Page 1 of 64 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: 07/ 07/ 2005 MEMORANDUM SUBJECT: Napropamide: Final HED Chapter of the Reregistration Eligibility Decision ( RED) Document. PC Code: 103001, Case #: 2450, DP Barcode: D312976 Regulatory Action: Phase 4 Reregistration Action Risk Assessment Type: Single Chemical Aggregate FROM: Susan Stanton, Environmental Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

AND John Liccione, Toxicologist Danette Drew, Chemist Seyed Tadayon, Chemist Reregistration Branch 3 Health Effects Division ( 7509C)

THROUGH: Catherine Eiden, Branch Chief Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Demson Fuller; Chemical Review Manager Reregistration Branch I SRRD ( 7508C)

The attached risk assessment for napropamide has been revised to incorporate review of additional product chemistry data and residue field trial data for basil. These data were submitted by the registrant, United Phosphorus, Inc., and/ or USDA's IR 4 program in response to HED's Page 2 of 64 preliminary, Phase 1 risk assessment.

Since the preliminary risk assessment was completed, the registrant has proposed several label changes, including a reduction in the maximum application rate for cranberries. The registrant has also indicated that the company will not support existing tolerances for cucurbit vegetables and coffee. The changes proposed by the registrant would result in lower estimates of dietary and non dietary exposure to napropamide. However, because the estimated risks based on HED's previous exposure assessments are well below our level of concern, a revised risk assessment reflecting the proposed changes is not warranted and has not been conducted. Page 3 of 64 Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.1 Summary of Registered/ Proposed Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . 12 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 14 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.4 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 15 3.5 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 16 3.5.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.5.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 16 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 23 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 23 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 23 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 24 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.3.2 Evidence that supports not requiring for a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 24 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 24 4.4.2 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . 24 Page 4 of 64 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 25 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 27 4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . 29 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 32 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.2 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 6.1.2 Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 41 6.3.1 Residential Handler Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 <IP_ADDRESS> Handler Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . 41 <IP_ADDRESS> Data and Assumptions For Handler Exposure Scenarios 42 <IP_ADDRESS> Residential Handler Exposure and Risk Estimates . . . . . 43 6.3.2 Residential Postapplication Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . 43 <IP_ADDRESS> Residential Postapplication Exposure Scenarios . 43 <IP_ADDRESS> Data & Assumptions for Residential Postapplication Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 <IP_ADDRESS> Residential Postapplication Exposure and Risk Estimates 45 6.3.3 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 49 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Page 5 of 64 9.1 Short/ Intermediate/ Long Term Handler Risk . . . . . . . . . . . . . . . . . . . . . . . . . . 53 9.2 Short/ Intermediate/ Long Term Postapplication Risk . . . . . . . . . . . . . . . . . . . . . 57 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.2 Residue and Product Chemistry Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Page 6 of 64 1.0 Executive Summary The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure data bases for the pesticide active ingredient napropamide and has conducted a human health risk assessment in support of the Reregistration Eligibility Decision ( RED) for this active ingredient.

Use Information Napropamide [ N, N diethyl 2( 1 naphthalenyloxy) propionamide] is a selective preemergence herbicide belonging to the amide class of pesticides. It controls weeds by preventing root cell elongation, thus disrupting the growth process during germination. Napropamide is registered to control broadleaf weeds and annual grasses on numerous food/ feed and non food/ feed use sites, including fruits and nuts, vegetables, ornamentals, turf/ lawns, forestry sites and tobacco.

Toxicology The available toxicity data on napropamide are adequate to assess the chemical's hazard potential. Technical napropamide has low ( category III/ IV) acute toxicity via the oral, dermal and inhalation routes of exposure. It is moderately irritating to the eye ( category II) but does not cause skin irritation or dermal sensitization. The most common effect in animal studies ( dogs, mice and rats) from long term oral exposure was a decrease in body weight or body weight gain, with females being more sensitive than males to effects on body weight. Microscopic liver lesions, spongiosis hepatis and hepatocyte fatty vacuolization were also observed in male rats; however, these effects were not accompanied by increased liver weight or changes in clinical chemistry.

Napropamide did not cause developmental toxicity in fetuses from either rats or rabbits and did not adversely affect reproductive parameters in rats over three generations. There is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses after in utero and/ or postnatal exposure to napropamide in the developmental and reproduction studies. Doseresponse relationships are well characterized and clear NOAELs/ LOAELs have been identified for the critical effects. Therefore, the special FQPA safety factor can be reduced to 1X, since the degree of concern is low and there are no residual uncertainties for pre and/ or postnatal toxicity.

No evidence of neurotoxicity was observed in any study. Based on the weight of evidence, a developmental neurotoxicity ( DNT) study is not required for napropamide.

No evidence for carcinogenicity was seen in mice or rats. The chemical was negative for gene mutation in four studies ( Bacillus subtilis, Salmonella typhimurium, mouse host mediated, CHO) and did not induce micronucleus formation in the mouse or unscheduled DNA synthesis in rat hepatocytes. Positive results for gene mutation were obtained in mouse lymphoma cells with and Page 7 of 64 without metabolic activation at concentrations that also cause significant cytotoxicity and in Chinese hamster lung cells with activation in the absence of cytotoxicity.

A chronic reference dose ( cRfD) of 0.12 mg/ kg/ day was established for napropamide based on the NOAEL of 12 mg/ kg/ day in the rat chronic/ oncogenicity study and an uncertainty factor of 100 ( 10x for interspecies extrapolation and 10x for intraspecies variation). Decreased weight gain in females and an increased incidence of liver lesions in males occurred in this study at the LOAEL of 48/ 55 mg/ kg/ day. An acute reference dose ( aRfD) was not established, since an endpoint attributable to a single exposure was not identified from the available database.

Residue Chemistry The available residue chemistry data are adequate to assess human dietary exposure to napropamide from the consumption of treated food commodities. The residue of concern for tolerance enforcement and risk assessment is napropamide per se for plant commodities. Based on the findings of the livestock metabolism studies, HED has determined that 40 CFR § 180.6( a)( 3) is applicable to napropamide; there is no reasonable expectation of finite residues in ruminants or poultry.

Environmental Fate The available environmental fate data for napropamide are adequate to assess the residues of concern in drinking water. Since no major transformation products were identified in any study, the residue of concern consists of parent napropamide only.

Residential Exposure There is a potential for exposure in residential settings during the application process for homeowners who use products containing napropamide. There is also a potential for exposure from entering residential areas treated with napropamide. In both cases, the duration of exposure is expected to be short term only. As a result, short term risk assessments have been completed for both residential handler and postapplication scenarios. Since a dermal endpoint of concern was not identified for napropamide, the routes of exposure considered in the assessments included only inhalation ( residential handler exposure) and oral ( post application exposure).

Chemical specific exposure data are not available for napropamide. Residential handler exposure was assessed using the Pesticide Handlers Exposure Database ( PHED ver. 1.1) and data from the Outdoor Residential Exposure Task Force ( ORETF). The residential handler and postapplication assessments were conducted in accordance with the EPA's draft Standard Operating Procedures for Residential Exposure Assessments ( R SOPs) adopted December 18, 1997 and revised on February 22, 2001. Page 8 of 64 Aggregate Risk Short and long term ( chronic) aggregate risk assessments were conducted for napropamide. The short term assessment considered both dietary ( food + water) and residential exposures. The long term assessment considered dietary exposure only, since the current uses of napropamide are not expected to result in long term residential exposure.

The results of the deterministic, Tier 1chronic dietary assessment indicate that the combined exposure to napropamide from food and water is well below HED's level of concern, with estimated exposures representing < 2% of the cPAD for the U. S. population and all population subgroups, including infants and children. When the chronic dietary exposure is combined with short term residential exposure, the resulting aggregate risks for adults and children are also below HED's level of concern. The MOE of concern for short term aggregate risk is 100. Since the estimated short term aggregate risk MOEs for adults and children ( toddlers) are 14,340 and 260, respectively, short term aggregate risk is not considered to be of concern for napropamide.

Occupational Exposure Exposure to pesticide handlers is likely during the occupational use of napropamide in a variety of occupational environments. Since no chemical specific handler exposure data are available for napropamide, short and intermediate term inhalation exposures were assessed using data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1. PHED data were used with other HED standard values for areas treated per day, body weight and the level of personal protective equipment ( PPE) and engineering controls to assess handler exposures to napropamide. Using these assumptions, the calculated occupational handler exposures for all exposure scenarios do not exceed HED's level of concern ( i. e., MOEs > 100). Short and intermediateterm inhalation MOEs range from 200 ( loading granulars for aerial application to cranberry) to more than 33,000 ( Mixing/ loading/ Applying liquid for handgun application on lawns). Dermal exposure was not assessed, since a dermal endpoint of concern has not been identified for napropamide.

Conclusions Napropamide is a relatively low toxicity pesticide whose potential routes of exposure include food, drinking water and residential areas. Under the conditions of its current use, human health risks to workers handling the pesticide or to the general population are below HED's level of concern. Aggregate risk MOEs from the consumption of food/ drinking water and from exposure to the pesticide in residential settings exceed 100 for all populations, including infants and children. Page 9 of 64 O CH 3 O N CH 3 CH 3 2.0 Ingredient Profile Napropamide [ N, N diethyl 2( 1 naphthalenyloxy) propionamide] is a selective preemergence herbicide belonging to the amide class of pesticides. It controls weeds by preventing root cell elongation, thus disrupting the growth process during germination. It does not control established weeds.

2.1 Summary of Registered/ Proposed Uses Napropamide is registered to control broadleaf weeds and annual grasses on numerous food/ feed and non food/ feed use sites. Food/ feed uses include almond, apple, apricot, artichoke, asparagus, avocado, blackberry, blueberry, boysenberry, broccoli, Brussels sprouts, cabbage, cauliflower, cherry, citrus fruits ( grapefruit, lemon, orange, tangelo, and tangerine), cranberry, currant, eggplant, fig, filbert ( hazelnut), grapes, kiwifruit, loganberry, mint, nectarine, olive, peach, pear, pecan, pepper, persimmon, pistachio, plum, pomegranate, prune, raspberry ( black and red), rhubarb, strawberry, sweet potato, tomato and walnut ( black and English). Non food/ feed uses include ornamentals ( herbaceous plants, ground covers, woody shrubs and vines and shade trees), lawns and turf, potting/ topsoil and forestry uses ( conifer release), as well as tobacco.

Napropamide products are registered in the U. S. to United Phosphorus, Inc. under the trade name Devrinol. Currently registered end use formulations include dry flowables, flowables, emulsifiable concentrates and granular products containing 2 to 50% active ingredient. Napropamide is applied at 2 to 6 lbs. a. i./ A on all crops/ sites except cranberries, where applications at up to 15 lbs. a. i./ A are allowed. Applications are generally made using ground equipment, including ground boom and hand held sprayers, granular application equipment, and chemigation equipment. Aerial application is permitted on cranberries. The Restricted Entry Interval ( REI) is 12 hours for all agricultural uses of napropamide.

2.2 Structure and Nomenclature TABLE 2.2. Test Compound Nomenclature Chemical Structure Empirical Formula C17H21NO2 Common name Napropamide TABLE 2.2. Test Compound Nomenclature Page 10 of 64 IUPAC name ( RS) N, N diethyl 2( 1 naphthyloxy) propionamide CAS name N, N diethyl 2( 1 naphthalenyloxy) propanamide CAS Registry Number 15299 99 7 Chemical Class Amide Known Impurities of Concern None End use products ( EPs):

70506 27 21.8% EC 2 lb/ gal EC Devrinol 2 E Selective Herbicide 70506 281 21.8% EC 2 lb/ gal EC Devrinol 2 E Ornamental Selective Herbicide 70506 31 43.2% FlC 4 lb/ gal FlC Devrinol 4 F Selective Herbicide  Flowable 70506 33 2% G Devrinol 2 G Ornamental Selective Herbicide 70506 34 10% G Devrinol 10 G Selective Herbicide 70506 36 50% DF Devrinol 50 DF Selective Herbicide 70506 37 43.2% FlC 4 lb/ gal FlC Devrinol 4 F Ornamental Selective Herbicide 70506 38 50% DF Devrinol 50 DF Ornamental Herbicide 70506 39 2% unidentified formulation Devrinol Lawn and Ornamental Selective Herbicide 70506 63 24.1% EC 2 lb/ gal EC Devrinol 2 EC Ornamental Selective Herbicide 70506 64 24.1% EC 2 lb/ gal EC Devrinol 2 EC Selective HErbicide 34704 771 4% G Napropamide Oxadiazon 4 2 Granules 1Reregistration of this product is not supported. The registrant, United Phosphorus Inc., has requested voluntary cancellation.

2.3 Physical and Chemical Properties Napropamide has relatively low volatility, indicating only a slight potential for human exposure via the inhalation route.

TABLE 2.3. Physicochemical Properties of Napropamide Parameter Value Reference Melting point 68 70 ° C MRID 41610201; D303463; 9/ 30/ 04 pH 8.9 at 22 ° C MRID 41610201; D303463; 9/ 30/ 04 Density, bulk density, or specific gravity 0.584 g/ mL at 22 ° C MRID 41610201; D303463; 9/ 30/ 04 TABLE 2.3. Physicochemical Properties of Napropamide Parameter Value Reference Page 11 of 64 Water solubility 74 mg/ L at 25 ° C MRID 41610201; D303463; 9/ 30/ 04 Solvent solubility at 20 ° C Miscible with acetone, chlorobenzene, ethanol, and dichloromethane 4.5 g/ 100 mL in kerosene 17.7 g/ 100 mL in n octanol 55.5 g/ 100 mL in xylene D210989, 7/ 27/ 95, K. Dockter Vapor pressure 1.7 x 10 7 torr or 2.3 x 10 5 Pa at 25 ° C MRID 41610201; D303463; 9/ 30/ 04 Dissociation constant, pKa Not applicable; napropamide is neither an acid nor a base.

Octanol/ water partition coefficient 2.1 x 103 ( log KOW = 3.3) MRID 41610201; D303463; 9/ 30/ 04 UV/ visible absorption spectrum Neutral ( 201.8 nm): A = 1.1144, 0= 58560mol 1cm  1 Acidic ( 215nm): A = 1.1198, 0= 58844mol 1cm  1 Basic: unstable in alkaline solution MRID 46459102; D314409 & D314416, 3/ 17/ 05, P. Horng 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Napropamide is rapidly absorbed, metabolized, distributed, and excreted by the rat following oral administration. The major metabolic routes in the rat are ring hydroxylation and N deethylation followed by conjugation with glucuronic acid and sulfate. The major metabolites identified were 4 hydroxy napropamide, 5 hydroxy napropamide, and 4 hydroxy[ N ethyl 2( 1 naphthoxy)] propionamide. Highest residue concentrations were found in blood, followed by liver and intestine 96 hours after dosing. No major sex differences in residues or metabolic profiles have been observed after an oral dose. Following dermal application, total absorption increased with dose; however, the fraction that was absorbed was inversely related to dose. Excretion is almost exclusively and completely via the urine and feces after both oral and dermal administration.

The metabolic pathway of napropamide in plants is similar to its pathway in rats: desethylation of the parent compound, followed by further desethylation and hydrolysis to yield naphthoxypropionic acid ( which was found as glycoside conjugate); and hydroxylation of the naphthyl ring to yield 4 and 5 hydroxy metabolites. Natural incorporation of 14C into plants occurs as a result of the degradation of napropamide applied to the soil to give 14CO 2 , which is taken in by the plant and incorporated into plant sugars during photosynthesis. Page 12 of 64 The metabolic pathway of napropamide in livestock also appears to be similar. Because of the very low TRR levels found in the livestock metabolism studies, the metabolites were not identified/ characterized in all tissues. However, the metabolites that were identified ( napthoxypropionic acid, desethylnapropamide, and 4 hydroxydesethyl napropamide) are similar to metabolites identified in plants and rats, suggesting a similar metabolic pathway.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The qualitative nature of the residue in plants is understood. Acceptable metabolism studies with napropamide have been conducted on three dissimilar crops ( apple, cabbage, and tomato). Brief summaries of the available plant metabolism studies are presented below.

Apple Ring labeled napropamide was applied to soil in a 4 sq. meter area around an apple tree. Two applications were made; the first at green cluster at a rate of 4.11 lb ai/ A ( 1.03x), and the second approximately five months later at 4.04 lb ai/ A ( 1.01x), to give a preharvest interval ( PHI) of 35 days. Application rate and timings adequately reflected label directions. The first and second year crops were harvested and analyzed for total radioactive residues ( TRR).

In the first year's crop, the fruit TRR was 0.0032 ppm. The radioactivity was fractionated, and no fraction had a residue level greater than 0.002 ppm. Because of the low residues detected, additional analysis was not performed. In the second year's crop, the fruit TRR was 0.0098 ppm. The radioactivity was also fractionated, and no fraction had a residue level greater than 0.006 ppm. Because of the low residues detected, additional analysis was not performed.

Cabbage Ring labeled napropamide was applied to soil in a pot at a slightly exaggerated rate of 2.25 lb ai/ A ( 1.125x). The PHI ranged from 55 to 63 days. The TRR found in the cabbage heart sample was 0.125 ppm. Of this, 94.5% was extractable and a total of 90.7% of the TRR was characterized and 59.9% of the TRR was identified. Natural incorporation into sugars accounted for 50.1% of the TRR. The major metabolites identified were: naphthoxypropionic acid ( 3.0% TRR); desethylnapropamide ( 2.5% TRR); and 5 hydroxy napropamide ( 1.2% TRR). The parent compound accounted for 0.8% of the TRR.

In whole cabbage, the TRR found was 0.457 ppm. Of this amount, 89.1% was extractable and a total of 77.0% of the TRR was characterized and 35.2% of the TRR was identified. Natural incorporation into sugars accounted for 12.6% of the TRR. The major identified metabolites were: 5 hydroxy napropamide ( 6.7% TRR); 1,4 naphthoquinone ( 4.9% TRR); Page 13 of 64 napthoxypropionic acid ( 2.9% TRR); and desethylnapropamide ( 2.3% TRR). The parent compound accounted for 0.9% TRR. Page 14 of 64 Tomato Ring labeled napropamide was applied to soil in a pot at a slightly exaggerated rate of 2.25 lb ai/ A ( 1.125x). Fruits were harvested when ripe; PHI ranged from 67 to 122 days. The TRR found in/ on tomatoes was 0.051 ppm. Of this amount, 92.3% was extractable, and a total of 83.7% of the TRR was characterized and 43.9% of the TRR was identified. Natural incorporation into sugars accounted for 21.2% of the TRR. The major metabolite found was o phthalic acid ( 6.1% TRR), followed by 5 hydroxydesethyl napropamide ( 4.5% TRR) and 5 hydroxynaphthoxypropionic acid ( 4.2% TRR).

3.2.2 Description of Livestock Metabolism The qualitative nature of the residue in livestock is understood. HED has received and reviewed acceptable ruminant and poultry metabolism studies with napropamide. Brief summaries of the available animal metabolism studies are presented below.

Ruminants ( MRID 42775801)

Two lactating goats were orally dosed with [ 14C] napropamide twice daily at levels equivalent to 11.2 ppm and 8.5 ppm in the diet ( average of 9.9 ppm) for four consecutive days. During the testing period, milk was collected twice daily, in the morning and afternoon. The goats were sacrificed 23 24 hours after the last dose, and the following samples were collected: liver, kidney, omental fat, subcutaneous fat, perirenal fat, muscle from foreleg and rump, urine from bladder, bile, and gastrointestinal tract. For both goats, approximately 90% of the total administered dose was eliminated in the urine and feces. The mean excretion of radioactivity in milk was very small ( 0.084% of dose). The amount of radioactivity found in liver ( 0.170% of dose) and kidney ( 0.007% of dose) was also small.

The TRR in milk over each 24 hour period encompassed in the study ranged from 0.0068 ppm to 0.0089 ppm, and levels plateaued after 24 hours. The TRRs averaged 0.0031 ppm in muscle and 0.0066 ppm in fat. The identification and/ or characterization of radioactive residues in milk, muscle, and fat was not necessary because TRR levels were less than 0.010 ppm.

The TRR in liver of Goat 2 was 0.165 ppm. Radioactive residues in liver were adequately identified and/ or characterized. Napropamide and desethylnapropamide were determined in liver at 0.3% TRR. Approximately 40% of the TRR was associated with trichloroacetic acid precipitated proteins. Following extensive fractionation of solubilized radioactivity from liver debris, no components were present at > 0.010 ppm.

The TRR in the kidney of Goat 2 was 0.034 ppm. Radioactive residues in kidney were adequately identified and/ or characterized. The only identified metabolite in kidney was napropamide at 1.8% TRR. TLC analysis of various kidney fractions indicated the presence of 13 Page 15 of 64 unknowns, the largest being 4.7% TRR. About 19.0% of the TRR remained associated with trichloroacetic acid precipitated proteins.

Poultry Gelatin capsules containing [ 14C] napropamide were orally administered to 10 laying hens once daily for ten consecutive days. Each bird received an average of 8.3 ppm napropamide in the diet ( range of 7.4 ppm to 10.1 ppm). Eggs were collected twice daily from each chicken. The hens were sacrificed 23 24 hours after the last dose, and the following samples were collected: skin plus subcutaneous fat, peritoneal fat, leg muscle, breast muscle, liver, kidney, and gastrointestinal tract and contents. Most of the administered dose was found in the excreta ( average of 92.1%). Additionally, 2.51% of the administered dose was found in cage washings. Liver and kidney, the tissues with the highest TRR levels, contained only 0.046% and 0.006% of the administered dose, respectively.

The TRR levels in all tissues were low. Liver and kidney were the tissue with the highest TRR levels, with values of 0.105 ppm and 0.0455 ppm respectively. TRR levels in muscle were < 0.0034 ppm, and levels in skin and fat were < 0.0078 ppm. Radioactive residue levels in the egg whites were reasonably constant over the dosing period, and were always < 0.010 ppm. Residue levels in egg yolks rose to a plateau of between 0.0373 ppm to 0.0419 ppm on days 6 10 of the study.

Radioactive residues in poultry liver were adequately characterized. About 29.5% of the TRR in liver was solvent extractable. Napthoxypropionic acid accounted for a total of 13.7% TRR and desethylnapropamide accounted for 2.5% TRR. Following extensive fractionation, no other fractions had TRR levels > 0.010 ppm.

Radioactive residues in egg yolk were also adequately characterized. About 83.6% of the TRR was solvent extractable. The following components were identified: napthoxypropionic acid ( 6.1% TRR), napropamide ( 5.2% TRR), desethylnapropamide ( 4.1% TRR), and 4 hydroxydesethyl napropamide ( 3.9% TRR). No other fractions had TRR levels > 0.010 ppm.

3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation An acceptable confined rotational crop study with napropamide has been submitted and reviewed. In this study, wheat, carrots, and lettuce were planted at intervals of 60, 180, and 364 days in pots containing sandy clay loam soil. The soil was treated with [ 14C] napropamide at 4.4 lb ai/ A ( 2.2x the maximum registered rate on annual crops). TRR accumulated $ 0.01 ppm in/ on wheat forage ( 0.08 0.41 ppm), wheat straw ( 0.50 1.85 ppm), wheat grain ( 0.04 0.11 ppm), carrot root ( 0.04 0.14 ppm), carrot tops ( 0.08 0.16 ppm), and lettuce ( 0.04 0.08 ppm) at all plantback intervals ( PBI). All samples of 60 day PBI as well as 180 and 364 day PBI wheat forage and wheat straw were subjected to extraction/ characterization of residues. The metabolites identified in the Page 16 of 64 various matrices of rotational crops corresponded to the metabolites identified in the plant metabolism studies and were found in approximately similar proportions. Napropamide and desethyl napropamide were found in all crops.

3.3 Environmental Degradation The environmental fate data are complete and indicate that napropamide can be persistent in the environment. Napropamide is stable to hydrolysis and biodegradation. Major degradates (> 10 % of applied) were not formed in the metabolism studies, although napththoxy propionic acid was formed at up to 5.8 % in anaerobic aquatic metabolism studies ( representing sediment). Photolysis is the only relatively rapid degradation process, with a half life of 6.8 minutes in water and 28 days on soil. Two napropamide isomers and a dimer of one of the isomers were identified in water that had been exposed to light, but no photolytic degradates other than CO2 have been identified in soil exposed to light.

3.4 Toxicity Profile of Major Metabolites and Degradates 1,4 Naphthoquinone, a compound known to cause severe eye, skin and upper respiratory tract irritation, was identified in the plant metabolism studies ( cabbage only). However, based on the low levels seen in plants, it is not of toxological concern. Other plant metabolites were also identified in rat metabolism studies; therefore, their potential toxic effects are assumed to have been taken into account in the rat studies ( Napropamide. Reregistration Case No. 2450. Outcome of the 3/ 16/ 93 Meeting of the HED Metabolism Committee; Steven A. Knizner; April 7, 1993) Page 17 of 64 3.5 Summary of Residues for Tolerance Expression and Risk Assessment 3.5.1 Tabular Summary Table 3.5. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Napropamide, per se Napropamide, per se Rotational Crop Napropamide, per se1 Not Applicable1 Livestock Ruminant Not Applicable2 Not Applicable2 Poultry Not Applicable2 Not Applicable2 Drinking Water Napropamide, per se Not Applicable 1Residues are not expected in rotational crops and rotational crop tolerances are not required, provided labels specify a 60 day Plant Back Interval ( PBI) for leafy vegetables, a 180 day PBI for cereal grains, and a 365 day PBI for all other crops. Any labels that do not already specify the appropriate crop restrictions should be amended. Rotational crops were not included in the risk assessment. 2 HED has determined that 40 CFR § 180.6( a)( 3) is applicable to napropamide; there is no reasonable expectation of finite residues in ruminants or poultry.

3.5.2 Rationale for Inclusion of Metabolites and Degradates The results of the plant metabolism studies were presented on 3/ 16/ 93 to the HED Metabolism Committee. The Metabolism Committee concluded that the residue of concern in plants is napropamide, per se. The Committee's conclusion was based on the following considerations: ( 1) the concentration of quinones detected in the metabolism studies was sufficiently low so as not to be of toxicological concern; and ( 2) the other plant metabolites found in these studies were also seen in rat metabolism studies. In addition, these metabolites were present at low levels and would not likely be found if they were included in the plant analytical method.

The metabolites identified in the various matrices of rotational crops corresponded to the metabolites identified in the plant metabolism studies and were found in approximately similar proportions. Therefore, the residue of concern in rotational crops is also napropamide, per se.

Based on the findings from the livestock metabolism studies, HED has determined that 40 CFR § 180.6( a)( 3) is applicable to napropamide; there is no reasonable expectation of finite residues in ruminants or poultry. This determination is based on the low level of residues observed in the goat metabolism study where the test animals were dosed with [ 14C] napropamide at an average Page 18 of 64 level of 9.9 ppm in the diet which is equivalent to 120x the maximum dietary burden of 0.083 ppm to dairy cattle. This determination is also based on the fact that there are no poultry or swine feedstuffs associated with the raw agricultural commodities with established tolerances.

No major degradates (> 10% of the applied) of napropamide were formed in any of the environmental fate studies. Based on the results of these studies, the residue of concern in drinking water is napropamide, per se.

4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization Napropamide has generally low acute toxicity with no deaths occurring at approximately the limit dose for oral, inhalation and dermal studies ( Table 4.1a). Clinical signs of toxicity suggestive of irritation were observed in animals treated orally or by inhalation. The chemical caused moderate eye irritation which cleared after 7 days but did not cause skin irritation and is not a sensitizer.

The most common effect in animal studies from long term oral exposure was a decrease in body weight or body weight gain ( Table 4.1b). Females were more sensitive than males to effects on body weight. In chronic studies a decrease in body weight and body weight gain by female dogs ( 500 mg/ kg/ day) and rats ( 55 mg/ kg/ day) and male and female mice ( 455 and 568 mg/ kg/ day) was the basis for the study LOAEL. The NOAELs ( m/ f) for chronic toxicity in dogs, rats and mice were 70/ 70, 11/ 12 and 55/ 70 mg/ kg/ day, respectively. Microscopic lesions were observed in livers from male rats fed 48 mg napropamide/ kg/ day for two years. These lesions in male rats, spongiosis hepatis and hepatocyte fatty vacuolization, were not accompanied by increased liver weight or changes in clinical chemistry.

No evidence of neurotoxicity was observed in any study. Daily dermal application to rats for 21 days did not cause any systemic or local effects up to the limit dose of 1000 mg/ kg/ day.

Decreased maternal body weight gain was also the only endpoint of toxicity observed in developmental toxicity studies with rats and rabbits ( 1000 and 300 mg/ kg/ day, respectively). No evidence of developmental toxicity was observed in fetuses from either species up to and including the limit dose.

Napropamide did not adversely affect reproductive parameters in rats over three generations. Offspring body weight was decreased at the highest dose ( 100 mg/ kg/ day) beginning as early as PND 7 and cumulative weight gain by the high dose pups of all three generations was decreased during lactation. Therefore, both lactational effects prior to PND 14 and systemic effects after the pups began eating the treated diets probably contributed to reduced growth. Lower preweaning pup body weight continued into the early part of the premating interval for parental animals. The NOAEL for parental and offspring toxicity ( decreased body weight) was 30 mg/ kg/ day. Page 19 of 64 No evidence for carcinogenicity was seen in mice or rats. Administration of napropamide to mice for 18 months and to rats for 24 months did not result in an increase in overall tumor incidence or an increase in the incidence of any specific type of tumor. The chemical was negative for gene mutation in four studies ( Bacillus subtilis, Salmonella typhimurium, mouse host mediated, CHO) and did not induce micronucleus formation in the mouse or unscheduled DNA synthesis in rat hepatocytes. Positive results for gene mutation were obtained in mouse lymphoma cells with and without metabolic activation at concentrations that also cause significant cytotoxicity and in Chinese hamster lung cells with activation in the absence of cytotoxicity.

Napropamide is rapidly absorbed, metabolized, distributed and excreted by the rat following oral administration. The major metabolic routes in the rat are ring hydroxylation and N deethylation followed by conjugation with glucuronic acid and sulfate. No toxic metabolites have been identified. Highest residue concentrations were found in blood, followed by liver and intestine 96 hours after dosing. No major sex differences in residues or metabolic profiles have been observed after an oral dose. Following dermal application, total absorption increased with dose; however, the fraction that was absorbed was inversely related to dose. Excretion is almost exclusively and completely via the urine and feces after both oral and dermal administration.

The toxicity data base for napropamide is complete. No data gaps have been identified.

Table 4.1a Acute Toxicity Profile  Napropamide Guideline No. Study Type MRID( s) Results Toxicity Category 870.11 Acute oral [ rat] 40362902 LD50 = > 5000 mg/ kg IV 870.12 Acute dermal [ rabbit] 40362902 LD50 = > 2000 mg/ kg III 870.13 Acute inhalation [ rat] 42231501 LC50 = > 4.8 mg/ L IV 870.24 Acute eye irritation [ rabbit] 40362902 moderate II 870.25 Acute dermal irritation [ rabbit] 40362902 none IV 870.26 Skin sensitization [ guinea pig] 40362903 negative Nonsensitizing Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity ( rat) 00113809 ( 1970) Unacceptable/ guideline ( not upgradable) M& F: 0, 13, 25, 50 mg/ kg/ d NOAEL = 50 mg/ kg/ day LOAEL = not identified animals could have tolerated a higher dose Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 20 of 64 870.3150 90 Day oral toxicity ( dog) 00113810 ( 1970) Unacceptable/ guideline ( upgradable) M& F: 0, 16, 40, 100 mg/ kg/ d NOAEL = > 100 mg/ kg/ day LOAEL = not identified ( animals could have tolerated a higher dose; no homogeneity, stability, and concentration data in the dietary formulations)

870.3200 21/ 28 Day dermal toxicity ( rat) 42006701 ( 1991) Acceptable/ guideline M& F: 0, 10, 100, 1000 mg/ kg/ d NOAEL = 1000 mg/ kg/ day LOAEL = not identified 870.3250 90 Day dermal toxicity ( species) not required 870.3465 90 Day inhalation toxicity ( species) not required 870.3700a Prenatal developmental in ( rat) 128104 ( 1982) Acceptable/ guideline F: 0, 30, 110, 400 mg/ kg/ d ( GD 6 15) Maternal NOAEL = 110 mg/ kg/ day LOAEL = 400 mg/ kg/ day based on decreased body weight gain. Developmental NOAEL = 400 mg/ kg/ day LOAEL = not identified 870.3700a Prenatal developmental in ( rat) 42006703 ( 1990) Acceptable/ guideline F: 0, 100, 300, 1000 mg/ kg/ d ( GD 6 15) Maternal NOAEL = 300 mg/ kg/ day LOAEL = 1000 mg/ kg/ day based on decreased body weight gain. Developmental NOAEL = 1000 mg/ kg/ day LOAEL = not identified 870.3700b Prenatal developmental in ( rabbit) 142118 ( 1984) Unacceptable/ guideline ( not upgradable) F: 0, 10, 50, 200 mg/ kg/ d ( GD 7 19) Maternal NOAEL $ 200 mg/ kg/ day LOAEL = not determined Developmental NOAEL $ 200 mg/ kg/ day LOAEL = not determined ( supplementary data due to lack of frank toxicity)

870.3700b Prenatal developmental in ( rabbit) 42006704 ( 1990) Acceptable/ guideline F: 0, 100, 300, 1000 mg/ kg/ d ( GD 7 19) Maternal NOAEL = 100 mg/ kg/ day LOAEL = 300 mg/ kg/ day based on decreased body weight gain. Developmental NOAEL = 1000 mg/ kg/ day LOAEL = not identified 870.3800 Reproduction and fertility effects ( rat) 92125069 Acceptable/ guideline M: 0, 9.9, 29.6, 98.8 mg/ kg/ d F: 0, 12.7, 39.4, 130.7 Parental/ Systemic NOAEL = 29.6/ 39.4 mg/ kg/ day LOAEL = 98.8/ 130.7 mg/ kg/ day based on decreased body weight in F1 females and F2 males and females. Reproductive NOAEL = 98.8/ 130.7 mg/ kg/ day LOAEL = not identified. Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 21 of 64 mg/ kg/ d Offspring NOAEL = 29.6/ 39.4 mg/ kg/ day LOAEL = 98.8/ 130.7 mg/ kg/ day based on decreased pup body weights.

870.4100b Chronic toxicity ( dog) 41156602 Acceptable/ guideline M& F: 0, 10, 70, 500 mg/ kg/ d NOAEL = 70 mg/ kg/ day LOAEL = 500 mg/ kg/ day based on decreased body weight and body weight gain in females.

870.4200 Carcinogenicity ( mouse) 00081613 ( 1978) Unacceptable/ guideline M& F: 0, 10, 30, 100 mg/ kg/ d NOAEL = 30 mg/ kg/ day LOAEL = 100 mg/ kg/ day based on decreased body weight in females after week 98. ( animals could have tolerated a higher dose; inconsistencies in number of animals for which pathology was reported) no evidence of carcinogenicity 870.4200 Carcinogenicity ( mouse) 42189101 ( 1992) Acceptable/ guideline 0, 60, 450, 3500, 7000 ppm M: 0, 7.4, 55, 455, 931 mg/ kg/ d F: 0, 9.4, 70, 568, 1216 mg/ kg/ d NOAEL = 55/ 70 mg/ kg/ day LOAEL = 455/ 568 mg/ kg/ day based on decreased body weight and body weight gain in males and females. no evidence of carcinogenicity 870.4300 Chronic/ Carcinoge nicity ( rat) 00081614 ( 1978) Unacceptable/ guideline M& F: 0, 10, 30, 100 mg/ kg/ d NOAEL = 100 mg/ kg/ day LOAEL = not identified animals could have tolerated a higher dose 870.4300 Chronic/ Carcinoge nicity ( rat) 42189102 ( 1992) 43068801 ( 1993) Acceptable/ guideline 0, 250, 1100, 5000 ppm M: 0, 11, 48, 221 mg/ kg/ d F: 0, 12, 55, 261 mg/ kg/ d NOAEL = 11/ 12 mg/ kg/ day LOAEL = 48/ 55 mg/ kg/ day based on decreased weight gain in females and slightly increased incidence of spongiosis hepatis in males. no evidence of carcinogenicity Gene Mutation 870.5100 ( Bacillus subtilis) 00025880 ( 1980) Acceptable/ guideline negative up to 2000 : g/ disk Gene Mutation 870.5100 ( Salmonella typhimurium) 00025880 ( 1980) Acceptable/ guideline negative up to 5000 : g/ disk with and without metabolic activation Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 22 of 64 Gene Mutation 870.5100 ( host mediated; mice) 00025880 ( 1980) Acceptable/ guideline negative after doses of 1 or 4 g/ kg Gene Mutation 870.5300 ( mouse lymphoma cells) 00147490 ( 1984) Acceptable/ guideline positive for forward mutation at 0.016 0.08 mg/ mL with and without metabolic activation; significant cytotoxicity Gene Mutation 870.5300 ( CHO) 00162137 ( 1985) Acceptable/ guideline negative for forward mutation up to 0.45 mg/ mL with and without metabolic activation Gene Mutation 870.5300 ( Chinese hamster lung cells) 41582201 ( 1986) Acceptable/ guideline positive at 10, 50, 100 : g/ mL with metabolic activation; negative without metabolic activation; no cytotoxicity Cytogenetics 870.5375 ( human fibroblasts) 00162135 ( 1986) Unacceptable/ guideline inconclusive due to study deficiencies Micronucleus 870.5395 ( mouse) 00147489 ( 1984) 00162136 ( 1986) Acceptable/ guideline negative at doses of 556, 1667, 5000 mg/ kg Unscheduled DNA Synthesis 870.5550 ( rat hepatocytes) 41610208 ( 1990) Acceptable/ guideline ( males only) negative in cultured hepatocytes isolated from male rats treated with a single oral dose of up to 2000 mg/ kg 870.6200a Acute neurotoxicity screening battery not required 870.6200b Subchronic neurotoxicity screening battery not required 870.6300 Developmental neurotoxicity not required 870.7485 Metabolism and pharmacokinetics ( rat) Acc. # 091008 Unacceptable/ guideline 30 mg/ kg rapid absorption, metabolism, distribution, and excretion; major metabolic routes are ring hydroxylation and Ndeethylation followed by conjugation with glucuronic acid and sulfate ( acceptable with 42758901, 42758902) Table 4.1b Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 23 of 64 870.7485 Metabolism and pharmacokinetics ( rat) 42027702 ( 1991) 42027703 ( 1991) Unacceptable/ guideline 30, 300 mg/ kg rapid absorption and extensive metabolism; recovered radioactivity was urine = feces >> tissues; highest concentrations in blood followed by liver, spleen, kidneys; 14 metabolites identified ( acceptable with 42758901, 42758902)

870.7485 Metabolism and pharmacokinetics ( rat) 42758901 ( 1990) 42758902 ( 1993) Acceptable/ guideline 30 ( multiple), 300 ( single) mg/ kg no sex or dose related differences in residues or metabolic profile; after 96 hr highest concentrations found in blood, abdominal vein, liver, and intestine; major metabolites were 4 hydroxy napropamide, 5 hydroxy napropamide, and 4 hydroxy[ N ethyl 2( 1 naphthoxy)] propionamide 870.7600 Dermal penetration ( rat) 40838601 ( 1988) Acceptable/ guideline 1.13, 2.55, 5.56, 77.9 mg/ rat total absorption increased with dose; fraction of given radioactivity that was absorbed was inversely related to dose; maximum absorption 26.1%; urine and feces excretion roughly equal over 96 hours Special studies none required 4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base Data are adequate for evaluation of effects resulting from in utero and post natal exposure. Acceptable developmental toxicity studies have been conducted in rodents and non rodents and a reproductive toxicity study in rodents is available.

4.2.2 Evidence of Neurotoxicity No evidence of neurotoxicity was observed in any study. No clinical signs of toxicity were noted in subchronic and chronic studies in dogs, rats, or mice.

4.2.3 Developmental Toxicity Studies Developmental toxicity studies have been conducted with napropamide in the rat and rabbit. Both species were administered 0, 100, 300 or 1000 mg/ kg/ day by oral gavage. Rats were treated on GDs 6 15 and rabbits were treated on GDs 7 19. Maternal toxicity was evident in both as decreased body weight gain and food consumption during the treatment interval. In rats the most pronounced effects were during GDs 6 9 in which body weight gain was decreased by 84% and food consumption was decreased by 21% in the high dose group. For rabbits, the effects were cumulative for the entire dosing interval. Does administered 300 mg/ kg/ day had weight gain decreased by 37%, while high dose animals had a mean weight loss for GDs 7 19. It should be noted that the standard deviation about the mean for both mid and high dose group weight gain Page 24 of 64 values was much greater than the mean value, suggesting that only a few does in each group were affected. High dose rabbits also had reduced food consumption during GDs 7 13.

No developmental toxicity was observed in either species up to and including the limit dose. Fetal body weight was similar between the treated and control groups and no treatment related external, visceral, or skeletal abnormalities were found.

4.2.4 Reproductive Toxicity Study In a three generation reproduction toxicity study napropamide was administered to male and female rats at nominal dose levels of 0, 10, 30, and 100 mg/ kg bw/ day. The premating intervals were approximately 7 weeks for the F 0 animals and approximately 11 weeks for the F 1 and F 2 animals. Two litters were produced in each generation. Reproductive performance was not affected in any generation. The only evidence of parental toxicity was slightly lower absolute body weight for the high dose F 1 and F 2 males and females at the beginning of the premating interval. Weight gain during premating was comparable between the treated and control groups of all generations.

Offspring body weight was decreased at the highest dose beginning as early as PND 7. At 100 mg/ kg, decreased ( 94 11%; p# 0.05) body weights were noted in the F 2a pups on PND 7 and 14, in the F 1b and F 3a pups on PND 14 and 21, and in the F 1a and F 2a pups on PND 21. Decreases in body weights also were observed in the 100 mg/ kg F 2b and F 3b pups ( 94 9%; not significant). Although the data were not available to evaluate weight gain throughout lactation, it appears that cumulative weight gain by the high dose pups of all generations was decreased. Therefore, both lactational effects prior to PND 14 and systemic effects after the pups began eating the treated diets probably contributed to reduced growth. The lower body weight for adults at the beginning of premating is a continuation of the preweaning effects. Recovery of body weight to the control level was apparent for both F 1 and F 2 adults during the premating interval.

4.2.5 Additional Information from Literature Sources No additional information on the toxicity of napropamide was identified in the open literature.

4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility There is no indication of increased susceptibility of fetuses or offspring in the developmental and reproduction studies.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility Page 25 of 64 There is no degree of concern and there are no residual uncertainties. No quantitative or qualitative sensitivity was observed in the rat and rabbit developmental studies or in the 3 generation reproduction study in the rat. Based on the lack of evidence of pre and/ or postnatal susceptibility resulting following exposure to napropamide, and considering the lack of residual uncertainties for pre and/ or postnatal toxicity, no special FQPA safety factor is needed ( i. e., 1X). There is no concern for developmental neurotoxicity resulting from exposure to napropamide.

4.3 Recommendation for a Developmental Neurotoxicity Study 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study None of the available data support the recommendation for a developmental neurotoxicity study.

4.3.2 Evidence that supports not requiring for a Developmental Neurotoxicity study The available data on the toxicity of napropamide do not support the recommendation for a developmental neurotoxicity study.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 An endpoint attributable to a single exposure was not identified from the available database.

4.4.2 Acute Reference Dose ( aRfD)  General Population An endpoint attributable to a single exposure was not identified from the available database.

4.4.3 Chronic Reference Dose ( cRfD)

Study Selected: chronic/ oncogenicity rat OPPTS: 870.4100b MRID No.: 42189102 and 43068801 Executive Summary: In a chronic toxicity/ carcinogenicity feeding study ( MRIDs 42189102 and 43068801), napropamide ( purity 94.1%) was fed to groups of 60 ( treated groups) or 70 ( controls) Crl: CD ( SD) BR rats/ sex/ group for 104 weeks ( females) or 101 weeks ( males) at dose levels of 0, 250, 1100, or 5000 ppm ( corresponding to 0, 11, 48, or 221 mg/ kg/ day for males and 0, 12, 55, or 261 mg/ kg/ day for females). Of these, twenty controls and 10 treated animals/ sex/ dose group were sacrificed at 52 weeks. An additional satellite group of 20 Page 26 of 64 animals/ sex were fed a diet containing 10,000 ppm napropamide ( corresponding to 522 and 582 mg/ kg/ day, respectively, for males and females) for 52 weeks.

A 1100 ppm, statistically significantly decreased weight gain was observed in females ( up to 19% less than controls during the first year of the study). At 5000 ppm, body weight gain was also decreased in males ( up to 12% less than controls). Increased severity of chronic progressive glomerulonephropathy and incidence of spongiosa hepatis and hepatocyte fatty vacuolization were observed in males; in both sexes mild anemia and slight diuretic effects were also reported at 5000 ppm. Mildly reduced food consumption was observed in females. Body weight gain was markedly depressed ( up to 28%, males and 45%, females). Males at 10,000 ppm had increased incidence and severity of hepatocyte fatty vacuolization. The LOAEL for systemic toxicity is 1100 ppm for male and female rats ( 48/ 55 mg/ kg/ day), based on decreased weight gain in females and slightly increased incidence of spongiosis hepatis in males. The NOAEL is 250 ppm ( 11/ 12 mg/ kg/ day).

Neither male nor female rats developed neoplastic lesions that could be attributed to treatment with napropamide for up to 104 weeks. Dosing was considered adequate to test for carcinogenicity of napropamide in rats.

This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a combined chronic toxicity/ oncogenicity rodent feeding study ( 83 5).

Dose and Endpoint for establishing cRfD: Chronic NOAEL of 12 mg/ kg/ day based on decreased weight gain in females and increased incidence of liver lesions in males at 48/ 55 mg/ kg/ day.

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies extrapolation.

Comments about Study/ Endpoint/ UF: The duration of dosing and the endpoint are appropriate for this scenario.

Chronic RfD = 12 mg/ kg/ day = 0.12 mg/ kg/ day 100 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

Study Selected: multi generation OPPTS: 870.3800 MRID No.: 92125069 Executive Summary: In a three generation reproduction toxicity study ( MRID 92125069), Devrinol Technical ( Napropamide; 94.6% a. i.; Lot/ batch # 4059 17 1) was administered to Charles River CD ® rats ( 15 males/ dose; 30 females/ dose) at nominal dose levels of 0, 10, 30, and Page 27 of 64 100 mg/ kg bw/ day ( equivalent to 0/ 0, 9.9/ 12.7, 29.6/ 39.4, and 98.8/ 130.7 mg/ kg bw/ day). The P animals were given test article diet formulations for approximately 7 weeks prior to mating, then were mated ( 1 male with 2 females) to produce the F 1a litters. The P females were allowed to rest for 10 days after weaning of the F 1a litter, then were mated with a different P male in the same treatment group to produce the F 1b litters. One week after weaning, F 1b animals ( 15 males/ dose; 30 females/ dose) were selected to become the parents of the F 2 generations. This process was repeated for a total of 3 generations, with 2 litters per generation produced. F 1b animals were given test formulations for 11 weeks prior to mating to produce the F 2a litters; F 2b animals were given test formulations for 11 weeks prior to mating to produce the F 3a litters.

No treatment related findings were noted at 10 ppm in the parents or offspring.

At 100 mg/ kg, pre mating body weights were decreased ( 98 13%; p# 0.05) in the F 1 females at Week 26, and in the F 2 males and females at Week 55. Body weights of P, F 1 , and F 2 generation females were unaffected by treatment throughout gestation and lactation. There were no treatment related differences in absolute or relative food consumption in either sex throughout the duration of this study, and there were no effects of treatment on the duration of gestation or on male and female fertility indices.

The LOAEL for parental toxicity is 100 mg/ kg/ day ( equivalent to 98.8/ 130.7 mg/ kg bw/ day [ M/ F]), based on decreased body weights in the F1 females and F2 males and females. The NOAEL is 30 mg/ kg/ day ( equivalent to 29.6/ 39.4 mg/ kg bw/ day [ M/ F]).

At 100 mg/ kg, decreased( 94 11%; p# 0.05) body weights were noted in the F 2a pups on PND 7 and 14, in the F 1b and F 3a pups on PND 14 and 21, and in the F 1a and F 2a pups on PND 21. Decreases in body weights also were observed in the 100 mg/ kg F 2b and F 3b pups ( 94 9%; not significant). The only decreases in the 30 mg/ kg group were noted in the F 3a males ( 98%; p# 0.05).

The LOAEL for offspring toxicity 100 mg/ kg/ day ( equivalent to 98.8/ 130.7 mg/ kg bw/ day [ M/ F]), based on decreased pup body weights. The NOAEL is 30 mg/ kg/ day ( equivalent to 29.6/ 39.4 mg/ kg bw/ day [ M/ F]).

The LOAEL for reproductive performance was not observed. The NOAEL for reproductive performance is 100 mg/ kg/ day ( equivalent to 98.8/ 130.7 mg/ kg bw/ day [ M/ F]).

This study is classified as Acceptable/ guideline and satisfies the guideline requirements ( OPPTS 870.3800; OECD 416) for a three generation reproduction study in the rat.

Dose and Endpoint: The offspring toxicity NOAEL of 30 mg/ kg/ day based on decreased pup body weight at 100 mg/ kg/ day.

Uncertainty Factor ( UF): NA Page 28 of 64 Comments about Study/ Endpoint/ UF: Reductions in offspring body weight began as early as PND 7, and was also affected late in lactation after the pups started eating the treated food. Body weights were decreased in parental F1 and F2 males and females. This endpoint is appropriate for duration of exposure and applies to the population of concern.

4.4.5 Dermal Absorption Executive Summary: In a dermal absorption study ( MRID 40838601), male CD rats ( 28/ dose) were administered a mixture of DEVRINOL 50 WP ® ( 51.7% a. i.( w/ w) DEVRINOL; Lot # SFH 2702), [ naphthoxy 1 14C] DEVRINOL ( Lot # WRC 10887 47 01) and 50 WP carrier ( Lot # WFJ 2301). This was applied as a 1: 100, 1: 50, 1: 25, or 1: 2 dilution of DEVRINOL 50 WP ( about 1.31, 2.55, 5.56, and 77.9 mg DEVRINOL/ rat, respectively). Four rats/ dose were sacrificed 1, 4, 10, 24, 48, 72, or 96 hours after application. Several in vitro and in vivo pilot studies were conducted that indicated the experimental protocol for assessing DEVRINOL ( 1: 100 dilution) dermal absorption was acceptable.

No animals died as a result of the treatment in the main study. Dermal absorption was most rapid during the first hour, after which absorption continued to increase for only the three lower doses, slowing after 24 hours. The total absorbed radioactivity after 96 hours ( sum of radioactivity in carcass, skin, urine, feces and blood) increased with dose ( 350, 380, 840, and 1370 :

gequivalents DEVRINOL for low to high dose). However, the fraction of the given radioactivity that was absorbed was inversely related to dose ( 26.1%, 15.1%, 14.9%, and 1.8% for the low to high dose, respectively). Excretion paralleled absorption, the total excreted radioactivity increasing with dose, whereas the % administered radioactivity excreted was inversely related to dose. Over 96 hours, roughly equal amounts of radioactivity were excreted in the urine and feces for all doses ( urine: 12.56%, 7.81%, 5.92%, and 0.69% of given dose; feces: 12.27%, 6.45%, 6.61%, and 0.50% of given dose, respectively, for low to high dose). The excreted radioactivity accounted for 97%, 97%, 89%, and 85% of the radioactivity that penetrated the skin after 96 hours for the low to high dose, respectively. This indicated that at the two highest doses DEVRINOL entry into the bloodstream was greater than its rate of excretion, and is consistent with the lack of a decrease in blood radioactivity at 96 hours at these two doses.

The average recovery of administered radioactivity was 91 97% for the 4 dose groups ( 94% overall), indicating acceptable mass balance accounting. DEVRINOL tissue distribution and metabolite characterization were not performed.

This study is classified as Acceptable/ Guideline and meets the requirements for a dermal absorption study in the rat.

4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) Page 29 of 64 Short and Intermediate Term Dermal Endpoints: No hazard was identified; therefore, no quantification is required. Systemic toxicity was not seen at the limit dose in a dermal toxicity study in the rat. Additionally, there are no developmental concerns.

Long Term Dermal Endpoints:

Study Selected: chronic/ oncogenicity rat OPPTS: 870.4100b MRID No.: 42189102 and 43068801 Executive Summary: In a chronic toxicity/ carcinogenicity feeding study ( MRIDs 42189102 and 43068801), napropamide ( purity 94.1%) was fed to groups of 60 ( treated groups) or 70 ( controls) Crl: CD ( SD) BR rats/ sex/ group for 104 weeks ( females) or 101 weeks ( males) at dose levels of 0, 250, 1100, or 5000 ppm ( corresponding to 0, 11, 48, or 221 mg/ kg/ day for males and 0, 12, 55, or 261 mg/ kg/ day for females). Of these, twenty controls and 10 treated animals/ sex/ dose group were sacrificed at 52 weeks. An additional satellite group of 20 animals/ sex were fed a diet containing 10,000 ppm napropamide ( corresponding to 522 and 582 mg/ kg/ day, respectively, for males and females) for 52 weeks.

A 1100 ppm, statistically significantly decreased weight gain was observed in females ( up to 19% less than controls during the first year of the study). At 5000 ppm, body weight gain was also decreased in males ( up to 12% less than controls). Increased severity of chronic progressive glomerulonephropathy and incidence of spongiosa hepatis and hepatocyte fatty vacuolization were observed in males; in both sexes mild anemia and slight diuretic effects were also reported at 5000 ppm. Mildly reduced food consumption was observed in females. Body weight gain was markedly depressed ( up to 28%, males and 45%, females). Males at 10,000 ppm had increased incidence and severity of hepatocyte fatty vacuolization. The LOAEL for systemic toxicity is 1100 ppm for male and female rats ( 48/ 55 mg/ kg/ day), based on decreased weight gain in females and slightly increased incidence of spongiosis hepatis in males. The NOAEL is 250 ppm ( 11/ 12 mg/ kg/ day).

Neither male nor female rats developed neoplastic lesions that could be attributed to treatment with napropamide for up to 104 weeks. Dosing was considered adequate to test for carcinogenicity of napropamide in rats.

This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a combined chronic toxicity/ oncogenicity rodent feeding study ( 83 5).

Dose and Endpoint for Risk Assessment: Chronic oral NOAEL of 12 mg/ kg/ day based on decreased weight gain in females and increased incidence of liver lesions in males at 48/ 55 mg/ kg/ day. Page 30 of 64 Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies extrapolation.

Comments about Study/ Endpoint/ UF: Long term oral exposure to rats resulted in decreased body weight and microscopic lesions in the liver. While liver toxicity was adequately assessed in the 21 day dermal study, the consequences of longer term exposure are unknown. Therefore, a NOAEL of 12 mg/ kg/ day from the chronic oral study in rats is recommended for use in long term dermal exposure scenarios. A dermal absorption factor ( i. e., 26.1%) is used for route to route extrapolation.

4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term)

Short and Intermediate Term Inhalation Endpoints:

Study Selected: multi generation OPPTS: 870.3800 MRID No.: 92125069 Executive Summary: In a three generation reproduction toxicity study ( MRID 92125069), Devrinol Technical ( Napropamide; 94.6% a. i.; Lot/ batch # 4059 17 1) was administered to Charles River CD ® rats ( 15 males/ dose; 30 females/ dose) at nominal dose levels of 0, 10, 30, and 100 mg/ kg bw/ day ( equivalent to 0/ 0, 9.9/ 12.7, 29.6/ 39.4, and 98.8/ 130.7 mg/ kg bw/ day). The P animals were given test article diet formulations for approximately 7 weeks prior to mating, then were mated ( 1 male with 2 females) to produce the F 1a litters. The P females were allowed to rest for 10 days after weaning of the F 1a litter, then were mated with a different P male in the same treatment group to produce the F 1b litters. One week after weaning, F 1b animals ( 15 males/ dose; 30 females/ dose) were selected to become the parents of the F 2 generations. This process was repeated for a total of 3 generations, with 2 litters per generation produced. F 1b animals were given test formulations for 11 weeks prior to mating to produce the F 2a litters; F 2b animals were given test formulations for 11 weeks prior to mating to produce the F 3a litters.

No treatment related findings were noted at 10 ppm in the parents or offspring.

At 100 mg/ kg, pre mating body weights were decreased ( 98 13%; p# 0.05) in the F 1 females at Week 26, and in the F 2 males and females at Week 55. Body weights of P, F 1 , and F 2 generation females were unaffected by treatment throughout gestation and lactation. There were no treatment related differences in absolute or relative food consumption in either sex throughout the duration of this study, and there were no effects of treatment on the duration of gestation or on male and female fertility indices.

The LOAEL for parental toxicity is 100 mg/ kg/ day ( equivalent to 98.8/ 130.7 mg/ kg bw/ day [ M/ F]), based on decreased body weights in the F1 females and F2 males and females. The NOAEL is 30 mg/ kg/ day ( equivalent to 29.6/ 39.4 mg/ kg bw/ day [ M/ F]). Page 31 of 64 At 100 mg/ kg, decreased( 94 11%; p# 0.05) body weights were noted in the F 2a pups on PND 7 and 14, in the F 1b and F 3a pups on PND 14 and 21, and in the F 1a and F 2a pups on PND 21. Decreases in body weights also were observed in the 100 mg/ kg F 2b and F 3b pups ( 94 9%; not significant). The only decreases in the 30 mg/ kg group were noted in the F 3a males ( 98%; p# 0.05).

The LOAEL for offspring toxicity 100 mg/ kg/ day ( equivalent to 98.8/ 130.7 mg/ kg bw/ day [ M/ F]), based on decreased pup body weights. The NOAEL is 30 mg/ kg/ day ( equivalent to 29.6/ 39.4 mg/ kg bw/ day [ M/ F]).

The LOAEL for reproductive performance was not observed. The NOAEL for reproductive performance is 100 mg/ kg/ day ( equivalent to 98.8/ 130.7 mg/ kg bw/ day [ M/ F]).

This study is classified as Acceptable/ guideline and satisfies the guideline requirements ( OPPTS 870.3800; OECD 416) for a three generation reproduction study in the rat.

Dose and Endpoint: The offspring toxicity NOAEL of 30 mg/ kg/ day based on decreased pup body weight at 100 mg/ kg/ day.

Uncertainty Factor ( UF): NA Comments about Study/ Endpoint/ UF: Appropriate inhalation toxicity studies were not available for any exposure scenario. In the three generation reproduction study in the rat, reductions in offspring body weight began as early as PND 7, and was also affected late in lactation after the pups started eating the treated food. Body weights were decreased in parental F1 and F2 males and females. This endpoint is appropriate for duration of exposure and applies to the population of concern. For route to route extrapolation, absorption via the inhalation route is assumed to be equivalent to oral absorption.

Long Term Inhalation Endpoints:

Study Selected: chronic/ oncogenicity rat OPPTS: 870.4100b MRID No.: 42189102 and 43068801 Executive Summary: In a chronic toxicity/ carcinogenicity feeding study ( MRIDs 42189102 and 43068801), napropamide ( purity 94.1%) was fed to groups of 60 ( treated groups) or 70 ( controls) Crl: CD ( SD) BR rats/ sex/ group for 104 weeks ( females) or 101 weeks ( males) at dose levels of 0, 250, 1100, or 5000 ppm ( corresponding to 0, 11, 48, or 221 mg/ kg/ day for males and 0, 12, 55, or 261 mg/ kg/ day for females). Of these, twenty controls and 10 treated animals/ sex/ dose group were sacrificed at 52 weeks. An additional satellite group of 20 Page 32 of 64 animals/ sex were fed a diet containing 10,000 ppm napropamide ( corresponding to 522 and 582 mg/ kg/ day, respectively, for males and females) for 52 weeks.

A 1100 ppm, statistically significantly decreased weight gain was observed in females ( up to 19% less than controls during the first year of the study). At 5000 ppm, body weight gain was also decreased in males ( up to 12% less than controls). Increased severity of chronic progressive glomerulonephropathy and incidence of spongiosa hepatis and hepatocyte fatty vacuolization were observed in males; in both sexes mild anemia and slight diuretic effects were also reported at 5000 ppm. Mildly reduced food consumption was observed in females. Body weight gain was markedly depressed ( up to 28%, males and 45%, females). Males at 10,000 ppm had increased incidence and severity of hepatocyte fatty vacuolization. The LOAEL for systemic toxicity is 1100 ppm for male and female rats ( 48/ 55 mg/ kg/ day), based on decreased weight gain in females and slightly increased incidence of spongiosis hepatis in males. The NOAEL is 250 ppm ( 11/ 12 mg/ kg/ day).

Neither male nor female rats developed neoplastic lesions that could be attributed to treatment with napropamide for up to 104 weeks. Dosing was considered adequate to test for carcinogenicity of napropamide in rats.

This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a combined chronic toxicity/ oncogenicity rodent feeding study ( 83 5).

Dose and Endpoint for establishing cRfD: Chronic oral NOAEL of 12 mg/ kg/ day based on decreased weight gain in females and increased incidence of liver lesions in males at 48/ 55 mg/ kg/ day.

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies extrapolation.

Comments about Study/ Endpoint/ UF: Appropriate inhalation toxicity studies were not available for any exposure scenario. Long term oral exposure to rats resulted in decreased body weight and microscopic lesions in the liver. For route to route extrapolation, absorption via the inhalation route is assumed to be equivalent to oral absorption.

4.4.8 Margins of Exposure The following margins of exposure ( MOEs) represent HED's level of concern for occupational and residential ( non dietary) exposure risk assessments: Page 33 of 64 Route of Exposure Duration of Exposure Short Term ( 1 30 Days) Intermediate Term ( 1  6 Months) Long Term (> 6 Months)

Occupational Exposure Dermal N/ A N/ A 100 Inhalation 100 100 100 Residential ( non dietary) Exposure Oral 100 100 N/ A Dermal N/ A N/ A 100 Inhalation 100 100 100 For occupational exposure ( all durations), inhalation exposure risk assessments, an MOE of 100 is required. The MOE is based on 10x for intraspecies variation, and 10x for interspecies extrapolation. For residential exposures, an MOE of 100 is required, and is based on 10x for intraspecies variation, 10x for interspecies extrapolation and a 1x special FQPA factor.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated as follows: for short and intermediate term aggregate exposure risk assessments, the oral and inhalation routes can be combined because of the common toxicity endpoints ( decreased body weight) via these routes. No short or intermediate term dermal endpoint has been identified for napropamide, and no long term residential exposure is expected.

4.4.10 Classification of Carcinogenic Potential No evidence for carcinogenicity was seen in mice or rats. Administration of napropamide to mice for 18 months and to rats for 24 months did not result in an increase in overall tumor incidence or increase the incidence of any specific type of tumor. The chemical was negative for gene mutation in four studies ( Bacillus subtilis, Salmonella typhimurium, mouse host mediated, CHO) and did not induce micronucleus formation in the mouse or unscheduled DNA synthesis in rat hepatocytes. Positive results for gene mutation were obtained in mouse lymphoma cells with and without metabolic activation at concentrations that also cause significant cytotoxicity and in Chinese hamster lung cells with activation in the absence of cytotoxicity. Page 34 of 64 Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( females 13 49) Not applicable. Not applicable. No appropriate acute endpoint identified for these groups ( i. e., no toxic effect attributable to a single dose identified). Acute Dietary ( general population)

Chronic Dietary ( all populations) NOAEL = 12 mg/ kg/ day UF = 100 Chronic RfD = 0.12 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD FQPA SF = 0.12 mg/ kg/ day Chronic/ oncogenicity  rat LOAEL = 48/ 55 mg/ kg/ day ( m/ f) based on decreased weight gain in females and increased incidence of liver lesions in males Incidental Oral Short Term ( 1  30 days) NOAEL = 30 mg/ kg/ day Residential LOC = 100 Occupational LOC = 100 Reproductive toxicity  rat LOAEL = 100 mg/ kg/ day based on decreased pup body weight Incidental Oral Intermediate Term ( 1  6 months) NOAEL = 30 mg/ kg/ day Residential LOC = 100 Occupational LOC = 100 Reproductive toxicity  rat LOAEL = 100 mg/ kg/ day based on decreased pup body weight Dermal Short Term ( 1  30 days) Not applicable. Not applicable. No hazard was identified; therefore no quantification is required. Systemic toxicity not seen at the limit dose in a Dermal Toxicity Study. Additionally, there are no developmental concerns. Dermal Intermediate Term ( 1  6 months)

Dermal Long Term (> 6 months) oral study NOAEL = 12 mg/ kg/ day Residential LOC = 100 Occupational LOC = 100 Chronic/ oncogenicity  rat LOAEL = 48/ 55 mg/ kg/ day ( m/ f) based on decreased weight gain in females and increased incidence of liver lesions in males Inhalation Short Term ( 1  30 days) oral study NOAEL = 30 mg/ kg/ day ( inhalation absorption rate = 100%) Residential LOC = 100 Occupational LOC = 100 Reproductive toxicity  rat LOAEL = 100 mg/ kg/ day based on decreased pup body weight Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Page 35 of 64 Inhalation Intermediate Term ( 1  6 months) oral study NOAEL = 30 mg/ kg/ day ( inhalation absorption rate = 100%) Residential LOC = 100 Occupational LOC = 100 Reproductive toxicity  rat LOAEL = 100 mg/ kg/ day based on decreased pup body weight Inhalation Long Term (> 6 months) NOAEL = 12 mg/ kg/ day ( inhalation absorption rate = 100%) Residential LOC = 100 Occupational LOC = 100 Chronic/ oncogenicity  rat LOAEL = 48/ 55 mg/ kg/ day ( m/ f) based on decreased weight gain in females and increased incidence of liver lesion in males Cancer ( oral, dermal, inhalation) Classification: no evidence of carcinogenicity UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * Refer to Section 4.5 4.5 Special FQPA Safety Factor Based on the above discussed hazard and exposure data, no special FQPA safety factor is needed ( i. e., 1X) and there are no residual uncertainties for pre and/ or post natal toxicity.

° The dietary food exposure assessment utilizes tolerance level residues and 100% crop treated ( CT) information for all commodities. By using these screening level assumptions, chronic exposures/ risks will not be underestimated.

° The dietary drinking water assessment utilizes values generated by models and associated modeling parameters which are designed to provide conservative, health protective, highend estimates of water concentrations.

4.6 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 recommendations of Page 36 of 64 its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

In the available toxicity studies on napropamide, there was no estrogen, androgen, and/ or thyroid mediated toxicity. When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, napropamide may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data Reference: Review of Napropamide Incident Reports, DP Barcode: D303447, Jerome Blondell, 11/ 04/ 04 5.1 Incident Reports Relatively few incidents of illness have been reported due to napropamide. However, it appears to be irritating to eyes and skin and has been associated with difficulty breathing when used in enclosed spaces. This conclusion is based on information from the following data sources:

I. OPP Incident Data System Incident# 7791 4: A pesticide incident occurred in 1998, when an adult female splashed some of the product in her mouth. Reportedly, she had oral burns, laryngeal swelling, and excess secretions. It was unknown if napropamide was mixed with another product. No further information on the disposition of the case was reported.

Incident# 13857 17: A pesticide incident occurred in 2003, when an adult female was exposed working in a greenhouse and had difficulty breathing and pain in the chest. No further information on the disposition of the case was reported.

II. Poison Control Center Data  1993 through 2001 A total of six exposures were reported to Poison Control Centers for the nine year period 1993 2001. Three of these case reported minor symptoms, primarily dermal irritation. Page 37 of 64 III. California Data  1982 through 2002 Detailed descriptions of 20 cases submitted to the California Pesticide Illness Surveillance Program ( 1982 2002) were reviewed. In nine of these cases was napropamide determined to be the primary cause of illness. The principle symptoms reported involved irritation of the eyes and/ or skin.

IV. National Pesticide Information Center On the list of the top 200 chemicals for which NPIC received calls from 1984 1991, inclusively, napropamide was not reported to be involved in human incidents.

V. NIOSH SENSOR Out of 4,221 reported cases from 1998 2002, just two involved napropamide alone. In a Florida case the worker splashed napropamide on himself and developed blisters. A Texas case reported difficulty breathing when using a napropamide product in an enclosed area. Both cases were considered probable with no more than moderate severity.

VI. Scientific Literature No scientific literature was located concerning acute poisoning due to exposure to napropamide.

5.2 Other Napropamide is not included in the Agricultural Health Survey ( AHS) Applicator questionnaire and is not on the current National Health and Nutrition Examination Survey ( NHANES) list.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile Tolerances are established under 40 CFR § 180.328 ( a) and ( b) for negligible residues ( 0.1 ppm) of napropamide per se in/ on various raw agricultural commodities. No meat/ milk/ egg/ poultry tolerances are established for napropamide residues.

The qualitative nature of the residue in plants is understood. Acceptable metabolism studies with napropamide have been conducted on three dissimilar crops ( apple, cabbage, and tomato). The results of these studies were presented on 3/ 16/ 93 to the HED Metabolism Assessment Review Committee ( MARC). The HED MARC concluded that the residue of concern in plants is Page 38 of 64 napropamide per se and that the current tolerance expression is adequate; the tolerance is expressed in terms of residues of the parent compound only.

The qualitative nature of the residue in livestock is understood. HED has received and reviewed acceptable ruminant and poultry metabolism studies with napropamide. Based on the findings from these studies, HED has determined that 40 CFR § 180.6( a)( 3) is applicable to napropamide; there is no reasonable expectation of finite residues in ruminants or poultry. As a result of this determination, HED has recommended that waivers be granted from the requirements to: conduct a ruminant and poultry feeding study ( 860.1480), develop a residue analytical method for meat/ milk/ poultry/ eggs ( 860.1340), and conduct a storage stability study for meat/ milk/ poultry/ eggs ( 860.1380). This recommendation is based on the low level of residues observed in the goat metabolism study where the test animals were dosed with [ 14C] napropamide at an average level of 9.9 ppm in the diet which is equivalent to 120x the maximum theoretical dietary burden of 0.083 ppm to dairy cattle ( 74x the MTDB of beef cattle). This recommendation is also based on the fact that there are no poultry and swine feedstuff associated with the raw agricultural commodities with established tolerances. A data collection method and an enforcement method may be required if the registrants wish to register new food/ feed uses in the future Residue analytical methods for plant commodities are available for the purposes of tolerance enforcement and data collection. The Pesticide Analytical Manual, Volume I, indicates that napropamide is completely recovered (> 80% recovery) using Multiresidue Method Sections 302 ( Luke Method; Protocol D) and 401 ( Krause N methyl carbamate Method; Protocol A). In addition, PAM Volume II lists a GLC method as Method I ( WRC 71 35) for the determination of napropamide per se in/ on plant commodities.

The current PAM Volume II method uses benzene, a hazardous or toxic reagent. HED is recommending that the data collection methods ( GC/ NPD methods with confirmation by GC/ MSD), which were used in the analysis of samples from the magnitude of the residue studies, be subjected to method validations required for enforcement purposes.

There are adequate storage stability data to support the storage intervals and conditions of samples collected from the residue field studies. These data indicate that napropamide is reasonably stable under frozen storage conditions in/ on: ( i) alfalfa hay, almond nutmeat, apple, and soybean seed for > 3 years; ( ii) wheat grain and straw for up to 2.5 years, and; ( iii) corn ear, orange, and pepper for up to  2 years. There are also adequate storage stability data for representative processed commodities. These data indicate that residues of napropamide are reasonably stable under frozen storage conditions in apple juice and pomace, orange juice, oil, and dried pulp for up to 36 38 months.

There are adequate magnitude of the residue data to support the registered uses of napropamide on Brassica leafy vegetables and fruiting vegetables as well as on the individual crops of artichokes, asparagus, coffee, mint, pomegranate, rhubarb, sweet potato, and tobacco. The Page 39 of 64 available residue data for the above commodities indicate that residues of napropamide are mostly nondetectable (< 0.05 ppm) following applications of representative formulations according to the maximum registered use patterns. The registered uses on napropamide on pistachio are supported by residue data translated from almonds.

There are limited but adequate data to support the reinstatement of uses of napropamide on basil, marjoram, rosemary, and savory ( summer and winter). The product label for the 50% DF formulation ( EPA Reg. No. 70506 36) should be amended to reflect the parameters of the use pattern for which residue data are available for these herb crops.

Additional magnitude of the residue data are required for the crop groups of citrus fruits, pome fruits, stone fruits, berries, and tree nuts as well as the individual crops of avocado, fig, grape, kiwifruit, olives and persimmon. There are presently no registered uses of napropamide on cucurbit vegetables. Unless the basic registrants of napropamide or other interested parties propose uses and submit supporting data, the established tolerance for cucurbit vegetables should be revoked.

Adequate processing studies with napropamide have been submitted for apples, figs, grapes, oranges, plums, and tomatoes. These studies indicate that residues of napropamide do not concentrate above the analytical method's LOQ of 0.05 ppm in the respective processed commodities of the above crops except in citrus oil where a processing factor of 35x was reported. A coffee processing study and a mint processing study remain reregistration requirements.

An acceptable confined rotational crop study has been submitted and reviewed. The metabolites identified in the various matrices of rotational crops corresponded to the metabolites identified in the plant metabolism studies and were found in approximately similar proportions. Napropamide and desethyl napropamide were found in all crops. HED has determined that limited/ extensive field rotational crop data ( OPPTS 860.1900) are not required provided the registrants accept the Agency's recommendation to establish a 60 day plantback interval ( PBI) for leafy vegetables, a 180 day PBI for cereal grains, and a 365 day PBI for all other crops. Any labels that do not already specify the appropriate crop restrictions should be amended.

6.1.2 Chronic Dietary Exposure and Risk Reference: Napropamide Chronic Dietary Exposure Assessment for the Reregistration Eligibility Decision, DP Barcode: D305599, Susan Stanton, 10/ 29/ 04 A chronic dietary risk assessment was conducted using the Lifeline   Model Version 2.0 which uses food consumption data from the United States Department of Agriculture's ( USDA's) Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. In this analysis the chronic dietary exposure and risk estimates resulting from food intake were determined for the general U. S. population and various population subgroups. An endpoint of Page 40 of 64 concern attributable to a single dose was not identified for napropamide; therefore, an acute RfD was not established and an acute dietary risk assessment was not conducted.

The chronic analysis assumed 100% crop treated and tolerance level residues ( Tier 1) for all commodities. Processing factors were based on the results of processing studies for commodities where such data were available ( apple juice, citrus juice/ oil, figs, grape juice/ raisins, prunes and tomato juice/ puree/ paste). For all other commodities, default processing factors were used.

Drinking water was incorporated directly in the dietary assessment using the Tier 1point estimate for ground water generated by the SCI GROW model ( See sec. 6.2, below).

The resulting dietary exposure estimates were less than 2% of the cPAD for the U. S. population and all population subgroups. Napropamide dietary exposure ( food + water) was estimated at 0.000574 mg/ kg/ day for the U. S. population (< 1% of the cPAD) and 0.002218 mg/ kg/ day ( 1.8% of the cPAD) for the most highly exposed population subgroup ( children, 1 2 years old).

Table 6.1: Summary of Chronic Dietary Exposure and Risk for Napropamide Population Subgroup cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.12 0.000574 < 1.0 All Infants (< 1 year old) 0.001439 1.2 Children 1 2 years olda 0.002218a 1.8a Children 3 5 years old 0.001645 1.4 Children 6 12 years old 0.000772 < 1.0 Youth 13 19 years old 0.000415 < 1.0 Adults 20 49 years old 0.000452 < 1.0 Adults 50+ years old 0.000464 < 1.0 Females 13 49 years old 0.000492 < 1.0 a The values for the population with the highest risk are bolded.

6.2 Water Exposure/ Risk Pathway Reference: Drinking Water Assessment for Napropamide for Terrestrial Uses; DP Barcode: D305601; James Breithaupt; 8/ 17/ 04; and Revised Drinking Water Assessment for Napropamide; DP Barcode: D305601; James Breithaupt; 11/ 12/ 04 Napropamide is persistent ( half life of 446 days) but not particularly mobile ( median K oc = 577 ml/ g) and is therefore not expected to pose a significant risk of ground water contamination. As of 2001, the USGS had not detected napropamide in ground water. Surface water contamination is possible through run off from treated fields. In its 8/ 17/ 04 assessment EFED provided Page 41 of 64 estimates of napropamide concentrations in drinking water using tier 2 ( PRZM EXAMS) and tier 1 ( SCI GROW) models for surface and ground water, respectively. The modeling results are summarized below:

Table 6.2. Summary of Estimated Surface and Ground Water Concentrations for Napropamide.

Exposure Duration Napropamide Surface Water Conc., ppb a Ground Water Conc., ppb b Acute ( 1 in 10 annual peak concentration) 112 4.5 Chronic Non Cancer ( 1 in 10 annual mean concentration) 0.5 4.5 a From the Tier II PRZM EXAMS  Index Reservoir model. Input parameters are based on ground application to Georgia pecan at the maximum foliar application rate of 4 lbs. a. i./ A, an aerobic soil metabolic half life of 1338 days ( 3X 446 day half life in MRID 41105901), a photolysis half life of 0.003 days and a K d value of 8 mg/ g. b From the SCI GROW model assuming a maximum seasonal use rate of 4 lbs./ A; a K oc of 577 ml/ g; and a half life of 446 days. The following crop scenarios resulted in the highest estimated concentration ( 4.5 ppb): CA almonds, FL citrus, OR/ PA apple, CA grape and GA pecan). Estimated concentrations for other crops ( OR berry, PA turf, FL tomato and NC tobacco) were lower.

In its 11/ 12/ 04 drinking water assessment, EFED revised its estimates of napropamide concentrations in surface water. The revised acute and chronic estimates are 258.6 ppb and 5.1 ppb, respectively. Input parameters were the same as in the previous assessment ( see footnote a, above), except for the photolysis half life, which was recalculated to be 0.018 days. HED completed its chronic dietary and short term aggregate risk assessments using the drinking water estimates provided in EFED's original assessment, dated 8/ 17/ 04. The revised chronic surface water estimate of 5.1 ppb is slightly higher than the drinking water estimate ( 4.5 ppb) that was used in HED's assessments; however, because of the minimal impact the revised estimate would be expected to have on overall dietary or aggregate risk, HED determined that new dietary/ aggregate assessments were not warranted. HED's rationale is explained in more detail in section 7. Page 42 of 64 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway Reference: Napropamide: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: D295638; Seyed Tadayon; 11/ 17/ 04 There is a potential for exposure in residential settings during the application process for homeowners who use products containing napropamide. There is also a potential for exposure from entering areas treated with napropamide. As a result, risk assessments have been completed for both residential handler and postapplication scenarios. The residential use of napropamide is limited to outdoor foliar applications to ornamentals and turf.

6.3.1 Residential Handler Exposures The Agency uses the term " handlers" to describe those individuals who are involved in the pesticide application process. The agency believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by the Agency, as homeowners are assumed to complete all elements of an application with little use of any protective equipment.

<IP_ADDRESS> Handler Exposure Scenarios The purpose of this section is to describe how the exposure scenarios are defined. Much of the process for residential uses is identical to that considered for the occupational assessment with a few notable exceptions that include:

° Residential handler exposure scenarios are only considered to be short term in nature due to the episodic uses associated with homeowner products;

° A tiered approach for personal protection using increasing levels of PPE is not used in residential handler risk assessments. Homeowner handler assessments are based on the assumption that individuals are wearing shorts, short sleeved shirts, socks, and shoes.

° Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing/ loading if needed as well as the application;

° Label use rates and use information specific to residential products serve as the basis for the risk calculations as opposed to the rates used in the occupational assessment; and ° Area/ volumes of spray or chemical used in the risk assessment are based on HED guidance specific to residential use patterns. Page 43 of 64 Exposure to pesticide handlers is likely during the residential use of napropamide in a variety of environments including ornamental and turf uses. The anticipated use patterns and current labeling indicate several major residential exposure scenarios based on the types of equipment and techniques that can potentially be used to make napropamide applications. The quantitative exposure/ risk assessment developed for residential handlers is based on these scenarios.

Applying granulars for hand application Applying granulars for shaker can application Loading/ applying granulars for belly grinder application Loading/ applying granulars for push type spreader application <IP_ADDRESS> Data and Assumptions For Handler Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below. In addition to these factors, unit exposure values were used to calculate risk estimates. These unit exposure values were taken from the Pesticide Handlers Exposure Database ( PHED) or from Outdoor Residential Exposure Task Force ( ORETF) data.

The assumptions and factors used in the risk calculations include:

C Exposure factors used to calculate daily exposures to handlers were based on applicable data if available. For lack of appropriate data, values from a scenario deemed similar enough by the assessor might be used. In this assessment PHED mixer/ loader/ applicator data for aerosol can application is used to assess pumptrigger sprayer applications. The nature of these application methods are believed to be similar enough to bridge the data.

C The Agency always considers the maximum application rates allowed by labels in its risk assessments to consider what is legally possible based on the label.

C Residential risk assessments were not based on what could be applied in a typical workday like with the occupational risk assessments presented above. Instead, the HED based calculations on what would reasonably be treated by homeowners such as the size of a lawn, or the size of a garden. This information was used by the HED to define chemical use values for handlers which in turn were coupled with unit exposure values to calculate risks. The factors used for the napropamide assessment were those presented in the Health Effects Division Science Advisory Committee Policy 12: Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment which was completed on February 22, 2001. The following daily volumes handled and area treated, excerpted from the policy and used in each residential scenario, include: Page 44 of 64 S 0.023 A/ day for hands and shaker cans S 0.5 A/ day for belly grinder and push type spreader Residential Handler Exposure Studies: The unit exposure values that were used in this assessment were based on studies completed by the Pesticide Handler Exposure Database ( PHED, Version 1.1 August 1998) and the ORETF.

<IP_ADDRESS> Residential Handler Exposure and Risk Estimates The residential handler exposure and risk estimates are presented in Table 6.3.1 below.

Table 6.3.1: Napropamide Short Term Residential Handler Risks Exposure Scenario Crop or Target Application Ratea ( lb ai/ unit) Amount Handled Daily b Inhalation Dose ( mg/ kg/ day) Inhalatio n MOEc Mixer/ Loader/ Applicator Applying Granulars for Hand application ( 1) ornamentals 6 0.023 0.0011 28000 Applying Granulars for Shaker can application ( 2) ornamentals 6 0.023 0.0011 28000 Loading/ Applying Granulars for Belly Grinder application ( 3) turf 3 0.5 0.0016 19000 Loading/ Applying Granulars for Push type spreader application ( 4) turf 3 0.5 0.00016 190000 Footnotes a Application rates are the maximum application rates determined from EPA registered labels for napropamide. b Amount handled per day values are EPA estimates of amount treated based on revised Residential SOPs ( 2/ 01). c Baseline inhalation MOE = NOAEL ( 30 mg/ kg/ day) / inhalation daily dose ( mg/ kg/ day), where inhalation dose = daily unit exposure ( µ g/ lb ai) x application rate x amount handled per day x conversion factor ( 1mg/ 1,000 µ g / body weight ( 60 kg adult).

For residential handlers, the estimated exposures for all scenarios do not exceed the Agency's level of concern for risk assessments in non occupational settings.

6.3.2 Residential Postapplication Exposures <IP_ADDRESS> Residential Postapplication Exposure Scenarios There are a number of residential postapplication exposure scenarios for different segments of the population including toddlers and adults. Risks were calculated for only a few scenarios, since no dermal endpoint of concern has been identified. In general, postapplication inhalation risks following outdoor applications are considered negligible. Therefore, at this time, EPA is only assessing non dietary ingestion exposures for toddlers ( i. e., soil ingestion and hand/ object tomouth Page 45 of 64 Residential postapplication exposures will most likely occur for short term durations only. Intermediate term exposures are not likely because of the intermittent nature of applications by homeowners, and are therefore not included in this assessment.

The SOPs For Residential Exposure Assessment define several scenarios that apply to uses specified in current napropamide labels. The Agency used this guidance to define the toddler exposure scenarios included in this postapplication exposure assessment. The SOPs and the associated scenarios are presented below:

C Dose from hand to mouth activity from treated turf calculated using SOP 2.3.2: Postapplication dose among toddlers from incidental non dietary ingestion of pesticide residues on treated turf from hand to mouth transfer.

° Dose from object to mouth activity from treated turf calculated using SOP 2.3.3: Postapplication dose among toddlers from incidental non dietary ingestion of pesticide residues on treated turf from object to mouth transfer.

C Dose from soil ingestion activity from treated turf calculated using SOP 2.3.4: Postapplication dose among toddlers from incidental non dietary ingestion of pesticide residues from ingesting soil in a treated turf area.

Napropamide may be applied as a granular product to turf, and episodic ingestion of these granules by children may occur. An episodic granular ingestion assessment for children was not performed, however, since no acute dietary endpoint of concern was identified for napropamide.

<IP_ADDRESS> Data & Assumptions for Residential Postapplication Exposure Scenarios A series of assumptions and exposure factors served as the basis for completing the residential postapplication risk assessments. Each assumption and factor is detailed below.

° The Agency combines or aggregates risks resulting from exposures to individual chemicals when it is likely they can occur simultaneously based on the use pattern and the behaviours associated with the exposed population. Within a residential assessment, this can take two forms. The first is to add together individual exposures from all likely sources of exposure such as after an application to turf or inside a home. For napropamide, the Agency has added together different kinds of exposures associated with the chemical's use on turf ( hand to mouth, object to mouth and soil ingestion). These represent the standard set of exposures that are typically added together when chemicals are used on turf or inside a home, because it is logical they can co occur. The second is to add exposures from different residential exposure scenarios that can possibly co occur such as when a homeowner makes an application and then checks their garden for insects a few hours later on the same day. This type of aggregation is not relevant for napropamide, since a Page 46 of 64 dermal endpoint of concern has not been identified and other exposure scenarios have not been assessed.

° Exposures of children playing on treated turf ( exercising) have been addressed using the latest Agency approaches for this scenario including:

S 5 percent of the application rate has been used to calculate the 0 day residue levels used for defining risks from hand to mouth behaviours. Measured TTR values   even if available   are not used because of differences in transferability versus what would be expected during hand to mouth behaviours.

S 20 percent of the application rate has been used to calculate the 0 day residue levels used for defining risks from object to mouth behaviours. Measured TTR values   even if available   are not used because of differences in transferability versus what would be expected during hand to mouth behaviours. A higher percent transfer has been used for object to mouth behaviour because it involves a teething action believed to be more analogous to DFR/ leaf wash sample collection where 20 percent is also used.

S 3 year old toddlers have mean weight of 15 kg.

S Short term hand to mouth exposures are based on a frequency of 20 events/ hour. A surface area per event of 20 cm2 representing the palmar surfaces of three fingers is assumed.

S Saliva extraction efficiency is 50 percent, meaning that every time the hand goes in the mouth approximately ½ of the residues on the hand are removed.

S Object to mouth exposures are based on a 25 cm2 surface area.

S Exposure durations are expected to be 2 hours based on information in the Agency's Exposure Factors Handbook S Soil residues are contained in the top centimetre and soil density is 0.67 mL/ gram.

S Hand, object to mouth and soil ingestion are added together to represent an overall risk from exposure to treated turf.

° Postapplication residential risks are based generally on maximum application rates or values specified in the SOPs For Residential Exposure Assessment.

<IP_ADDRESS> Residential Postapplication Exposure and Risk Estimates Non dietary Ingestion Exposure From Treated Turf: Non dietary ingestion exposure levels from treated turf were calculated using the following equations. These values were then used to calculate MOEs.

The following illustrates the approach used to calculate the non dietary ingestion exposures that are attributable to hand to mouth behaviour on treated turf ( SOP 2.3.2): Page 47 of 64 Oral Dose ( mg/ kg/ day) =

AR ( lb ai/ A) x CF x F x SA ( cm2) x EXT x FQ( events/ hr) x ET( hrs/ day) x ( 0.001mg/ µ g) BW ( kg)

Where:

Dose = oral dose on day of application ( mg/ kg/ day) AR = application rate ( lb ai/ A) CF = conversion factor ( 11.2) to convert lb ai/ A to µ g/ cm2 ( 1 lb ai/ A x 4.54E+ 8 µ g/ lb x 2.47E 8 A/ cm2 = 11.2 µ g/ cm2) F = fraction of residue dislodgeable from wet hands ( unfitness) SA = surface area of 1 to 3 fingers ( cm2) EXT = extraction rate by saliva ( unfitness) FQ = frequency of hand to mouth events ( events/ hour) ET = exposure duration ( hours/ day) BW = body weight ( kg)

Assumptions: SA  The surface area of 1 to 3 finger is 20 cm2 FQ  The frequency of hand to mouth events is 20 events per hour for shortterm F  The fraction of residue dislodge able from wet hands is 5% EXT  The extraction rate by saliva is 50%. ET  The time spent outdoors is 2 hours/ day The following illustrates the approach used to calculate exposures that are attributable to objectto mouth behaviour on treated turf that is represented by a child mouthing a handful of turf ( SOP 2.3.3):

Oral Dose ( mg/ kg/ day) = AR ( lb ai) x CF x F x SA ( cm2) x F.( events/ hr) x ( 0.001mg/ µ g) BW ( kg) Where:

Dose = oral dose on day of application ( mg/ kg/ day) AR = application rate ( lb ai/ A) CF = conversion factor ( 11.2) to convert lb ai/ A to µ g/ cm2 ( 1 lb ai/ A x 4.54E+ 8 µ g/ lb x 2.47E 8 A/ cm2 = 11.2 µ g/ cm2) F = fraction of residue dislodge able from wet hands ( unfitness) SA = surface area of 1 to 3 fingers ( cm2/ day) FQ = frequency of hand to mouth events ( events/ hour) BW = body weight ( kg)

Assumptions: Page 48 of 64 SA  The surface area of 1 to 3 finger is 20 cm2/ day FQ  The frequency of hand to mouth events is 20 events per hour for shortterm F  The fraction of residue dislodge able from wet hands is 5% ET  The time spent outdoors is 2 hours/ day The following illustrates the basics of the approach used to calculate exposures that are attributable to soil ingestion ( SOP 2.3.4):

Oral Dose = AR( lb ai/ A) x F( 1.0/ cm) x IgR( mg/ day) x ( 4.54E+ 8 µ g/ lb) x ( 2.47E 8 A/ cm2) x ( 0.67 cm3/ g) x ( 1E 6 g/ µ g) BW ( kg) Where:

Dose = oral dose on day of application ( mg/ kg/ day) AR = application rate ( lb ai/ A) F = fraction or residue retained on uppermost 1 cm of soil IgR = ingestion rate of soil ( mg/ day) CF1 = weight unit conversion factor to convert the lbs ai in the application rate to µ g for the soil residue value ( 4.54 x 108 µ g/ lb) CF2 = area unit conversion factor to convert the surface area units ( ft2) in the application rate to cm2 for the SR value ( 2.47 x 10 8 acre/ cm2) CF3 = volume to weight unit conversion factor to convert the volume units ( cm3) to weight units for the soil residue value ( 0.67 cm3/ g soil) CF4 = weight unit conversion factor to convert the µ g of residues on the soil to grams to provide units of mg/ day ( 1E 6 g/ µ g) BW = body weight ( kg)

Assumptions: F  The fraction or residue retained on uppermost 1 cm of soil is 100 percent based on soil incorporation into top 1 cm of soil after application ( 1.0/ cm) IgR  The ingestion rate of soil is 100 mg/ day Residential Postapplication Risk Calculations: For postapplication exposure, the margin of exposure ( MOE) was calculated as follows:

Short term Oral MOE = NOAEL ( 30 mg/ kg/ day) Oral Dose Residential postapplication risk is summarised in Table 6.3.2. a. Page 49 of 64 Table 6.3.2a: Short Term Postapplication Residential Risk Estimates from Oral Exposure to Napropamide Exposure Scenario Route of Exposure Population Application Ratea Ave. Daily Dose ( mg/ kg/ day) MOEb Hand to Mouth Activity on Turfc Oral Toddler 6 0.09 335 Object to Mouth Activity on Turfd Oral Toddler 6 0.0224 1340 Incidental Soil Ingestione Oral Toddler 6 0.0003 100000 Footnotes:

a Application rates represent maximum label rates from current EPA registered labels . b MOEs calculated using residues which would be found on day of treatment. Oral MOE = Oral NOAEL ( 30 mg/ kg/ day for short term/ Oral Dose ( mg/ kg/ day). An MOE of 100 represents HED's level of concern. c Hand to mouth Dose Calculation: oral dose to child ( 1 6 year old) on the day of treatment ( mg/ kg/ day) = [ application rate ( lb ai/ acre) x fraction of residue dislodgeable from potentially wet hands ( 5%) x 11.2 ( conversion factor to convert lb ai/ acre to µ g/ cm2)] x median surface area for 1 3 fingers ( 20 cm2/ event) x hand to mouth rate ( 20 events/ hour) x exp. time ( 2 hr/ day) x 50% saliva extraction factor x 0.001 mg/: g] / bw ( 15 kg child). d Object to Mouth Activity on  Turf Dose Calculation: oral dose to child ( 1 6 year old) on the day of treatment = [ application rate ( lb ai/ acre) x fraction of residue dislodgeable ( 5%) x 11.2 ( conversion factor to convert lb ai/ acre to µ g/ cm2)] x median surface area for 1 3 fingers ( 25 cm2/ event) x hand to mouth rate ( 20 events/ hour) x 0.001 mg/: g]] / bw ( 15 kg child). e Incidental Soil ingestion  Dose Calculation: oral dose to child ( 1 6 year old) on the day of treatment ( mg/ kg/ day) = [( application rate ( lb ai/ acre) x fraction of residue retained on uppermost 1 cm of soil ( 100% or 1.0/ cm) x 4.54E+ 08 µ g/ lb conversion factor x 2.47E 08 acre/ cm2 conversion factor x 0.67 cm3/ g soil conversion factor) x 100 mg/ day ingestion rate x 1.0E 06 g/ µ g conversion factor] / bw ( 15 kg). Note: Assumptions used in dose calculations ( e. g., transfer coefficients) are from Residential SOPs ( revised 2/ 01).

Residential Post Application Risk Summary:

The Agency considered a number of residential postapplication exposure scenarios for different segments of the population including toddlers and adults. Short term, non dietary ingestion risks were estimated for toddlers' activities on turf. Intermediate term risk was not estimated, since toddler postapplication exposures will most likely occur for short term durations only. Risk estimates for short term and intermediate term dermal exposures were not calculated for adults or children because no short or intermediate term dermal endpoint of concern was identified in the toxicity database. Also, an episodic granular ingestion assessment for children was not performed, since no acute dietary end point was identified for napropamide.

The Agency aggregates risk values resulting from separate postapplication exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behaviour associated with the exposed population. For napropamide, the Agency aggregated risk values ( i. e., MOEs) for postapplication exposures of toddlers associated with turf applications by combining risks from all oral exposures via transfer of residues from turf to hands to mouth. Page 50 of 64 Table 6.3.2. b: Short term ( aggregate) Napropamide Residential Scenarios for Postapplication Risk Estimates Exposure Scenario Margins of Exposure ( MOEs) ( UF= 100) Dermal Oral ( Non Dietary) Total Non Dietary Riska Short term Exposures Toddler Turf: 6 lb ai/ A Hand to Mouth N/ A 335 265 Object to Mouth N/ A 1340 Incidental Soil Ingestion N/ A 10000 a The following formula is used to calculate total MOE values by combining the route specific MOEs: MOE total = 1/(( 1/ MOE a) + ( 1/ MOE b) +.... ( 1/ MOE n)). Where: MOE a, MOE b, and MOE n represent MOEs for each exposure route of concern.

The aggregated residential risk MOE is > 100 and is, therefore, not of concern.

6.3.3 Other ( Spray Drift, 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, spray drift could also be a potential source of exposure with ground application methods. Napropamide may be applied using ground equipment on a variety of agricultural crops ( fruits, nuts, vegetables, forestry sites and tobacco) and may be applied aerially on cranberries. As indicated in this assessment, applications of napropamide directly to residential turf do not result in exposures of concern. Based on this assessment, HED believes it is unlikely that there is a higher potential for risk from exposure to spray drift from agricultural uses of this chemical.

7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate ( add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For most pesticide active ingredients, water monitoring data are considered inadequate to determine surface and ground water drinking water exposure estimates, so model estimates have been used to estimate residues in drinking water ( EDWCs). In order to determine if aggregate risks are of concern, HED has historically calculated drinking water levels of comparison, or DWLOCs. The DWLOC is the maximum amount of a pesticide in drinking water that would be acceptable in light of combined exposure from food and residential pathways. The calculated DWLOCs were then compared to the EDWCs provided by EFED to determine if a potential concern existed for dietary exposure to residues in drinking water.

In order to fully implement the requirements of FQPA, HED and EFED have been working toward refining the screening level DWLOC approach to conducting aggregate risk assessments that combine exposures across all pathways. As part of this process, EFED and HED have Page 51 of 64 agreed that chronic and cancer EDWCs can be used directly in chronic/ cancer dietary exposure assessments to calculate aggregate dietary ( food + water) risk. This is done by using the relevant model value as a residue for drinking water ( all sources) in the dietary exposure assessment. The principal advantage of this approach is that the actual individual body weight and water consumption data from the CSFII are used, rather than assumed weights and consumption for broad age groups. This refinement has been used in estimating the dietary exposure component in the napropamide aggregate risk assessments.

7.1 Acute Aggregate Risk A toxicological endpoint of concern attributable to a single dose has not been identified for napropamide. Therefore, an acute aggregate risk assessment has not been conducted.

7.2 Short Term Aggregate Risk Short term aggregate exposure takes into account residential exposure plus average exposure levels from residues of napropamide in food and water ( considered to be a background exposure level). The registered residential uses of napropamide constitute short term exposure scenarios, and endpoints have been selected for short term incidental oral and inhalation exposures. The acceptable MOE for short term exposure is 100 for both routes of exposure. The oral and inhalation routes may be combined because of the common toxicity endpoints ( decreased body weight) via these routes.

Table 7.2. Short Term Aggregate Risk Population Short  Term Scenario NOAEL mg/ kg/ day Level of Concern1 Max Exposure2 mg/ kg/ day Average Food + Water Exposure mg/ kg/ day Residential Exposure3 mg/ kg/ day Aggregate MOE ( food and residential) 4 Adult Female5 30 MOE # 100 0.3 0.0005 0.0016 14340 Children, 1 2 yrs. old6 30 MOE # 100 0.3 0.00222 0.113 260 1Level of Concern ( MOE) based on 10x for interspecies variation and 10x for intraspecies variation. 2 Maximum Exposure ( mg/ kg/ day) = NOAEL/ Level of Concern ( MOE) = 30 mg/ kg/ day/ 100 = 0.3 mg/ kg/ day 3 Residential Exposure = Oral exposure ( toddler postapplication scenarios) or Inhalation exposure ( adult residential handler scenarios). There is no dermal endpoint of concern for napropamide. 4 Aggregate MOE = [ NOAEL ÷ ( Avg Food and Water Exposure + Residential Exposure)] Page 52 of 64 5Adult population subgroup with highest dietary ( food + water) exposure and highest residential handler exposure. Dietary exposure from Table 6.1; Residential exposure from Table 6.3.1 ( highest exposure scenario  loading/ applying granulars for belly grinder application) 6Population subgroup with highest dietary ( food + water) exposure and only subgroup with anticipated post application residential exposure. Dietary exposure from Table 6.1; Residential exposure = sum of ave. daily doses from all 3 toddler exposure scenarios in Table 6.3.2a ( 0.09mg/ kg/ day + 0.0224 mg/ kg/ day + 0.0003 mg/ kg/ day = 0.113 mg/ kg/ day)

The estimated short term aggregate MOEs for adults and children are greater than 100 and, therefore, do not exceed HED's level of concern.

7.3 Intermediate Term Aggregate Risk There are no intermediate term exposure scenarios for napropamide, based on its current use patterns.

7.4 Long Term Aggregate Risk The chronic aggregate risk assessment considered exposures from food and water only, because there are no residential uses expected to contribute to chronic exposures for this chemical. Since water exposure was incorporated directly into the Lifeline dietary exposure analysis, the dietary risk estimates reported in section 6.1 represent the total chronic aggregate risk for napropamide. The chronic aggregate risk estimates for the U. S. population and all subgroups are < 2% of the cPAD and, therefore, below HED's level of concern.

7.5 Cancer Risk A cancer aggregate risk assessment is not required, since there was no evidence of carcinogenicity in the toxicology studies submitted for napropamide.

Note Regarding EFED's Revised Drinking Water Estimates and Their Impact on HED's Dietary and Aggregate Risk Assessments:

The drinking water value used in HED's LifeLine chronic dietary exposure and aggregate risk assessments was taken from EFED's August 17, 2004 drinking water memo. In that memo, EFED provided drinking water estimates for surface water ( chronic, non cancer) and ground water of 0.5 ppb and 4.5 ppb, respectively. HED incorporated the higher of the two values, 4.5 ppb, directly in the LifeLine model, rather than comparing it to a calculated DWLOC for napropamide. The resulting dietary ( food + water) exposure estimates represent less than 2 % of the cPAD for all population subgroups, including infants and children.

On November 12, 2004 EFED provided HED with a revised drinking water assessment for napropamide. Although the estimated ground water concentration remains at 4.5 ppb, the estimated surface water concentrations have been revised upward, with the non cancer chronic concentration now estimated at 5.1 Page 53 of 64 ppb. The revised surface water estimate is slightly higher than the 4.5 ppb value used in HED's dietary assessment.

Since the difference between the revised estimated surface water concentration and the drinking water value used in the dietary assessment is slight ( 0.6 ppb or 0.0006 ppm = 0.0006 mg/ l) and the overall dietary risk is low, HED has determined that a new dietary/ aggregate assessment is not warranted. This conclusion is based on preliminary calculations showing that the additional exposure would not significantly increase dietary or aggregate risk for napropamide.

Effect on Dietary Risk: Dietary exposure from food and water is estimated to be 0.00222 mg/ kg/ day, equivalent to 1.85% of the cPAD, for children ( the most highly exposed subgroup). The increase in exposure and risk from an additional 0.0006 ppm in drinking water would not be significant for children, as shown below:

Increase in Exposure = 0.0006 mg x 1 liter x 1 child = 0.00006 mg/ kg/ day liter child/ day 10 kg Increase as % of cPAD = 0.00006 mg/ kg/ day x 100 = 0.05% of the cPAD 0.12 mg/ kg/ day Effect on Aggregate Risk: The short term aggregate MOE for children from dietary ( food + water) and residential exposure is estimated to be 260. The MOE is calculated based on the NOAEL of 30 mg/ kg/ day from the rat reproduction study. Residential exposure is by far the biggest contributor to the estimated aggregate risk for napropamide. The estimated MOE from residential exposure alone is 265. The estimated MOE from food + water ( using the estimate of 4.5 ppb for drinking water) is 13,514 ( 30 mg/ kg/ day ÷ 0.00222 mg/ kg/ day). The incremental risk from slightly higher drinking water exposure would not significantly alter the estimated aggregate risk:

Dietary Risk = 30 mg/ kg/ day = 13,158 ( 0.00222 mg/ kg/ day + 0.00006 mg/ kg/ day)

Short term Aggregate Risk = 1 = 260 ( unchanged) ( 1/ 265) + ( 1/ 13,158)

8.0 Cumulative Risk Characterization/ Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to napropamide and any other substances and napropamide does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that napropamide has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and Page 54 of 64 procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway Reference: Napropamide: Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Decision Document; DP Barcode: D295638; Seyed Tadayon; 11/ 17/ 04 9.1 Short/ Intermediate/ Long Term Handler Risk Napropamide Handler Exposure Scenarios: Exposure to pesticide handlers is likely during the occupational use of napropamide in a variety of occupational environments. The anticipated use patterns and current labeling indicate several occupational exposure scenarios based on the types of equipment and techniques that can potentially be used for napropamide applications. The quantitative exposure/ risk assessment developed for occupational handlers is based on the following scenarios.

Mixer/ Loaders:

Dry Flowables for Groundboom application Loading Granulars for Tractor Drawn Spreaders application Dry Flowables for Chemigation application Loading Granulars for Tractor Drawn Spreaders application Loading Granulars for Aerial application Dry Flowables for Chemigation application Mixing/ Loading Liquids for Chemigation application Mixing/ Loading Liquids for Groundboom application Mixing/ Loading Liquids for High Pressure HandWand application Applicators:

Sprays for Groundboom application Applying Granulars for Tractor Drawn Spreaders application Applying Granulars for Aerial application Sprays for Groundboom application Sprays for High Pressure HandWand application Mixer/ Loader/ Applicators: