UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances March 14, 2003 SUBJECT: Carbaryl: Revised HED Risk Assessment  Phase 5 Public Comment Period, Error Correction Comments Incorporated; DP Barcode: D287532, PC Code: 056801 FROM: Jeffrey L. Dawson, Chemist/ Risk Assessor Reregistration Branch 1 Health Effects Division ( 7509C)

THRU: Whang Phang, PhD, Branch Senior Scientist Reregistration Branch 1 Health Effects Division ( 7509C)

TO: Anthony Britten, Chemical Review Manager Reregistration Branch 3 Special Review & Reregistration Division ( 7508C)

Attached is HED's risk assessment of the insecticide carbaryl for purposes of issuing a Reregistration Eligibility Decision ( RED) Document for this active ingredient. This document is based on several disciplinary science chapters which include: Toxicology  D282980; Dietary Exposure  D288479; Product and Residue Chemistry  D283328; Occupational and Residential Exposure  D287251; and Estimated Environmental Concentrations  D288455. A response to comments document was also prepared which summarizes and illustrates specifically how the comments were addressed for the risk assessment. Many elements of this assessment remain unchanged from the previous version. However, changes have been made based on comments and other information received in the interim by the Agency. No specific changes were made related to hazard characterization except that additional characterization language has been developed related to several issues ( e. g., FQPA 10x factor) and a rationale for use of the short term oral endpoint to calculate risks for the suburban biological monitoring study has been included. For the dietary risk assessment, the major changes are updated percent crop treated values, use of a water concentration distribution in the acute aggregate assessment, and additional characterization language related to use of the carbamate market basket survey. The estimated environmental concentrations have also been significantly altered to reflect input changes for PRZM EXAMS. A water monitoring study was also completed by Bayer which was used only to characterize the most recent water modeling results. In the occupational and residential assessments, transfer coefficients were modified, headgear was considered for airblast applicators, dog collar transferable residues were used, the approach for pet products was modified, Residential Exposure Joint Venture use data were considered, and the results of a large suburban resident biological monitoring study were included. This chapter also addresses the probabilistic assessment which has been submitted by Bayer.

Reviewers: RARC ( 6/ 6/ 01 Report), Revision ( 6/ 7/ 02) Reviewed By Paula Deschamp HUMAN HEALTH RISK ASSESSMENT Carbaryl U. S. Environmental Protection Agency Office of Pesticide Programs Health Effects Division ( 7509C) Jeffrey L. Dawson, Chemist/ Risk Assessor Date: March 14, 2003 HUMAN HEALTH RISK ASSESSMENT Carbaryl Risk Assessment Team:

Risk Assessor: Jeffrey L. Dawson,

Dietary Risk: Felecia Fort Product and Residue Chemistry: Felecia Fort Occupational and Residential Exposure: Jeffrey L. Dawson Epidemiology: Jerome Blondell, MPH, PhD Monica Spann, MPH Virginia Dobozy, VMD, MPH Toxicology: Virginia Dobozy, VMD, MPH Kit Farwell, DVM Drinking Water Estimates: R. David Jones, Ph. D. E. Laurence Libelo, Ph. D. Elizabeth Behl, Ph. D.

Statistician: Steve Nako, Ph. D.

Probabilistic Assessment Team: Bart Suhre, M. S. Jeff Evans William Smith, Ph. D. Alan Dixon Sheila Piper, M. S. David Miller, M. S. Steve Nako, Ph. D. David Hrdy Table of Contents 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . 22 2.1 Chemical Structure and Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.2 Physical Properties of Carbaryl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.2.1 Determination of Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.2.2 Degree of Concern Analysis and Residual Uncertainties . . . . . . . . . . . . . . . . . . 28 3.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.4 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.0 NON OCCUPATIONAL RISK ASSESSMENT AND CHARACTERIZATION . . . . . . . . . . . 31 4.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.2 Dietary Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.2.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4.2.2 Acute Dietary Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 4.2.3 Chronic Dietary Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4.2.4 Cancer Dietary Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4.2.5 Characterization/ Uncertainties of the Dietary Risk Estimates . . . . . . . . . . . . . . 43 4.3 Estimated Environmental Concentrations In Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 4.3.1 Environmental Fate Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 4.3.2 Monitoring Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 4.3.3 Modeling EECs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 4.4 Residential Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 4.4.1 Home Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 4.4.2 Deterministic Residential Handler Risk Assessment . . . . . . . . . . . . . . . . . . . . . . 49 <IP_ADDRESS> Deterministic Residential Handler Noncancer Risks ( 52) <IP_ADDRESS> Residential Handler Cancer Risks ( 56) 4.4.3 Deterministic Residential Postapplication Risk Assessment . . . . . . . . . . . . . . . . 58 <IP_ADDRESS> Deterministic Residential Postapplication Exposure and Noncancer Risks ( 63) <IP_ADDRESS> Deterministic Residential Postapplication Exposure and Risks For Cancer ( 70) 4.4.4 Risks Based On Carbaryl Suburban Resident Biomonitoring Study . . . . . . . . . . 71 <IP_ADDRESS> Noncancer Risks Based On Biological Monitoring Data ( 77) <IP_ADDRESS> Cancer Risks Based On Biological Monitoring Data ( 79) 4.4.5 Residential Risk Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.4.6 Exposure From The Use of Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 4.4.7 Other Residential Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION . . . . . . . . . . . . . 85 5.1 Calculation of Aggregate Risks and DWLOCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 5.2 Acute Aggregate Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5.3 Chronic Aggregate Risks and DWLOCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 5.4 Short term Aggregate Risks and DWLOCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 5.5 Intermediate term Aggregate Risks and DWLOCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 5.6 Aggregate Cancer Risks and DWLOCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 5.7 Summary of Non Probabilistic Aggregate Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 5.8 Companion Probabilistic Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . 93 6.0 CUMULATIVE RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 7.0 OCCUPATIONAL RISK ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 7.1 Occupational Handler Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 7.1.1 Occupational Handler Non Cancer Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 7.1.2 Occupational Handler Cancer Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 7.2 Postapplication Exposures and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 7.2.1 Occupational Postapplication Noncancer Risks . . . . . . . . . . . . . . . . . . . . . . . . 116 7.2.2 Occupational Postapplication Exposure and Risk Estimates for Cancer . . . . . . 118 7.3 Occupational Risk Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 8.0 HUMAN AND DOMESTIC ANIMAL INCIDENT DATA REVIEW . . . . . . . . . . . . . . . . . . 125 9.0 DATA NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 APPENDIX 1: Toxicology Profile APPENDIX 2: Incident Review 5 1.0 EXECUTIVE SUMMARY The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the carbaryl database and conducted a human health risk assessment for the reregistration of the chemical. Carbaryl is a list A reregistration chemical and is also subject to court specified deadlines resulting from a Natural Resources Defense Council ( NRDC) petition of the Agency. This assessment incorporates error corrections and begins phase 5 of the public participation process. The principal registrant for carbaryl is Bayer CropSciences Corporation, hereafter referred to as Bayer.

Use Patterns:

Carbaryl [ 1 napthyl methylcarbamate] is one of the most widely used broadspectrum insecticides in agriculture, professional turf management, professional ornamental production, and in the residential pet, lawn, and garden markets. Carbaryl formulations include baits, dusts, pet collars, flowable concentrates, emulsifiable concentrates, granulars, soluble concentrates, and wettable powders. Carbaryl is used in agriculture to control pests on terrestrial food crops including fruit and nut trees ( e. g., apples, pears, almonds, walnuts, and citrus), many types of fruit and vegetables ( e. g., cucumbers, tomatoes, lettuce, blackberries, and grapes), and grain crops ( e. g., corn, rice, sorghum, and wheat). Carbaryl is also used for direct animal treatments to control pests on companion animals such as dogs and cats. There are other uses for ornamentals and turf, including production facilities such as greenhouses, golf courses, and residential sites that can be treated by professional applicators ( e. g., annuals, perennials, shrubs). Carbaryl can also be used by homeowners on lawns, for home and garden uses, and on companion animals. There are no labels for indoor uses within a residence. In agriculture, groundboom, airblast, and aerial applications are typical. Other applications can also be made using handheld equipment such as low pressure handwand sprayers, backpack sprayers, and turfguns. Homeowners can also use other types of application equipment including trigger sprayers, hose end sprayers, and ready to use dust packaging. Carbaryl also has more specialized uses that can lead to exposures in the general population such as an adulticide for mosquito control, for grasshopper control by USDA/ APHIS, and for Ghost and Mud shrimp control in oyster beds in Washington State. These more specialized use patterns were also considered in this assessment as were the timing of applications based on the emergence of various pest complexes.

Exposure Data:

Many types of carbaryl specific data were considered in the development of this assessment related to exposure through the diet, from drinking water, and in occupational or residential settings. Use data were available that refined various exposure factors in the assessment. These included the Sevin User Survey completed by Bayer and the Residential Exposure Joint Venture survey of residential pesticide users. For dietary exposures, many sources of data were used including: updated ( 2002) percent crop treated values; various processing factors; 1994 to 1998 CSFII results ( Continuing Survey of Food Intake By Individuals); and many sources of residue data that included crop field trials, data from FDA's monitoring program, USDA's Pesticide Data Program, and a carbamate market basket survey ( CMBS). For drinking water exposures, estimated environmental concentrations ( EECs) are based on model estimates. Current EECs reflect the latest information pertaining to the fate characteristics of carbaryl in the environment ( i. e., many new sources of residue dissipation data are reflected in the current assessment). A water monitoring study was also completed by Bayer but not 6 used quantitatively due to site selection and sample frequency concerns. NAWQA data for carbaryl were also considered for similar purposes because it is frequently detected. Many sources of data were used to calculate the occupational and residential risks associated with the use of carbaryl. To address occupational exposures, several scenario specific handler exposure studies were used ( e. g., trigger sprayer, commercial pet groomers, and granular backpack users). Dislodgeable foliar residue studies on several crops and a turf transferable residue study were also used. In addition, preliminary results from a biological monitoring study on tree fruit thinners and harvesters were used to characterize postapplication exposures for similar activities. To address residential exposures, the dislodgeable foliar and turf transferable residue studies were also used, a study that quantified transferable residues from dogs wearing pet collars was used, the Residential Exposure Joint Venture information was used, and the results from a suburban resident biological monitoring study were used. It should also be noted data from several population based exposure studies ( e. g., NHEXAS & NHANES) were used for comparative purposes to further describe and characterize the results of this assessment. Finally, a probabilistic aggregate assessment using the CARES model was submitted which is also addressed.

Hazard Characterization:

Carbaryl is a carbamate insecticide where the mode of toxic action is through cholinesterase inhibition ( ChEI). In most of the toxicology studies in which ChEI activity was measured, it was the endpoint used for setting the No Observed Adverse Effect Level ( NOAEL) for risk assessment, the dose at which no adverse effects were observed. For chronic duration exposures, a NOAEL could not be defined in the toxicology study so a Lowest Observed Adverse Effect Level ( LOAEL), the lowest dose where the first adverse effects were observed, was selected.

The Agency is required by the Food Quality Protection Act to consider the special sensitivities of various susceptible populations such as infants and children. Dietary exposures were calculated using FDA and PDP monitoring data, a carbamate market basket survey ( CMBS), and percent crop treated information. Residential exposures were calculated using a number of carbaryl specific studies. In the toxicology database, no quantitative or qualitative evidence of increased susceptibility in rat or rabbit fetuses following in utero exposure in the standard developmental toxicity studies was observed. There was a low level of concern for evidence of susceptibility seen in the developmental neurotoxicity study, and there was evidence of increased susceptibility in offspring in the 2 generation reproduction study. For carbaryl, a safety factor of 3x was applied to chronic duration exposures to account for the lack of a NOAEL in the selected chronic dog toxicity study ( i. e., the use of a LOAEL). The Agency decided that the FQPA Safety Factor should be reduced to 1x for other durations of exposure and that this was adequate to protect susceptible populations because there are no residual uncertainties in the exposure databases, the toxicology database is complete, and the endpoints and NOAELs for risk assessment were well defined, and the acute and chronic RfDs would be protective of these effects so the special FQPA safety factor was reduced to 1x.

Carbaryl has been classified as a Group C possible human carcinogen based on an increased incidence of hemangiosarcomas and combined hemangiomas/ hemangiosarcomas in CD 1 mice at 100 ppm and above ( 15 mg/ kg/ day). A linear low dose extrapolation approach was used for risk assessment; the Q1* is 8.75 x 10 4 ( mg/ kg/ day) 1 based on the mouse vascular tumors.

Endpoints for acute and chronic dietary exposure risk assessments were selected by the HED 7 Hazard Identification Assessment Review Committee ( HIARC). The dose level used for the acute dietary risk assessment was a NOAEL from a developmental neurotoxicity study conducted with rats ( 1 mg/ kg/ day). The dose level used for the chronic dietary risk assessment was a LOAEL which was defined in a chronic dog feeding study ( 3.1 mg/ kg/ day). Because a NOAEL could not be defined in the chronic study, an additional factor of 3x was added to the customary 100x factor ( i. e., 10x for interspecies extrapolation and 10x for intraspecies variation) to account for the uncertainty associated with a lack of a NOAEL. The acute and chronic reference doses ( RfD) were 0.01 mg/ kg/ day ( i. e., 1/ 100 for the acute RfD and 3.1/ 300 for the chronic RfD).

There are many potential ways people can be exposed to carbaryl in occupational and residential settings. The Agency considers exposures for those involved in the application of carbaryl ( i. e., handlers) and those who can come into contact with carbaryl residues after application ( i. e., reentry or postapplication). Both cancer and non cancer risk assessments were conducted for residential handlers and for people in the general population who might be exposed postapplication from lawn, garden, or pet uses of carbaryl or from more specialized uses such as mosquito adulticide applications and uses on oyster beds in Washington state. Similarly, both handler and postapplication risks were calculated for those people who could be exposed as part of their jobs such as a grower treating their crop or someone harvesting fruit. Endpoints for occupational and residential exposures from various routes ( i. e., dermal, inhalation, and incidental oral) and differing durations ( i. e., short term, intermediate term, and chronic) were selected by the HIARC. [ Note: The Agency completed residential assessments based on standard deterministic approaches and based on the recent suburban resident biological monitoring study. Each analysis demanded slightly different use of the hazard data as described below.] Based on current policy, short term exposure was defined as 1 to 30 days, intermediate term exposures as 30 days to six months, and chronic exposures as six months to a lifetime. [ Note: Not all routes and durations are applicable to each population.] The toxicity endpoints selected for these carbaryl risk assessments are again based on neurotoxic effects associated with the inhibition of ChEI. The short and intermediateterm dermal risk assessments for carbaryl are based on NOAEL of 20 mg/ kg/ day defined in a rat dermal toxicity study using technical material where decreases in red blood cell cholinesterase in males and females and brain cholinesterase in males were observed. The short term inhalation and nondietary ingestion risk assessments for carbaryl are based on a NOAEL of 1 mg/ kg/ day which was defined in a rat developmental neurotoxicity study where alterations in FOB measurements and cholinesterase inhibition ( plasma, whole blood, and brain) were observed. This value was also used to calculate risks from the suburban resident biomonitoring study because it eliminated route to route extrapolation; the dose values from the study could be attributed to various exposure routes; oral absorption is fast and essentially quantitative; and, when adjusted for absorption, the effective NOAEL from the dermal toxicity study is similar to that observed in the oral study. The intermediate term inhalation and nondietary ingestion risk assessments are based on a NOAEL of 1 mg/ kg/ day that was defined in a subchronic neurotoxicity study in rats. The chronic risk assessments, regardless of how exposures occur ( e. g., skin or inhaled) are based on a LOAEL of 3.1 mg/ kg/ day that was defined in a 1 year dog feeding study. In some assessments, a dermal absorption factor is required. A rat dermal absorption study using radiolabeled 14C carbaryl was used to define a factor of 12.7 percent; this value was used to calculate the 1 At the present time, information from the industry sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. The primary concern was rubbing sampled commodities during the rinsing process except for broccoli and tomato because this created a potential for residue loss from the mechanical action associated with rubbing. A separate assessment was also completed using other sources of high quality residue data ( e. g., PDP) for comparative purposes to more completely inform the risk management process.

8 oral equivalent dermal dose for noncancer chronic duration exposures and for the calculation of cancer risks. No inhalation toxicity studies were available for risk assessment purposes so a route to route extrapolation was used to address risks from inhalation exposures. Absorption via the inhalation route is presumed to be equivalent to oral absorption.

Carbaryl is a reversible inhibitor of acetylcholine esterase. In an acute time course study, following a single gavage dose of carbaryl, brain cholinesterase inhibition had returned to pre treatment values by 8 hours in the 10 mg/ kg group, by 24 hours in the 30 mg/ kg group, and by 48 hours in the 90 mg/ kg group. No cumulative effects were shown in a subchronic neurotoxicity feeding study, cholinesterase inhibition was similar when determined at week 4, 8, or 13.

Dietary Risk Estimates:

Potential dietary exposure to carbaryl occurs through food and water although this section addresses food only consumption. Food and water consumption combined ( i. e., aggregate exposures) are addressed below. Tolerances for residues of carbaryl are currently expressed in terms of carbaryl and its hydrolysis product, 1 naphthol ( calculated as carbaryl) for most raw agricultural commodities. However, HED is recommending that carbaryl per se be regulated in plants. In livestock commodities, carbaryl; 5,6 dihydro 5,6 dihydroxy carbaryl; and 5 methoxy 6 hydroxy carbaryl and all residues which can be hydrolyzed to carbaryl, 5,6 dihydro 5,6 dihydroxy carbaryl, or 5 methoxy 6 hydroxy carbaryl under acidic conditions should be included in the tolerance expression and risk assessment for all endpoints of dietary concern. Once the tolerances for plants are revised, they will be compatible with Codex MRLs except for livestock commodities.

A Tier 3/ 4 dietary risk assessment, which is the most highly refined assessment possible at this time, was conducted. Both acute and chronic dietary risk assessments were conducted. Dietary exposure was determined, considering the level of carbaryl residue on food commodities and their potential consumption by multiple subpopulations. Dietary risk was then calculated by comparing dietary exposure to the acute or chronic PADs. Data on anticipated carbaryl residues were determined based mainly on USDA Pesticide Data Program ( PDP) and Food and Drug Administration ( FDA) monitoring data. Field trial data were used for certain commodities. In addition, separate acute analysis was conducted incorporating the results of the Carbamate Market Basket Survey ( CMBS). 1 The percentage of the crop treated ( estimated maximum percentage and weighted average percentage for the acute and chronic analyses, respectively) was also considered. Carbaryl acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM FCID   , Version 1.3), which incorporates consumption data from USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1994 1996 and 1998. The 1994 96, 98 data are based on the reported consumption of more than 20,000 individuals over two nonconsecutive survey days. Foods " as consumed" ( e. g., apple pie) are linked to EPA defined food 9 commodities ( e. g. apples, peeled fruit  cooked; fresh or N/ S; baked; or wheat flour  cooked; fresh or N/ S, baked) using publicly available recipe translation files developed jointly by USDA/ ARS and EPA. Consumption data are averaged for the entire U. S. population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment. Values greater than 100 percent of the PAD exceed HED's level of concern.

Estimated acute dietary exposure ( again, water is not included) for carbaryl at the 99.9th percentile is below the level of concern for all population subgroups regardless of the data set used. The results of the acute dietary assessment when CMBS data have not been used indicate risks estimates are 43% and 94% for the general U. S population and children ( 1 2 years old), the highest exposed population subgroup, respectively. When CMBS data were incorporated, the highest exposed subpopulation was children ( 1 2 years old) at 86 percent of the aPAD. A sensitivity analysis was completed by the Agency ( not using the CMBS) to evaluate the impacts of eliminating strawberries. Eliminating strawberries has the most impact as risk estimates for children ( 1 2 years old) occupied 71 percent of the aPAD.

Estimated chronic dietary risks for all population subgroups are not of concern. Estimated chronic dietary exposures for all population subgroups resulted in < 1 percent of the cPAD being occupied.

The cancer dietary exposure assessment was conducted using the Q 1* approach ( i. e., linear, low dose extrapolation). Dietary exposure is determined from consumption and residue data, as was done for the acute and chronic dietary assessments. The food exposure is then multiplied by the Q 1* ( 8.75 x 10 4) ( mg/ kg/ day) 1 for carbaryl to determine the increased risk of cancer from consuming carbaryl residues in food over a lifetime ( 70 years). Risks estimates above 1 x 10 6 are of concern. Results indicate a maximum lifetime risk of 2.14 X 10 8 for the general US population.

Concentrations in Water:

Monitoring data ( NAWQA & a Bayer monitoring study) for carbaryl residues in ground and surface water are available, but they are of limited utility in developing estimated environmental concentrations ( EECs) for risk assessment. The key issues with using Bayer's surface water monitoring study were the number of sites were limited and therefore the vulnerability of the selected sites was questionable. Samples were also collected too infrequently to ensure that peak concentrations were captured. As a result, computer modeling was used to estimate surface ( PRZM 3.12 and EXAMS 2.98.04) and ground ( SCI GROW 2.2) water concentrations expected from normal agricultural use. For the acute dietary calculation, the distribution of modeled surface water concentrations, which were output from PRZM/ EXAMS, were integrated into the probabilistic assessment in a manner analogous to data for any other commodity. For the other types of assessments, the model estimates ( i. e., otherwise known as Estimated Environmental Concentrations or EECs) were compared to drinking water levels of concern ( DWLOCs), the theoretical concentration of pesticide in drinking water that would be an acceptable upper limit in light of the aggregate exposure to that pesticide from other sources ( food and residential use). The maximum calculated acute and chronic surface water EECs ( 316 ppb and 14.2 ppb, respectively) resulted from use on citrus in Florida. In Florida, the majority of drinking water is derived from groundwater (> 90%) so high surface water concentrations do not necessarily indicate high exposure. As a result, both Florida and the results for Pennsylvania apples and sweetcorn in Ohio ( the 10 next highest EECs for acute and chronic exposures, respectively) have also been considered ( 62.9 ppb for acute and 5.53 ppb for chronic exposures, respectively). Groundwater EECs for the acute and chronic assessments were both 0.8 ppb as calculated with SCI GROW.

Use of Consumer Products ( Residential Handler Risks Based On Deterministic Approaches):

Combined ( dermal and inhalation) risks were calculated for 17 scenarios ( i. e., 52 site/ area/ rate combinations within those scenarios) considered representative of the residential uses of carbaryl. Noncancer MOEs associated with most scenarios ( 40 of 52 considered) are generally not of concern because they exceed the Agency's uncertainty factors for noncancer risk assessments ( i. e., MOE $ 100). The scenarios of concern involve the use of dusts ( in gardens and on pets) and for some liquid sprays on gardens. Cancer risks were also calculated for a single day of use then the allowable annual number of days exposure was defined based on a cancer risk limit of 1x10 6. Based on a single day of exposure, cancer risks for most scenarios are in the 10 8 to 10 10 range although there is one scenario where the risks slightly exceed 1x10 6 ( dusting dogs = 1.09x10 6) even for a single day of use. It should be noted that there are 5 scenarios where the allowable days per year of exposure is less than or equal to 5 which should be considered in conjunction with the Sevin User Survey data from Bayer that indicates 5 uses per year is the 84th percentile. The database for carbaryl is fairly complete compared to many other chemicals. Recent, high quality data generated by the Bayer Corporation, the ORETF ( Outdoor Residential Exposure Taskforce, Bayer is a member), and the Wellmark Corporation have been used to address the key residential uses of carbaryl on lawns, flower and vegetable gardens, and pets. Use and usage inputs from the recent Residential Exposure Joint Venture survey of pesticide users also appear to be essentially consistent with the use information provided by the Bayer Corporation at the 1998 SMART meeting. No key data gaps have been identified by the Agency at this time for residential handlers. However, it is likely that there are scenarios that remain unaddressed by the Agency at this time due to a lack of data or other meta information. The Agency will address other appropriate scenarios as they are identified. The results of this deterministic assessment should also be considered in conjunction with the assessments completed based on the biological monitoring study and the probabilistic aggregate calculations using the CARES model described below.

Residential Exposures ( Postapplication Risks Based On Deterministic Approaches):

HED considered a number of residential postapplication exposure scenarios for toddlers, youthaged children and adults. Short term and intermediate term risks from declining residues were calculated for multiple scenarios, including exposures to treated lawns ( toddlers and adults), golf courses ( adults), gardens ( adults and youth aged children) and pets ( toddlers). Exposures from more limited uses such as a mosquito adulticide and in oyster beds were also considered. Short term MOEs were calculated based on the residue concentrations for each day while intermediate term risks were calculated using a 30 day average based on residue decline. The Agency has short term risk concerns for exposures to adults doing heavy yardwork, for toddlers playing on treated lawns, and for toddlers that have contact with treated pets ( except those treated with collars). Activities associated with home gardening ( e. g., harvesting) and golfing for adults, children in contact with pets wearing collars, home gardening for youth aged children or any age or activity considered in the mosquito adulticide or oyster bed assessments do not have risk concerns even on the day of application ( i. e., MOEs $ 100 on the day of application). For adults, the MOEs for heavy yardwork do not meet or exceed risk targets ( i. e., MOE $ 100) up to 5 days after application. For toddlers, the Agency has concerns for pet treatments and also 11 for lawn uses. In fact, pet uses ( except for collars) never reach acceptable levels even 30 days after application and not until 18 days at the maximum application rate considered on turf. Toddler MOEs from pet and turf uses represent total exposures from multiple pathways. For the pet uses, dermal and hand to mouth exposures essentially both equally contribute to the overall estimate. For the turf uses, dermal and hand to mouth exposures are also the key contributors to the overall estimates. The Agency does not have intermediate term risk concerns for adults and youth aged children for any of the uses considered including lawncare, home gardens, golfing, and any aspect of adulticide mosquito control or uses in oyster beds. In contrast, the Agency does have intermediate term risk concerns for all toddler exposure scenarios considered ( i. e., non collar pet treatments and lawncare uses). As with the shortterm MOEs, pet and turf uses represent total exposures where the significant contributions to overall exposures are again made equally from the dermal and hand to mouth exposures.

Cancer risks were also considered for adults in residential settings. In all cases, the cancer risks were not the predominant concern. Risks did not exceed 1x10 6 on the day of application for any scenario considered. All postapplication cancer risks were calculated based on an annual frequency of 1 exposure per year. It is likely that additional events could occur but data linking postapplication activities and carbaryl use patterns are not available. To address this issue, the Agency calculated the number of exposures that can occur under a cancer risk ceiling of 1x10 6 and determined that from 20 days per year to exposures every day of the year could occur under the risk ceiling depending upon the scenario. The results of this deterministic assessment should also be considered in conjunction with the assessments completed based on the suburban resident biological monitoring study and the probabilistic aggregate calculations using the CARES model described below.

Residential Risks Calculated Based On Suburban Resident Biological Monitoring Study The suburban resident biological monitoring study for carbaryl has been used by the Agency to examine the exposure patterns and associated risks that can occur in households where the lawn and gardens or ornamentals have been treated. The results of this study should be considered in conjunction with the results of the deterministic assessments described above and the probabilistic aggregate assessment completed using the CARES model described below. The biomonitoring study quantified absorbed dose levels of carbaryl in 106 people in 23 households in California and Missouri. Lawns were treated at each residence. Additionally gardens or ornamental plants were also treated at each residence. Based on use information, the population which was monitored in the study could be construed to represent a population which has the highest possible potential for exposure associated with it because of the concurrent applications to different areas ( i. e., in all cases lawns and another area was treated). However, the Agency believes that the lawn use was the key contributor to overall exposures which should be considered when interpreting the associated risks. The Residential Exposure Joint Venture use survey results should also be considered when interpreting the results of this study. This survey indicates that about 1.2 percent of the general population uses carbaryl on lawns and those who also concurrently use it on vegetables and ornamentals represent at most 0.18 and 0.44 percent of the general 12 population, respectively. It should also be noted that about 50 percent of the 1.2 percent of lawn users in the general population use carbaryl for spot treatments only which would not likely lead to significant exposures.

The Agency placed individuals into likely groups for its analysis that included applicators, nonapplicator adults, and children of various age brackets. There are different possible methods for calculating risks from this study because of the random nature of the exposure patterns and what the pharmacokinetics analysis determined about the excretion profile for carbaryl. Because of this, the Agency considered a number of possible approaches for evaluating the data in conjunction with this information about pharmacokinetics. The Agency recommended an approach in which post application total dose values were used to calculate risk estimates ( i. e., daily outputs were added together since the study monitored residues for 96 hours after application which is the time it takes for single carbaryl dose to be eliminated from the body) with the knowledge that this approach could overestimate exposure if multiple exposure events occurred early in the monitoring period. It should be noted, however, that if the key exposure events occurred later in the monitoring period that the total value could underestimate exposure due to incomplete sample collection. The Agency also used the data in the same manner as Bayer which calculated risks based on individual daily dose values, not corrected for mass balance. This approach would be more likely to underestimate dose based on what is known about the pharmacokinetics and excretion profile for carbaryl.

It is clear that the manner in which noncancer risks were calculated has an impact on the resulting risks ( i. e., total versus daily dose). For both techniques, however, the Agency has a concern ( i. e., MOEs< 100) at the upper percentiles of exposure for adults and children alike regardless of how the risks were calculated ( e. g., 95th % tile and up). In the Agency's approach, risks are also of concern based on whatever measure of central tendency is considered for all populations ( MOEs ~ 10 to 70) except for the oldest children and non applicator adults. If single day values are considered, risks are not of concern based on geometric means but are of concern if the arithmetic mean is considered for children under 10 years of age ( MOEs ~ 50 to 90). Risks are of most concern for applicators and the youngest children because they had the most opportunity for exposure ( i. e., applicators were in proximity to product and young children spent the most time outdoors on treated lawns). Additionally, it should be noted that cancer risks are not a concern compared to the noncancer risk estimates as with the deterministic assessments. The distributions of absorbed dose in this study were also compared to those in the corresponding deterministic assessments which are intended to represent screening level, upper percentile exposures. In fact, the dose estimates calculated in the deterministic assessments are similar to those determined in this study at the upper percentiles of exposure. The biological monitoring data were also compared to several population based monitoring studies ( e. g.., NHEXAS and NHANES). This analysis indicates that central tendency values and the upper percentiles were similar to results seen in these studies. This can be used to illustrate that exposures which are of a risk concern can occur in the general population and that the deterministic risk assessment approaches are in fact screening level in nature as their estimates approximate the upper percentile of the monitored populations.

In summary, the biological monitoring study clearly illustrates that exposures leading to risks of concern for applicators and younger children can occur in households where carbaryl is used. Additionally, risks are of concern at the highest percentiles of exposure ( 95th % tile and up) regardless of how dose estimates are calculated. If the Agency approach for calculating total dose is considered, risks 13 at the central tendency are also of concern. If the Bayer approach for calculating risks based on single day dose values is considered, risks are not of concern based on geometric means but it should be kept in mind that this approach does not account for mass balance as defined in the pharmacokinetic analysis of the excretion profile for carbaryl.

Aggregate Risks and DWLOCs:

The Food Quality Protection Act requires that the Agency consider aggregate risk for each chemical ( i. e., all sources of exposure including food water, and residential are considered in total). Aggregate risks are typically calculated by considering food or food and residential ( depends upon the specific scenario), subtracting these from the allowable exposure limit, and, if the exposure limit has not been exceeded, then calculating Drinking Water Levels of Concern ( DWLOCs) to compare to surface or groundwater Estimated Environmental Concentrations ( EECs). If EECs exceed the DWLOCs ( i. e., the allowable concentrations) then there is a risk concern. Conversely, if EECs don't exceed the DWLOCs then there is not a risk concern. The aggregate assessment for carbaryl is also groundbreaking in that it relies on the Agency's standing policies for these assessments but it includes the first acute aggregate assessment where a water concentration distribution from PRZM/ EXAMS has been directly integrated into DEEM/ FCID. In essence, the data for water were treated as the data would be for any food commodity. As such, DWLOCs have been calculated for all scenarios except the acute aggregate assessment. In fact, the results for the acute assessment have been presented like a food only assessment using the 99.9th % tile as level of concern. Results for additional percentiles of exposure have also been presented to allow for a more informed risk management decision.

The remaining assessments were completed using the Agency's standard DWLOC/ EEC approach ( i. e., chronic, short/ intermediate term, and cancer). It should be noted, however, that residential risks alone were of concern for most scenarios which would preclude the calculation of DWLOCs. However, to allow for a more informed risk management decision, a few residential scenarios were selected to calculate illustrative aggregate risk estimates. In most cases, these were estimates based on average application rates and not label maximum rates. Other scenarios were selected that had public health concerns associated with them. Bayer has also recently submitted a probabilistic aggregate assessment which should be considered in conjunction with this assessment. It is also recommended that the results of the suburban resident biological monitoring study be considered because the exposure measurements from that study represent aggregate exposure estimates for that populaiton even though it is clear that residential uses account for the largest portion of the overall exposure ( i. e., homeowner products were used in every case).

The results of the acute aggregate assessment indicate that inclusion of water in the analysis provided similar results to the dietary assessment. In essence, the addition of water had no impact on the results. The analyses show that the highest exposed population subgroup, children ( 1 2 years old) consumed 93% of the aPAD. The acute dietary exposure estimate for the general U. S. population was 43% of the aPAD. In the short term assessment, the Agency selected representative scenarios where residential risks alone were not of concern including mosquito control, oyster harvesting, golfing, garden harvest, and several handler uses. Regardless of the drinking water source, aggregate risks were not of concern for the selected scenarios keeping in mind those that were selected represented average application rates or public health scenarios and the Agency has risk concerns for residential exposures alone for many scenarios at higher application rates. Separate intermediate term aggregate risk and 14 DWLOC calculations were not completed for carbaryl because the short term aggregate risk estimates essentially presented the same results since the hazard inputs were numerically identical. The only major differences would be related to the postapplication residential exposures where, instead of a single day exposure estimate, the exposures represented a 30 day average. Aggregate chronic and cancer risks were not of concern for any subpopulation regardless of the source of drinking water.

Cumulative Risks:

Carbaryl is a member of the carbamate class of pesticides. This class also includes aldicarb, methomyl and oxamyl among others. The N methyl carbamates, as a group, have been determined to share a common mechanism of toxicity ( July 2001 memo from Office Director Marcia Mulkey). However, a cumulative risk assessment has not been performed as part of this review because the Agency is currently examining approaches for completing this type of assessment. EPA's Office of Research and Development is currently investigating the pharmacokinetics and pharmcodynamics of Nmethyl carbamates which will provide a more solid scientific foundation for the cumulative assessment of these pesticides in the future.

The issue of completing a cumulative risk assessment for organophosphate and carbamate cholinesterase inhibiting compounds has also been raised. The Agency does not believe that calculation of cumulative risks for the organophosphorus ( OP) pesticides and N methyl carbamates ( including carbaryl) is appropriate. Both classes of compounds inhibit acetylcholinesterase ( ChE), but there are differences in pharmacokinetics and pharmacodynamics between the two groups that raise significant uncertainty regarding the appropriateness of dose addition and that will have a significant impact on cumulative toxicity. Thus, these two classes of anticholinesterase compounds have a very different time course of events including: time to peak effect, compound half life in the body, duration of action, and recovery time after exposure.

Companion Probabilistic Aggregate Risk Assessments Bayer has submitted a probabilistic aggregate assessment using the CARES model which has been reviewed by the FIFRA Science Advisory Panel. The Agency has begun evaluating the inputs and analysis for the CARES assessment. Because of the late submission date related to the release of this assessment, the Agency has only completed a preliminary analysis and review of the submission. It should also be noted that to date, the Agency has not identified any issues that are significant enough to preclude the use of this analysis in the regulatory decision making process. The Agency will develop separate document that describes the inputs and results of these efforts in more detail at a later date which will also be considered in the risk management decision making process.

Given the recent submission date, and the short time for the preliminary evaluation, it is still too early to draw any final conclusions about Bayer's use of the CARES model to assess human health risks from carbaryl uses. It will take the EPA some time to complete and in depth analysis and come to any conclusions about its validity. In this preliminary analysis the focus for the Agency has been 3 to 5 year old children since they are thought to be a highly exposed segment of the population and the results can be compared to the Agency's deterministic assessment for children playing on turf ( i. e., based on Jazzercize) because that model is intended to represent children of that age. Also the results of the suburban resident biological monitoring study can be used for comparison. In the analysis, several 15 preliminary conclusions have been drawn including risks for the general population at the 99.9th % tile do not appear to be of concern. These risks are driven primarily by dietary exposures. These results should be considered in the context with the knowledge that residential use occurs in a very small percentage of the population ( i. e., ~ 0.4%) in a manner which could significantly impact exposures ( i. e., lawn broadcast applications). It should also be pointed out that the exposure estimates for the general population closely mirror those calculated in the Agency's dietary risk analyses and in various population based biological monitoring studies ( e. g.., NHANES). The Agency recognizes that residential uses can also lead to significant personal exposures so it completed a residential lawn broadcast treatment " users only" assessment. That analysis shows risk concerns beginning at the central tendency of exposure and that MOEs at the upper percentiles are in the 5 to 10 range. It also appears that for the " user only" population that dietary and drinking water exposures are small contributors. It should be pointed out that this result is very consistent with the results of the biological monitoring study and that the deterministic assessment for children playing on lawns ( i. e., based on Jazzercize) closely approximates the upper percentile exposures calculated with CARES. To reiterate, the conclusions presented here are considered preliminary and the results and interpretation of Bayer's CARES submission may be altered by the Agency pending further review.

Occupational Handlers:

There is significant potential for exposure to carbaryl users in a variety of agricultural and commercial settings. Tasks associated with occupational carbaryl use include mixing, loading and applying the chemical or guiding aerial applications ( flaggers). All these activities are collectively referred to as handler tasks. A total of 28 scenarios were considered representative of the range of handler activities, crops or acres treated and equipment used. The risks from dermal and inhalation exposures were calculated and then added together to obtain overall risk estimates at varying levels of personal protection. Risks from long term ( chronic) exposures were only calculated for a limited number of scenarios in the ornamental/ greenhouse industry. The short and intermediate term risk assessments were conducted, as described above ( i. e., hazard inputs were unchanged including target MOE = 100). The long term risk assessment for carbaryl was based on a 1 year dog feeding study where effects ( ChEI) were observed at 3.1 mg/ kg/ day ( LOAEL). The target MOE was 300 ( customary 100x plus 3x for use of LOAEL).

Risks were calculated assuming one of eight possible levels of personal protection equipment, ranging from a baseline of typical work clothing ( long sleeved shirt and long pants, no respiratory protection and no chemical resistant gloves) to engineering controls, such as a closed cab or closed loading system. Current carbaryl labels typically require that handlers wear long pants, long sleeved shirts, and gloves but do not require respirators. For most scenarios, the noncancer risks for this personal protection ensemble do not meet Agency risk requirements and additional levels of personal protection are required to achieve Agency risk targets. In fact, in many cases engineering controls such as closed loading systems or closed cab tractors are needed. The Agency does have risk concerns over the use of carbaryl in some agricultural and other occupational settings regardless of the level of personal protection used ( i. e., MOEs at any level of personal protection are < targets). As would be expected, these scenarios with the highest associated risk also have high daily chemical use amounts based on application rates or high acreages treated or the exposures for the scenarios in question are relatively high. Generally, the areas that appear to be problematic include: large acreage aerial and chemigation applications in agriculture or for wide area treatments such as mosquito control; airblast 2 The Agency has defined a range of acceptable cancer risks based on a policy memorandum dated August 14, 1996, by Office of Pesticide Programs Director Dan Barolo. This memo refers to a predetermined quantified " level of concern" for occupational carcinogenic risk. Occupational carcinogenic risks that are 1 x 10 6 or lower require no risk management action. For those chemicals subject to reregistration, the Agency is to carefully examine uses with estimated risks in the 10 6 to 10 4 range to seek ways of cost effectively reducing risks. If carcinogenic risks are in this range for occupational handlers, increased levels of personal protection are warranted as is commonly applied with noncancer risk estimates ( e. g., additional PPE or engineering controls). Carcinogenic risks that remain above 1.0 x 10 4 at the highest level of mitigation appropriate for that scenario remain a concern.

16 applications at higher rates; pet grooming; and the use of certain handheld equipment for applications to turf or gardens ( e. g., bellygrinder). This general trend was essentially the same for exposures of any duration. Several data gaps were also identified in many different use areas that include: dust use for animal grooming and in agriculture; various specialized hand equipment application methods ( e. g., powered backpack, power hand fogger, and tree injection); and nursery operations such as seedling dips.

The risk of cancer for occupational handlers was calculated for two populations, private growers ( 10 applications per year) and commercial applicators ( 30 applications per year), using the same 28 scenarios. According to Agency policy, acceptable cancer risks for occupational exposure to pesticides can vary from 1x10 4 to 1x10 6, depending on the course of action taken by the Agency as outlined in the subject policy2. Risks for corresponding scenarios based on cancer concerns were generally less than the corresponding noncancer results across all scenarios. In fact, in all but one scenario, cancer risks were < 1x10 4 at current carbaryl label requirements of single layer clothing, gloves, and no respirator for both private growers and commercial applicators ( i. e., mixing/ loading wettable powders for wide area aerial applications). Higher levels of personal protection reduce this risk to < 1x10 4 in both populations. If a 1x10 6 risk level is specified as a concern, results are similar in that risks for a majority of scenarios are < 1x10 6 at current label requirements. In fact, only 8 of the 140 scenarios considered for private applicators have cancer risks > 1x10 6 ( and less than 1x10 4) even with the most protective ensembles of protective clothing or engineering controls. For commercial applicators, results indicate that risks for about half of the scenarios considered are < 1x10 6 at current label requirements and that only 21 of the 140 scenarios considered have cancer risks > 1x10 6 ( and less than 1x10 4) even with the most protective ensembles of either protective clothing or engineering controls.

Occupational Postapplication ( Reentry Workers):

Workers can be exposed to carbaryl residues when entering previously treated areas to perform certain activities, such as harvesting. Current label requirements specify 12 hour Restricted Entry Intervals ( REIs) while Pre Harvest Intervals ( PHIs) are less than 7 days for most crops with some as long as 28 days. Non cancer risks from short and intermediate term dermal postapplication exposure were calculated for 18 representative crop groupings. The risks from long term dermal exposures were calculated for only a limited number of scenarios in the greenhouse and floriculture industries. For each scenario, the risk on the day of application was calculated, along with the time required to reach the target MOE, allowing for dissipation of the carbaryl residues. For all but the lowest exposure scenarios in some crops, MOEs do not meet or exceed target MOEs until several days after application. If shortterm risks are considered, MOEs meet or exceed target MOEs generally in the range of 3 to 5 days after application for lower to medium exposure activities and from 8 to 12 days after application in most 17 higher exposure scenarios. If intermediate term risks are considered, MOEs are not of concern based on a 30 day average exposures except for higher level exposures such as harvesting in some crops. Chronic exposures are of concern for the cut flower industry but not for other general greenhouse and nursery production activities.

Cancer risks were calculated for private growers and professional farmworkers with the only difference being the annual frequency of exposure days. Cancer risks for private growers and commercial farmworkers are generally in the 10 8 to 10 6 range on the day of application. If a 1x10 4 cancer risk is the target, the current REI would be adequate for all scenarios considered in the assessment. If a 1x10 6 cancer risk is used, then durations longer than the current REI should be considered for some higher exposure scenarios. It should be noted that the cancer risk calculations are less restrictive than noncancer risk estimates for the same scenarios in all cases. Many mechanized or partially mechanized processes are possibly associated with the use of carbaryl that may limit or eliminate exposures ( e. g., combines for grain harvest). Guidance contained in the Worker Protection Standard ( WPS) on this issue should be considered when interpreting the results of this assessment as the WPS provides specifics on addressing tasks that would not potentially be subject to a Restricted Entry Interval ( REI). Additionally, it should also be noted that the preliminary results of a biological monitoring study for tree fruit thinners and harvesters supports the exposure estimates used by the Agency in this assessment.

Human and Domestic Animal Incidents:

HED evaluated reports of human carbaryl poisonings and adverse reactions associated with its use from the following sources: OPP Incident Data System ( IDS); Poison Control Centers' Toxic Exposure Surveillance System; California Department of Pesticide Regulation; the National Pesticide Telecommunications Network ( NPTN); open literature; and an unpublished study submitted by the registrant. The data from IDS indicated that a majority of cases from carbaryl exposure involved dermal reactions. A number of other cases involved asthmatics and people who experienced hives and other allergic type reactions. It is noted that the dermal sensitization study in the guinea pig was negative. Reports of allergic type reactions in humans could be evidence of a difference in species sensitivity or could be attributable to inert ingredients in the marketed formulations. It is recommended that labels for products should advise that carbaryl can cause sensitizing effects in some people. According to California data, about half of the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers that were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties. The Poison Control Center cases involving non occupational adults and older children showed an increased risk in five of the six measures used for comparing carbaryl incidents to all other pesticides. The carbaryl cases were almost twice as likely to require serious health care ( hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome ( life threatening effects or significant residual disability) than other pesticides. This pattern of increased risk was not seen among occupational reports or in young children. This may mean that careless handling by non professionals is a particular hazard. Five case report studies suggested that carbaryl may be a cause of chronic neurological or psychological problems. Some of these effects appear to be consistent with those reported from organophosphate poisoning. However, unlike organophosphates, no controlled studies have been undertaken. If such effects occur as a result of overexposure to carbaryl, they appear to be relatively rare. The effects reported among the five case reports 18 are too inconsistent to draw any conclusions, but do suggest the need for further study. The epidemiologic study submitted by the registrant compared mortality rates in plant workers exposed to carbaryl to the general population. HED concluded that the sample of workers was too small and the period of follow up too short to permit definitive conclusions.

The incident reports on domestic animals in IDS were evaluated. Based on limited data, there is some evidence that young kittens may be susceptible to adverse reactions to carbaryl. It is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96 6 ( should not be used in kittens less than 12 weeks of age).

Issues For Consideration:

The database for carbaryl is sufficient for conducting a risk assessment for reregistration purposes. However, the results of the risk assessment hinge on the interpretation of elements in certain key pieces of data that include: use of various residue data, characterization of the carbamate market basket survey, site selection in the water monitoring study, revised PRZM EXMS estimates, transfer coefficient updates for tree fruit workers, updated data and methods for calculating exposure to pets, use information from the Residential Exposure Joint Venture, Bayer's evaluation of pharmacokinetics in humans, and use of results from the suburban resident biological monitoring study. In the dietary assessment, all residue data translation was done based on current Agency policy and the use of the best data available for each situation. In conjunction, the Agency used the most current dietary intake information for the assessment ( i. e., CFSII 1994 1998). Also, the Agency has attempted to characterize the impact of rubbing certain commodities during sample collection in the market basket survey because carbaryl residues are believed to be surface residues as it is a contact and not a systemic insecticide. In fact, use of the CMBS data had very little impact on the overall results of the assessment so this issue becomes less critical for risk managers to consider.

The Agency does not believe that the quantitative use of Bayer's recent carbaryl water monitoring study is appropriate for the risk assessment purposes because selection of the monitored sites was not adequately justified ( i. e., they were deemed to be vulnerable by Bayer but the justification provided was inadequate and sample collection was too infrequent). As such, the estimated environmental concentrations ( EECs) for surface water used in the assessment were from revised PRZM EXAMs calculations in which the inputs were modified to reflect the most recent environmental fate parameters and water treatment factors for carbaryl. Data from Bayer's surface water monitoring study and national monitoring by NAWQA were, however, used to characterize the modeled results.

For occupational exposures ( handlers and post application), the most major changes were modification of the transfer coefficients for tree fruit harvesters/ thinners and the addition of scenarios that address the USDA/ APHIS grasshopper control program. Outside of these issues, the overall risk picture for occupational exposures remains unchanged. It is clear that the reduction for tree fruit harvesters ( and all related activities except thinning) from 3000cm2/ hr to 1500 cm2/ hr is appropriate based on the data. The transfer coefficient value for tree fruit thinners remained at 3000 cm2/ hr, however, which is supported by results of a recent biological monitoring study of tree fruit thinners and harvesters completed by Bayer using carbaryl presented at the International Society of Exposure Analysis meeting in 2002. Exposure factors used to address grasshopper control scenarios were defined based on direct input from APHIS. 19 The risk picture for residential exposure scenarios is complex in that assessments for homeowner/ users and the general population have been completed using deterministic methods and also based on the results of a suburban resident biological monitoring study. The CARES probabilistic aggregate exposure assessment should also be considered in the overall risk picture. For pet uses, data from a study which quantified transferable residues from dogs wearing pet collars were used. This study is of marginal quality but the associated risks for collars are above the Agency's level of concern. However, the Agency would like a higher quality confirmatory study for this scenario because MOEs are just slightly above the level of concern. For other pet products, these data essentially confirm the Agency's concerns over their use ( e. g., dusts and liquids). In the other residential deterministic assessments, the risk picture remains essentially unchanged from previous assessments. The Agency has concerns over children's exposure on treated turf and for various homeowner use products, especially dusts.

The results of the suburban resident biological monitoring study indicate that there are risk concerns particularly for younger children and applicators which mirrors the results of the deterministic assessments. However, there are many interpretative issues related to the use of these data including how the monitored population relates to the overall population of carbaryl users and the general United States population ( i. e., these are key factors for tolerance review under FQPA and exposure pathway review under FIFRA). There are also issues related to how the risks were calculated because of the excretion profile of carbaryl and the unrestricted activities of those monitored in the study. It is clear that carbaryl users who treat turf in a manner that can lead to significant exposure ( e. g., broadcast) represent about 0.5 percent of the United States population and that when these turf applications are combined with ornamental or garden applications that an even smaller percentage of the population is represented. However, it should be pointed out that the Agency believes the predominant source of exposure is from the treated turf and it is expected that there would be little or no difference in the results of this study if turf alone was treated in each residence. It is also clear that for applicators and young children, if treatments occur, exposures will occur at levels that are of concern to the Agency for the higher percentiles of exposure based on this study. Bayer and the Agency essentially agree on this point. There are differences between Bayer and the Agency, however, based on central tendency exposure statistics in that Bayer's calculations do not indicate a risk concern while the Agency's do. The major difference is that Bayer's approach does not account for mass balance as defined in the excretion profile for carbaryl. The Agency approach, conversely, indicates risk concerns at the central tendency and it accounted for mass balance. Bayer argues, however, that how the population monitored in the biomonitoring study relates to the general population is key for framing any risk management decision. It is Bayer's position that central tendency exposures from the study represent very high percentile exposures in the general population. The Agency does not disagree. However, it should be pointed out that the approach for FIFRA risk analysis ( not tolerance evaluation under FQPA) has always been to consider users themselves based on calculations that represent the upper percentiles of exposure for users to ensure that they are adequately protected. As such, for user populations, it is recommended that risk management decisions be based on higher percentile exposures. If this is the case, Bayer concurs with the Agency that there are risk concerns related to the residential use of carbaryl. If central tendency estimates are used, it should be pointed out that the Agency does not concur with Bayer's approach for calculating dose estimates because of a lack of accounting for mass balance. Conversely, when mass balance is accounted for there are risk concerns even for central tendency exposure estimates. 20 The results and interpretation of the probabilistic assessment for carbaryl, especially when considered in context with the other types of assessments and data, are very consistent with the various assessments that have been completed. For example, the general population assessment agrees closely with the Agency's dietary assessment completed using DEEM/ FCID. This is logical because the percentage of residential users in the general population is relatively very small so it would be anticipated that residential use would not drive an assessment for the general population. In order to allow for a more informed risk management decision, the Agency also considered " users only" in an assessment and again, the results are very similar to what would be expected based on the suburban resident biological monitoring study and the Agency's deterministic approaches for calculating residential exposure. There are remaining key issues that the Agency will address in its more detailed review of Bayer's probabilistic assessment. These include: the Agency will carefully evaluate each input parameter; the Agency will carefully examine the methods and choices related to execution of the CARES model related to carbaryl; and the Agency will better define how the results of a true probabilistic aggregate assessment will be integrated into the risk assessment and risk management processes.

One final issue to consider is how the results for each residential risk assessment approach relate to one another and also how accurate the exposure calculations are for carbaryl. To do this, the Agency compared the deterministic residential exposure estimates to those calculated in the biomonitoring study and in the probabilistic analysis. Agency deterministic methods are intended to provide upper percentile ( i. e., protective) estimates of exposure which is exactly what appears to be the case because Agency deterministic predictions overlap very closely with the upper percentiles of exposure in the biomonitoring study and probabilistic analysis. The Agency also compared the biomonitoring results to several population based monitoring studies ( e. g., NHANES and NHEXAS) and found that the distributions are very similar at the central tendency and at the upper percentiles which also supports the accuracy and protective nature of the Agency's deterministic methods. Results also appear to be consistent with results of the probabilistic assessment.

Overall Risk Summary This risk assessment is based on the latest exposure data, toxicology information, and use data. The overall results indicate that the Agency has risk concerns for several marketplaces where carbaryl is used. Dietary risks are generally not of concern regardless of what data are considered ( i. e., FDA\ PDP or CMBS). Residential handler and postapplication risks are of concern across many areas. However, the manner of interpretation of the suburban resident biological monitoring study and the results of the companion probabilistic assessment are critical in evaluating residential uses. To allow for a more informed risk management decision, the Agency considered aggregate exposures for selected residential scenarios which were not already of concern when calculated using deterministic methods ( i. e., some at typical rates and selected public healthuses). Even though surface water concentrations are high, aggregate risks for the selected scenarios were not of concern in these deterministic assessments. The Agency also has presented risk estimates for residential users based on the suburban biological monitoring study which indicates a risk concern for applicators and small children even at the central tendency of exposure for those populations. The companion probabilistic assessment also needs to be considered. When exposures in the general population were evaluated, risks at the 99.9th % tile are not of concern but it should be pointed out that there is a very small percentage of the population that would potentially be affected through residential exposure. If residential users only are considered in a 21 probabilistic manner, the results very closely mirror that observed in the biological monitoring study where risks are of concern ( depending on interpretation of the data and the probabilistic assessment results) for small children at the central tendency of exposure. The upper bounds of the distribution for these children also closely mimics the Agency's deterministic methods which is consistent with the characterization of that approach. Occupational handler risks can be mitigated through the use of additional protective measures over and above the current label such as engineering controls ( e. g., closed cabs or loading systems). Current label REIs are 12 hours. For almost every crop/ activity combination considered except some low exposure activities, the current REI appears to be inadequate. 22 O O N H CH 3 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION The product chemistry chapter was prepared by Felicia Fort of the Health Effects Division ( November 14, 2000  DP Barcode 240989). All information below is excerpted from that chapter unless specifically noted. Section 2.1: Chemical Structure and Identification presents the nomenclature and structures associated with carbaryl and its metabolites. Section 2.2: Physical Properties of Carbaryl presents information about the properties of carbaryl.

2.1 Chemical Structure and Identification Chemical Name: 1 naphthyl methylcarbamate Empirical Formula: C12H11NO2 Molecular Weight: 201.2 CAS Registry No.: 63 25 2 Chemical ID No.: 056801 Structures of carbaryl and major metabolites are shown below in Figure 1.

Figure 1. Structures of Carbaryl and Major Metabolites Name Structure Carbaryl 1 Naphthyl N methylcarbamate 5,6 dihydro 5,6 dihydroxy carbaryl Figure 1. Structures of Carbaryl and Major Metabolites Name Structure 3 From the EPA Technology Transfer Network, Office of Air Quality Planning and Standards, Air Toxics Website ( www. epa. gov/ ttn/ atw)

23 OH 5 methoxy 6 hydroxy carbaryl 1 Naphthol 2.2 Physical Properties of Carbaryl Physical state: white to light tan solid Melting point: 1420C Solubility: water ( 40 ppm at 25 C), dimethyl formamide (# 45 g/ 100 mL); acetone, cyclohexanone, and isophorone (# 25 g/ 100 mL); methylethyl ketone (# 20 g/ 100 mL); dichloromethane (# 15 g/ 100 mL); ethanol and ethyl acetate (# 10 g/ 100 mL); mixed aromatic solvents and xylene (# 3 g/ 100 mL); and kerosene (# 1 g/ 100 mL). Vapor pressure: 0.000041 mm Hg at 260C3 Specific gravity: 1.23 at 200C Octanol/ water partition coefficient ( Kow): 217 24 3.0 HAZARD CHARACTERIZATION The hazard component of the risk assessment is presented in this section. Section 3.1: Hazard Profile presents a discussion of the available toxicity data for carbaryl. Section 3.2: FQPA Considerations discusses the susceptibility of sensitive populations such as children and the uncertainties associated with that analysis. Section 3.3: Dose Response Assessment describes which data were selected for risk assessment purposes. Section 3.4: Endocrine Disruption describes issues related to EDSTAC and the screening process for possible chemicals of concern.

3.1 Hazard Profile The updated Toxicology Chapter of the RED was prepared by Dr. Virginia Dobozy ( D282980). The toxicology data base is of good quality and is essentially complete. A 90 day inhalation study with cholinesterase measurements is required. The database provides sufficient information for selecting toxicity endpoints for risk assessment and therefore, supports a reregistration eligibility decision for the currently registered uses.

Carbaryl is a carbamate insecticide. Its primary mode of toxic action is through cholinesterase inhibition ( ChEI) after single or multiple exposures. In most of the toxicology studies in which ChEI was measured, it was the endpoint used to set the Lowest Observed Adverse Effect Level ( LOAEL).

The acute toxicity studies showed that carbaryl was relatively toxic with acute oral dosing ( Tox. Category II); but the acute dermal and inhalation toxicities were low ( Tox. Categories III and IV, respectively). Carbaryl was not a dermal or eye irritant and was not a dermal sensitizer in animal studies ( Table 1). However, human incidents of dermal irritation and dermal manifestations of an allergic response have been reported ( see section 7.4 below for more information).

Table 1: Acute Toxicity of Carbaryl Guideline No. Study Type MRIDs # Results Toxicity Category 81 1 Acute Oral  rat ( 99% a. i.) 00148500 LD50 for males = 302.6 mg/ kg; for females = 311.5 mg/ kg; combined = 307.0 mg/ kg II 81 2 Acute Dermal  rabbit ( 99% a. i.) 00148501 LD50 > 2000 mg/ kg III 81 3 Acute Inhalation  rat ( 99% a. i.) 00148502 LC50 > 3.4 mg/ L IV 81 4 Primary Eye Irritation  rabbit ( 99% a. i.) 00148503 not a primary eye irritant IV 81 5 Primary Skin Irritation  rabbit ( 99% a. i.) 00148504 not a primary skin irritant IV Table 1: Acute Toxicity of Carbaryl Guideline No. Study Type MRIDs # Results Toxicity Category 25 81 6 Dermal Sensitization  guinea pig ( 99% a. i.) 00148505 negative NA 81 7 Acute Delayed Neurotoxicity ( Hen) * negative at 2000 mg/ kg ( approximate LD50) NA 81 8 Acute Neurotoxicity  rat 43845201 43845204 systemic LOAEL = 10 mg/ kg for males and females based on significant inhibition of RBC, plasma, whole blood and brain cholinesterase; NOAEL < 10 mg/ kg a. i. = active ingredient * Carpenter, C. P., Weil, C. S., Palm, P. E., Woodside, N. W., Nair, J. H. and Smyth, H. F. Mammalian Toxicity of 1 napthyl Nmethyl carbamate ( Sevin Insecticide). J. Agric. Food Chem. 9( 1): 30 39, 1961.

The neurotoxicity data showed that carbaryl was not a delayed neurotoxicant in the hen. In the acute neurotoxicity study in the rat after a single dose of 10 mg/ kg carbaryl, ChEI was observed in plasma, whole blood, red blood cells ( RBC) and brain. At the next higher dose ( 50 mg/ kg), clinical signs typical of carbamate toxicity were observed. In the subchronic neurotoxicity study after 90 days of administration, clinical signs of toxicity were seen at the same dose ( 10 mg/ kg/ day) as plasma, whole blood, RBC and brain ChEI. There was no evidence of structural neuropathology in these studies.

No subchronic studies in the rat or dog are available, except for the subchronic neurotoxicity study in rats and 4 week dermal toxicity studies in rats ( one with technical chemical and two with formulations). One of the dermal toxicity studies was useful for risk assessment. In this study, the systemic NOAEL was 20 mg/ kg/ day based on decreased RBC ChEI in males and females and brain ChEI in males at 50 mg/ kg/ day. The chronic toxicity data showed that, in dogs, decreases in plasma, RBC and brain ChEI were observed at 10 mg/ kg/ day; clinical signs of toxicity were also observed in both sexes at 31 mg/ kg/ day. Brain and plasma ChEI were decreased in female dogs at 3.1 mg/ kg/ day. In the mouse, clinical signs of toxicity were not typical of ChEI, but there was ChEI ( plasma, RBC and brain) at 146 mg/ kg/ day. In the chronic toxicity study in rats, carbaryl at the highest dose ( 350 mg/ kg/ day in males and 485 mg/ kg/ day in females) caused a variety of toxic effects in the liver, kidneys and urinary bladder. It also induced an increase in the incidence of thyroid follicular cell hypertrophy and degeneration of sciatic nerves and skeletal muscle. RBC ChEI was decreased in males at 60 mg/ kg/ day and in females at 79 mg/ kg/ day. The lowest LOAEL in the chronic studies was in the chronic dog study, i. e., 3.1 mg/ kg/ day, which was the lowest dose in females. In a follow up 5 week study in dogs to clarify the NOAEL for ChEI, plasma ChEI was decreased in males at 3.83 mg/ kg/ day; no effects were observed at 1.43 mg/ kg/ day. 26 In a prenatal developmental toxicity study in the rat, maternal toxicity was observed at the same dose ( 10 mg/ kg/ day) as developmental toxicity; the NOAEL was 4 mg/ kg/ day. Developmental effects included decreased fetal body weight and increased incomplete ossification of multiple bones. In a prenatal developmental toxicity study in the rabbit, the maternal and developmental LOAELs were 50 mg/ kg/ day and 150 mg/ kg/ day, respectively. The respective NOAELs were 5 mg/ kg/ day and 50 mg/ kg/ day. The only evidence of developmental toxicity was a decrease in fetal body weight. These studies showed no evidence of a qualitative or quantitative increased susceptibility. In the reproduction study, there was evidence of a quantitative offspring susceptibility. The LOAEL for parental systemic toxicity was 1500 ppm ( 92.43 124.33 mg/ kg/ day for males and 110.78 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption. The NOAEL was 300 ppm ( 23.49 31.34 mg/ kg/ day for males and 26.91 36.32 mg/ kg/ day for females). The LOAEL for offspring toxicity was 300 ppm ( 23.49 31.34 mg/ kg/ day for males and 26.91 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival. The NOAEL was 75 ppm ( 4.67 5.79 mg/ kg/ day for males and 5.56 6.41 mg/ kg/ day for females). In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. Clinical signs of toxicity and plasma and brain ChEI were seen in maternal animals at the same dose ( 10 mg/ kg/ day) as changes in brain morphometric measurements ( decreases in cerebellar measurements in females on Day 11 post partum) were observed in offspring; however, brain measurements were not conducted at the next lower dose.

The Health Effects Division's ( HED) Cancer Assessment Review Committee ( CARC)( 11/ 7/ 01) classified carbaryl as Likely to be carcinogenic in humans based on an increased incidence of hemangiosarcomas in male mice at all doses tested ( 100, 1000 and 8000 ppm). The Q1*, based on the CD 1 mouse dietary study with ¾ Interspecies Scaling Factor, is 8.75 x 10 4 ( mg/ kg/ day) 1 in human equivalents. In addition to the required carcinogenicity studies in mice and rats, the registrant submitted a special study in genetically modified mice. Carbaryl was administered to heterozygous p53 deficient ( knockout) male mice in the diet at concentrations of up to 4000 ppm ( 716.6 mg/ kg/ day) for six months. There was no evidence of neoplastic or preneoplastic changes in the vascular tissues of any organ. A model validation study demonstrated that vascular tumors occur in heterozygous p53 deficient mice within six months of administration of a known genotoxic carcinogen ( urethane).

A recent review of the data from the submitted studies and the published literature show that carbaryl is clastogenic in vitro. The wide variety of induced aberrations ( both simple and complex) was consistent between the submitted micronucleus study and the open literature. However, there are inconsistencies relative to the requirement for S9 activation. Nevertheless, the two in vivo studies for micronuclei induction or chromosome aberrations were negative. Similarly, the 6 month p53 knockout transgenic mouse bioassay was negative. Carbaryl was also negative for DNA binding in the livers of mice treated with 8000 ppm for 2 weeks. Metabolism studies identified epoxide intermediates of carbaryl which were found to be conjugated to glucuronide, rapidly metabolized and excreted as any endogenous epoxide would be. Overall, these findings indicate that carbaryl produces epoxides and its DNA reactivity is manifested as chromosomal aberrations in cultured mammalian cells. Other in vitro 27 studies indicate carbaryl's effects on karyokinesis and cytokinesis, as well as stress genes associated with oxidative damage. Based on these considerations, the CARC concluded that there is a concern for mutagenicity, which is somewhat lessened because of the lack of an effect in in vivo mutagenicity studies.

The metabolism data in the rat indicated that radiolabeled carbaryl was readily absorbed with oral dosing, distributed to various organs, metabolized and formed conjugated metabolites with compounds such glucuronic acid. A total of 20 components was found, and 2 major metabolites were identified, naphthyl sulfate and naphthyl glucuronide. Much of the radioactivity was eliminated within 24 hours after dosing ( 86% in urine and 11% in feces). Seven days post dosing, negligible amounts of the administered dose were found in tissues. Several special metabolism studies were conducted to explore a mechanism for the increase in tumor incidence in mice. The results appear to show that high doses of carbaryl treatment ( 1154 mg/ kg) led to a " phenobarbital" type of induction of liver xenobioticmetabolizing enzymes and interaction of carbaryl with chromatin protein in mice. A dermal absorption study indicated that 12.7% of a carbaryl formulation ( 43.9% a. i.) was absorbed. [ Note: Bayer provided a synopsis of research related to the pharmacokinetics of carbaryl in humans which is described in more detail in Section 4.4.4: Risks Based On Carbaryl Suburban Resident Biomonitoring Study. This synopsis indicates 40 percent of carbaryl is eliminated in the urine, excretion of a single dose takes 96 hours for complete elimination, and 50 percent of each single dose is eliminated in the first 24 hours post administration.]

The toxicology profile for carbaryl is presented in Appendix 1.

3.2 FQPA Considerations The HIARC ( February 19, 2002 meeting) concluded that there is a concern for pre and/ or postnatal toxicity resulting from exposure to carbaryl.

3.2.1 Determination of Susceptibility There was no evidence of quantitative or qualitative susceptibility following in utero exposures in developmental studies in the rat and rabbit.

In the reproduction study, there was evidence of quantitative susceptibility of offsprings. The LOAEL for parental systemic toxicity was based on decreased body weight, weight gain, and feed consumption; the NOAEL was 27 mg/ kg/ day in males and 30 mg/ kg/ day in females. In the offspring the LOAEL was based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival; the NOAEL was 5 mg/ kg/ day in males and 6 mg/ kg/ day in females. No adverse effects were observed in the reproductive parameters.

In the developmental neurotoxicity study, there was evidence of qualitative susceptibility. For maternal toxicity, the LOAEL was based on decreased body weight gain, alterations in Functional 28 Observational Battery measurements and inhibition of plasma, whole blood and brain cholinesterase activity; the NOAEL was 1 mg/ kg/ day. For developmental neurotoxicity, the LOAEL was based on the morphometric changes seen in the brain of the offsprings; the NOAEL was 1 mg/ kg/ day.

3.2.2 Degree of Concern Analysis and Residual Uncertainties The HIARC concluded that there are no residual concerns related to the 2 generation reproduction study because the dose response for the offspring effects is well characterized and these effects occurred at a dose level which is above that used for establishing the Chronic Reference Dose ( cRfD) for chronic dietary risk assessment.

The HIARC established the Chronic RfD using the LOAEL of 3.1 mg/ kg/ day in the chronic toxicity study in dogs. Since a NOAEL was not established in this study, an additional uncertainty factor of 3X was applied to the LOAEL ( i. e, UFL). The HIARC determined that 3X is adequate to account for the lack of a NOAEL in this case because: 1) the study was well conducted and there are sufficient data from subchronic and other chronic studies in other species that support cholinesterase inhibition as the critical effect for Carbaryl; 2) the data indicate that the dog is more sensitive to the cholinergic effects of Carbaryl and using this species to establish the RfD provides additional protection for the effects seen in the rat ( including the reproduction and developmental neurotoxicity studies); 3) the magnitude of plasma cholinesterase inhibition ( 12 23% decrease) seen in this study was comparable to the magnitude of inhibition ( 22%) seen in the 5 week study in dogs  indicating no cumulative effect following long term exposure; 4) the cholinesterase inhibition seen in females at the LOAEL in this study was not accompanied by clinical signs ( response was not judged to be severe); and 5) no inhibition was seen for any cholinesterase compartment in males at this dose ( response was seen in only one sex).

The HIARC concluded that the extrapolated NOAEL of 1 mg/ kg/ day used to establish the Chronic RfD for Carbaryl is below the NOAEL for offspring toxicity ( 5 mg/ kg/ day) in the 2 generation reproduction study and is protective of chronic dietary exposures to infants and children.

The HIARC concluded that there was a low level of concern for the developmental effects seen in the developmental neurotoxicity study and no residual uncertainties with respect to this study based on the following evidence:

° Any concern for the lack of brain morphometric measurements in the offspring at the mid dose ( 1 mg/ kg/ day) was negated since even at the high dose of 10 mg/ kg/ day, the morphometric changes were minimal and therefore, it is unlikely that adverse effects would be seen at the middose level ( 1 mg/ kg/ day  10% of the LOAEL).

° Any concern for the lack of comparative data in adults and offspring for cholinesterase inhibition was negated since no FOB alterations were seen in pups. Other studies in the data base show that when cholinesterase inhibition was seen in adult animals, it usually was accompanied by FOB alterations. Additionally, the results of the National Institute for Environmental Health Sciences study ( discussed above) indicate that there is no difference in cholinesterase inhibition in pups and adults. The dose related decrease in cholinesterase activity in the brain and blood of dams at 29 gestation day 19 was very similar to the fetal brain cholinesterase levels taken at the same time.

The HIARC established the Acute RfD for Carbaryl using the NOAEL of 1 mg/ kg/ day in the developmental neurotoxicity study in rats which is protective of single dose exposures to infants and children.

3.3 Dose Response Assessment The HIARC evaluated the toxicology data base of carbaryl, reassessed the Reference Dose ( RfD) established in 1994 and selected the toxicological endpoints for acute dietary, as well as occupational and residential exposure risk assessments at a meeting on July 7, 1998. Re evaluations of the FQPA Safety Factor recommendation were done on April 28 and November 15, 1999, after the submission of prenatal developmental toxicity studies in the rat and rabbit, respectively. A re evaluation of the endpoints for risk assessment was conducted on March 1, 2001, February 19, 2002 and April 25, 2002. Table 2 contains a summary of the hazard doses and endpoints selected for use in the various human health risk assessments. Endpoints were selected for a broad spectrum of risk assessments, including acute and chronic dietary, short, intermediate and long term dermal and inhalation exposures and short and intermediate term incidental exposure. For the chronic dietary and the long term dermal and inhalation exposure endpoints, a LOAEL was selected, which necessitated an additional 3x uncertainty factor.

A common toxicological endpoint exists for the dermal, inhalation, and incidental oral routes. Therefore, the Margins of Exposure ( MOEs) can be combined for aggregate occupational and residential risk assessments.

Table 2. Summary of Toxicological Dose and Endpoints for Carbaryl for Use in Human Risk Assessment Exposure Scenario Dose ( mg/ kg/ day) & Total UF Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment Dietary, Nondietary Ingestion & Biomonitoring based Risk Assessments Acute Dietary general population including infants and children NOAEL = 1 UF = 100 1 Developmental Neurotoxicity  rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes on the first day of dosing in maternal animals Acute RfD and aPAD = 0.01 mg/ kg/ day Chronic Dietary all populations LOAEL= 3.1 UF = 300 1 Chronic toxicity  dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females.

Chronic RfD and cPAD = 0.01 mg/ kg/ day [ Note: A NOAEL could not be defined in this study. Therefore, an additional factor of 3 has been applied to account for the data deficiency.] Table 2. Summary of Toxicological Dose and Endpoints for Carbaryl for Use in Human Risk Assessment Exposure Scenario Dose ( mg/ kg/ day) & Total UF Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 30 Short term Incidental Oral & Biological Monitoring ( 1  30 Days) [ Residential Only] NOAEL= 1 Res. UF = 100 1 Developmental Neurotoxicity  rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes and decreases in RBC, whole blood, plasma and brain cholinesterase Intermediate Term Incidental Oral ( 1  several months) [ Residential Only] NOAEL= 1 Res. UF = 100 1 Subchronic Neurotoxicity  rat LOAEL = 10 mg/ kg/ day based on increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase.

Non Dietary Dermal & Inhalation Risk Assessments Short Term Dermal ( 1  30 days) NOAEL= 20 Res. UF = 100 Occ. UF = 100 1 4 week dermal toxicity with technical  rat systemic LOAEL = 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males.

Intermediate term Dermal ( 30 days  several months) NOAEL= 20 Res. UF = 100 Occ. UF = 100 1 4 week dermal toxicity with technical  rat systemic LOAEL = 50 mg/ kg/ day based on statistically significant decreases in RBC cholinesterase in males and females and brain cholinesterase in males.

Long Term Dermal ( Several months to a lifetime) LOAEL= 3.1 Res. UF = 300 Occ. UF = 300 1 Chronic toxicity  dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females.

[ Note: A NOAEL could not be defined in this study. Therefore, an additional factor of 3 has been applied to account for the data deficiency. Also, this study is not route specific as it was conducted via oral administration. Route to route extrapolation is required using an adsorption factor of 12.7 percent which is based on a rat dermal absorption study.]

Short Term Inhalation ( 1  30 days) NOAEL= 1 Res. UF = 100 Occ. UF = 100 1 Developmental Neurotoxicity  rat LOAEL = 10 mg/ kg/ day based on an increased incidence of FOB changes and statistically significant decreases in RBC, whole blood, plasma and brain cholinesterase [ Note: This study is not route specific as it was conducted via oral administration. Route to route extrapolation is required using an adsorption factor of 100 percent.]

Intermediate Term Inhalation ( 30 days  several months) NOAEL= 1 Res. UF = 100 Occ. UF = 100 1 Subchronic Neurotoxicity  rat LOAEL = 10 mg/ kg/ day based on increased incidence of FOB changes; decrease in RBC, whole blood, plasma and brain cholinesterase.

[ Note: This study is not route specific as it was conducted via oral administration. Route to route extrapolation is required using an adsorption factor of 100 percent.] Table 2. Summary of Toxicological Dose and Endpoints for Carbaryl for Use in Human Risk Assessment Exposure Scenario Dose ( mg/ kg/ day) & Total UF Hazard Based Special FQPA Safety Factor Endpoint for Risk Assessment 31 Long Term Inhalation ( Several months to a lifetime)

[ Occupational only] LOAEL= 3.1 Occ. UF = 300 1 Chronic toxicity  dog LOAEL = 3.1 mg/ kg/ day based on plasma and brain cholinesterase inhibition in females.

[ Note: A NOAEL could not be defined in this study. Therefore, an additional factor of 3 has been applied to account for the data deficiency. Also, this study is not route specific as it was conducted via oral administration. Route to route extrapolation is required using an adsorption factor of 100 percent.]

Cancer Classification: C Q1* = 8.75 x 10 4 ( mg/ kg/ day) 1 3.4 Endocrine Disruption EPA is required under the Federal Food Drug and Cosmetic Act, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there were scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

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

4.0 NON OCCUPATIONAL RISK ASSESSMENT AND CHARACTERIZATION This section of the risk assessment addresses exposures to individuals in the general population that are not exposed as part of their employment. These exposures can occur through the diet and/ or they can occur because people have contact with carbaryl residues while using consumer products containing carbaryl or by being in areas that have been previously treated. Section 4.1: Summary of Registered Uses below summarizes available products and also describes the uses of those products. Products intended for commercial sales ( e. g., in agriculture) and consumer products are included as each type of product can contribute to non occupational exposures through the diet, via residential use, or through commercial use in areas frequented by the general population such as golf courses. Section 4.2: Dietary Risk Assessment describes the residue and consumption data used in the dietary risk assessment, the risks associated with various populations of interest through the diet, and characterization of those 32 risks. Section 4.3: Water Risk Assessment describes how water concentrations were determined, calculation of risks, and characterization of those risks. Section 4.4: Residential Risk Assessment describes how risks were calculated for people who use consumer products containing carbaryl and for those who are exposed as a result of being in areas that have been previously treated. Results based on the Agency's standard deterministic approaches and the suburban resident biological monitoring study are included in this section.

4.1 Summary of Registered Uses All products ( e. g., manufacturing and various end use formulations) and the associated use patterns for carbaryl are described below. A brief overview of the types of equipment and application rates is also provided. The information in this section summarizes all use patterns of carbaryl as both commercial products and products intended for sale to homeowners can contribute to exposures in the general population. The need to have a thorough understanding of the use patterns for consumer products is self explanatory. Understanding the use of commercial products is key for the development of the dietary and drinking water assessments. It is also critical for evaluating some residential postapplication exposures in public places ( e. g., for golfers).

Carbaryl ( 1 naphthyl N methyl carbamate) is a broad spectrum carbamate insecticide marketed in a variety of end use products for both occupational and homeowner use. End use product names include Adios, Bugmaster, Carbamec, Carbamine, Crunch, Denapon, Dicarbam, Hexavin, Karbaspray, Nac, Rayvon, Septene, Sevin, Tercyl, Tornado, Thinsec, and Tricarnam. Use sites include but are not limited to the following: fruit and nut trees; vegetable crops; field and forage crops; grapes; forestry; lawns and other turf such as golf courses; ornamental trees, shrubbery, annuals, and perennials; wide area treatment targets such as residential mosquito adulticide uses and oyster beds; and companion animals ( e. g., dogs and cats). Table 3 summarizes all ( homeowner and occupational products) currently available technical and manufacturing products along with their corresponding EPA registration numbers.

Table 3: Technical and Manufacturing Carbaryl Products Formulation EPA Reg. No. (% active ingredient)

Technical 34704 707 ( 99%); 45735 24 ( 99%); 264 324 ( 99%), 325 ( 97.5%); 19713 75 ( 99%)

Manufacturing Product 264 328 ( 80%); 264 325 ( 97.5%) 769 971 ( 80%); 5481 190 ( 46%) 19713 369 ( 50 %); 432 982 ( 97.5%); 73049 238 ( 1%)

Based on a review ( 2/ 27/ 01) of the Office of Pesticide Programs   Reference Files System ( REFS), there are over 300 active product labels ( i. e., includes both homeowner and occupational products). Carbaryl formulations include dusts, emulsifiable concentrates, soluble concentrates, water dispersable granulars, flowable concentrates, wettable powders, granulars, baits, pet dips and pet shampoos, aerosol sprays, ready to use pump sprayers, and pet collars ( i. e., treated articles). Table 4 33 summarizes the approximate number of Section 3 registered products in each formulation category and the range of percent active ingredient. A complete listing of all the registration numbers under each category can be found in the Occupational/ Residential Exposure Assessment chapter ( D287251). This chapter also includes in the Appendices, the Qualitative Usage Analysis For Carbaryl and the RED Use Profile Report prepared by the Agency's Biological and Economic Analysis Division which were recently updated ( i. e., 2002). The major changes from the previous QUA are related to the percent crop treated values are reflected in this assessment. In most cases they generally went down. Many of the products described can be used in a variety of settings ranging from agriculture and commercial facilities to residential areas.

Table 4: Carbaryl End Use Product Formulations Formulation Type Number of Products Range of Percent Active Ingredient Emulsifiable Concentrates & Flowable Concentrates 57 0.3  80 Wettable Powders & Soluble Granules 36 0.5  95 Dusts 130 0.3  80 Granular 45 1.43  15 Bait 55 1.3  13 Dips, Shampoos 2 0.5  60 Pet collars ( treated articles) 2 8.5  16 Ready to Use Pump Sprayers & Aerosol Cans 6 0.12  1 Equipment used to apply carbaryl in residential settings includes dust shaker cans, garden hoseend sprayers, trigger sprayers, low pressure handwands, belly grinders, push type spreaders, aerosol cans, and pet collars. In an occupational setting, carbaryl can be applied by airblast, aerial application, chemigation, groundboom, power duster, low and high pressure handwand, backpack, compressed air sprayer, fogger, hand held duster, hose end sprayer, duster cans, and aerosol cans. Depending on the crop, the maximum number of carbaryl applications per season can range from 1 to 8. A variety of application rates are available on the carbaryl labels, ranging from 1 lb ai/ acre for curcurbits to 16 lb ai/ acre for a foliar treatment of citrus in California. Some products are marketed in a single marketplace while others are sold for use in multiple settings. Based on sales information provided by Bayer CropScience at the SMART meeting with EPA on September 24, 1998, it appears that approximately 34 34 percent of carbaryl use is by homeowners in residential settings, 59 percent is used in agriculture, and the remaining 7 percent is used in the nursery, landscape and golf course industries. It should be noted also that Bayer's Sevin User Survey and results from the Residential Exposure Joint Venture were used to develop the residential aspects of this assessment.

The application parameters for major crop groups or application targets were defined by the physical nature of the use site, the physical nature of the formulation, the equipment needed for application and the application rate. The timing of use and related pest complexes were also considered in the development and characterization of the risk estimates. [ Note: OPP/ BEAD is also developing a substitutes analysis which will be used to characterize how changes in market share might affect the results of this assessment  this will be considered during the risk management phase of the Agency's process.] Selected crop groupings and application targets along with corresponding typical ( if available) and maximum application rates that are used in the risk assessment are presented in Table 5 below.

Table5: Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft2 ( units may vary) lb ai/ A/ acre ( units may vary) max. apps/ season lb ai/ season Average Rates Alfalfa, clover, trefoil 1.5 1/ cutting 1.5/ cutting 1.1  Asparagus 2 4  postharvest 3  broadcast 2  postharvest 6  broadcast 10  postharvest 0.9 0.023  0.094 Beans ( fresh & dried), cowpeas, peas 1.5 4 6 0.9 0.012 0.047 Beets, carrot, horseradish, radish, parsnip 2  foliar 2.2  soil broadcast 6  foliar 4  soil 6 0.8 0.012 0.047 Blueberries 2  foliar 0.5 lb/ 1000 ft2  soil 5 10 1.7 0.012 0.047 Cole Crops ( broccoli, brussel sprouts, cabbage, cauliflower, chinese cabbage, collards, kale, kohlrabi, mustard greens) 2  foliar 2.2  soil broadcast 4 6 0.8 0.012 0.047 Caneberries 2  foliar 2.2  soil broadcast 5 4 10 Not specified 1.7 0.012 0.047 Celery, Dandelion 2  foliar 2.2  soil broadcast 4 6 1.0 0.012 0.047 Citrus 16 ( foliar in CA only) 10 ( foliar in FL only) 7.5  foliar 1 lb/ 100 gal. 1 Not specified 8 Not specified 20 Not specified 20 Not specified 2.7 to 3.4 ( lemons & oranges) 0.023 0.176 Corn ( field and pop) 2 4 8 1.0 0.012 0.047 Corn ( sweet) 2  foliar 2.2  soil broadcast 8 4 16 Not specified 1.3 0.012 0.047 Cranberry 2 5 10 2.0 0.012 0.047 Cucurbits ( cucumber, melon, pumpkin, squash) 1 6 6 1.1 0.012 0.047 Fruiting Vegetable ( tomato, eggplant, pepper) 2 7 8 1.0 0.012 0.047 Table5: Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft2 ( units may vary) lb ai/ A/ acre ( units may vary) max. apps/ season lb ai/ season Average Rates 35 Grapes 2 5 10 1.4 0.012 0.047 Grasses Grown For Seed 1.5 2 3 0.8 ( based on hay)

Leafy Vegetable ( head and leaf lettuce, endive, mustard green) 2  foliar 2.2  soil broadcast 5 4 6 Not specified 1.1 0.012 0.047 Nuts ( almond, chestnut, pecan, pistachio, walnut, etc.), foliar or dormant/ delayed 5 4 15 2.5 ( pecans) 0.047 0.12 Nuts ( almond, chestnut, pecan, walnut), foliar in CA 1 lb ai/ 100 gal Not specified Not specified Not specified 0.047 0.12 Ornamental 2.2 or 2% solution   1.5 0.023 Oyster beds ( SLN only) 10 Not specified Not specified   Peanut 2 5 8 0.8 0.012 0.047 Pome fruit 3 8 15 1.2 ( based on apples) 0.012 0.07 Potatoes & Tubers ( turnips) 2 6 6 0.8  Rangeland/ pastures 1 1 1 0.9  Rice 1.5 2 4 1.1  Right of Way 1.5 3 0.4  Sorghum 2 4 6 1.1  Stone fruit ( apricot, cherry, nectarine, peach, plum/ prune), foliar or dormant/ delayed 3 4  CA only 3 foliar & 1 dormant/ delayed 14 1.1 0.047 0.12 Stone fruit ( apricot, cherry, nectarine, peach, plum/ prune), foliar 1 lb ai/ 100 gal Not specified Not specified Not specified 0.047 0.12 Strawberries 2 5 10 1.4 0.012 0.047 Sugar beets 1.5 to 2 2 to 4 4 1.3 0.012 0.047 Sweet Potatoes 2 foliar 8 lb/ 100 gal drip 8 foliar Not specified 8 foliar 1.2 1.6 foliar Not specified 0.012 0.047 Sunflower 1.5 2 3 0.7 0.012 0.047 Tobacco 2 4 8 1.1  Tree farm 1  2 0.7  Turf/ golf 8 liquids 9 granulars  0.8/ 1000sf 2 to 4 0.047 to 0.25 ( lawns) [ maximum levels for different products] Wheat, flax 1.5 2 3 0.8  Ants 2% sol    2% sol Mosquito Control 2

Outdoor Banding 2% sol    2% sol Table5: Application Rates Considered in Risk Assessment Crop or Target Occupational Products Residential Products lb ai/ 1000 ft2 ( units may vary) lb ai/ A/ acre ( units may vary) max. apps/ season lb ai/ season Average Rates 4 At the present time, information from the industry sponsored Carbamate Market Basket Survey has been approved for use in dietary risk assessments with appropriate characterization of uncertainties associated with the conduct of the study. The primary concern was rubbing sampled commodities during the rinsing process except for broccoli and tomato because this created a potential for residue loss from the mechanical action associated with rubbing. A separate assessment was also completed using other sources of high quality residue data ( e. g., PDP) for comparative purposes to more completely inform the risk management process.

36 Domestic Animals ( e. g., cats/ dogs) Dust 0.2 lb ai/ dog Sha. 0.01 lb ai/ dog    Dust 0.2 lb ai/ dog Sha. 0.01 lb ai/ dog Domestic Animals ( e. g., cats/ dogs) 1.3 oz/ dog collar    1.3 oz/ dog collar Note: In many cases an application rate per area ( e. g., 1000 ft2) is provided but a 1 to 2 % ai w/ v solution can be used to make similar applications where volume outputs are difficult to regulate ( i. e., handheld equipment where area treated is difficult to define).

4.2 Dietary Risk Assessment The Product and Residue Chemistry Chapters ( D283328; May 30, 2002) and the Dietary Exposure Analysis ( D288479; March 11, 2003) were prepared by Felecia Fort. Potential exposure to residues of carbaryl in the diet occurs through food and water. Carbaryl is used late in the season at maximum seasonal rates of 6 12 lb ai/ acre. [ Note: There is also a section 3 registration that allows use on citrus up to 16 lb ai/ acre only in the state of California.] Post harvest intervals ( PHIs) range from 1 29 days but most are one week or less. The qualitative nature of carbaryl residues in plants and animals is adequately understood. The carbaryl residue to be regulated in plants is carbaryl per se. The residues of concern in meat and milk are the free and conjugated forms of carbaryl, 5,6 dihydro 5,6 dihydroxy carbaryl, and 5 methoxy 6 hydroxy carbaryl. Adequate Pesticide Data Program ( PDP) and Food and Drug Administration ( FDA) monitoring residue data are available for the vast majority (> 80%) of commodities. Detectable residues were found in 31 of 42 crops. In field trials, residues were less than the Limit of Quantitation ( LOQ) in 5 crops but were quantifiable in all other raw agricultural commodities ( RACs).

The dietary exposure assessment is a Tier 3/ 4 assessment, which is the most highly refined assessment that can be conducted at this time. HED has provided anticipated residues ( ARs) for carbaryl based on USDA PDP and FDA monitoring data, along with field trial data, for many commodities. In addition, separate acute assessments were conducted incorporating the results of the Carbamate Market Basket Survey ( CMBS) 4. 37 Section 4.2.1: Residue Profile provides information on the residue data used to complete the dietary risk assessments. Section 4.2.2: Acute Dietary Risk Assessment presents the acute assessment with and without the CMBS data. Section 4.2.3: Chronic Dietary Risk Assessment presents the results for this duration of exposure. Section 4.2.4: Cancer Dietary Risk Assessment presents cancer risks. Section 4.2.5 Characterization/ Uncertainties of the Risk Estimates provides information that should be considered along with the numerical results of this assessment.

4.2.1 Residue Profile Tolerances for residues of carbaryl are currently expressed in terms of carbaryl ( 1 naphthyl Nmethylcarbamate including its hydrolysis product 1 naphthol, calculated as carbaryl, for most raw crop commodities ( RACs) [ 40 CFR § 180.169( a)]. The established tolerances for residues in/ on pineapples, pome fruits, avocados, and fresh dill are expressed in terms of carbaryl per se [ 40 CFR § 180.169( d) and ( e)]. Tolerances for residues in livestock commodities are expressed as carbaryl, including its metabolites 1 naphthol ( naphthyl sulfate), 5,6 dihydrodihydroxy carbaryl, and 5,6 dihydrodihydroxy naphthol, calculated as carbaryl [ 40 CFR § 180.169( b) and ( c)]. A tolerance for residues in pineapple bran is expressed in terms of carbaryl per se [ 40 CFR § 186.550]. The HED Metabolism Committee concluded that the carbaryl residue to be regulated in plants is carbaryl per se ( DP Barcode D221979, S. Hummel, 2/ 8/ 96). The Committee also concluded that carbaryl, 5,6 dihydro 5,6 dihydroxy carbaryl, 5 methoxy 6 hydroxy carbaryl and all residues which can be hydrolyzed to carbaryl, 5,6 dihydro 5,6 dihydroxy carbaryl and 5 methoxy 6 hydroxy carbaryl under acidic conditions should be included in the tolerance expression and risk assessment for all endpoints of dietary concern only for livestock commodities ( C. Olinger, D255855, 6/ 21/ 99). An interim tolerance of 0.5 ppm has been established for carbaryl and its 1 naphthol metabolite in eggs [ 40 CFR § 180.319]. Tolerances of 2 ppm and 10 ppm have been established for residues of carbaryl in pineapples and bananas, respectively. The registrant intends to support the tolerances for residues of carbaryl in/ on these commodities as import tolerances.

Currently, the Codex MRLs and U. S. tolerances are not compatible because the U. S. tolerance expression includes metabolites. Once the U. S. tolerance definition is amended, it will be compatible with the definition for Codex MRLs. The Metabolism Committee has also recommended that the tolerance expression for livestock commodities include the free and conjugated forms of carbaryl; 5,6 dihydro 5,6 dihydroxy carbaryl; and 5 methoxy 6 hydroxy carbaryl. The Codex MRLs and U. S. tolerances cannot be made compatible for livestock commodities with respect to the tolerance definition.

The reregistration requirements for plant and livestock metabolism are fulfilled. Acceptable metabolism studies depicting the qualitative nature of residues in lettuce, radish, soybeans, ruminants and poultry have been submitted and evaluated. For the purpose of reregistration, adequate magnitude of the residue data are available on the following crops: alfalfa, almond, asparagus, beans ( dried and succulent), blueberry, broccoli, cabbage, celery, cherry, citrus fruits, clover, corn ( sweet and field), cucurbits ( cantaloupes, cucumbers and squash), cranberry, flax, grape, head and leaf lettuce, mustard greens, okra, peanut, peas ( dried and succulent), pecan, pepper, pistachio, pome fruits, potato, prickly pear cactus, raspberry, rice, sorghum, soybean, spinach, stone fruits, strawberry, sunflower, sweet potato, tobacco, tomato, walnut. Geographical representation is adequate and a sufficient number of trials reflecting representative formulation classes were conducted. Carbaryl residues were < LOQ in/ on 38 sweet potato, sugar beets, corn grain, flax seed, and peanuts. Quantifiable residues were detected in all other RACs. For a given crop, residue levels were quite variable overall, probably owing to climactic variations, but were generally consistent within any specific field trial location. There are data gaps which are listed in Section 8.0: Data Needs/ Label Requirements.

Adequate PDP monitoring data are available for the following commodities: potatoes, carrots, sweet potato, celery, spinach, lettuce ( head), broccoli, succulent peas ( processed) , succulent beans, soybean, tomatoes, cantaloupe, winter squash, orange, orange juice, apple, apple juice, pear, peach, wheat, sweet corn, strawberry, banana, grape, grape juice, pineapple, rice, cherry, cucumber, and milk. FDA monitoring data were used for the commodities, lettuce ( leaf), cabbage, watermelon, raspberry, blueberry, asparagus, and cranberry. Monitoring data were translated to similar crops when possible, generally according to the HED SOP 99.3 " Translation of Monitoring Data". Monitoring data from the years 1994 through 2001 ( PDP) and the years 1992 through 1998 ( FDA) were considered. Field trial data were used for the commodities, almonds, pecans, walnuts, field corn grain, flax seed, okra, olive, peanuts, pistachio, sugar beets, and sunflower. For oysters and dill, tolerances of 2 ppm and 0.2 ppm, respectively was used in the assessment.

HED conducts dietary risk assessments using using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM FCID   , Version 1.3), which incorporates consumption data from USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1994 1996 and 1998. The 1994 96, 98 data are based on the reported consumption of more than 20,000 individuals over two non consecutive survey days. Foods " as consumed" ( e. g., apple pie) are linked to EPAdefined food commodities ( e. g. apples, peeled fruit  cooked; fresh or N/ S; baked; or wheat flour  cooked; fresh or N/ S, baked) using publicly available recipe translation files developed jointly by USDA/ ARS and EPA. For acute dietary risk assessments, the entire distribution of consumption events for individuals is multiplied by a randomly selected distribution of residues ( probabilistic analysis, referred to as " Monte Carlo" ) to obtain a distribution of exposures in mg/ kg/ day. For chronic dietary risk assessments, the 2 day average for each subpopulation is combined with average residues in commodities to determine average exposures ( mg/ kg/ day).

Anticipated residue estimates were prepared using USDA Pesticide Data Program ( PDP) data, if available. Alternatively, FDA surveillance monitoring data from the years 1992 98 were used if sufficient samples were available. Data from crop field trials were used if there were insufficient PDP or FDA monitoring data. In addition, a separate acute assessment was conducted incorporating the results of the Carbamate Market Basket Survey ( CMBS) as described above ( i. e., rubbing fruit may reduce residues, use of other high quality data leads to a more informed risk management decision). HED used CMBS data for citrus fruit and banana in all acute assessments since these commodities are peeled before consumption.

The Biological and Economic Analysis Division ( BEAD) provided information ( F. Hernandez, 12/ 17/ 02) on the percent crop treated (% CT). For the chronic analysis, the weighted average % CT was incorporated; for the acute analysis, the estimated maximum % CT was used when appropriate. In acute analyses ( except blended commodities) the adjustment for % CT is incorporated in the residue distribution files ( RDFs) via addition of zero residue values corresponding to the % of crop not treated. 39 For blended/ not furthered processed commodities where monitoring data are available, the entire distribution of monitoring data with no further adjustment for % CT were used. For blended/ processed commodities where monitoring data are available and for all blended commodities where field trial data were used, % CT is incorporated into a point estimate. For the chronic analyses, the % CT is listed as Adjustment Factor 2 in the DEEM analysis. One half the weighted average of the limits of detection was used in the dietary assessment for all treated non detectable residues. Detectable residues from composite monitoring data for non blended food forms were used to generate residue values in single units using the methods described in the H. Allender paper dated 5/ 26/ 99 " Statistical methods for Use of Composite Data in Acute Dietary Risk Assessment." The " decomposited" residues were then included in residue distribution files ( RDF) for the probabilistic analysis. BEAD supplied percent crop treated data were incorporated into the anticipated residue or residue distribution file when appropriate. [ Note: Single serving apple and peach PDP data were used for non blended peach and apple food forms, respectively, instead of data that had been previously decomposited ( Allender method).]

A separate dietary assessment was conducted utilizing the CMBS results. The CMBS Task Force conducted a year long, national survey of carbamate residues on selected food commodities purchased at grocery stores. Residue data from a market basket survey are considered close approximations to residues potentially found at most ` dinner plates.' These data are generally considered the most appropriate survey type for use in pesticide risk and exposure assessment. The CMBS collected up to 400 single serve samples of 8 different crops ( apple, banana, broccoli, grape, lettuce, orange, peach and tomato). These data were used in the acute dietary analysis directly via RDFs incorporating % CT for all food forms which are considered to be partially or not blended. For blended commodities, the entire distribution of data with no further adjustment for % CT was used. If CMBS data were not available, then PDP or FDA monitoring or field trial data were used. CMBS data were translated to similar commodities when feasible; however, if PDP monitoring data were available for the processed commodity, then CMBS data were not translated ( i. e., PDP orange juice data were used instead of CMBS data for oranges). The dietary risk assessments were completed with and without the results of the CMBS ( except for banana and citrus CMBS data) for comparative purposes, again as described above ( i. e., rubbing fruit may reduce residues, use of other high quality data leads to a more informed risk management decision).

Most of the carbaryl processing factors were obtained from processing studies submitted by the registrant. The rice processing factors were from a review by Thurston Morton ( D216242, 9/ 17/ 98).

4.2.2 Acute Dietary Risk Assessment The following equations were used to calculate dietary exposure and non cancer risk for carbaryl.

Dietary exposure ( mg/ kg/ day) = consumption x residue Dietary risk (% PAD) = dietary exposure ( mg/ kg/ day) x 100 population adjusted dose ( mg/ kg/ day) 40 The population adjusted dose ( PAD) is the adjusted RfD reflecting the retention or removal of the FQPA safety factor. For carbaryl, the FQPA safety factor has been reduced to 1x. The resulting acute PAD ( aPAD) and chronic PAD ( cPAD) are both 0.01 mg/ kg/ day. The doses and endpoints selected by the HIARC for these risk assessments are discussed in more detail in Section 3.3: Dose Response Assessment above.

For this Tier 3/ 4 Assessment, estimated acute dietary exposure at the 99.9th percentile of exposure are below HED's level of concern without incorporating the CMBS results ( except for banana and citrus) for all population subgroups based on 1994 to 1998 CFSII data ( Table 6). The highest exposed subpopulation incorporating all commodities using PDP and FDA monitoring data without CMBS data ( except banana and citrus) was children( 1 2 years old) at 94 percent of the aPAD. Prior to the calculation of these risk estimates, residues in poultry were the key contributors to the risks for various populations. Since then, Bayer has indicated that poultry uses will be deleted ( i. e., poultry uses were not considered in this assessment). As such, it appears that consumption of strawberries is the critical contributor to acute dietary risks. A sensitivity analysis was conducted by eliminating strawberries and by eliminating crops where no detectable residues were found ( Table 7). This analysis showed that risk estimates were not significantly affected by assuming zero in place of ½ LOD on samples reported as not detectable. Eliminating strawberries reduced exposures of children ( 1 2 years) to 71 percent of the aPAD.

Table 6. Results of Acute Dietary Exposure Analysis ( Market Basket Survey Data Not Included except for citrus and bananas)

Population Subgroup** aPAD ( mg/ kg/ day) 95th Percentile 99th Percentile 99.9th Percentile Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % aPAD General U. S. Population 0.01 0.000474 5 0.001303 13 0.004294 43 All Infants (< 1 year old) 0.01 0.000761 8 0.002772 28 0.006747 67 Children 1 2 years old 0.01 0.001886 19 0.003526 35 0.009390 94 Children 3 5 years old 0.01 0.001230 12 0.002433 24 0.008084 81 Children 6 12 years old 0.01 0.000748 7 0.001474 15 0.005434 54 Youth 13 19 years old 0.01 0.000367 4 0.000826 8 0.003248 32 Adults 20 49 years old 0.01 0.000299 3 0.000752 8 0.002925 29 Females 13 49 years old 0.01 0.000284 3 0.000751 8 0.003227 32 Adults 50+ years old 0.01 0.000287 3 0.000786 8 0.002971 30 ** The values for the highest exposed population are bolded. 41 Table 7. Results of the Carbaryl Sensitivity Analyses.

Acute  All Commodities at the 99.9th percentile of exposure ( Market Basket Survey Data Not Included)