a more detailed review.

<IP_ADDRESS> Swimming There are potential postapplication exposures to dihalodialkylhydantoin associated with use of swimming pools and spas. Because the exposure will most likely be much greater for swimming pools than for spas, based on the amount of time spent in the water, only swimming pool scenarios have been considered.

The SWIMODEL has been used to estimate swimmer exposure/ risk to dihalodialkylhydantoin ( Dang, 1996). Dermal, inhalation, and ingestion routes were considered in the model. Table 13 presents the dermal, inhalation, and ingestion MOEs based on the results of the SWIMODEL. MOEs for all scenarios are much greater than the target MOE of 100. The swimming scenario is unique in that adults ( not just children) are also exposed through the incidental oral route. The HIARC selected the NOAEL of 500 mg/ kg/ day as the incidental oral endpoint for children based on decreased body weight gain in maternal rabbits seen at the next Page 36 of 57 highest dose. However, for the swimming scenario it is important to highlight the fact that the acute dietary NOAEL is 100 mg/ kg/ day based on skeletal effects in offspring at the next highest dose. This may be a more appropriate endpoint for pregnant swimmers. As indicated in Table 10, the MOEs for ingestion would be sufficiently protective of using the more sensitive endpoint for pregnant swimmers. See ORE Chapter for a more detailed review.

Table 10. Margins of Exposure for Swimming Poola Age Type of Swimmer Dermal MOE Inhalation MOE Ingestion MOE Adult Competitive 2500000 52,100 47000 Adult Non competitive 7700000 501,000 280000 Child 7 10 yr Competitive 5800000 98,000 58000 Child 7 10 yr Non competitive 3000000 93,300 29000 aMOE = NOAEL ( mg/ kg/ day)/ Dose( mg/ kg/ day). Dermal route is based on an absorbed dose, and therefore, the oral endpoint is used to setimate risk. The inhalation and ingestion NOAELs are 100 mg/ kg/ day and 300 mg/ kg/ day ( intermediate term), respectively. Target MOE = 100.

5.0 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 dihalodialkylhydantoin, the standards of FQPA must still be met, including " that there is reasonable certainty that no harm will result from aggregate exposure to pesticide chemical residue, including all anticipated dietary exposures and other exposures for which there are reliable information." Aggregate exposure is the total exposure to a single chemical ( or its residues) that may occur from dietary ( i. e., food and drinking water), residential, and other non occupational sources, and from all known or plausible exposure routes ( oral, dermal, and inhalation). Aggregate risk assessment were conducted for acute ( 1 day), shortterm ( 1 30 days), intermediate term ( 1 6 months) and chronic ( several months to lifetime) exposures.

5.1 Aggregate Dietary Risk 5.1.1 Acute Aggregate Risk Assessment The acute aggregate assessment includes dietary and drinking water exposures only. The acute dietary risk estimates from indirect food uses ( i. e., use in food contact packaging and treated articles) are less than 2% of the aPAD in all considered scenarios. Thus, the acute dietary ( food) risk estimate associated with halohydantoins is below the Agency's level of concern. Drinking water exposure is not expected, but could occur from application of the pesticide to industrial water systems. Drinking water monitoring data are not available; therefore, AD calculated drinking Page 37 of 57 water level of comparisons ( DWLOCs), which are discussed below to account for potential drinking water exposures from the exposure from once through cooling tower uses.

The short term EEC for dihalodialkylhydantoin in surface water as estimated from the PDM4 Model was 36 ppb, or 36 ug/ L. Details of this analysis can be found in the Ecological hazard chapter of this RED. As shown in Table 11, the acute DWLOCs are greater than the EEC, indicating that acute aggregate food and drinking water exposure do not exceed the Agency's level of concern.

Table 11. Acute Aggregate Exposure and Risk Population Subgroup aPAD mg/ kg/ day Acute Food Exp1 mg/ kg/ day Max Acute Water Exp2 mg/ kg/ day Surface Water EEC3 mg/ L Acute DWLOC4 mg/ L Potential Risk Concern Females 13 50 years 1.0 4.6x10 4 0.999 0.036 29986 No Females 13 50 years ( alternate FDA method) 0.016 0.984 29520 No 1Acute food exposure = estimated daily intake ( mg/ person/ day) / body weight ( 70 kg) 2 Maximum acute water exposure ( mg/ kg/ day) = [( aPAD ( mg/ kg/ day)  acute food exposure ( mg/ kg/ day)] 3 Based on PDM4 model. 4 Acute DWLOC(

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

g]

Table 12 presents the total chronic dietary exposure estimate for dihalodialkylhydantoin, and the chronic DWLOCs. The chronic PAD and the chronic dietary ( food) exposure ( from Table 7) for that subgroup were used to calculate the chronic DWLOC. Two methods were used to calculated dietary exposure, and calculations are presented using both methods.

Based on the use of the PDM4 model as detailed in the Ecological hazard chapter of this RED, the chronic maximum EEC for dihalodialkylhydantoin in surface water was calculated as 313 ppb, or 313 ug/ L. As shown in Table 12, the chronic DWLOCs are greater than the EEC, indicating that aggregate food and drinking water exposure do not exceed the Agency's level of concern. Page 38 of 57 Table 12. Chronic Aggregate Exposure and Risk Population Subgroup cPAD mg/ kg/ day Chronic Food Exp1 mg/ kg/ day Max Chronic Water Exp2 mg/ kg/ day Surface Water EEC3 mg/ L Chronic DWLOC4 mg/ L Potential Risk Concern General Population 3.0 3.94x10 4 2.999 0.3 104986 No General Population ( alternate FDA method) 0.0137 2.986 104520 No Females 13 50 years 1.0 4.60x10 4 0.999 29986 No Females 13 50 years ( alternate FDA method) 0.016 0.984 29520 No 1Chronic food exposure = estimated daily intake ( mg/ person/ day) / body weight ( 70 kg [ M]; 60kg[ F]) 2 Maximum chronic water exposure ( mg/ kg/ day) = [( cPAD ( mg/ kg/ day)  chronic food exposure ( mg/ kg/ day)] 3 Based on PDM4 model. 4 Chronic DWLOC(

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

g]

5.2 Aggregate Risk 5.2.1 Short and Intermediate term Aggregate Risk Dermal and Inhalation aggregate risks were considered only for the short term in the aggregate risk evaluation. This is because homeowner cleaning scenarios are considered shortterm exposures only and thus do not involve intermediate or long term exposure. Further, not all of the non  dietary scenarios mentioned in this risk assessment have been aggregated, as it is unlikely that all of the scenarios mentioned in the exposure assessment have a reasonable probability of occuring together. For purposes of this aggregate assessment, the dietary exposure ( food + water) is aggregated only with the cleaning scenarios involving wiping of hard surfaces, mopping, and cleaning of toilets for adults. For toddlers, the dietary exposure is aggregated with the single dermal scenario of floor contact, and the dietary exposure is aggregated separately with the single incidental oral floor scenario. This is because the study and endpoint defining the toxicity by the dermal route was different than the study and endpoint defining toxicity by the dermal route. Clothing is not included in the aggregate risk because a screening level assessment was performed in which it was assumed that, over the course of a day, the amount of chemical transferred is the full quantity of chemical present in the clothing. As noted in the ORE chapter, this is a conservative assumption and should not be considered as representative of the true rate at which the chemical would be transferred. Table 13 presents a summary of the aggregate dermal and inhalation short term risk for Page 39 of 57 adults. As shown, the aggregate MOE for both the dermal and inhalation exposure was not of concern.

Calculation of aggregate MOEs for toddlers from dietary exposure and either dermal or inhalation exposure from the floor treatment also showed no risk of concern. Short term aggregate MOEs were calculated as 1000 and 5000 for the dermal and inhalation exposure scenario, while intermediate term aggregate MOEs were calculated as 909 and 3333 for the dermal and inhalation exposure scenario respectively. Page 40 of 57 Table 13 Short Term Aggregate Risk and DWLOC Calculations for Adults ( 1/ MOE Approach  All Target MOEs Identical)

Population Short Term Scenario Target Aggregate MOE MO E food1 MOE dermal2 MOE inhalation 3 Short Term Aggregate MOE ( food and dermal residential) 4 Short term Aggregate MOE ( food +

inhalation residential) 5 MOE water6 Allowable water exposure7 ( mg/ kg/ day) Surface Water EEC8 (

g/ L) DWLOC9 (

g/ L)

Adult 100 3649 6 7090 196000 5988 31250 101 4.9 4 147000 1 MOE food = [( short term oral NOAEL)/( chronic dietary exposure)] Oral NOAEL of 500 mg/ kg/ day with chronic exposure of 0.0137.

2MOE dermal = [( short  term dermal NOAEL)/ dermal residential exposure)] dermal NOAEL of 390 mg/ kg/ day used with total exposure of 0.055 mg/ kg/ day from cleaning scenarios.

3 MOE inhalation = [( inhalation NOAEL)/( high end inhalation residential exposure)] Inhalation NOAEL of 100 mg/ kg/ day used with total exposure of 0.00051 mg/ kg/ day 4 Aggregate MOE ( food and dermal residential) = 1 ÷ [ [( 1 ÷ MOE food) + ( 1 ÷ MOE dermal)]]

5 Aggregate MOE ( food and inhalation residential) = 1 ÷ [ [( 1 ÷ MOE food) + ( 1 ÷ MOE inhalation)]]

6 Water MOE = 1 ÷ [[( 1 ÷ Target Aggregate MOE)  ( 1 ÷ Aggregate MOE ( food and residential)]]

7 Allowable water exposure = Short or Intermediate Term Oral NOAEL ÷ MOE water 8using PDM4 model 9 DWLOC(

g/ L) = [ allowable water exposure ( 4.9mg/ kg/ day) x body weight ( 60kg)]

[ water consumption ( 2L) x 10 3 mg/

g] Page 41 of 57 6.0 OCCUPATIONAL EXPOSURE EPA has assessed the exposures and risks to occupational workers that handle and apply dihalodialkylhydantoin in memorandum attached as ORE Chapter. This section summarizes the results of the occupational exposure/ risk assessment.

6.1 Industrial Processes ( Handlers)

Dihalodialkylhydantoin products are used in a variety of industrial applications, all of which relate to preventing slime formation in water systems. Concentrations of dihalodialkylhydantoin in these products range from 90% to 98%, are generally formulated as tablets, pellets, briquettes, or granules. The remaining formulations are either gels, wettable powders, or ready to use solutions, and all may be considered as solid ( as opposed to liquid) formulations.

The handlers were identified as those individuals who use dihalodialkylhydantoin in industrial/ commercial water systems to limit microbial growth. Systems in which dihalodialkylhydantoin is used include recirculating cooling water, once through cooling water, pulp and paper process water, photo processing water, and transportation cleaning systems. The application rates were assumed to be the maximum rates listed on the product labels. The amount of pesticide handled were based on a report containing use information for selected scenarios related to antimicrobials ( Dang, 1996). The risks were assessed to the handlers using the dermal and inhalation exposure data for loading powder formulations from the proprietary Chemical Manufacturers Association ( CMA) antimicrobial exposure study ( USEPA, 1999).

The following two primary handler exposure scenarios have been identified:

° Placing the dihalodialkylhydantoin tablets/ pellets into cooling and process water systems, and ° Pouring dihalodialkylhydantoin granules/ powders into a feeder for cooling and process water systems.

These two types of exposure scenarios were assessed for each of the water systems in question. The methods for applying gels, briquettes, and ready to use solutions are nearly identical to at least one of the two methods described above, based on the directions on the label. Therefore, although the two exposure scenarios considered include only products that are tablets, pellets, granules, or wettable powders, these scenarios should be sufficient to describe the risks associated with all formulations.

The results of the MOE analysis are presented in Table 14. For industrial use, the shortand intermediate term dermal and inhalation MOEs for the primary handlers wearing long pants, long sleeved shirts, chemical resistant gloves, goggles, and a face shield ( as required by the label) were determined. Dermal MOEs range from a high of 151,000 for solid pour in photo processing water systems, to 76 for solid place in once through cooling water systems. Except for oncethrough cooling water systems, all MOEs are above the EPA required margin of exposure ( 100). Page 42 of 57 Table 14. Short and Intermediate term Risks Associated with Industrial Uses of Dihalodialkylhydantoin Exposure Scenario Method of Application Dermal Dose ( mg/ kg/ day) a Dermal MOE b Inhalation Dose ( mg/ kg/ day) a Inhalation MOE b Recirculating Cooling Water Solid Place 1.0 390 0.0216 4630 Solid Pour 0.0391 9960 0.00127 78800 Once Through Cooling Water Solid Place 5.1 76 0.11 909 Solid Pour 0.20 1950 0.0065 15385 Wastewater Treatment Solid Place 2.5 156 0.054 1850 Solid Pour 0.0979 3990 0.00317 31500 Pulp and Paper Process Water Solid Place 0.333 2730 0.00720 32,400 Solid Pour 0.0130 69,700 0.000423 552,000 Photo Processing Water Solid Place 0.0661 5900 0.00143 70100 Solid Pour 0.00259 151000 0.0000838 1190000 Air Washer Solid Place 2.5 156 0.054 1850 Solid Pour 0.0979 3990 0.00317 31500 Evaporative Cooler Solid Place 2.45 159 0.0529 1890 Solid Pour 0.0959 4070 0.00311 32200 Cannery Water Solid Place 2.45 159 0.0529 1890 Solid Pour 0.0959 4070 0.00311 32200 a Dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Appl. rate ( lb ai/ gallon) * gallons handled / Body weight ( 70 kg). See Occupational and Residential Exposure chapter for specific details. b MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ Where short and intermediate term dermal and inhalation NOAEL = 390 mg/ kg/ day and 100 mg/ kg/ day, respectively]. Target MOE is 100.

6.2 Material Preservatives and Commercial/ Institutional/ Industrial Premises and Equipment and Swimming Pools ( Handlers)

Commercial use of dihalodialkylhydantoin is similar in purpose to industrial use   it is used to prevent slime formation in water systems. In addition, it is used as a material preservative in paints, etc. Six scenarios have been identified to represent the high end exposure potential for these uses:

° Liquid pour of product into paint during manufacturing as a material preservative, ° Solid place of product in air conditioner / humidifier drip pans, ° Solid place of product in ornamental fountains, ° Solid place of product for use in transportation cleaning water systems, ° Commercial painters ( brush/ airless sprayer); ° Solid place/ pour of product in commercial swimming pools and spas.

The material preservative use assessed for paints is believed to be representative of the other preservative uses on the labels such as detergents, fabric softeners, household cleaning Page 43 of 57 products, surfactants, polymer emulsions, coatings, textiles, adhesives, sealants and caulks, and inks. Therefore, a separate commercial use of household cleaning products has not be assessed.

Very little data are available at this time regarding typical amounts of product handled by workers. For a worker performing air conditioning maintenance in a large institution, it has been assumed that 3 air conditioner units were maintained at a time. A large ornamental fountain was assumed to be the same size as an average residential swimming pool. Assumptions for the in bay car wash are based on information from the International Carwash Association and from anecdotal evidence. The EPA calculated the exposures for workers at a commercial/ public swimming pool, using the assumption that a large commercial/ public swimming pool size is 200,000 gallons, and that a large commercial spa's volume is ~ 1000 gallons.

The results of the MOE analysis for both baseline ( ungloved) and PPE ( gloved) scenarios are presented in Table 15 and 16, respectively. For commercial uses, the short and intermediate term dermal MOEs for the handlers wearing PPE range from 140 to 151,000. An MOE lower than the target MOE was found for only one scenario   placing tablets into public swimming pools wearing baseline protection ( MOE= 46). However, the product labels state that gloves should be worn when placing tablets into swimming pools. When gloves are used ( see Table 16) the risks are mitigated for the placing of tablets ( MOE = 7,500).

Metal Working Fluids:

The potential inhalation and dermal exposure may exist when using treated metal working fluid. 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 Chemical Engineering Branch ( CEB) model ( U. S. EPA, 1991). Exposure assumptions used in the model are presented in Dang, 1997. The CEB model uses measured and/ or assumed airborne oil mist concentrations for metal working operations. Since no measured concentrations are available for hydantooins, the high end oil mist concentration is based on the OSHA's Permissible Exposure Limit ( PEL) of 5 mg/ m3 ( NIOSH, 1998). The label indicates that 0.45% ( i. e., 0.0045) of the product is added to metal working fluids and of that, only 52.4% is the active ingredient. Therefore, the upper bound air concentration of hydantoin that a worker is exposed to is 5 mg/ m3 x 0.0045 x 0.524 or an air concentration of 0.012 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 dose was calculated to be 0.0017 mg/ kg/ day, resulting in a long term MOE of 59,000. 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.

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 www. epa. gov/ opptintr/ exposure/ docs/ chemsteer. htm . The weight fraction of hydantoin in metal working fluids is 0.0024 ( 0.0045 formulated product added to oil x 0.524 ai in formulated product = 0.0024). Based on the model for emersion of hands in metal working fluids, the long term Page 44 of 57 dermal dose is estimated at 0.3 mg/ kg/ day. The long term dermal MOE is 1,300 ( i. e., dermal NOAEL of 390 mg/ kg/ day / potential dose of 0.3 mg/ kg/ day). The dermal MOE is above the target MOE of 100, and therefore, the risk is not of concern.

Table 15. Short and Intermediate term Risks Associated with Material Preservatives and Commercial, Institutional, and Swimming Pool Uses of Dihalodialkylhydantoin ( Baseline Clothing Scenario) a Exposure Scenario Method of Application Dermal Dose ( mg/ kg/ day) a Dermal MOE b Inhalation Dose ( mg/ kg/ day) a Inhalation MOE b Material Preservatives and Commercial/ Institutional Premises Material Preservative Pour Liquid 0.2 1900 0.0054 19000 Air Conditioner / Humidifier Drip Pans Solid Place 0.454 860 0.000058 1,730,000 Ornamental Fountains Solid Place 0.771 506 0.0000985 1,010,000 Transportation Cleaning Solid Place 0.148 2630 0.0000189 5,280,000 Swimming Pools / Spas Swimming Pools ( Residential   backyard) Solid Place 0.12 3200 0.000015 6500000 Solid Pour 0.85 460 0.00046 220000 Swimming Pools ( Commercial/ Public) Solid Place 1.2 325 0.000153 653000 Solid Pour 8.46 46 0.00457 21900 Spas Solid Place 0.396 984 0.0000506 1,970,000 Solid Pour 2.8 139 0.00151 66,500 a Dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Appl. rate ( lb ai/ gallon) * gallons handled / Body weight ( 70 kg). See Occupational and Residential Exposure chapter for specific details. b MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ Where short and intermediate term dermal and inhalation NOAEL = 390 mg/ kg/ day and 100 mg/ kg/ day, respectively]. Target MOE is 100. Page 45 of 57 Table 16. Short and Intermediate term Risks Associated with Commercial, Institutional, and Swimming Pool Uses of Dihalodialkylhydantoin ( with gloves only) a Exposure Scenario Method of Application Dermal Dose ( mg/ kg/ day) a Dermal MOE b Inhalation Dose ( mg/ kg/ day) a Inhalation MOE b Commercial/ Institutional Premises Air Conditioner / Humidifier Drip Pans Solid Place 0.017 22,940 0.000058 1,730,000 Ornamental Fountains Solid Place 0.029 13,450 0.0000985 1,010,000 Transportation Cleaning Solid Place 0.0057 68,420 0.0000189 5,280,000 Swimming Pools / Spas Swimming Pools ( Commercial/ Public) Solid Place 0.046 8480 0.000153 653000 Solid Pour 0.0517 7538 0.00457 21900 Spas Solid Place 0.0072 5,420 0.0000506 1,970,000 Solid Pour 0.00814 47,900 0.00151 66,500 a Dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Appl. rate ( lb ai/ gallon) * gallons handled / Body weight ( 70 kg). See Occupational and Residential Exposure chapter for specific details. b MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ Where short and intermediate term dermal and inhalation NOAEL = 390 mg/ kg/ day and 100 mg/ kg/ day, respectively]. Target MOE is 100.

6.3 Agricultural Premises and Aquatic Area Uses ( Handlers)

One agricultural premise use and one aquatic area use have been identified.

° Solid pour/ place of product into chemigation systems, ° Solid pour of product into vehicle and foot baths at greenhouse entrances.

Use of dihalodialkylhydantoin in chemigation systems is via loading of a brominator feed system, through which the product is dispensed via dissolution as feed water is passed through the tank. The amount of dihalodialkylhydantoin that will be used in the irrigation systems will depend greatly on the size of the greenhouse/ nursery and the amount of irrigation necessary for the particular crop/ climatic conditions. The amount of footbaths that should be used for the assessment is also in question. From anecdotal evidence, 1 gal of water is used for each footbath, and 1" of water use for irrigation can be assumed. It has also been assumed that, for chemigation, the product will be used on 10 acres of crop. From these assumptions, the total amount of water applied for chemigation is 270,000 gallons. This scenario is not representative of the available exposure data and the uncertainty level is deemed high. The exposures maybe overestimated because of the extrapolation to such a high amount of water applied. The estimated MOEs are presented in Table 17. All MOEs calculated are of concern ( i. e., MOEs less than the target MOE of 100). No postapplication exposures were considered. Page 46 of 57 Table 17. Short and Intermediate term Risks Associated with Agricultural Premises and Aquatic Areas Uses Exposure Scenario Method of Application Absorbed Dermal Dose ( mg/ kg/ day) a Dermal MOE b Inhalation Dose ( mg/ kg/ day) a Inhalation MOE b Aquatic Areas Greenhouse and Nursery Irrigation Systems Solid Place 27.5 14.2 0.595 168 Solid Pour 1.08 362 0.0289 3460 Solid Place NA NA 0.595 168 Solid Pour 176 2.21 0.0953 1050 Agricultural Premises Greenhouse Foot Bath Solid Pour 0.00002 19,500,000 0.000000536 187000000 0.00327 119000 0.00000177 56600000 a Dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Appl. rate ( lb ai/ gallon) * gallons handled / Body weight ( 70 kg). See Occupational and Residential Exposure chapter for specific details. b MOE = NOAEL ( mg/ kg/ day) / Daily Dose [ Where short and intermediate term dermal and inhalation NOAEL = 390 mg/ kg/ day and 100 mg/ kg/ day, respectively]. Target MOE is 100.

6.4 Postapplication Exposure ( All Occupational Uses)

Postapplication inhalation exposures may occur in the 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 dihalodialkylhydantoin are likely to be minimal compared to handler exposure because of dilution during processing. 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 expected and the vapor pressure of dihalodialkylhydantoin is low.

7.0 ENVIRONMENTAL FATE ASSESSMENT 7.1 Environmental Fate Assessment The Agency does not have a complete database for environmental fate studies on dihalodialkylhydantoin. However, hydrolysis appears to be the major route for dissipation. Dihalodialkylhydantoin has been shown to hydrolyze relatively rapidly. It also degrades rapidly in an anaerobic aquatic environment with an observed half life of less than 4 hours; there are indications that this short half life appeared to be independent of aerobic or anaerobic conditions. The rapid hydrolysis, under abiotic conditions, show half lives of less than 30 days in pH 5, pH 7, and pH 9 ( in buffered solutions), which indicated that hydrolysis is an early step in the degradation process. However, the major degradate, dimethylhydantoin ( DMH), was hydrolytically stable at pH 5, pH 7, and pH 9 and may possibly leach in the soil profile or move with surface water runoff Page 47 of 57 and may pose environmental concerns. An aqueous photolytic study on dimethylhydantoin, conducted at pH 7 and at 25 ± 1

C in the presence of xenon arc as light source, yielded a first order rate constant of 7.89x10 4/ day which translates into a half life of 878 days. Aqueous photolytic stability means that surface water runoff of DMH can be a source of concern for drinking water contamination. The Agency lacks any data on halohydantoins as far as mobility ( soil column leaching) is concerned, as well as binding constants to soils to indicate if dihalodialklhydantoins will be persistent in soils. Because of lack of data, the Agency cannot assess if halohydantoins are bioaccumulative and if these can be a source of concern for the aquatic organisms.

7.2 Environmental Fate and Transport Dihalodialkylhydantoin degrades relatively rapidly in water under abiotic conditions. However, there is environmental concern for soil or surface water contamination from the major degradate DMH, as DMH is hydrolytically and photolytically stable. No additional fate data on dimethylhydantoins are available to further assess fate of this chemical.

8.0 ECOTOXICOLOGY and ENVIRONMENTAL RISK ASSESSMENT 8.1 Ecotoxicity Data:

Halogenated hydantoins show varying toxicity, depending on the number of halogens ( bromine or chlorine) on the molecule. The halogens dissociate from the DMH core upon exposure to water; therefore, DMH was considered to be the moiety of concern for environmental exposure and ecological toxicity. A summary of ecotoxicological endpoints for DMH is provided in the table, below: Page 48 of 57 Table 18: Summary of Ecotoxicity Endpoints Test type Species % a. i. Endpoint EPA MRID # Toxicity Category Avian acute oral ( 71 1/ 850.2100) Northern bobwhite ( Colinus virginianus 96 LD50 = 1839mg/ kg NOEL = 1350 mg/ kg 147319 Slightly toxic Avian dietary ( 71 2/ 850.2200) Northern bobwhite ( Colinus virginianus) 96 LC50 > 5620 ppm 147321 Practically nontoxic Avian dietary ( 71 2/ 850.2200) Mallard ( Anas platyrhynchos) 97.2 > 5000 ppm NOEC = 5000 ppm 432899 03 Practically nontoxic Freshwater fish acute ( 72 1/ 850.1075) Rainbow trout ( Oncorhynchus mykiss) 97.1 LC50 > 972 mg/ L NOEC = 972 mg/ L 423736 01 Practically nontoxic Freshwater fish acute ( 72 1/ 850.1075) Bluegill ( Lepomis macrochirus) 97.1 LC50 > 1,017 mg/ L NOEC = 1,017 mg/ L 423685 01 Practically nontoxic Fish early lifestage ( 72 4/ 850.1300) Fathead minnow ( Pimephales promelas) 99.9 NOEC = 14 mg/ L( dry weight) LOEC = 29 mg/ L 427217 02 ( chronic endpoints are not assigned a toxicity category)

Freshwater invertebrate acute ( 72 2/ 850.1010) Daphnia magna 97.1 EC50 > 1070 mg/ L NOEC = 1070 mg/ L 423736 03 Practically nontoxic Marine/ estuari ne fish acute ( 72 3a/ 850.1075) Sheepshead minnow ( Cyprinodon variegatus) 97.1 LC50 > 1006 mg/ L NOEC = 1006 mg/ L 423747 01 Practically nontoxic Marine/ estuari ne invertebrate acute ( 72 3c/ 850.1045) Mysid ( Mysidopsis bahia) 97.1 LC50 > 921mg/ L ( limit test) 423736 02 Practically nontoxic Marine/ estuari ne bivalve acute ( 72 3b/ 850.1025) Eastern oyster ( Crassostrea virginica) shell deposition 97.2 EC50 > 125 mg/ L NOEC = 125 mg/ L 432899 02 Practically nontoxic As indicated in the above table, DMH demonstrates low toxicity to terrestrial and aquatic animals. Page 49 of 57 8.2 Environmental Exposure Modeling The PDM4 Model was used to estimate exposure from once through cooling tower uses. The details of this model are found in the Environmental Modeling Chapter of this document. A low flow power plant ( 100 + 10 million gallons per day) was used as the scenario providing the maximum concentrations of DMH in the receiving water, e. g., the " worst case" scenario. Actual concentrations in receiving waters are likely lower, and will likely not show the increasing trend indicated in Table 19, due to higher flow rates and possible degradation/ dissipation of DMH by mechanisms other than hydrolysis. A summary of the estimated environmental concentrations ( EECs) over time is provided below:

Table 19: Summary of Estimated Environmental Concentrations of DMH in Rivers Receiving Outfall from Low Flow Power Plants Using Once Through Cooling Systems Time Period Modeled Peak Concentration of DMH Duration of Peak Concentration 4 days 36.0 ppb 24 hours 30 days 210 ppb 24 hours 60 days 313 ppb 24 hours The model was also used to determine the percent of days per year various " concentrations of concern" were exceeded for several power plant scenarios. Details of these results are provided in the Environmental Modeling Chapter.

8.3 Environmental Risk Assessment a. Terrestrial Organisms:

No model is available to estimate exposure and risk to birds and mammals from discharge of once through cooling system effluents into surface waters. The low EECs, coupled with the generally low toxicity of DMH to birds and mammals, make risk to these organisms unlikely. There are no data available to assess the phytotoxicity of DMH at this time; therefore, the risk to terrestrial/ semi aquatic plants cannot currently be assessed.

b. Aquatic Organisms:

Using the worst case scenario of a low flow power plant using hydantoins for oncethrough cooling system treatment, the following risk quotients ( RQ) were calculated for aquatic organisms: Page 50 of 57 Table 20: Aquatic Organism Risk Quotients for DMH Used in Once Through Cooling of Low Flow Power Plants Endpoint Type Species Value EEC ( from Table 7) RQ ( EEC/ LC50)

Freshwater Fish Acute Rainbow trout ( Oncorhynchus mykiss) LC50 > 972 mg/ L ( MRID  423736 01) 36.0 ppb ( 0.036 mg/ L) 0.000037 Freshwater Invertebrate Acute Daphnia magna EC50 > 1070 mg/ L NOEC = 1070 mg/ L ( MRID 423736 03) 36.0 ppb ( 0.036 mg/ L) 0.000034 Freshwater Fish Chronic Fathead minnow ( Pimephales promelas) NOEC = 14 mg/ L LOEC = 29 mg/ L ( MRID  427217 02) 313 ppb ( 0.313 mg/ L) 0.022 Using the very conservative EECs provided by modeling the low flow power plant, no LOCs are exceeded. Expressed as number of days exceedance, using the most sensitive parameter of 14.0 mg/ L ( 14000 ppb) ( freshwater fish chronic NOEC) as the " concentration of concern" and the exceedance curve generated in the Environmental Modeling chapter, the chance of this concentration being exceeded by any of the power plant scenarios is extremely low, less than once every two years. Other uses of hydantoin products are indoor or contained ( e. g., swimming pool) uses, and should not result in appreciable environmental exposure when products are used as labeled. Risk to freshwater fish and aquatic invertebrates is not anticipated from the use of hydantoins in once through cooling systems. Marine/ estuarine fish are generally less sensitive than freshwater fish to hydantoins, and marine/ estuarine invertebrates are comparably as sensitive to DMH as freshwater invertebrates, so the freshwater RQ are presumed to be protective of marine/ estuarine species. Risk to aquatic plants cannot be assessed due to the lack of phytotoxicity data.

8.4 Endangered Species Considerations The Agency has developed the Endangered Species Protection Program to identify pesticides whose use may cause adverse impacts on endangered and threatened species, 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. Page 51 of 57 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.

Risk to Endangered birds and mammals is not anticipated from the use of hydantoin products due to low exposure and low toxicity. Calculated RQs for fish and aquatic invertebrates from the once through cooling use are well below LOCs for Endangered species; other uses of hydantoin products are indoor or contained ( e. g., swimming pool) uses, and should not result in appreciable environmental exposure when products are used as labeled. Therefore, risk to Endangered fish and aquatic invertebrate species is not anticipated from the use of hydantoin products. Risk to Endangered plants cannot be addressed due to the lack of phytotoxicity data.

9.0 INCIDENT REPORT ASSESSMENT Dihalodialkylhydantoin is an active ingredient used in a variety of products ( e. g. for treatment of swimming pools, spas and hot tubs, and toilet bowl water. The purpose of this chapter is to review the evidence of health effects in humans resulting from exposure to dihalodialklhydantoins. In particular, the acute and chronic toxicity, teratogenic/ reproductive effects, and carcinogenicity are discussed.

Two approaches are used in this section:

° The potential health effects of dihalodialkylhydantoin in humans, reported as incident reports from different sources, are summarized.

° A literature search of chronic health effects associated with dihalodialkylhydantoin exposure, including results of epidemiological studies, are summarized.

There are many incidences that have been reported associated with exposure to end use products containing dihalodialklhydantoins. Dermal, ocular, and inhalation are the primary routes of exposure. Most of the incidences are related to irritation and/ or allergic type reaction. The most common symptoms reported for cases of dermal exposure were skin irritation/ burning, rash, itching, skin discoloration/ redness, blistering, allergic type reactions including hives/ welts, allergic contact dermatitis, and bleeding also have been reported. The most common symptoms reported for cases of ocular exposure were eye irritation/ burning. Eye pain and swelling of eyes also has been reported in some incidences.

The most common symptoms reported for cases of inhalation exposure were respiratory irritation/ burning, irritation to mouth/ throat/ nose, coughing/ choking, shortness of breath, dizziness, flu like symptoms, headache. Seizure and heart palpitation also have been reported.

Although oral exposure is considered a minor route of exposure for Dihalodialkylhydantoin use, irritation to mouth/ throat/ nose, vomiting/ nausea/ abdominal pain have been reported in the cases of ingestion. Page 52 of 57 9.1 Incident Report Data Associated with Health Effects of Dihalodialkylhydantoin Exposure The following databases have been consulted for the poisoning incident data on the active ingredient dihalodialklhydantoins:

° OPP Incident Data System ( IDS)  The Incident Data System of The Office of Pesticide Programs ( OPP) of the Environmental Protection Agency ( EPA) contains reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or allegations only, unless otherwise stated. Typically, no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or enough documentation, risk mitigation measures may be suggested. A total of 126 individual incident cases submitted to the EPA Office of Pesticide Programs involving the use of dihalodialkylhydantoin containing products were reviewed to determine the effects of exposure to dihalodialklhydantoins. The reported routes of exposure for the 126 cases were dermal ( 44%), ocular ( 25%), ingestion ( 7%) and inhalation ( 43%).

° Poison Control Centers  as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1996 for all pesticides. Most of the national Poison Control Centers ( PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System, which obtains data from about 65 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc. All the incidences reported in the Poison Control Center database were included in the OPP's IDS. No additional data were reported in the Poison Control Center database covering the years 1993 1996.

° California Department of Pesticide Regulation  California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure ( worker activity), type of illness ( systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided. Detailed descriptions of 28 cases with a definite, probable, or possible relationship to dihalodialkylhydantoin were submitted to the California Pesticide Illness Surveillance Program and reviewed. All the reported cases were occupational related. The illness types were classified as being systemic ( 5 cases), eye ( 16), skin ( 8), respiratory ( 12), or a combination of the types.

° National Pesticide Telecommunications Network ( NPTN)  NPTN is a toll free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984 1991, inclusive, has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others. No incidences were reported in the NPTN database Page 53 of 57 related to dihalodialklhydantoin exposure.

° Published Incident Reports  Several papers have been published outlining the problems associated with the use of dihalodialklhydantoin. The chemical 1 bromo 3 chloro 5,5 dimethylhydantoin ( BCDMH), one of four dihalodialkylhydantoin. BCDMH is commonly used as an alternative to chlorine in the disinfection of swimming pools. Sodium bromide is one end product of BCDMH disinfection. Several case studies of exposure to BCDMH have been reported in the literature and some are briefly summarized here:

° A survey performed in 1990 revealed that in chlorinated pools, rashes occurred in 2 out of 1.7 million bathers, while in BCDMH pools, rashes occurred in 43 out of 31,000 bathers. The incidence of rashes appears to occur more often in the elderly population; approximately 20% in those over 70 years old and only about 0.2% in those under 20 years old. The reaction to BCDMH is considered to be an irritant contact dermatitis, rather than an allergic mechanism, since people who develop rashes do not test positive to patch tests of a 1% solution of DiHalo ® , a formulation of BCDMH ( Penny, 1991).

° Rycroft and Penny ( 1983) reported cases happened in swimming pools in United Kingdom. Nineteen brominated pools were visited and 65 patients with rashes were seen. In one swimming pool, it was estimated that at least 5% of users of the pools had experienced itching after swimming and most had developed rashes.

° Penny ( 1999) summarized the typical features of a BCDMH. In most cases, exposure to BCDMH results in the development of an intensely itchy rash which starts within 12 hours of the exposure. Progression of the reaction leads to widespread dermatitis of varying distributions which occasionally include lesions and can be associated with fever and malaise. Re exposure can be considerably hazardous especially shortly after occurrence of the rash and many people find the symptoms so severe that they can no longer swim in pools treated with BCDMH. In some cases, people who develop rashes are unable to return to chlorinated pools, which suggests a cumulative trauma irritant dermatitis. It is believed that exposure causes the skin defenses to become damaged and that subsequent exposure to weaker irritants may then cause problems.

° Morgan ( 1983) reported on a local swimming pool which had changed from using a chlorine disinfectant to DiHalo ® . After the switch in disinfectant, 121 people developed a skin reaction. Seven of the 21 affected were children.

° Malteen et al. ( 1985) discussed the effects of exposure to Aquabrom, an antimicrobial agent used in indoor swimming pools. Children and elderly were observed to develop generalized dermatitis after frequent visits to the pools. Once young girl exhibited deviations from normal resistance values after her forearm skin was exposed to the chemical on 4 consecutive days, for 1 hour per day at a .05% concentration. An elderly male exhibited both decreased resistance and water vapor loss after his skin was exposed. Clear deviations from normal were also Page 54 of 57 exhibited by the elderly male subject after 5 consecutive days of 1 hour exposures at a 0.01% concentration of Aquabrom and after 10 days of 1 hour exposure at a 0.002% concentration of Aquabrom. The common usage concentration was reported to be between 0.0003% and 0.001%, which allows for a narrow safety margin between the concentration used here which produced results and the concentrations normally used.

° Loughney and Harrison ( 1998) report a case on a 46 year old physiotherapist who did hydrotherapy work and developed an intense itching and redness of the skin after exposure to the swimming pool used at work. The itching and redness progressed into a persistent itching of the skin with a generalized dry condition. The patient's exposure was determined to be 3 sessions per week in the pool with each session lasting 3 hours. The pool was disinfected by a closed dosing system with a bromine based disinfectant. Workplace visits and interviews with the staff revealed that 6 out of 15 pool users had mild symptoms of skin irritation and one had a severe case of eczema.

9.2 Epidemiological Data Associated with Chronic Health Effects of Halohydantoin Exposure There are no epidemiological data that can be located associated with chronic health effects due to halohydantoin exposure.

10.0 Data Gaps 82 4/ 870.3465 90 Day Inhalation 72 4b/ 850.1400 Invertebrate life cycle testing freshwater TGAI1 123 1/ 850.4225 Seedling emergence dose   response in rice TEP2 123 1/ 850.4250 Vegetative vigor dose response in rice TEP 123 2/ 850.4400 Aquatic vascular plant dose response toxicity Lemna sp. TGAI or TEP 123 2/ 850.5400 Acute algal dose response toxicity  4 species TGAI or TEP Page 55 of 57 11.0 REFERENCES Toxicology  ( References in MRID order)

MRID 00252096 reference information not available MRID 265457( 1) Lawlor, T. E., B. Head, V. O. Wagner, B. E. Carter, S. M. Olewine, and R. J. Plunkett ( 1986). Salmonella/ mammalian microsome plate incorporation mutagenicity assay on 5,5 dimethylhydantoin. Microbiological Associates Inc. Bethesda, MD. Study No. T4638.501. April 1, 1986. Unpublished.

MRID 265457( 2) Putman, D. L., M. J. Zito, L. J. Belinsky, D. O. Azorsa, and F. K. Garvert ( 1986). Chromosome aberration assay in Chinese Hamster ovary ( CHO) cells. Microbiological Associates Inc. Bethesda, MD. Study No. T4638.337. May 1, 1986. Unpublished.

MRID 265457( 3) Curren, R. D., L. Dunn, M. Ernst, N. Durvasula, and V. Portner ( 1986). Unscheduled DNA Synthesis in rat primary hepatocytes. Microbiological Associates Inc. Bethesda, MD. Study No. T3638.380. May 5, 1986. Unpublished MRID 42009201 Federici, T. M. ( 1991). A 90 Day Subchronic Oral Toxicity Study in Rats with DMH. Exxon Biomedical Sciences, Inc. East Millstone, N. J. Lab study No. 169070. July 25, 1991.

MRID 42173901 Selim, S. ( 1991). Absorption, Distribution, Metabolism and Excretion ( ADME) Studies of 5,5 Dimethylhydantoin in the Rat. Lonza Inc. Fair Lawn, N. J. Lab study No. P01982. November 17, 1991.

MRID 42123802 Selim, S. ( 1991). Absorption, Distribution, Metabolism and Excretion ( ADME) Studies of 5 Ethyl, 5 Methylhydantoin in the Rat. Lonza, Inc. Fair Lawn, N. J. Study No. PO2000. November 15, 1991.

MRID 42205401 Beyer, B. K. ( 1992). Developmental Toxicity Study in Rabbits with 5 Ethyl 5 Methylhydantoin ( MEH). Exxon Biomedical Sciences, Inc., Toxicology Laboratory, East Millstone, NJ 08875 2350. February 3, 1992. Laboratory Project ID. 166834RB. MRID 42205401. Unpublished.

MRID 42413101 Nemec, M. D. ( 1992). A Developmental Toxicity study of Dimethylhydantoin in Rabbits. WIL Research Laboratories, Inc. Ashland, OH. Lab study No. WIL 12174. July 23, 1992.

MRID 42432701 Driscoll, C. D. and T. L. Neeper Bradley ( 1992). Developmental toxicity Evaluation of 5,5 Dimethylhydantoin ( DMH) Administered by Gavage to CD Rats. Bushy Run Research Center. Export, PA. Study No. 91N0048. July 30, 1992. Page 56 of 57 MRID 42462502 Nemec, M. D. ( 1992). Two generation Reproduction Study of Dimethylhydantoin Administered Orally in Rats. WIL Research Laboratories, Inc. Ashland, OH. Study No. WIL 12153 August 25, 1992.

MRID 43173901 Chun, J. S. and K. A. Loughran ( 1994). Ninety Day Dermal Toxicity Study with 5,5 Dimethylhydantoin ( DMH) in CD Rats. Bushy Run Research Center, Union Carbide Corp. 6702 Mellon Road, Export, PA. Study No. 92N1016. March 10, 1994.

MRID 43290601 Neeper Bradley, T. and M. Kubena ( 1994). Two Generation Reproduction Study in CD Rats with ( inert ingredient) Administered in the Diet. Bushy Run Research Center. Lab project No. 91N0094. Unpublished.

MRID 43397701 Hermansky, S. J. and Loughran ( 1994). Chronic Dietary Oncogenicity Study with 5,5 Dimethylhydantoin ( DMH). Bushy Run Research Center, Union Carbide Corp. 6702 Mellon Road, Export, PA. Lab study No. 91N0112. August 31, 1994.

MRID 43397702 Hermansky, S. J. and C. L. Benson ( 1994). Chronic Dietary Toxicity/ Oncogenicity Study with 5,5 dimethylhydantoin ( DMH) in Rats. Bushy Run Research Center, Union Carbide Corp. 6702 Mellon Road, Export, PA. Lab project No. 91N00113. August 31, 1994.