UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES March 13, 2002 MEMORANDUM SUBJECT: DIURON: The REVISED HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 035505. Case 0046. DP Barcode D281396.

FROM: Diana Locke Ph D. and Carol Christensen Risk Assessors Reregistration Branch II Health Effects Division ( 7509C)

THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch II Health Effects Division ( 7509C)

TO: Margaret Rice, Chief and Richard Dumas, Team Leader Reregistration Branch II Special Review and Reregistration Division ( 7508W)

The attached REVISED Human Health Assessment for the 3( 3,4 dichlorophenyl) 1,1 dimethylurea ( diuron) RED document was generated as part of Phase 2 of the Interim Public Participation Process. Comments received from the Registrant during the Phase I Error Only review period have been incorporated in this version of the HED Human Health Assessment for Diuron. The Health Effects Division's ( HED) chapter reflects the Agency's current guidelines concerning the retention of the Food Quality Protection Act ( FQPA) factor and risk assessment. This chapter includes a summary of the product chemistry from Ken Dockter, residue chemistry and dietary risk assessment from John Punzi, toxicology review from Yung Yang, occupational and residential exposure from Renee Sandvig and Christina Jarvis, incidence review from Ruth Allen, drinking water exposures from Ibrahim Abdel Saheb [ Environmental Fate and Effects Division ( EFED)], as well as risk assessment and characterization from Diana Locke. Carol Christensen incorporated the changes to the risk assessment in response to error only comments. The Environmental Fate and Effects Division ( EFED) revised the drinking water exposure assessment based upon Registrant comments. The new memorandum entitled " Drinking Water Reassessment for Diuron and its Degradates" dated March 11, 2002 has been incorporated into the Revised HED Chapter of the Reregistration Eligibility Decision Document ( RED) as appropriate. TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . 7 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.3.1 Acute RfD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3.2 Chronic RfD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3.3 Short term ( 1 30 days) Incidental Oral Exposure . . . . . . . . . . . . . . . . . . . . . . 14 3.3.4 Intermediate term ( 1 6 months) Incidental Oral Exposure . . . . . . . . . . . . . . . 15 3.3.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.3.6 Short ( 1 30 days) and Intermediate term ( 1 6 months) Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.3.7 Long term ( 6 months to life time) Dermal Exposure . . . . . . . . . . . . . . . . . . . . 15 3.3.8 Inhalation Exposure ( All Durations) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.3.9 Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 <IP_ADDRESS> Combined Chronic Toxicity/ Carcinogenicity Study in Rats . . . . . . . . 16 <IP_ADDRESS> Carcinogenicity Study in Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 <IP_ADDRESS> Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . 17 3.3.10 Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3.3.11 Mechanism of Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 3.4 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 3.5 Potential Tetrachloroazobenzene Contamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . 22 4.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.2.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4.2.2 Acute Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.2.3 Chronic Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.2.4 Cancer Dietary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.3 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.4 Residential Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.4.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 <IP_ADDRESS> Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 <IP_ADDRESS> Postapplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.4.2 Recreational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4.4.3 Other ( Spray Drift; Farm Worker Children, etc.) . . . . . . . . . . . . . . . . . . . . . . 37 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS . . . . . . . . . . . 40 5.1 Acute Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 5.2 Short term Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 5.2.1 Aggregate Short term Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 5.2.2 Short term DWLOC Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 5.4 Chronic Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 5.4.1 Chronic Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 5.4.2 Chronic DWLOC Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 5.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 5.5.1 Aggregate Cancer Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 5.5.2 Cancer DWLOC Calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 5.5.3 Additional Cancer Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 6.0 CUMULATIVE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 7.0 OCCUPATIONAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 7.1 Agricultural and Non crop/ Utility Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 7.1.1 Handler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 <IP_ADDRESS> Noncancer Exposure and Risk Estimates . . . . . . . . . . . . . . . . . . . . 52 <IP_ADDRESS> Cancer Exposure and Risk Estimates . . . . . . . . . . . . . . . . . . . . . . . 53 7.1.2 Postapplication Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 <IP_ADDRESS> Noncancer Postapplication Exposure and Risk Estimates . . . . . . . . 55 <IP_ADDRESS> Postapplication Exposure and Risk Estimates for Cancer . . . . . . . . . 56 <IP_ADDRESS>.1 Private Growers ( 10 Days Exposure Per Year) . . . . . . . . . . . . . . 56 <IP_ADDRESS>.2 Commercial Farm Workers ( 30 Days Exposure Per Year) . . . . . . 56 7.2 Mildewcide in Paints, Solvents, Adhesives, and Coatings . . . . . . . . . . . . . . . . . . . . . . . 56 7.2.1 Occupational Handler Exposures/ Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 <IP_ADDRESS> Noncancer Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 <IP_ADDRESS> Cancer Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 7.2.2 Postapplication Exposures to Paint Containing Diuron . . . . . . . . . . . . . . . . . . 58 7.3 Algaecide in Commercial Fish Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 7.3.1 Handlers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 <IP_ADDRESS> Noncancer Exposures/ Risks for Pond Uses . . . . . . . . . . . . . . . . . . 59 <IP_ADDRESS> Cancer Exposures/ Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 7.3.2 Occupational Postapplication Exposures to Commercial Fish Ponds . . . . . . . . 60 7.4 Incident Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 8.0 DATA NEEDS/ LABEL REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 1 DIURON 1.0 EXECUTIVE SUMMARY Diuron [ 3( 3,4 Dichlorophenyl) 1,1 dimethylurea] is a pre and post emergent herbicide that controls a wide variety of annual and perennial broad leafed and grassy weeds on both crop and noncrop sites. The mechanism of herbicidal action is the inhibition of photosynthesis. Products containing diuron are intended for both occupational and residential uses. Occupational uses include agricultural food and non food crops; ornamental trees, flowers, and shrubs; paints and coatings; ornamental fish and catfish production; rights of way and industrial sites. Residential uses include ponds, aquariums, and paints. Diuron is formulated as a technical product and formulation intermediate, granular, pellet/ tablet, wettable powder, dry flowable, emulsifiable concentrate, flowable concentrate, soluble concentrate, and ready to use solution. Diuron is applied using the following equipment: groundboom sprayer, aerial equipment, chemigation, rights of way sprayer, high pressure handwand, low pressure handwand, tractor drawn spreader, granular backpack spreader, push type spreader, airless sprayer, paintbrush, shaker type applicator, backpack sprayer, belly grinder, and by hand. Products intended for residential use may be applied using a spoon, by hand, by airless sprayer, or by paintbrush/ roller. Application rates range from 0.8 lbs active ingredient ( ai)/ acre for corn to 87.1 lbs ai/ acre for non crop areas.

Diuron has low acute toxicity ( Toxicity Category 3 4) by the oral, dermal, or inhalation exposure routes. Diuron is not an eye or skin irritant, and not a skin sensitizer. The primary target organs are the hematopoietic system, the bladder, and renal pelvis. Erythrocyte damage resulted in hemolytic anemia and compensatory hematopoiesis, which were manifested as significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit, and increased mean corpuscular volume ( MCV), mean corpuscular hemoglobin ( MCH), abnormal erythrocyte forms, reticulocyte counts, and leukocyte count. Consistent observations of erythrocytic regeneration were seen in chronic toxicity studies in rats, mice and dogs. Gross pathology findings in chronic rat and mouse studies showed increased incidences of urinary bladder edema and wall thickening at high doses. Microscopic evaluation showed dose related increases in the severity of epithelial focal hyperplasia of the urinary bladder and renal pelvis in both sexes. The available data did not reveal any developmental or reproductive toxicity. The HED Carcinogenicity Peer Review Committee ( CPRC) characterized diuron as a " known/ likely" human carcinogen based on urinary bladder carcinomas in both sexes of the Wistar rat, kidney carcinomas in the male rat, and mammary gland carcinomas in the female NMRI mouse. The CPRC also recommended a low dose linear extrapolation model with a Q1 * of 1.91 x 10 2 ( mg/ kg/ day) 1 be applied to the animal data for the quantification of human risk, based on the urinary bladder carcinomas in the rat. Diuron was not mutagenic in bacteria or in cultured mammalian cells and no indication of DNA damage in primary rat hepatocytes was observed. There were marginal statistically significant increases in cells with structural aberrations in a Sprague Dawley rat in vivo bone marrow chromosomal aberration assay. However, the levels of aberrations were within historical 2 control range and assessed negative.

There are no adverse effects attributed to a single exposure identified in any available studies. In addition, diuron has low acute toxicity and no developmental or neurotoxic concerns. Therefore, no acute dietary endpoint was chosen and no acute dietary risk assessment was conducted. Also, no systemic toxicity was observed following repeated dermal dosing up to 1200 mg/ kg/ d. Therefore, no short or intermediate term dermal endpoints were chosen either. The short term incidental oral and the inhalation endpoints are based on decreased maternal body weight and food consumption observed in a rabbit developmental toxicity study [ No Observable Adverse Effect Level ( NOAEL) = 10 mg/ kg/ d]. The intermediate term incidental oral and intermediate term inhalation endpoints are based on hematological effects observed at 10 mg/ kg at 6 months in the chronic rat study. The NOAEL is 1 mg/ kg/ d. The chronic dietary, and long term dermal and inhalation endpoints are based on hemolytic anemia and compensatory hematopoiesis [ Lowest Observable Adverse Effect Level ( LOAEL) = 1.0 mg/ kg/ d]. Since the dose and endpoint for establishing the chronic dietary reference Dose ( RfD) is a LOAEL and a NOAEL was not established, a total uncertainty factor ( UF) of 300 was applied ( UF of 100 to account for both interspecies extrapolation and intra species variability, an additional UF of 3 to account for the lack of a NOAEL). The FQPA Safety Factor Committee recommended that the FQPA safety factor be reduced to 1x since there is no indication of quantitative or qualitative increased susceptibility of rats or rabbits to in utero or postnatal exposure.

Estimated chronic dietary ( food) risk estimates associated with the use of diuron do not exceed the Agency's level of concern for any population subgroup including the most highly exposed subgroup, children ages 1 6 years. The chronic dietary risk for children 1 6 years of age is approximately 7% of the chronic Population Adjusted Dose ( cPAD = 0.003 mg/ kg/ d) and approximately 3% for the general U. S. population. The chronic exposure analysis utilized field trial data which include residues of the parent diuron and its metabolites that are hydrolyzable to 3,4 dichloroaniline ( 3,4 DCA); 3,4 dichlorophenylurea and 3( 3,4 dichlorophenyl) 1 methylurea. The analysis also included processing data, where applicable, and percent crop treated information. Approximately 40% of the exposure to diuron from food is from orange juice and orange juice concentrate. The estimated cancer dietary risk associated with the use of diuron indicates a borderline exceedance above 1 x 10 6 and shows a lifetime risk estimate of 1.68 x 10  6 for the general population but, is not of concern. Though this is the most refined assessment achievable based on the available data/ information, it may also be considered conservative since the exposure analysis used data from field trials conducted at the highest application rates and some processing data are still outstanding.

The Agency has determined that there are potential occupational exposures to mixers, loaders, applicators and other handlers during the usual use patterns associated with diuron. Based on the agricultural and non crop use patterns, 31 major occupational exposure scenarios were identified and are expected to be of short ( 1 30 days) and intermediate ( 1 6 months) term duration. For these durations, the Level of Concern ( LOC) or target Margin of Exposure ( MOE) for occupational workers is 100. MOEs > 100 are not considered to be of concern. Calculations of occupational noncancer 3 risk based on inhalation exposures during agricultural and non crop uses indicate that the inhalation MOEs are more than 100 at the highest possible level of mitigation for all of the short term occupational exposure scenarios, except applying sprays with a high pressure handwand. Sixteen of the 31occupational scenarios were identified as having intermediate term durations of exposure. Of these, none have a non cancer risk of concern for intermediate term inhalation exposure at the highest level of mitigation Potential occupational cancer risks from diuron use were assessed. Both the potential inhalation and dermal exposures were included in the cancer risk assessment and a 4% dermal absorption factor ( upper bound estimate) was applied to dermal exposures. In general, the Agency is concerned when occupational cancer risk estimates exceed 1 x 10 4. The Agency will seek ways to mitigate the risks, to the extent that it is practical and economically feasible, to lower the risks to 1 x 10 6 or less. Out of a total of 31occupational handler scenarios, five have cancer risks greater than 1 x 10 4 at the highest feasible level of mitigation and are of concern. Twenty six of the occupational handler scenarios have cancer risks between 1 x 10 4 and 1 x 10 6 at the highest feasible level of mitigation. Both occupational and residential ( see below) cancer risk assessments are considered protective based on conservative exposure assumptions and a high end dermal absorption factor. The Agency has determined that there are potential postapplication exposures to workers during the agricultural and non crop uses associated with diuron. However, a noncancer postapplication assessment was not conducted, since only dermal exposures are expected and no dermal toxicity is expected from short or intermediate term exposures. For the postapplication cancer assessment, only the crops whose foliage can be sprayed without damage were assessed for postapplication exposure to foliage. The crops that can be sprayed without foliage damage are oats, wheat, birdsfoot trefoil, clover, grass grown for seed, alfalfa, asparagus, pineapple, and sugarcane. Postapplication cancer risks for private growers ( 10 days of exposure per year) were calculated at both the typical application rate and the maximum application rates. All potential cancer risks to private growers were estimated to be less than 1 x 10 4 on the day of treatment. Postapplication cancer risks for commercial applicators ( 30 days per year) were calculated at the typical application rate only. All potential cancer risks to commercial applicators were less than 1 x 10 4 on the day of treatment. Since diuron is applied directly to the soil, there may also be significant postapplication exposure to diuron resulting from contact with treated soil when planting seedlings, moving irrigation lines, or other soil related activities.

Occupational risk assessments were conducted for the use of diuron as a mildewcide in paint. Four occupational handler scenarios were identified for the use of diuron in paint and are expected to be of short and intermediate term exposure duration. The calculations of short and intermediate term inhalation risk from the use of diuron in paint indicate that MOEs are more than 100 at the assessed level of mitigation for all the exposure scenarios, except applying paints with an airless sprayer ( indoors). At the assessed level of mitigation, all four scenarios have potential cancer risks between 1 x 10 4 and 1 x 10 6. However, it is likely that risks are even lower since the cancer assessment incorporated a number of conservative assumptions, such as maximum application rate and an upper bound dermal absorption factor. Occupational postapplication exposures to paint containing diuron may occur in industrial settings around open vats used in paint processing. Inhalation and dermal exposures may also occur while maintaining industrial equipment. No postapplication exposure data 4 have been submitted to determine the extent of postapplication exposures in the industrial settings. Nonetheless, inhalation exposures are expected to be minimal because of the low vapor pressure of diuron ( 2 x 10 7 mm Hg at 30 E C) and aerosol formation is not expected. Dermal postapplication exposures are expected to be lower than when handling/ loading the formulated product. Therefore, postapplication exposures in the industrial settings are expected to be minimal and not of concern.

Occupational risk assessments were also conducted for the use of diuron as an algaecide in commercial fish ponds. Four short term occupational handler scenarios were identified for the use of diuron in commercial fish production and the inhalation MOEs from all four of the commercial fish production scenarios were greater than 100 at the baseline level of mitigation and are not of concern. With maximum mitigation measures ( engineering control level), all four scenarios have estimated cancer risks of less than 1 x 10 6 and are not of concern. Occupational postapplication exposure to diuron in treated fish production ponds is not likely to result in a risk of concern based on the extremely high dilution rate.

The Agency has determined that there are potential exposures to residential mixers, loaders, and applicators during 1) loading ready to use liquids, 2) applying paints/ stains with a paintbrush, and 3) applying paints with an airless sprayer ( outdoor applications only). Residential exposures to diuron are expected to be short term. For residential handlers, calculations of noncancer risk indicate that the inhalation MOEs are more than 100 for all of the exposure scenarios and are not of concern. For residential populations, cancer risks less than 1 x 10 6 are not considered to be of concern. All residential handler scenarios have a potential cancer risk greater than 1 x 10 6 and are of concern, except for the loading ready to use liquids for ponds and aquariums scenario, which is not of concern. The Agency notes that cancer risk estimates to residential handlers of diuron treated paint are based on two exposures per year, which is considered a high end assumption.

Postapplication inhalation or dermal exposure resulting from the indoor use of diuron in paints is also expected to be minimal because of the low vapor pressure of diuron, and because diuron treated paint is only likely to be used in rooms where high humidity is expected ( i. e. a bathroom), and would rarely be used in the entire house. Postapplication inhalation and dermal exposure resulting from the use of diuron in residential ponds and aquariums is also expected to be minimal based on the extremely high dilution rate.

When potential food and residential inhalation exposures were combined for short term aggregate risk estimates, they resulted in aggregate short term MOEs = 1043 and 1045 for adult males and females, respectively. Based on the lack of systemic toxicity expected by the dermal route, it was not appropriate to combine residential dermal and inhalation exposure estimates for risk assessment purposes. Based on labeled uses, no intermediate or long term residential handler, or postapplication exposures of any duration, are expected. Based on supported uses, no incidental oral exposures are expected. Aggregate short term risk estimates for diuron and its metabolites hydrolyzable to 3,4 DCA would combine exposures from food ( average), water, and inhalation. Since measured drinking water 5 data ( monitoring data) are limited and cannot be quantitatively included in the risk assessment, estimates of allowable levels of drinking water were calculated instead. The Agency determined that it was unlikely that more than one of the residential handler activities would occur concurrently during a shortterm time period. Therefore, the Agency took the protective approach of including the exposures from the activity which could potentially result in the most exposure to the homeowner, applying paint with an airless sprayer, in the aggregate assessment. The Agency can conclude with reasonable certainty that residues of diuron plus its metabolites hydrolyzable to 3,4 DCA, resulting from applications of diuron, in drinking water would not likely result in a short term aggregate risk to male and female adult homeowners above the Agency's level of concern.

Aggregate chronic ( noncancer) risk estimates include the contribution of risk from dietary sources ( food + water) and residential sources. However, based on the labeled uses, no long term or chronic residential exposures are expected. Chronic risk estimates from exposures to food alone, do not exceed the Agency's level of concern. However, the Agency cannot conclude with reasonable certainty that residues of diuron, plus its metabolites hydrolyzable to 3,4 DCA, in drinking water would not likely result in an aggregate chronic risk to infants, children, or adults above the Agency's level of concern. The Agency based this determination on a comparison of estimated concentrations of diuron and its metabolites in surface waters to back calculated " drinking water levels of comparison" ( DWLOCs) for diuron plus its metabolites. The estimated ground water concentrations are not expected to exceed the DWLOCs.

Estimated exposure to food alone results in a cancer risk for the U. S. general population that is not of concern. However, residential exposures to applicators applying paint with a paintbrush or airless sprayer may result in potential cancer risks that are of concern. Since potential cancer risks from exposures during residential activities, alone, are of concern, no aggregate cancer risk and no DWLOCs were calculated. Any potential additional exposure to residues in water are of concern.

The Metabolism Assessment Review Committee ( MARC) recommended that a separate dietary cancer assessment be conducted for N'( 3 chlorophenyl) N, N dimethyl urea ( MCPDMU), a potential residue of concern in drinking water, but not found in food ( in plant or animal metabolism studies). The MARC raised concerns for MCPDMU based on an analogous compound, N'( 4 chlorophenyl) N, N dimethyl urea ( monuron). With the exception of the position of the chlorine, the structures are identical. There are cancer concerns for monuron but the target organs are different than those affected by diuron. In the absence of the data needed for a more comprehensive evaluation of MCPDMU, the carcinogenic risk assessment was conducted using the Q1 * of monuron [ 1.52 x 10 2 ( mg/ kg/ day) 1] that is based on male rat liver neoplastic nodule and/ or carcinoma combined tumor rates. The calculated potential cancer risk to the U. S. general population from exposure to MCPDMU in catfish is 1.02 x 10 7 and is not of concern. However, the estimated concentration of MCPDMU in surface water exceeds the DWLOC and is of concern.

In summary, diuron has low acute toxicity and no systemic toxicity was observed following 6 repeated dermal dosing. ! The potential dietary risks, based on food alone, are not of concern. However, the estimated chronic surface water concentrations exceed the DWLOCs. ! The aggregate short term risk ( food + water + residential) is not of concern. ! Occupational noncancer risks based on inhalation exposures during agricultural and non crop uses are not of concern at the highest possible level of mitigation for all of the short term occupational exposure scenarios, except applying sprays with a high pressure handwand. Intermediate term handler risks from agricultural and non crop uses are not of concern at the highest possible level of mitigation for all assessed exposure scenarios. Out of a total of 31 agricultural and non crop occupational handler scenarios, five have potential cancer risks greater than 1 x 10 4 at the highest feasible level of mitigation and are of concern, and 26 have cancer risks between 1 x 10 4 and 1 x 10 6 at the highest feasible level of mitigation. Though there are potential postapplication exposures to workers during the agricultural and non crop uses associated with diuron, a noncancer postapplication assessment was not conducted, since no dermal toxicity is expected from short or intermediate term exposures. All potential postapplication cancer risks to private growers and commercial applicators were estimated to be less than 1 x 10 4 on the day of treatment. ! Occupational risk assessments were also conducted for the use of diuron as a mildewcide in paint. With mitigation, there are no concerns for noncancer risks to occupational handlers exposed to paints containing diuron, except for intermediate term inhalation risks from applying paints with an airless sprayer ( indoors). With mitigation, all occupational mildewcide scenarios have potential cancer risks between 1 x 10 4 and 1 x 10 6. Postapplication exposures are expected to be minimal. ! The occupational handler scenarios identified for the use of diuron in commercial fish production have estimated noncancer risks that are not of concern at the baseline level of mitigation. With maximum mitigation measures, all the fish production scenarios have estimated cancer risks of less than 1 x 10 6 and are not of concern. Postapplication exposures to diuron in treated fish production ponds is minimal and not of concern. ! For residential handlers exposed during paint and, pond and aquarium uses, the noncancer risks are not of concern but, potential cancer risks are greater than 1 x 10 6 and are of concern, except for the loading ready to use liquids for ponds and aquariums scenario, which is not of concern. Postapplication inhalation and dermal exposure resulting from the use of diuron in ponds and aquariums, and from the indoor use of diuron in paints, is expected to be minimal. 7 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION Diuron [ 3( 3,4 dichlorophenyl) 1,1 dimethylurea]

Empirical formula: C9H10Cl 2N2O Molecular weight: 233.1 CAS Registry No.: 330 54 1 PC Code: 035505 NH N CH 3 CH3 O Cl Cl The product chemistry data base is not complete; new confidential statement of formula ( CSF) data are required which reflect preliminary analyses of current products together with discussions of formation of impurities. Trace amounts of a manufacturing impurity, tetrachloro azobenzene ( TCAB), that are of toxicological concern, may be present ( see Section 3.5). The available Generic Series 830 physical and chemical properties of diuron are given below ( Diuron. List A Reregistration Case 0046. PC Code 035505. Product Chemistry Chapter for the Reregistration Eligibility Decision [ RED] Document. DP Barcode D274489. Ken Dockter. June 26, 2001).

Table 1. Generic Series 830 Physical and Chemical Properties GLN MRID Data 6302 Color 1 White 6303 Physical state 1 Crystal 6304 Odor 1 None 7200 MP 1 158o C 7840 Water solubility 1 42 ppm @ 25o C 7950 vp 1 2 x 10 7 mm Hg @ 30o C 7550 Log Pow 2 2.68 6320 Corrosion characteristics 43842201 Not corrosive 8 6313 Stability to normal and elevated temperatures, metals, and metal ions 43842201 Stable for 2 yrs. in double polyethylene bag inside a fiber drum under warehouse conditions. Metals and metal ion data not given.

7050 UV/ Visible absorption NG NG: Not Given.

1 Diuron. CASRN: 330 54 1. http:// toxnet. nlm. nih. gov/ egi bin/ sis/ search.

2 Reddy, K. N. and M. A. Locke. 1996. Molecular Properties as Descriptors of Octanol Water Partition Coefficients of Herbicides. Water, Air and Soil Pollution Vol. 86: pp 389 405.

3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile Diuron is a substituted urea herbicide for the control of a wide variety of annual and perennial broad leaved and grassy weeds on both crop and non crop sites. The mechanism of herbicidal action is the inhibition of photosynthesis. Diuron has a low acute toxicity ( Toxicity Category 3 or 4) by the oral, dermal, or inhalation exposure routes. Diuron is not an eye or skin irritant, and not a skin sensitizer. A rat metabolism study indicated that diuron is rapidly absorbed and metabolized within 24 hours post dose at the low dose and within 48 hours post dose at the high dose. The urine is the major route of excretion in both sexes. A small amount of diuron is detected in the feces. The highest tissue residue levels were found in the liver and kidneys 4 days post 14C diuron dose. The metabolism of diuron involved N oxidation, some ring hydroxylation, demethylation, dechlorination, and conjugation to sulfate and glucuronic acid ( Diuron  Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision. Yung Yang. 0ctober 2, 2001).

The primary diuron target organs are the hematopoietic system, bladder, and renal pelvis. Erythrocyte damage resulted in hemolytic anemia and compensatory hematopoiesis, which are manifested as significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit, and increased mean corpuscular volume ( MCV), mean corpuscular hemoglobin ( MCH), abnormal erythrocyte forms, reticulocyte counts, and leukocyte count. Consistent observations of erythocytic regeneration are seen in chronic toxicity studies in rats, mice and dogs. Gross pathology findings in chronic rat and mouse studies showed increased incidences of urinary bladder edema and wall thickening at high doses. Microscopic evaluation showed dose related increases in the severity of epithelial focal hyperplasia of the urinary bladder and renal pelvis in both sexes. 9 Although the developmental toxicity study in rats is classified as unacceptable, the data base as a whole is adequate for pre and post natal toxicity evaluation and did not reveal developmental or reproductive toxicity. The NOAELs for maternal/ parental toxicity were either less than or equal to the NOAELs for fetal or reproductive toxicity.

The HED Carcinogenicity Peer Review Committee ( CPRC) characterized diuron as a " known/ likely" human carcinogen, based on urinary bladder carcinomas in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse. The CPRC also recommended a low dose linear extrapolation model with a Q1 * of 1.91 x 10 2 ( mg/ kg/ day) 1 be applied to the animal data for the quantification of human risk, based on the urinary bladder carcinomas in the rat. Diuron was not mutagenic in bacteria or in cultured mammalian cells and no indication of DNA damage in primary rat hepatocytes was observed. There were marginal statistically significant increases in cells with structural aberrations in a Sprague Dawley rat in vivo bone marrow chromosomal aberration assay. However, the levels of aberrations were within the historical control range and assessed negative.

The Hazard Identification Assessment Review Committee ( HIARC) determined that a 28 day inhalation study is required to address the concern for inhalation exposure potential based on the use pattern. The registrant can follow the 90 day inhalation study protocol but cease exposure at 28 days. The HIARC also determined that a repeated chronic dog study is not required; a new study would not provide additional data since the observed effects are similar in the rat and the rat is the more sensitive species for this chemical.

Table 2. Acute Toxicity of Diuron Guideline No. Study Type MRID # Results Toxicity Category 870.1100 Acute Oral 00146144 LD50 = 4721 mg/ kg ( M) > 5000 mg/ kg ( F) III 870.1200 Acute Dermal 00146146 LD50 > 2000 mg/ kg III 870.1300 Acute Inhalation 40228803 LC50 > 7.1 mg/ L IV 870.2400 Primary Eye Irritation 00146147 At 48 hrs, all irritation had cleared. III 870.2500 Primary Skin Irritation 00146148 All irritation had cleared by 72 hrs. IV 870.2600 Dermal Sensitization 00146149 Nonsensitizer N/ A 870.6200 Acute Neurotoxicity N/ A Not available N/ A 10 Table 3. Subchronic, Chronic and Other Toxicity Guideline #/ Study Type MRID # ( year)/ Classification/ Doses Results 870.3100 90 Day oral toxicity in rats MRID 40886502 ( 1988) Acceptable/ Nonguideline 0, 4, 10, or 25 ppm ( 0, 0.3, 0.7, or 1.6 mg/ kg/ day for males and 0, 0.3, 0.8, 1.8 mg/ kg/ day for females) The NOAEL can not be determined based on equivocal findings in the urinary bladder including blood vessel dilation, reduced transparency, and increased firmness.

870.3200 21/ 28 Day dermal toxicity in rabbits MRID 42718301 ( 1992) Acceptable/ Guideline 0, 50, 500, or 1200 mg/ kg/ day Systemic toxicity NOAEL = 1200 mg/ kg/ day ( HDT)

870.3465 90 Day inhalation toxicity Not available Not available 870.3700a Prenatal developmental toxicity in rats MRID 40228801 ( 1986) Unacceptable/ Guideline 0, 16, 80, or 400 mg/ kg/ day Maternal toxicity NOAEL = 16 mg/ kg/ day. Maternal toxicity LOAEL = 80 mg/ kg/ day, based on decreased body weight gain and food consumption.

Developmental toxicity NOAEL= 80 mg/ kg/ day. Developmental toxicity LOAEL = 400 mg/ kg/ day, based on whole litter resorption, reduced fetal body weights, and delayed ossification of the vertebrae and sternebrae.

870.3700b Prenatal developmental toxicity in rabbits MRID 40228802 ( 1986) Acceptable/ Guideline 0, 2, 10, or 50 mg/ kg/ day Maternal toxicity NOAEL = 10 mg/ kg/ day. Maternal toxicity LOAEL = 50 mg/ kg/ day, based on decreased body weight and food consumption.

Developmental toxicity NOAEL = 50 mg/ kg/ day ( HDT).

870.3800 Reproduction and fertility effects in rats MRID 41957301 ( 1990) Acceptable/ Guideline 0, 10, 250, or 1750 ppm. ( 0, 0.58, 14.8, or 101 mg/ kg/ day for males and 0, 0.71, 18.6, or 132 mg/ kg/ day for females, respectively. Parental NOAEL = 250 ppm ( 18.6 mg/ kg/ day). Parental LOAEL = 1750 ppm ( 132 mg/ kg/ day) based on decreased body weight, body weight gain, food consumption and food efficiency in both generations.

Reproductive NOAEL = 1750 ppm ( HDT).

Offspring NOAEL = 250 ppm ( 18.6 mg/ kg/ day). Offspring LOAEL = 1750 ppm ( 132 mg/ kg/ day) based on decreased body weight of the F1 and F2 pups during lactation.

870.4200b Chronic toxicity in dogs MRID 00091192 ( 1964) Unacceptable/ Guideline 0, 25, 125, 250, or 2500/ 1250 ppm ( 0, 1.8, 9.4, 18.8, or 93.8 mg/ kg/ day by conversion factor of 0.075) for 24 months. NOAEL = 125 ppm ( 9.4 mg/ kg/ day) in males and 250 ppm ( 18.8 mg/ kg/ day) for females. LOAEL = 250 ppm ( 18.8 mg/ kg/ day) for males and 1250 ppm ( 93.8 mg/ kg/ day) for females based on anemia and body weight losses. Guideline #/ Study Type MRID # ( year)/ Classification/ Doses Results 11 870.4300 Combined Chronic/ Carcinogenicity in rats MRID 40886501,43871901, 43804501, 44302003 ( 1986) Acceptable/ Guideline 0, 25, 250, 2500 ppm ( 0, 1.0, 10, or 111 mg/ kg/ day for males and 0, 1.7, 17, or 203 mg/ kg/ day for females) for 24 months. NOAEL = Not established. LOAEL = 25 ppm ( 1.0 mg/ kg/ day for males and 1.7 mg/ kg/ day for females) based on evidence of hemolysis and compensatory hematopoiesis ( decreased erythrocyte counts, increased reticulocyte counts, increased spleen weight and bone marrow activation).

Dosing was considered adequate.

870.4300 Carcinogenicity in mice MRID 42159501 ( 1983) Acceptable/ Guideline 0, 25, 250, or 2500 ppm ( 0, 5.4, 50.8, or 640.13 mg/ kg/ day for males and 0, 7.5, 77.5, or 867.0 mg/ kg/ day for females) for 24 months NOAEL = 250 ppm ( 50.8 and 77.5 mg/ kg/ day) for males and females. LOAEL = 2500 ppm ( 640.1 and 867.0 mg/ kg/ day) for males and females based on hemolytic anemia and liver toxicity in both sexes and urinary bladder toxicity in females.

Dosing was considered adequate.

870.5100 Gene mutation Salmonella typhimurium reverse gene mutation MRID 00146608 ( 1985), 40228805 ( 1991) Acceptable/ Guideline Independent trials were negative in S. typhimurium strains TA1535, TA97, TA98 and TA100 up to the highest doses tested ( 10 µ g/ plate  S9; 250 µ g/ plate + S9); higher concentrations ( $ 50 µ g/ plate  S9; 500 µ g/ plate + S9) were cytotoxic.

870.5300 Gene mutation Chinese hamster ovary ( CHO)/ HGPRT cell forward gene mutation assay MRID 00146609 ( 1985) Acceptable/ Guideline Independent tests were negative up to cytotoxic doses without S9 activation ( 1.250 mM, . 291 µ g/ mL) and with S9 activation ( 0.5 mM . 117 µ g/ mL).

870.5375 Chromosomal aberration in vivo rat bone marrow cytogenetic assay MRID00146611 ( 1985) MRID 44350301 ( 1997) ( revised) Acceptable/ Guideline The test was negative in Sprague Dawley rats up to cytotoxic doses. A significant ( p< 0.05) increase in the percentage of abnormal cells and the average number of aberrations per cell was seen but only when the data were combined for the high and mid dose males and females at the 48 hour sampling time. A significant positive linear trend was also recorded for the combined ( by sex) aberrations per cell and percentage abnormal cells. Nevertheless, the values fell well within the range of historical control ranges.

870.5375 Mouse Bone Marrow Micronucleus MRID 45494502 ( 1995) 80% ai, 45494503 ( 1995) 42.4% ai, 45494504 ( 1996) 80% ai, 45494505 ( 1998) 98.1% ai Acceptable/ Guideline Preliminary review indicates no evidence of cytogenetic effect in mice administered either technical grade or formulated diuron.

870.5550 Unscheduled DNA Synthesis MRID 00146610 ( 1985) Acceptable/ Guideline The test was negative up to cytotoxic doses ( $ 0.33 mM, equivalent to . 76 F g/ mL). Guideline #/ Study Type MRID # ( year)/ Classification/ Doses Results 12 870.7485 Metabolism and pharmacokinetics MRID 42010501 ( 1996) Acceptable/ Guideline Diuron was rapidly absorbed, metabolized and excreted. Urine was the major route of excretion. Metabolism of diuron involved Noxidation ring hydroxylation, demethylation, dechlorination, and conjugation to sulfate and glucuronic acid.

870.7600 Dermal penetration Not available for diuron. Not available.

3.2 FQPA Considerations There is an acceptable developmental toxicity study in rabbits and an acceptable two generation reproduction study in rats. A developmental toxicity study in rats was classified as unacceptable due to deficiencies in analytical data on the sample analysis; however, the HIARC considered the developmental toxicity study in rats adequate for the FQPA susceptibility assessment based on the observation that the developmental toxicity NOAEL was higher than the maternal NOAEL. The HIARC concluded that a developmental neurotoxicity ( DNT) study is not required.

There is no indication of increased susceptibility to young exposed to diuron in the available studies. In the developmental toxicity study in rabbits, there were no developmental effects at the highest dose tested. In the developmental toxicity study in rabbits and in the 2 generation rat reproduction study, developmental/ offspring effects were observed only at maternally/ parentally toxic dose levels.

No acute or subchronic neurotoxicity study is available. However, there are no neurotoxic signs in any of the submitted subchronic or chronic studies and a literature search did not reveal any studies relevant for assessing the potential neurotoxicity of diuron.

The FQPA Safety Factor Committee concluded that the safety factor could be removed ( 1x) for diuron because ( DIURON  Report of the FQPA Safety Factor Committee. Brenda Tarplee. August 7, 2001):

g) There is no indication of quantitative or qualitative increased susceptibility of rats or rabbits to in utero or postnatal exposure; h) A DNT study with diuron is not required; and i) The dietary ( food and drinking water) and non dietary ( residential) exposure assessments will not underestimate the potential exposures for infants and children.

3.3 Dose Response Assessment 13 Diuron has low acute toxicity and no developmental or neurotoxic concerns. Since no adverse effects attributable to a single exposure were identified in available studies, no acute dietary endpoint was chosen. Also, no systemic toxicity was observed following repeated dermal dosing up to 1200 mg/ kg/ d. Therefore, no short or intermediate term dermal endpoints were chosen either. The shortterm incidental oral and the inhalation endpoints are based on maternal decreased body weight and food consumption observed in a rabbit developmental toxicity study. The chronic dietary, intermediate term inhalation, and long term dermal and inhalation endpoints are based on hemolytic anemia and compensatory hematopoiesis ( DIURON: 2nd Report of the Hazard Identification Assessment Review Committee. Yung Yang. August 28, 2001).

3.3.1 Acute RfD None selected. No adverse effects attributed to a single exposure ( dose) were identified including in the rat or rabbit developmental toxicity studies.

3.3.2 Chronic RfD The study selected was an acceptable/ guideline chronic toxicity/ oncogenicity study ( MRID 40886501; supplemental MRIDs 43871901, 43804501, and 44302003), in which diuron ( 98.7% a. i) was administered to groups of 60 male and 60 female Wistar rats at dietary concentrations of 0, 25, 250, or 2500 ppm ( 0, 1.0, 10, or 111 mg/ kg/ d, respectively, for males and 0, 1.7, 17, or 203 mg/ kg/ d for females, respectively) for up to 24 months. At 12 months, 10 animals/ sex/ group were sacrificed for interim evaluation. Treatment with diuron did not affect the survival of rats. The only reported treatment related clinical sign was reddish discolored or bloody urine in some high dose males. A significant decrease in body weight and body weight gain was seen in both sexes of high dose rats throughout the study.

Diuron affected the hematopoietic system resulting in hemolytic anemia and compensatory hematopoiesis, which were manifested as significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte counts. See Diuron  Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision. Yung Yang. October 2, 2001. Gross pathology showed that the incidence of urinary bladder wall thickening was elevated at 24 months for low and high dose males and high dose females ( p< 0.05 or 0.01). Microscopic evaluation showed that epithelial focal hyperplasia of the urinary tract and renal pelvis increased in severity in both sexes at 12 and/ or 24 months, and increased in incidence in highdose males at 12 months and in high dose females at 12 and/ or 24 months with mid dose females showing an increased incidence at 24 months. Some gross and/ or microscopic changes were also seen in the liver ( increased weight, swelling, discoloration, vacuolar cell degeneration, round cell infiltration, hyperemia), although these effects were not clearly primary effects of treatment.

The dose and endpoint for establishing the chronic RfD is the LOAEL = 1.0 mg/ kg/ day based on 14 Chronic RfD = 1.0 ( LOAEL) mg/ kg/ day = 0.003 mg/ kg/ day 300 ( UF) evidence of hemolytic anemia and compensatory hematopoiesis ( decreased erythrocyte count, increased reticulocyte counts, increased spleen weight and bone marrow activation). A NOAEL was not established. A total UF of 300 was applied ( UF of 100 to account for both interspecies extrapolation and intra species variability, an additional UF of 3 to account for the lack of a NOAEL).

3.3.3 Short term ( 1 30 days) Incidental Oral Exposure The study selected was an acceptable/ guideline developmental toxicity study in rabbits ( MRID# 40228802). In the developmental toxicity study, 24 25 artificially inseminated New Zealand white rabbits per group were administered 0, 2, 10, or 50 mg/ kg/ day of Diuron ( 99% a. i.) by gavage on gestation days ( GD) 7 19, inclusive. On GD 29, all surviving does were sacrificed and examined grossly. One control animal died on GD 0 due to an anaphylactic shock reaction during insemination and one high dose doe aborted and was killed on GD 26. These deaths were considered unrelated to treatment. All remaining animals survived to scheduled termination. No treatment related clinical signs of toxicity were observed in any animal. Maternal liver weights were comparable between the treated and control groups and gross necropsy was unremarkable.

Maternal body weights, body weight gains, and food consumption for the low and mid dose groups were similar to the control levels throughout the study. Absolute body weights of the high dose does were significantly less than the controls on GD 20. Mean body weight gains by the high dose group were significantly reduced as compared with the controls during the intervals of GD 10 13, 13 16, and 7 20 ( weight loss). Weight gain by the high dose group was significantly greater than the controls during the post dosing interval. Food consumption by the high dose group was significantly less than the controls during the GD 13 16, 16 20 and 7 20 intervals. The maternal toxicity LOAEL was established at 50 mg/ kg/ day based on decreased body weights and food consumption during the dosing interval. The maternal toxicity NOAEL was established at 10 mg/ kg/ day.

At cesarean section, the pregnancy rates, numbers of corpora lutea, implantation sites, resorptions, and live fetuses, and fetal body weights were similar between the treated and control groups. No doseor treatment related external, visceral, or skeletal malformations/ variations were observed in any fetus. Therefore, the developmental toxicity NOAEL is $ 50 mg/ kg/ day and the developmental toxicity LOAEL is not identified.

The dose and endpoint selected for risk assessment is 10 mg/ kg/ day ( NOAEL) based on maternal toxicity ( decreased body weights and food consumption during the dosing interval) at 50 mg/ kg/ day ( LOAEL). An UF of 100 to account for both interspecies extrapolation and intra species variability was applied and, since the FQPA safety factor was reduced to 1x, the LOC is 100 and the calculated 15 MOEs must be 100 or above.

NOTE: This study was previously classified as unacceptable/ upgradable based on deficiencies in analytical data of sample analysis. However, the HIARC determined that this study is acceptable because the low nominal level of sample concentration was observed at the low dose only and the NOAEL was established at the mid dose with the LOAEL at the high dose. Therefore, the deficiencies in the analytical data did not affect the results of the study. The systemic toxicity ( expressed as maternal toxicity) is relevant for the populations ( infants and children) and duration ( 1 30 days) of concern.

Short term incidental oral LOC = 100 3.3.4 Intermediate term ( 1 6 months) Incidental Oral Exposure The study selected was the chronic toxicity/ carcinogenicity study in rats ( MRID# 40886501, 43871901, 43804501, 44302003). See Chronic RfD, section 3.3.2. The dose and endpoint for risk assessment was a NOAEL of 1.0 mg/ kg/ day based on hematological effects observed at 10 mg/ kg/ day ( LOAEL) at the 6th month observation. It is noted that this NOAEL/ LOAEL is different from the 24th month observation where the NOAEL is not established ( LOAEL= 1.0 mg/ kg/ day). The endpoint observed at the 6th month observation period is appropriate for this exposure duration and is relevant for the population of concern.

A UF of 100 and the FQPA safety factor of 1x were applied to the risk assessment; therefore the LOC = 100 and the calculated MOEs must be 100 or above.

Intermediate term incidental oral LOC = 100 3.3.5 Dermal Absorption No dermal absorption study is available. An upper bound estimation of dermal absorption of 4% was extrapolated using the maternal LOAEL of 50 mg/ kg/ day from the oral developmental toxicity study in the rabbit and the NOAEL of 1200 mg/ kg/ day ( HDT) from the 21 day dermal toxicity study in the rabbit: the ratio is 50/ 1200 or 4%.

Dermal absorption factor = 4%

3.3.6 Short ( 1 30 days) and Intermediate term ( 1 6 months) Dermal Exposure None selected. No systemic toxicity was seen following repeated dermal dosing at 1200 mg/ kg/ day in the rabbit dermal toxicity study. Also, there is no developmental toxicity concern. No hazard was identified and no quantitative assessment is required. 16 3.3.7 Long term ( 6 months to life time) Dermal Exposure The study selected was the chronic toxicity/ carcinogenicity study in rats ( MRID# 40886501, 43871901, 43804501, 44302003). See Chronic RfD, section 3.3.2. The dose and endpoint selected for risk assessment was 1.0 mg/ kg/ day ( LOAEL) based on evidence of hemolytic anemia and compensatory hematopoiesis ( decreased erythrocyte count, increased reticulocyte counts, increased spleen weight and bone marrow activation). A NOAEL was not established. An additional UF of 3 is applied to account for the lack of a NOAEL in this study. Therefore, the LOC = 300. An MOE < 300 with a dermal absorption factor of 4%, is potentially of concern.

3.3.8 Inhalation Exposure ( All Durations)

Except for an acute inhalation study, for which diuron was placed in Toxicity Category 4 ( LC 50 > 7.1 mg/ L), no other studies are available via this route. Therefore, the HIARC selected the NOAELs from oral studies for risk assessment. Since the doses identified for inhalation risk assessment are from oral studies, route to route extrapolation should be as follows:

The inhalation exposure component ( i. e., F g a. i./ day) using a 100% ( default) absorption rate and application rate should be converted to an equivalent oral dose ( mg/ kg/ day). Then, the oral equivalent doses should be compared to the following NOAELs/ LOAEL to calculate the MOEs.

Short term NOAEL= 10 mg/ kg/ day ( developmental rabbit study) Intermediate term NOAEL= 1.0 mg/ kg/ day ( chronic rat study at 6 month) Long term LOAEL= 1.0 mg/ kg/ day ( chronic rat study)

A UF of 100 for short and intermediate term exposures and a UF of 300 ( additional 3 is applied to account for the lack of a NOAEL in the study) for long term exposures, and the FQPA safety factor of 1x, were applied to the risk assessment; therefore the LOCs = 100, 100, and 300, respectively.

Short term inhalation LOC = 100 Intermediate term inhalation LOC = 100 Long term inhalation LOC = 300 3.3.9 Carcinogenic Potential <IP_ADDRESS> Combined Chronic Toxicity/ Carcinogenicity Study in Rats An acceptable/ guideline combined chronic toxicity/ carcinogenicity study in rats was submitted ( MRID# 40886501, 43871901, 43804501, 44302003). This study showed conclusive evidence for the carcinogenicity of diuron in male and female rats. The incidence of urinary bladder carcinoma was increased at 2500 ppm in both sexes ( males: 33/ 49 vs. 1/ 50 for controls; females: 11/ 50 vs. 0/ 48 for 17 controls; p< 0.01). The malignancies were usually characterized as transitional epithelial carcinomas. The slight increase ( not statistically significant) in the incidence of urinary bladder papillomas and the 3 neoplasms in the renal pelvis in high dose males ( one papilloma and two carcinomas) were also considered treatment related. Dosing was adequate based on numerous toxic effects ( hematological, microscopic, etc.) observed in the animals at all tested doses.

<IP_ADDRESS> Carcinogenicity Study in Mice An acceptable/ guideline carcinogenicity study in mice was submitted ( MRID# 42159501, 43349301). Treatment of up to 102 weeks with 2500 ppm diuron resulted in a significant increase in the incidences of mammary adenocarcinomas ( control, 4%; 2500 ppm, 12%, p # 0.05) and ovarian luteomas ( control, 6%; 2500 ppm, 14%, p # 0.01) in female NMRI ( SPF HAN) mice under the conditions of this study. However, the incidence of mammary adenocarcinoma in high dose females was at or near the high range of incidences seen in historic controls. Dosing was adequate based on observations at the highest dose tested, including decreased body weight of both sexes, increased spleen and liver weights in males and increased incidence of urinary bladder edema and epithelial hyperplasia, thickened mucosa and enlarged uterine horn in females.

<IP_ADDRESS> Classification of Carcinogenic Potential The HED Carcinogenicity Peer Review Committee ( CPRC) met on December 18, 1996 and classified diuron as a " known/ likely" human carcinogen, based on urinary bladder carcinomas in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse ( Carcinogenicity Peer Review of Diuron. Linda Taylor and Esther Rinde. May 8, 1997). The CPRC also recommended a low dose linear extrapolation model with a Q1 * of 1.91 x 10 2 ( mg/ kg/ day) 1 be applied to the animal data for the quantification of human risk, based on the urinary bladder carcinomas in the rat ( Diuron  Revised Q1*, ( 3/ 4' s Interspecies Scaling Factor), 1985 Wistar Rat 2 Year Dietary Study. PC 035505. Bernice Fisher. September 23, 1998).

3.3.10 Mutagenicity Acceptable genetic toxicology studies with diuron have been submitted to the Agency. Findings from these studies indicated the following:

Gene Mutations 1) Salmonella typhimurium reverse gene mutation assay ( MRID# 00146608/ 40228805): Independent trials were negative. 2) Chinese Hamster Ovary ( CHO)/ HGPRT) cell forward gene mutation assay ( MRID# 00146609): Independent tests were negative up to cytotoxic doses with/ without S9 activation.

Chromosome Aberrations 18 3) In vivo bone marrow cytogenetic assay in male Sprague Dawley rats administered 0, 50, 500 or 5000 mg/ kg/ day by single oral gavage ( MRID# 00146611 and 44350301): The test was negative. Signs of overt toxicity ( mortality, body weight loss, ocular discharge, depression, labored respiration, diarrhea, and tremors) were noted at 5000 mg/ kg. Cytotoxicity to the target organ as indicated by the significantly decreased ( p # 0.01) mitotic indices at 24 and 48 hours for high dose males; data combined for both sexes were also significantly decreased at 24 hours. A significant positive linear trend was also recorded for the combined ( by sex) aberrations per cell and the percentage of abnormal cells. Nevertheless, the values fell well within the range of historical controls.

4) Mouse bone marrow micronucleus assays ( MRIDs 45494502 05): Preliminary review indicates no evidence of cytogenetic effect in mice administered either technical grade or formulated diuron.

Other Mutagenic Mechanisms 5) Unscheduled DNA synthesis ( UDS) in primary rat hepatocytes assay ( MRID# 00146610): The test was negative up to cytotoxic doses.

Diuron was not mutagenic in bacteria or in cultured mammalian cells and no indication of DNA damage in primary rat hepatocytes was observed. There were marginal statistically significant increases in cells with structural aberrations in a Sprague Dawley rat in vivo bone marrow chromosomal aberration assay. However, the levels of aberrations were within the historical control range and assessed negative.

3.3.11 Mechanism of Carcinogenicity In 1996, the HED CPRC classified diuron as a " known/ likely" human carcinogen, based on urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse [ Diuron ( PC 035505): Assessment of Mode of Action on Bladder Carcinogenicity. Yung Yang. September 20, 2001]. The CPRC also recommended a low dose linear extrapolation model with Q1 * of 1.91x10 2 ( mg/ kg/ day) 1 be applied to the animal data for the quantification of human risk, based on the urinary bladder carcinomas in the rat.

The registrant has argued that this assessment needed reconsideration for the following reasons ( MRID 45494501): 1) there is no history of human carcinogenesis as a result of diuron exposure, 2) there is a plausible mode of action that discounts the relevance of the rat bladder carcinomas to humans, 3) the mouse historical data were not considered in their entirety and should be considered ` spontaneous," 4) the structure activity relationships actually decrease the weight of the evidence of diuron carcinogenicity rather than increase the weight, and 5) new guidelines are in place that separate the ` known' from ` likely' category.

The Agency's CPRC and Mechanism of Toxicity Assessment Review Committee ( MTARC) have reviewed the submitted information/ data [ Cancer Classification and Mechanism of Action ( MRID 19 45494501) and mutagenicity studies ( MRIDs 45494502 05)], considered the registrant's proposed mechanism of action and determined that diuron will not be re classified at this time ( DIURON: Cancer Classification and Mechanism of Action. Yung Yang. October 10, 2001). The Agency based its decision on: 1) the registrant did not submit any data or information to support its claim that there is no evidence of human carcinogenesis, 2) the submitted information is insufficient to support a mode of action on bladder carcinogenicity for diuron, 3) the mouse historical data have been reviewed and included in the updated DER ( MRIDs 42159501 and 43349301) and the Agency concluded that a positive oncogenic response was seen in high dose female mice compared to the control group, 4) there is insufficient evidence to support the notion that the structure activity relationships actually decrease the weight of the evidence of diuron carcinogenicity rather than increase the weight, and 5) preliminary reviews have been conducted on newly submitted in vivo cytogenetic mutagenicity studies [ Mouse bone marrow micronucleus assays ( MRIDs 45494502 05)] and no evidence of cytogenetic effect was seen in mice administered either technical grade or formulated diuron; however, these studies provide little additional information since the CPRC has already concluded that there is little or no concern for the mutagenic activity of diuron. 20 Table 4. Summary of Toxicology Endpoint Selection EXPOSURE SCENARIO DOSE ( mg/ kg/ day) ENDPOINT STUDY Acute Dietary No appropriate endpoint attributed to a single dose was identified. Therefore, an acute RfD was not established.

Chronic Dietary LOAEL = 1.0 UF = 300 FQPA SF = 1* Evidence of hemolytic anemia and compensatory hematopoiesis ( significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit, and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte count) Combined chronic toxicity/ carcinogenicity study in rats MRID 40886501, 43871901, 43804501, 44302003 Chronic RfD = 0.003 mg/ kg/ day cPAD = 0.003 mg/ kg/ day Incidental Oral, short term ( 1 30 days) NOAEL= 10 UF = 100 FQPA SF = 1* Decreased body weight and food consumption at maternal LOAEL of 50 mg/ kg/ day. Developmental toxicity study in rabbits MRID 40228802 LOC for residential MOE = 100 Incidental Oral, Intermediate Term ( 1 6 months) NOAEL = 1.0 UF = 100 FQPA SF = 1* Altered hematological parameters at LOAEL of 10 mg/ kg/ day, observed at 6 months. Chronic toxicity/ carcinogenicity study in rats MRID 40886501, 43871901, 43804501, 44302003 LOC for residential MOE = 100 Dermal, Short Intermediate Term No systemic toxicity was seen following repeated dermal dosing at 1200 mg/ kg/ day in the rabbit dermal toxicity study. Also, there is no developmental concern. No hazard was identified and no quantitative assessment is required.

Dermal, Long Term ( 6 months to lifetime

Absorption factor of 4% used for conversion from oral to dermal route LOAEL = 1.0 UF = 300 FQPA SF = 1* Evidence of hemolytic anemia and compensatory hematopoiesis ( significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit, and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte count). Chronic toxicity/ carcinogenicity study in rats MRID 40886501, 43871901, 43804501, 44302003 LOC for occupational/ residential MOE = 300 Inhalation, Short Term ( 1 30 days)** NOAEL = 10 UF = 100 FQPA SF = 1* Decreased body weight and food consumption at maternal LOAEL of 50 mg/ kg/ day. Developmental toxicity study in rabbits MRID 40228802 LOC for occupational/ residential MOE = 100 21 Inhalation, Intermediate Term ( 1 6 months)** NOAEL = 1.0 UF = 100 FQPA SF = 1* Altered hematological parameters at LOAEL of 10 mg/ kg/ day, observed at 6 months. Chronic toxicity/ carcinogenicity study in rats MRID 40886501, 43871901, 43804501, 44302003 LOC for occupational/ residential MOE = 100 Inhalation, Long Term ( 6 months to life time)** LOAEL = 1.0 UF = 300 FQPA SF = 1* Evidence of hemolytic anemia and compensatory hematopoiesis ( significantly decreased erythrocyte counts, hemoglobin levels, and hematocrit, and increased MCV, MCH, abnormal erythrocyte forms, reticulocyte counts, and leukocyte count). Chronic toxicity/ carcinogenicity study in rats MRID 40886501, 43871901, 43804501, 44302003 LOC for occupational/ residential MOE = 300 Cancer Known/ likely human carcinogen Urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinomas in the male rat ( a rare tumor), and mammary gland carcinomas in the female NMRI mouse Carcinogenicity study in rats and mice MRID 40886501, 43871901, 43804501, 44302003 and 42159501, 43349301 Q1* = 1.91 x 10 2 ( mg/ kg/ day) 1 * FQPA SF only applied to residential and other non occupational exposures ** An oral endpoint was used for inhalation exposure: inhalation exposure assumed equivalent to oral exposure.

3.4 Endocrine Disruption EPA is required under the 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).

When the appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, diuron may be subjected to additional screening and/ or testing to better 22 characterize effects related to endocrine disruption.

At this time, neither the available submitted studies on diuron nor the literature show any indication of endocrine disruption effects.

3.5 Potential Tetrachloroazobenzene Contamination Diuron has been reported to contain trace amounts of a manufacturing impurity, 3,3', 4,4' tetrachloroazobenzene, a. k. a. TCAB, which has been shown to be a cytochrome P450 enzyme inducer. A summary of short term bioassays compiled by the National Toxicology Program states that ( TOX 65, 1998),

" 3,3', 4,4' tetrachloroazobenzene caused typical dioxin like effects, such as thymic atrophy, an increase in liver weights, induction of hepatic cytochrome P4501A, and decreased mean body weight gains. Furthermore, in the 13 week studies, a sharp decrease in circulating thyroxine concentrations was observed even at the lowest dose ( 0.1 mg/ kg) tested in rats. Other effects included a decrease in epididymal spermatozoal concentration in mice, major effects on the hematopoietic system, and increased incidences of hyperplasia of the forestomach in 3 and 30 mg/ kg males and 30 mg/ kg females. A no observable adverse effect level ( NOAEL) was not reached in rats. The NOAEL in mice was 0.1 mg/ kg. Comparison of various dioxin like effects in these studies with those reported in the literature indicate that 3,3', 4,4' tetrachloroazobenzene is six to two orders of magnitude less potent than 2,3,7,8 tetrachlorodibenzo p dioxin."

Chronic toxicity/ carcinogenicity studies are not available for TCAB. The specific endpoint( s) and related dose levels that may be observed in chronic toxicity studies, or the specific carcinogenic potential of this compound is not known. However, since it is assumed that TCAB may have been present in all diuron toxicological test materials, including the test material for the chronic toxicity/ carcinogenicity studies, the Agency believes that the risks from exposure to diuron ( including carcinogenic potential) have not been underestimated.

4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION 4.1 Summary of Registered Uses Diuron is an herbicide currently registered for use on a variety of fruit, vegetable, nut, and field crops. At this time, products containing diuron are intended for both occupational and non occupational ( residential) uses. Occupational uses include agricultural food and non food crops; fruit and nut crops; ornamental trees, flowers, and shrubs; paints and coatings; ornamental fish and catfish production; and non crop areas such as rights of way and industrial sites. Non occupational uses include residential ponds, aquariums, and paints. 23 Diuron is a pre and post emergent herbicide that controls a wide variety of annual and perennial broad leafed and grassy weeds on both crop and non crop sites. Examples of the types of weeds that diuron is used to control include ( but are not limited to) the following: button weed, pigweed, carpetweed, poison ivy, milkweed, vines, chickweed, ragweed, aster, thistle, dandelion, morning glory, mustard, wild turnip, pepper weed, wild oat, Bermuda grass, orchard grass, crabgrass, love grass, fescue, velvet grass, rye grass, witch grass, and blue grass. Diuron is also used as a mildewcide in paints and an algaecide in ponds.

Diuron is formulated as a technical product and formulation intermediate ( 98.8 to 80 % ai), granular ( 0.2 % to 20 % ai), pellet/ tablet ( 0.51 % to 19 % ai), wettable powder ( 25 % to 80 % ai), dry flowable ( water dispersible granules; 40 % to 80 % ai), emulsifiable concentrate ( 2 % to 80 % ai), flowable concentrate ( 19 % to 47.5 % ai), soluble concentrate ( 5.1 % to 40 % ai), and ready to use solution ( 0.67 % to 19 % ai). Application rates range from 0.8 to 87.1 lbs ai/ acre.

Equipment for commercial use includes groundboom sprayer, aerial equipment, chemigation, rightsof way sprayer, high pressure handwand, low pressure handwand, tractor drawn spreader, push type spreader, airless sprayer, paintbrush, shaker type applicator, backpack sprayer, backpack granular spreader, belly grinder, and by hand. Products intended for residential use may be applied using a spoon, by hand, by airless sprayer, or by paintbrush/ roller.

Diuron is generally applied to the soil prior to germination of weed seeds or when weeds are in an active growth stage. Diuron may also be applied as a post emergent herbicide, either as a directed spray or over the top of resistant foliage. It may be applied one to two times per season, with the exception of sugarcane ( three times per season) to control a wide range of broad leafed and grassy weeds.

Occupational Use Sites The occupational crop use sites in this assessment have been grouped as follows:

Vegetables and Field Crops: alfalfa ( forage), artichokes, asparagus, barley, blackberries, boysenberries, blueberries, cane berries, corn ( field corn only), cotton, currants, dewberries, elderberries, gooseberries, grapes, huckleberries, loganberries, mint, oats, olives, peas ( field or southern), pineapples, raspberries, sorghum, sugarcane, and wheat.

Fruit and Nut Trees ( orchard crops), including apples, bananas, citrus, filberts ( hazelnuts), macadamia nuts, pecans, peaches, pears, papayas, plantains, and walnuts.

Ornamental Trees, Flowers, and Shrubs, including shade trees, citrus trees ( non bearing and nursery stock), tree plantings ( including ash, cedar, elm, oak, pine, poplar, and fir), Easter lilies, gladiolus, iris, lilies, narcissus, and ornamental grasses. 24 Cotton Defoliant ( state labels only)

Non crop Areas, including rights of way; industrial sites; drainage systems; irrigation systems; lakes, ponds, holding basins, and other similar sites that have been drained; airports and landing fields; fire plugs; cable closures; and warehouses.

Paints, Solvents, Adhesives, and Coatings Ornamental Fish and Catfish Ponds Residential Use Sites Residential Ponds and Aquariums Paints, Solvents, Adhesives, and Coatings 4.2 Dietary Exposure/ Risk Pathway Tolerances range from 0.05 ppm ( meats, milk) to 7 ppm in/ on asparagus ( Residue Chemistry Chapter for the Diuron Reregistration Eligibility Decision Document. John Punzi. July 29, 2001). Diuron is applied 1 or 2 times per season using single application rates of approximately 1 pound per acre. Usage data concerning domestic percent crop treated data from the Biological and Economic Assessment Division ( BEAD) indicate that ~ 50% of citrus, 25% of berries, 15% of nuts, 10% of cotton, grapes, peaches, or pome fruit, and 1% of field crops are treated with diuron. Nearly 10 million pounds of diuron are used annually in the United States.

Tolerances for residues of diuron in/ on plant and animal commodities are established under 40 CFR § 180.106. Diuron tolerances are currently expressed as diuron per se. The Agency is recommending that the tolerance expression for diuron be revised to include metabolites hydrolyzable to 3,4 dichloroaniline ( 3,4 DCA). This determination is based on the results of the reviewed plant and animal metabolism studies. Adequate analytical methods exist for data collection and tolerance enforcement in plants. Independent laboratory validation of the enforcement method is required for livestock methods prior to Agency validation. Label revisions are required for many crops in order to reflect the parameters of use patterns for which residue data are available. Many of the revisions concern retreatment intervals, preharvest intervals ( PHI's) and rotational crop restrictions.

The Metabolism Assessment Review Committee ( MARC) met on July 3, 2001 to discuss the metabolism of diuron in plants and animals from the results of wheat, corn, orange, ruminant, and poultry studies together with the environmental fate studies conducted in soil and water ( Diuron Metabolism Committee Briefing Memo. John Punzi. August, 27, 2001). 25 NH N O Cl Cl CH 3 CH 3 NH NH O Cl Cl CH 3 NH NH 2 O Cl Cl The 14C containing residues that were identified in plants ( Table 5): diuron, 3,4 dichlorophenylurea ( DCPU), and 3( 3,4 dichlorophenyl) 1 methylurea ( DCPMU). No other dichloroaniline containing metabolites were identified. The majority of radioactivity in the aqueous/ organic fractions was characterized as polar unknowns. Radiovalidation of a GC/ ECD data collection method which is similar to the enforcement method suggested that a good portion of these polar metabolites can be converted to 3,4 DCA.

Table 5. Parent and Major Metabolites Diuron: 3( 3,4 dichlorophenyl) 1,1 dimethylurea DCPMU; IN 15654: 3( 3,4 dichlorophenyl) 1 methylurea DCPU; IN R915: 3,4 dichlorophenylurea In animals, the principal residue identified was DCPU. The parent and other dichloroanilinecontaining metabolites ( i. e., 3,4 DCA and DCPMU) that can be determined by the current enforcement methods were detected in much smaller quantities. Four minor hydroxylated metabolites ( 2 OH DCA; 2 OH DCPU; 2 OH DCPMU; and N acetyl 2 OH DCA) were also detected; these metabolites were not observed in plants and would not be determined by the current enforcement method.

The major portion of radioactive residues in milk ( in lactating goats) was comprised of several conjugated polar components which collectively accounted for 56% of total radioactive residue ( TRR). These polar components also accounted for substantial portions of the total radioactivity in liver ( collectively 25% of TRR) and kidney ( collectively 23% of TRR). Attempts to further elucidate the nature of these polar materials using various techniques ( e. g., enzyme digestions, heat treatment) were not successful. Although these polar components were not wholly identified, the registrant noted that the results from a radiovalidation study suggest that a large portion of these polar components are hydrolyzable to 3,4 DCA and would be quantified using the residue enforcement method.

The environmental data base indicates that diuron has potential for leaching to ground and surface water. The environmental metabolism studies, conducted under a variety of conditions, demonstrate that monochlorinated methylphenyl urea ( MCMPU) and monochlorinated dimethylphenyl urea ( MCDMPU) can be formed under some conditions and that MCDMPU is a major degradate in aquatic aerobic and anaerobic studies. DCPMU was also identified as a major environmental degradate in several studies and 3,4 DCA, DCMU, PDMU were identified as minor metabolites.

The MARC concluded that for tolerance expression and risk assessment purposes, the residues of 26 concern in/ on plants and animals are diuron and its metabolites that are hydrolyzable to 3,4 DCA [ Diuron. Results of the Health Effects Division ( HED) Metabolism Assessment Review Committee( MARC) Meeting Held on 03 JULY 2001. John Punzi. August 10, 2001]. This decision was based on: 1) the assumption that the metabolites would not be any more toxic than the parent and 2) the consideration that the analytical methods used to collect the field trial data are not capable of measuring each metabolite individually. To account for the poor recovery of hydroxylated metabolites from milk, it was determined that the levels of diuron residues in milk identified in the ruminant feeding study would be multiplied by 10 ( The Metabolism Committee Meetings for Diuron Held on October 21 and November 5, 1993. Randy Perfetti. November 17, 1993) to account for all of the exposure to diuron related residues in the risk assessment.

The MARC also concluded that for risk assessment purposes, the residues of concern in drinking water are parent, and metabolites that are hydrolyzable to 3,4 DCA, and MCPDMU. The MARC raised concerns for MCPDMU based on an analogous compound, monuron. With the exception of the position of the chlorine, the structures are identical. There are cancer concerns for monuron but the target organs are different than those affected by diuron. The MARC recommended that a separate cancer assessment be conducted for MCPDMU.

4.2.1 Residue Profile Diuron is used on a wide variety of food and feed crops. Residue levels from United States Department of Agriculture ( USDA) and Food and Drug Administration ( FDA) monitoring programs do not include all the residues of concern needed for the Agency's diuron risk assessment ( diuron and metabolites convertible to 3,4 DCA) and would be inappropriate for this analysis. Anticipated residues ( ARs) from field trial data were utilized to estimate the dietary exposure to diuron from the diets of the U. S. population as well as certain population subgroups. These ARs were developed previously ( D250038, Rick Loranger. October 8, 1998 and D169227, Christina Swartz. April 27, 2001). The field trials were conducted at the highest application rates for the crop tested and therefore, the residues from these trials are considered high end. Available processing data for apple, citrus and grapes were available and indicated that there was no concentration, nor reduction, in residue values for these processed commodities ( i. e. juice, dried fruit). The sugarcane processing study showed a reduction of residues in refined sugar but a concentration of residues in molasses. With the exception of residue data from the processing of sugarcane into refined sugar and molasses, the only additional refinements to the residue data are the use of averaged percent crop treated (% CT) information ( Quantitative Usage Analysis for Diuron. Alan Halvorson. March 20, 2001 and Updated QUA. Alan Halvorson. April 27, 2001).

The registrants have committed to label changes which would restrict the application of diuron to asparagus plantings prior to the appearance of spears. Residues of diuron in/ on asparagus are reduced by approximately one order of magnitude ( from 2.8 to 0.26 ppm) by this proposed use. To examine the effect of the differing residue values for asparagus on the dietary risk, calculations were performed using 27 residue levels reflecting treatment of asparagus crops before and after spears appear. There were minimal changes in the chronic exposure estimates using data from pre emergence or post emergence applications of diuron to asparagus.

4.2.2 Acute Dietary Diuron is not acutely toxic. No adverse effects attributed to a single exposure were identified in any available study. Therefore, no acute dietary risk assessment was conducted.

4.2.3 Chronic Dietary A chronic exposure analysis for diuron and its metabolites that are hydrolyzable to 3,4 DCA was performed utilizing the Dietary Exposure Evaluation Model ( DEEMTM) software Version 7.73, which incorporates USDA's Continuing Surveys of Food Intake by Individuals ( CSFII), 1989 1992. The 1989 1992 data are based on the reported consumption patterns of more than 10,000 individuals over three consecutive days, and therefore represent more than 30,000 unique " person days" of data. Foods " as consumed" ( e. g. apple pie) are linked to raw agricultural commodities and their food forms ( e. g. apples cooked/ canned or wheat flour) by proprietary recipe translation files within DEEM. Consumption data are averaged for the entire U. S. population and within population subgroups for chronic exposure assessment. For chronic exposure and risk assessment, an estimate of the residue level in each food or food form ( e. g. orange or orange juice) on the commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total estimated exposure. The calculated chronic exposure ( residue x consumption) was compared to a cPAD of 0.003 mg/ kg/ day, which reflects an FQPA factor of 1x. Noncancer dietary exposure estimates are expressed in mg/ kg bw/ d and as a percent of the cPAD ( Diuron  Chronic Dietary Exposure Assessment ( PC Code 035505); DP Barcode D276683; Case 0046. John Punzi. September 10, 2001).

Estimated chronic dietary ( food) risk estimates associated with the use of diuron do not exceed the Agency's level of concern (> 100% cPAD) for any population subgroup including the most highly exposed population subgroup, children ages 1 6 years. The chronic dietary risk for children ages 1 6 years is 7% of the chronic PAD and 3% for the general U. S. population ( Table 6). Approximately 40% of the exposure to diuron from food is from orange juice and orange juice concentrate.

Table 6: Chronic Dietary Risk Estimates Population Exposure mg/ kg/ day % Chronic PAD U. S. Population 0.000088 3 All Infants (< 1 year) 0.000077 3 Population Exposure mg/ kg/ day % Chronic PAD 28 Children 1 6 years 0.00020 7 Children 7 12 years 0.000118 4 Females 13 50 years 0.000069 2 Males 13 19 years 0.000098 3 Males 20+ years 0.000066 2 Seniors 55+ years 0.000083 3 4.2.4 Cancer Dietary The estimated cancer dietary risk associated with the use of diuron indicates a borderline exceedance above 1 x 10 6 and shows a lifetime risk estimate of 1.68 x 10  6 for the general population but, is not of concern ( Table 7). As discussed earlier, the residues used in the calculations are from field trials conducted at the highest application rates and some processing data are still outstanding. Therefore, the exposure calculation is a conservative estimate. Again, the Agency assumed that exposure was to diuron and its metabolites that are hydrolyzable to 3,4 DCA. For the cancer risk assessment, the calculated chronic exposure ( residue x consumption) was calculated with a Q1* of 1.91 x 10 2 ( mg/ kg/ day) 1 in human equivalents.

Table 7. Summary of Dietary Exposure and Risk for Diuron Population Acute Dietary Chronic Dietary Cancer Dietary NA Exposure ( mg/ kg/ day) Risk (% cPAD) Exposure ( mg/ kg/ day) Lifetime Risk ( Q1*= 0.0191)

U. S. Population 0.000088 3 0.000088 1.68 x 10 6 All Infants < 1 year 0.000077 3 Not Applicable Children 1 6 years 0.000200 7 Children 7 12 years 0.000118 4 Females 13 50 years 0.000069 2 4.3 Water Exposure/ Risk Pathway The diuron drinking water exposure assessment was based primarily on 1) submitted environmental fate studies, 2) limited but targeted monitoring data for diuron and its degradates, and 3) monitoring data for the parent only. Although monitoring data for the parent and its degradates were not extensive, the 29 available measured data were revealing. For example, monitoring of 32 lakes in Texas showed that diuron was the predominant contaminate detected. Surface and ground water conclusions from these sources were compared with simulation model predictions. Monitoring sources included United States Geological Survey ( USGS) and published literature ( Drinking Water Assessment for diuron and its degradates. Ibrahim Abdel Saheb. March 11, 2001). There is no Maximum Contaminant Level Goal ( MCLG) or Maximum Contaminant Level ( MCL) established by the Agency's Office of Water for diuron.

Diuron has the potential to leach to ground water and to contaminate surface waters through run off. Environmental fate data analyzed by EFED show that diuron is persistent. Diuron is stable to hydrolysis at pH's 5, 7, and 9. The calculated half lives in aqueous and soil photolysis studies were 43 and 173 days, respectively. The half lives in aerobic and anaerobic soil metabolism studies were 372 and 1000 days, respectively. However, in viable laboratory aquatic systems, degradation appeared to be accelerated with half lives of 33 and 5 days in aerobic and anaerobic systems, respectively. The predominant degradate formed in both the soil photolysis and aerobic soil metabolism studies was DCPMU. The only significant (> 10 % of applied) degradate in the aerobic and anaerobic aquatic metabolism studies was MCDMPU. Diuron dissipated from bare ground plots with half lives ranging from 73 to 133 days, and the major degradate ( MCDMPU) dissipated from the same plots with half lives ranging from 217 to 1733 days. Diuron and MCDMPU residues were detected mainly at the upper 15 30 cm depths at all sites and sporadically detected below this depth. An upgradable adsorption/ desorption/ leaching study ( MRID# 44490501) showed that diuron has a low medium Koc ( 468 1666). In addition, diuron has low water solubility ( 42 ppm).

The degradate 3,4 DCA is an environmental degradate common to diuron, linuron, and propanil. EFED does not have sufficient fate and transport data on 3,4 DCA. In an aerobic soil metabolism study with the compound propanil, 3,4 DCA had a half life of 30 days ( MRID# 41537801), and in a water paddy the half life ranged from 2 3 days ( MRID# 42200401, 42200501). Even though these studies suggest that 3,4 DCA will not persist in soil or water, 3,4 DCA has been detected often in surface water. Thus, more data are needed to understand the fate of this degradate in soil and water. TCAB, also a compound of concern for human health ( see Section 3.5), was identified as having a minor presence in a diuron soil photolysis study ( MRID# 41719302) with a maximum concentration of 0.038 ppm.

Surface Water Exposure: EFED has targeted, but, limited monitoring data on the concentrations of diuron and its degradates in surface water.

A study on the occurrence of cotton herbicides and insecticides in the Playa lakes of the high plains of western Texas concluded that diuron was the major pesticide detected in water samples collected from 32 lakes with a mean concentration of 2.7 ppb. Diuron metabolites ( DCPMU, DCPU, and 3,4 DCA) were found in 71% of the samples analyzed. The mean concentrations of these metabolites were 0.45 ppb for DCPMU, 0.31 ppb for 3,4 DCA, and 0.2 ppb for DCPU. In this study, water samples 30 were taken within two days after diuron application to cotton in the region. Diuron usage on cotton in this part of the state reached an average of $ 1.379 lb ai/ mile/ yr. Even though, the monitoring of diuron concentrations from use on cotton in this part of the state is an example of a targeted study, the frequency of surface water sampling and the length of the sampling period were insufficient to satisfy the temporal and spatial requirements for regulatory purposes. This study has limited use in a national assessment because EFED does not expect western Texas to be one of the most vulnerable use areas for runoff. However, because the samples were taken within two days after application, the results may represent a lower bound of possible peak concentrations that could occur in drinking water in that area.

The USGS National Water Quality Assessment Program ( NAWQA) collected 1420 surface water samples from 62 agricultural stream sites during the period from 1992 1998. Sampling was for the parent only. One to two samples were collected each month throughout the year during periods when pesticide transport in the streams was expected to be low. At most sites, the sampling frequency was increased to 1 to 3 samples per week during periods when elevated levels of pesticides were expected in the streams. Diuron was detected in 7.32% of the samples ( detection limit = 0.05 ppb) with an average concentration of 0.13 ppb in 95% of samples. The maximum concentration of diuron was 13 ppb ( estimated concentration).

The monitoring data, though useful in a limited capacity, are either not nationally representative or did not monitor for any of the degradates and would underestimate potential drinking water exposures. Therefore, EFED calculated estimated exposure concentrations ( EEC) in surface waters employing Tier II surface water modeling using the Index Reservoir ( IR) and Percent Crop Area ( PCA) modifications to PRZM and EXAMS. The IR represents a potential vulnerable drinking water source from a specific area ( Illinois) with specific cropping patterns, weather, soils, and other factors. The PCA is a generic watershed based adjustment factor which represents the portion of a watershed planted to a crop or crops and will be applied to pesticide concentrations estimated for the surface water component of the drinking water exposure assessment. The IR PCA PRZM/ EXAMS model was used to determine estimated surface water concentrations of diuron and its degradates DCPMU, DCPU, 3,4 DCA, and N'( 3 chlorophenyl) N N dimethylurea ( MCPDMU). Modeling results are shown in Table 9. The modeled concentrations are higher ( 9 100 times) than the levels found in existing surface water monitoring data targeted to pesticide use areas.

Ground Water Exposure: EFED has limited targeted monitoring data on the concentrations of diuron and its degradates in groundwater. Table 8 shows validated monitoring data for diuron that were collected for the states of California ( CA), Florida ( FL), Georgia ( GA), and Texas ( TX) from 1971 1991.

Table 8. Groundwater monitoring data for diuron ( USEPA 1992). Number of wells sampled ( number of wells with residues).

State number of well ( detections) range of conc. ( ppb) 31 CA 2010 ( 82) 0.05  3.95 FL 15385 ( 9) 1.18  5.37 GA 70 ( 67) 1.00  5.00 TX 31 ( 2) 0.01  0.02 According to the Ground Water Protection Section of the Florida Department of Environmental Protection, ground water samples collected from wells between May/ 1990 and November/ 1997, showed diuron detections ranging from 0.94  12 ppb ( detection limit = 0.48 ppb). The arithmetic mean concentration was 2.44 ppb. Well water samples were collected from the following counties: Highlands, Jackson, Lake, Orange, and Polk. With the exception of the 12 ppb sample in Orange County, the majority of the detections were in Highlands County where citrus is grown. Diuron concentrations in Highlands County decreased with time to about 1 ppb but were detected every year. In Polk County, diuron concentrations showed a seasonal pattern, with the highest concentrations in the spring and lowest concentrations in the fall, but it was not detected in all years.

The USGS NAWQA analyzed pesticide occurrence and concentrations for major aquifers and shallow ground water in agricultural areas ( detection limit = 0.05 ppb). Analysis of 2608 samples ( major aquifers study) showed diuron in 71% of the samples analyzed with a maximum concentration of 0.34 ppb. The maximum diuron concentration in 897 samples from shallow groundwater sites was 2.0 ppb, with diuron detected in only 1.23% of samples analyzed ( USGS, 1998). A major component of the sampling design in the NAWQA study was to target specific watersheds and shallow ground water areas that are influenced primarily by a single dominant land use( agricultural or urban) that is important in the particular area. The ground water data were primarily collected from a combination of production and monitoring wells.

Even though the ground water monitoring data collected by NAWQA are from sites considered typical for use areas, the frequency of sampling and the length of sampling period were not sufficient to represent the temporal and spatial requirements for regulatory purposes. In addition, USGS studies only monitored for the parent. Therefore, the Screening Concentration in Groundwater ( SCI GROW) model was used to estimate potential ground water concentrations for diuron and its degradates. Modeling results are shown in Table 9. 32 Table 9. Estimated environmental concentrations in surface and ground water for diuron and its degradates from diuron use on citrus.

model EECs ( F g/ L) use( s) modeled PCA Diuron DCPM U DCPU 3,4 DCA MCPDMU one application of diuron on citrus @ 9.6 lb ai/ acre, ground application Default ( 0.87) Surface water/ peak 613 130 5.80 0.08 136 Surface water/ 1 10 year average 128 27.0 1.20 0.02 36.4 Surface water/ mean of annual values 85.0 18.0 0.80 0.01 25.5 Groundwater/ ( peak and long term average) 6.5 2.50 0.1 2X10 4 1.38 The IR PCA modeling results indicate that diuron and its degradates have the potential to contaminate surface waters by runoff in areas with large amounts of annual rainfall. Modeling results ( EECs) were several orders of magnitude ( ranging from 9 100 times) higher than diuron surface water monitoring data from known pesticide use areas. Though environmental metabolism studies indicate that MCPDMU is an environmental degradate of diuron, it either was not detected in any of the monitoring studies or the researchers did not look for it. Since EFED lacks complete environmental fate data ( such as the aerobic aquatic and anaerobic aquatic studies) on any of the degradates, the EECs for surface and ground water were based on half lives that were calculated on cumulative residues ( Drinking Water Assessment for diuron and its degradates. Ibrahim Abdel Saheb. March 11, 2001).

4.4 Residential Exposure/ Risk Pathway 4.4.1 Home Uses There are potential residential exposures from activities associated with: 1) pond and aquarium use and 2) paint use. Though there are existing labels for applications of granular formulations of diuron to turf, most are limited to industrial and non crop uses. Others ( reg. # 33560 46 and # 802 352) are either pending cancellation by the registrant or the registrant has agreed to place language specifically restricting residential uses on the label. Therefore, with these actions by the registrants of the labels mentioned above, no residential turf uses exist for diuron and a residential assessment for turf was not conducted ( Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document for Diuron. Renee Sandvig and Christina Jarvis. October 16, 2001).

Pond and Aquarium Use Three diuron products are designed for residential use as algaecide in ponds and aquariums and are being supported for reregistration. They are Pond Block ( 0.51% ai, reg. # 33034 1) and No More 33 Algae ( 0.67% ai, reg. # 33034 2), which are both in tablet/ block form, and No More Algae ( 0.67% ai, reg. # 33034 3), which is in ready to use liquid form. No exposure data exist for the use of the algaecide tablets/ blocks. Since the products are formulated as tablets/ blocks and dissolve in less than 5 minutes, minimal exposure is expected and was not quantified. Furthermore, exposure from the block/ tablet forms of diuron are expected to be less than exposure from the liquid formulation, since spillage may occur from measuring and pouring liquid diuron.

The No More Algae liquid is used at a rate of one teaspoon ( 5 ml) for every 10 gallons of aquarium or pond water. Treatment should be repeated once a month or when algae growth reappears. Residential exposure may result from measuring the liquid and pouring the liquid into the aquarium or pond. Unit exposure data from the Pesticide Handlers Exposure Database ( PHED) for the mixing/ loading of liquids will be used to assess this exposure. Dermal exposure for noncancer risk estimates was not calculated, since no toxicity by the dermal route is expected for this duration. Exposure is expected to be short term ( 1 to 30 days).

Paint Use Antimicrobial exposures to handlers are defined by the Antimicrobial Division ( OPP/ EPA) as " primary" and " secondary" handlers. The primary handlers are defined as those individuals exposed to the formulated product ( adding the diuron product into vats of paint during its manufacturing), while the secondary handlers are those individuals exposed to the active ingredient as a direct result of its incorporation into an end use product ( individuals using the caulk or paint that in itself is not a registered pesticidal product). HED has identified and assessed the primary handlers as those individuals who mix and load diuron formulation at the manufacturing facility for use as a mildewcide in adhesives, caulks, sealants, and paints. The secondary handlers are commercial and residential applicators who apply adhesives, caulks, sealants, and paints. Since diuron is only added during the manufacturing process, only the secondary handler use ( application of the products containing diuron) was assessed in the residential assessment.

No handler exposure data have been submitted to determine the extent of these exposures. Secondary residential handlers were assessed using an airless sprayer and a paint brush. Unit exposure data used to assess the exposure resulting from applying paint containing diuron with an airless sprayer and a paintbrush were taken from a previous chlorothalonil assessment ( Revised Occupational and Residential Exposure Assessment for the Chlorothalonil Reregistration Eligibility Decision ( RED). Jeff Evans. January 22, 1997). This assessment used data from a proprietary worker exposure study conducted on the use of chlorothalonil in paint. These data were merged with data contained in PHED to increase the number of replicates and the quality of the unit exposure data. The surrogate chlorothalonil study data are assumed to be representative of the exposure from the use of diuron using the same equipment, since the two chemicals are formulated together in three out of the four currently registered diuron paint products. The clothing and personal protective equipment ( PPE) scenarios for each type of exposure reflect the clothing and PPE worn in the study from which the unit exposure values were derived. The clothing worn in the chlorothalonil assessment were long pants and long 34 sleeved shirt, which are different from the short sleeved and short pants clothing normally considered possible for residential exposures. Therefore, for comparison, data representing both clothing scenarios ( long sleeves and long pants, as well as short sleeves and short pants) were also included in the assessment for the application of paint with an airless sprayer and a paint brush/ roller.

Although there is potential exposure during the application of the other treated materials ( e. g., caulks and sealants), they were not included in this assessment because no data are available to assess these uses. There is also a potential for exposure from applying paint with a roller. It is HED's professional judgement that the airless sprayer and paintbrush scenarios represent the high end exposures for diuron antimicrobial secondary uses and therefore, would likely be protective of the exposures from caulk and sealant uses and painting with a roller.

No data are available to determine whether or not diuron contained in paint products would be more or less readily absorbed through the skin. 35 <IP_ADDRESS> Handler The Agency has determined that there are potential exposures to residential mixers, loaders, and applicators during the usual use patterns associated with diuron. Based on the use patterns, five major residential exposure scenarios were identified for diuron: ( 1) Loading ready to use liquids; ( 2) Applying paints/ stains with a paintbrush; ( 3) Applying paints/ stains with a paintbrush ( study data); ( 4) Applying paints with an airless sprayer; and ( 5) Applying paints with an airless sprayer ( study data).

In addition to diuron's mildewcide use in paints and stains, it is also used in plaster, stuccos, sealants, caulking, and fillers. Unit exposure data only exists for the use of paints/ stains with airless sprayer and paintbrush. These exposure scenarios are assumed to have a higher exposure than the use of diuron in plaster, stucco, sealants, caulking and fillers, since less material would be applied in a day. Therefore, the paint/ stain assessment is considered protective for exposure resulting from the use of diuron in plaster, stucco, sealants, caulking, and fillers.

The exposures to residential secondary handlers are expected to be of a short term duration ( less than 30 days). For homeowners, the airless sprayer is assumed to be used for outdoor applications only. Homeowner use of diuron treated paint indoors is restricted to small rooms such as bathrooms, laundry rooms, etc. where the use of an airless sprayer is unlikely to occur. For the cancer risk assessment, homeowners applying diuron treated paint are assumed to be exposed two days per year, which is considered a high end assumption.

Short term Exposure/ Risk Table 10 presents the short term ( 1 30 days) dermal and inhalation exposures at baseline as well as the risk assessments for the inhalation exposures. No systemic toxicity was seen following repeated dermal dosing in the dermal toxicity study therefore, no quantitative assessment of risk by the dermal route is required. No PPE or engineering controls are assumed for residential exposures. Residential handlers are assumed to be wearing short sleeved shirts and short pants.

The short term risk assessment incorporated a NOAEL of 10 mg/ kg/ day for noncancer inhalation exposures and had an LOC or target MOE of 100, including the 1x FQPA factor. The calculations of short term inhalation risk indicate that the inhalation MOEs are more than 100 at the baseline level for the all the assessed exposure scenarios and are not considered risks of concern.

Cancer Exposure/ Risk To assess cancer risk, an average daily dose, a lifetime daily dose and a total cancer risk are calculated. For the cancer assessment, potential dermal exposure was included with a high end dermal absorption factor ( measured from a submitted study) of 4%. Assumptions included in the calculations were an average adult lifetime of 70 years and an exposure duration of 50 years. The number of exposures per year for the pond and aquarium uses are based on the label recommendations. The " No More Algae" liquid label states that " For regular maintenance, use once a month or as algae starts to 36 reappear." Therefore, 12 exposures per year were assumed. Homeowners applying diuron treated paint are exposed two days per year. Since it would be unusual for a homeowner to paint their house every year with diuron treated paint, this is considered a high end estimate.

Cancer risks equal to or less than 1 x 10 6 are not considered to be of concern. Risks greater than 1 x 10 6 for the general population are considered to be of concern. The residential cancer risk assessment was conducted using the diuron Q1* of 1.91 x 10 2 and is summarized in Table 11.

The following scenarios have cancer risks greater than 1 x 10 6 at the baseline level of exposure ( bracketed numbers can be matched to the exposure scenarios in the tables):

( 2) Applying paints/ stains with a paint brush;

( 3) Applying paints/ stains with a paint brush ( study data) for stains;

( 4) Applying paint with an airless sprayer; and ( 5) Applying paint with an airless sprayer ( study data).

The following scenarios have cancer risks less than 1 x 10 6 at the baseline level of exposure:

( 1) Loading ready to use liquids for ponds and aquariums All scenarios were assessed at the maximum rate of application. Average application rate for the paint use is unknown and is requested to refine this risk. The residential cancer risk is considered conservative since an upper bound dermal absorption rate was used ( no dermal penetration study was submitted), coupled with maximum application rates.

<IP_ADDRESS> Postapplication Postapplication inhalation and dermal exposure resulting from the use of diuron in ponds and aquariums is expected to be minimal. Diuron is applied to ponds/ aquariums in the form of a liquid and an effervescent tablet. Due to the high dilution rate of the liquid in pond and aquarium water ( 0.0000074 lb ai per gallon of water), and the effervescent nature of the tablet ( expected to dissolve in less than five minutes), postapplication exposure to diuron in pond and aquarium water is expected to be minimal. Furthermore, postapplication activities in and around ponds/ aquariums treated with diuron are assumed to be infrequent.

Postapplication inhalation and dermal exposure resulting from the indoor use of diuron in paints is also expected to be minimal. The Agency has conducted a screening level inhalation assessment using the Multi Chamber Concentration and Exposure Model ( MCCEM). MCCEM uses air infiltration and 37 interzonal air flow rates, together with user inputs for emission rates, decay rates, and outdoor concentrations to calculate time varying indoor concentrations and associated indoor inhalation exposure due to product or material emissions in several zones or chambers within a residence. The results of this model, coupled with diuron's low vapor pressure ( 2 x 10 7 mm Hg at 30 E C), show minimal postapplication inhalation exposure. Furthermore, diuron treated paint is only likely to be used in rooms where high humidity is expected ( i. e. a bathroom), and would rarely be used in the entire house. It is unlikely that a homeowner would receive a significant amount of postapplication inhalation exposure from diuron treated paint, as the very nature of its use is as a mildewcide, and any substantial loss of the active ingredient from the paint would render the product ineffective.

4.4.2 Recreational There are no recreational use sites for diuron.

4.4.3 Other ( Spray Drift; Farm Worker Children, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from groundboom application methods. The Agency has been working with the Spray Drift Task Force, EPA regional offices and state lead agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, of which U. S. pesticide registrants are members, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift and risks associated with aerial as well as other application types, where appropriate. 38 Table 10: Residential Short Term Baseline Table Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) a Inhalatio n Unit Exposure ( F g/ lb ai) b Data Source Site/ Use Application Ratec Amount Treatedd Dermal Dosee Inhalation Dose ( mg/ kg/ day) f Inhalation MOEg Mixer/ Loader Loading Ready to Use Liquids ( 1) 2.9 1.2 PHED V1.1 Pond 0.0000074 lb ai per gallon 3000 Gallons per day 0.00092 0.00000038 26,000,000 PHED V1.1 Pond 0.0000074 lb ai per gallon 1000 Gallons per day 0.00031 0.00000013 79,000,000 PHED V1.1 Aquarium 0.0000074 lb ai per gallon 50 Gallons per day 0.000015 0.0000000063 1,600,000,000 Applicator Applying Paint/ Stains with Paintbrush ( 2) 230 280 PHED V1.1 Paint 0.0532 lb ai per gallon 2 Gallons per day 0.35 0.00043 23,000 PHED V1.1 Stain 0.0532 lb ai per gallon 5 Gallons per day 0.87 0.0011 9,400 Applying Paint/ Stains with Paintbrush ( study data) ( 3) 290 507 Chlorothalonil Study/ PHED Paint 0.0532 lb ai per gallon 2 Gallons per day 0.44 0.00077 13,000 Chlorothalonil Study/ PHED Stain 0.0532 lb ai per gallon 5 Gallons per day 1.1 0.0019 5,200 Applying Paint with Airless Sprayer ( 4) 79 830 PHED V1.1 Paint 0.0532 lb ai per gallon 15 Gallons per day 0.90 0.0095 1,100 Applying Paint with Airless Sprayer ( study data) ( 5) 33.33 433 Chlorothalonil Study/ PHED Paint 0.0532 lb ai per gallon 15 Gallons per day 0.38 0.0049 2,000 Footnotes: a Baseline dermal exposure represents short pants, short sleeves and no gloves, except for the chlorothalonil study, MRID 43600102, which represent long pants, long sleeved shirts and no gloves. b Baseline inhalation unit exposure represents no respirator. c Application rates are based on the maximum application rates listed on the " No More Algae" liquid label and paint labels. d Amount treated per day are from EPA estimates of average aquarium and pond size and the maximum pond size listed on the label. Paint/ stain assumptions are from Expo SAC 39 policy # 12.15 e Daily Dermal Dose ( mg/ kg/ day) = ( Dermal Unit Exposure ( mg/ lb ai) x Application Rates ( lb ai/ A and lb ai/ sq. ft.) x Area Treated per day ( acres and square feet))/ body weight ( 70 kg). f Daily Inhalation dose ( mg/ kg/ day) = ( Inhalation Unit Exposure ( F g/ lb ai) x ( 1mg/ 1000 F g) Conversion Factor x Application Rate ( lb ai/ gallon) x Amount Treated per day ( gallons/ day))/ body weight ( 70 kg). g Short term Inhalation MOE = Inhalation NOAEL ( 10 mg/ kg/ day) / Daily Inhalation Dose ( mg/ kg/ day). 40 Table 11: Residential Cancer ( Q*) Risk Table Exposure Scenario ( Scenario #) Use site Application Rate Amount Treated Total Daily Dosea Baseline Daily LADDb, c Baseline Riskd Mixer/ Loader ( 12 days/ year)

Loading Ready to Use Liquids ( 1) pond 0.0000074 lb ai per gallon 3000 Gallons per day 0.000037 8.7 E 7 1.7 E 8 pond 0.0000074 lb ai per gallon 1000 Gallons per day 0.000012 2.9 E 7 5.5 E 9 aquarium 0.0000074 lb ai per gallon 50 Gallons per day 0.00000062 1.5 E 8 3.0 E 10 Applicator ( 2 days/ year)

Applying Paint/ Stains with Paintbrush ( 2) Paint 0.0532 lb ai per gallon 2 Gallons per day 0.014 5.5 E 5 1.1 E 6 Stains 0.0532 lb ai per gallon 5 Gallons per day 0.036 1.4 E 4 2.7 E 6 Applying Paint/ Stains with Paintbrush ( study data) ( 3) Paint 0.0532 lb ai per gallon 2 Gallons per day 0.018 5.0 E 5 9.5 E 7 Stains 0.0532 lb ai per gallon 5 Gallons per day 0.046 1.3 E 4 2.4 E 6 Applying Paint with Airless Sprayer ( 4) Paint 0.0532 lb ai per gallon 15 Gallons per day 0.045 1.8 E 4 3.4 E 6 Applying Paint with Airless Sprayer ( study data) ( 5) Paint 0.0532 lb ai per gallon 15 Gallons per day 0.020 5.5 E 5 1.1 E 6 Footnotes: a Total Daily Dose ( mg/ kg/ day) = Daily Dermal Dose ( mg/ kg/ day) * Dermal Absorption ( 4%) + Daily Inhalation Dose ( mg/ kg/ day). See Table 10 for daily dermal and inhalation doses. b The number of exposures per year are based on the label recommendations. The No More Algae Liquid label states that " For regular maintenance, use once a month or as algae starts to reappear." Therefore, 12 exposures per year were assumed. Two exposures per year assumed for residential person painting their home. 15 c Lifetime average daily dose ( LADD) ( mg/ kg/ day) = Total Daily Dose ( mg/ kg/ day) * ( number of days of exposure per year / 365 days/ year) * ( 50 years exposed / 70 years in a lifetime). d Cancer risk = LADD ( mg/ kg/ day) * Q1 ( 1.91E 2 mg/ kg/ day1). 41 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATIONS Risk is a function of exposure multiplied by hazard ( Risk = Exposure x Hazard). Exposure may be measured or modeled, depending on the available data. Ideally the exposure data would be chemical specific occupational or residential monitoring data, at the tap drinking water data, and close to theplate food residue data on all crops. In the absence of an ideal data set, surrogate data, and other factors are incorporated into the exposure assessments ( dietary and non dietary) to present a reasonable exposure picture based on the best available data. The hazard portion of the risk equation has several layers of safety built into it to provide a cushion between exposure and the dose at which adverse effects were seen in an animal study. Generally, endpoints are based on the dose at which no observable adverse effect is seen in an animal study. This is the No Observable Adverse Effect Level ( NOAEL). The Lowest Observable Adverse Effect Level ( LOAEL) is the next highest dose in an animal study, up from the NOAEL, at which the adverse effect of concern is seen. Since the toxicity studies used for endpoint selection are conducted in animals, and there are differences between individual humans, additional uncertainty factors for inter and intra species variability are integrated into the hazard portion of the risk equation. Since the passage of the FQPA, an additional layer of protection is factored in ( when appropriate) to provide an even greater safety cushion between exposure and toxic effects for particularly sensitive populations. It is in this light that expressions of risk ( risk numbers) should be viewed with an understanding that they are not portrayals of imminent toxic effects to humans but as a measure of the distance between potential exposure and possible toxic effects.

In accordance with current HED policy ( effective 03/ 11/ 99) the acute and chronic dietary endpoints are expressed as acute Population Adjusted Dose ( aPAD) and chronic PAD ( cPAD), and no longer as an adjusted Reference Dose ( RfD).

RfD = acute or chronic NOAEL Uncertainty Factor ( UF)

Generally, an UF of 100 is applied for intra and inter species differences.

PAD = acute or chronic RfD FQPA factor The use of the PAD will apply whether the FQPA factor is retained ( 10x or 3x) or not ( 1x). When a PAD is used, such as in the dietary assessment, the risk is expressed as a percentage of the PAD which is equal to the measured exposure divided by the PAD and then multiplied by 100 or:

Risk (% PAD) = Exposure x 100 PAD Occupational, residential ( when applicable), and the aggregate risk ( when appropriate) will still be 42 expressed as the Margin of Exposure ( MOE).

MOE = NOAEL ( mg/ kg/ d Exposure ( mg/ kg/ d)

Current HED policy requires that FQPA safety factors be retained for dietary and non occupational exposures, when appropriate, not occupational exposures ( Memorandum, Special Report of the FQPA Safety Factor Committee, B. Tarplee and J. Rowland, April 15, 1998). Therefore, an MOE of > 100 is generally needed in the occupational exposure risk assessment. For diuron, if there were long term occupational exposures ( none are expected) an MOE of > 300 would be needed since a 3x was factored in because a LOAEL was selected for the endpoint. Since the FQPA factor is 1x, for residential uses, MOEs > 100/ 300 are also needed for short and intermediate term, and long term exposures, respectively.

Generally, the Agency calculates Drinking Water Levels of Comparison ( DWLOC) for comparison to measured or modeled drinking water concentrations for the risk analysis. The DWLOC is the concentration in drinking water, as part of the aggregate exposure, that occupies no more than 100% of the PAD. The dietary exposure from food and DWLOC together, cannot be greater than 100% of the PAD. Any measured or modeled drinking water estimates that are less than the DWLOC are not of concern.

The Agency has calculated DWLOCs for chronic ( noncancer) and short term exposure to diuron and its degradates ( metabolites hydrolyzable to 3,4 DCA) in surface and ground water for the population subgroups; children 1 6 years ( most highly exposed population), infants < 1 year, females 13 50 years, and the general U. S. population. No adverse effects attributed to a single exposure to diuron were identified in any available studies. Therefore, no acute dietary risk assessment was conducted and hence, no acute DWLOC ( DWLOCacute) was calculated. The DWLOCcancer is the concentration in drinking water as a part of the aggregate chronic exposure that results in a negligible cancer risk ( 10 6). Residential exposures to adult handlers would be factored into the DWLOCcancer; however, the estimated residential risks alone are above the Agency's level of concern, therefore, DWLOCcancer = 0.

Since no systemic toxicity was seen in the dermal toxicity study, no short or intermediate term occupational or residential risk assessment by the dermal route was needed. The exception was for the cancer assessment, for which the oral study and a dermal absorption factor ( measured from a submitted study) were used. Based on the labeled uses, no incidental oral exposures are expected. Due to the lack of availability/ submission of acceptable/ guideline inhalation studies using diuron, occupational and residential risk assessments were conducted using endpoints selected from oral studies. To fully characterize the hazard and subsequent potential risk from exposures to diuron and its metabolites a 28 day inhalation study in rats is needed. 43 5.1 Acute Risk No adverse effects attributed to a single exposure to diuron were identified in any available studies. Therefore, no acute dietary risk assessment was conducted, no DWLOCacute was calculated, and hence, no acute aggregate risk was conducted.

5.2 Short term Risk 5.2.1 Aggregate Short term Risk Assessment When potential food and residential inhalation exposures are combined they result in aggregate short term MOEs = 1043 and 1045 for adult males and females, respectively, which are not of concern. Based on labeled uses, no intermediate or long term residential handler, or postapplication exposures of any duration, are expected.

Aggregate short term risk estimates for diuron and its metabolites hydrolyzable to 3,4 DCA would combine exposures from food ( average), water, and inhalation. Since measured drinking water data ( monitoring data) are limited and cannot be quantitatively included in the risk assessment, estimates of allowable levels of drinking water were calculated ( see DWLOCs below) instead. The Agency determined that it was unlikely that more than one of the residential handler activities would occur concurrently during a short term time period. Therefore, the Agency took the protective approach of including the exposures from the activity which could potentially result in the most exposure to the homeowner, applying paint with an airless sprayer, in the aggregate assessment. It should be noted that residential exposures are calculated at baseline ( no personal protective equipment, no engineering controls).

The " MOE approach" was used to calculate the short term aggregate risk, combining food and inhalation exposures, and using a NOAEL of 10 mg/ kg/ day. A UF of 100 ( 10x for interspecies extrapolation, 10x for intraspecies variability) and the 1x FQPA safety factor for diuron were applied to the assessment; therefore, an MOE of greater than 100 is not of concern.

5.2.2 Short term DWLOC Calculations Though some limited chemical specific water monitoring data are available, they are not nationally representative and not at the tap data. Though they may be indicative of surface water and ground water levels of diuron and its metabolites, under very limited conditions, the Agency believes that they are unsuitable to be quantitatively included in aggregate risk assessment. Therefore, estimated environmental concentrations ( EECs) were calculated by EFED to estimate the potential contribution to the averaged ( chronic) exposure from drinking water, and the EECs were compared to the short term DWLOCs. 44 The current Agency default body weight and consumption values are 10 kg and 1 liter/ day, respectively, for all infants and children, 70 kg and 2 liters/ day for adult males, and 60 kg and 2 liters/ day for adult females. These default values and others are presently under review in the Agency ( Office of Research and Development). If at a future time, the Agency decides to change the default assumptions used, the impact of the changes on the diuron risk assessment will be considered.

The DWLOCshort term is the concentration in drinking water, as part of the aggregate exposure, that combined with average food exposures and residential exposures and divided into the short term NOAEL, results in an MOE that is greater than the LOC or target MOE. Any measured or modeled drinking water estimates that are less than the DWLOC are not of concern. As part of the aggregate risk assessment for diuron, the short term assessment was handled using the reciprocal MOE equation (" 1/ MOE approach") for calculating the aggregate MOE and solving for the term MOEwater. The reciprocal MOE equation is only used when the toxic effects on which the endpoints are selected are the same and when the LOCs are identical for all MOEs in the calculation.

Based on the supported uses of diuron, no incidental oral ( hand to mouth) exposures are expected and therefore, were not factored into the aggregate and DWLOC calculations, i. e. no exposures to children are expected. Also, no systemic toxicity following repeated dermal dosing was observed in submitted studies therefore, dermal exposures were not factored into the equation either.

Taking into account the uses proposed in this action, the Agency can conclude with reasonable certainty that residues of diuron plus its metabolites hydrolyzable to 3,4 DCA, resulting from applications of diuron, in drinking water would not likely result in an aggregate short term risk to male and female adult homeowners above the Agency's level of concern. The Agency based this determination on a comparison of estimated concentrations of diuron and its metabolites ( DCPMU, DCPU, 3,4 DCA) in surface and ground waters to back calculated " levels of comparison" for diuron plus its metabolites in drinking water. The EECs in surface and ground waters were derived from water quality models that used conservative assumptions ( health protective) regarding the pesticide transport from the point of application to surface or ground water, and were supplemented with limited monitoring data.

Modeled Tier 2 ( PRZM/ EXAMS) estimates of concentrations of diuron plus its metabolites in surface water were below the short term DWLOCs for male and female adults and are not of concern. The EECs calculated by EFED were based on the highest labeled rate of application for citrus. Modeled Tier 1 SCI GROW estimates of ground water concentrations of diuron plus its metabolites were below the short term DWLOCs and are not of concern. 45 Table 12. Aggregate Short Term Risk and DWLOC Calculations ( Inhalation/ Oral Endpoints and NOAELs the Same)

Population Short  Term Scenario NOAEL mg/ kg/ d LOC1 Max Exposure2 mg/ kg/ d Average Food Exposure mg/ kg/ d Residential Exposure3 mg/ kg/ d Aggregate MOE ( food and residential) 4 Max Water Exposure5 mg/ kg/ d Surface Water EEC6 ( F g/ L) Ground Water EEC6 ( F g/ L) Short Term DWLOC7 ( F g/ L)

Adult Male 10 100 0.1 0.000088 0.0095 1043 0.09 104 9.1 3153 Adult Female 10 100 0.1 0.000069 0.0095 1045 0.09 104 9.1 2700 1 LOC ( Target MOE) includes safety factors totaling 100 for inter species extrapolation ( 10x) and intra species variability ( 10x). 2 Maximum Exposure ( mg/ kg/ day) = NOAEL/ LOC 3 Residential Exposure = Inhalation Exposure 4 Aggregate MOE = [ NOAEL ÷ ( Avg Food Exposure + Residential Exposure)] 5 Maximum Water Exposure ( mg/ kg/ day) = Target Maximum Exposure  ( Food Exposure + Residential Exposure) 6 The crop producing the highest level was used to assess exposure to diuron, DCPMU, DCPU, 3,4 DCA, total. 7 DWLOC( F g/ L) = [ maximum water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L) x 10 3 mg/ F g]

5.4 Chronic Risk 5.4.1 Chronic Aggregate Risk Assessment Aggregate chronic ( noncancer) risk estimates include the contribution of risk from dietary sources ( food + water) and residential sources. However, based on the labeled uses, no long term or chronic residential exposures are expected. Chronic risk estimates from exposures to food, associated with the use of diuron do not exceed the Agency's level of concern for the most highly exposed population subgroup, children ages 1 6 years of age. The chronic dietary ( food only) risk estimate for children ages 1 6 years of age was < 7% of the chronic PAD.