Page 1 of 42 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: June 6, 2006 MEMORANDUM SUBJECT: Revised Occupational Exposure and Risk Assessment for Azinphos Methyl ( Reflecting Recommendations from the Human Studies Review Board ( HSRB) Meeting held April 3 6, 2006)

FROM: Steven Weiss, Industrial Hygienist Seyed Tadayon, Chemist John Doherty, Toxicologist Reregistration Branch 3 Health Effects Division ( 7509P)

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

TO: Diane Isbell, Chemical Review Manager Special Review and Reregistration Division ( 7508W)

DP Barcode : 367772 PC Codes: 058001 In this document, which is for use in EPA's development of the azinphos methyl ( AZM, O, O Dimethyl S[( 4 oxo 1,2,3 benzotriazin 3( 4H) yl) methyl] phosphorodithioate) Re evaluation Decision, the Health Effects Division ( HED) presents the results of its revision of the human health risk assessment for the effects of occupational exposures to AZM. This document updates and supersedes the HED's 2001 handler and post application assessment ( DP Barcodes: D276108 and D276109).

Assumptions and resulting risk estimates for dietary exposures to AZM have not changed from those presented in the 2/ 18/ 99 human health risk assessment ( D252505) and reflected in the Interim Reregistration Eligibility Decision ( IRED) dated 10/ 30/ 2001. There are no residential uses of AZM Page 2 of 42 Executive Summary Changes Affecting AZM This assessment provides the updated occupational exposure and risk estimates for AZM. It includes risk estimates for handlers and post application workers. There have been several changes since the 2001 assessments affecting this revision:   use pattern changes,   product formulation changes,   exposure and toxicity data submitted, and   a Human Studies Review Board ( HSRB) meeting regarding the use of human toxicity study data in this risk assessment.

The following is a brief synopsis of these changes.

Use Pattern Changes:

Crops registered for AZM use were divided into three groups. Group 1 uses were cancelled after the IRED was issued ( 10/ 30/ 2001) and were removed from product labels. Group 1 uses included: beans ( succulent and snap), birdsfoot trefoil, broccoli, cabbage ( including Chinese), cauliflower, citrus, celery clover, cucumbers, eggplant, filberts, grapes, melons ( honeydew, muskmelon/ cantaloupe, watermelons, other melons) onions, green, onions, dry bulb, pecans, peppers, plums and dried plums, quince, spinach, strawberries, and tomatoes.

Group 2 uses are being phased out as of 9/ 30/ 2006. Group 2 uses include: cotton, cranberries, nectarines, peaches, potatoes, southern pine seed orchards, and caneberries ( blackberries, boysenberries, loganberries, raspberries application to cane and soil only).

Group 3 uses are the subject of this occupational risk assessment and include: almonds, apples and crab apples, blueberries ( low bush and high bush), Brussels sprouts ( application to soil at transplant only), cherries ( sweet and tart), nursery stock, parsley, pears, pistachios, and walnuts. This assessment is based on the AZM applications for the Group 3 crops/ use sites only.

Formulation Changes:

AZM is an organophosphate insecticide that is formulated as manufacturing product ( 88.1 percent active ingredient), and several wettable powder products ( 35 to 50 percent active ingredient). All wettable powder formulations are contained in watersoluble packaging. Registrations for all the liquid formulation products have been voluntarily cancelled by the registrant.

New Data:

New dislodgeable foliar residue ( DFR) data for blueberries, apples, sweet cherries, and ornamentals were also submitted. These studies were required as part of a Page 3 of 42 Data Call In ( DCI) for AZM. Data from the new exposure studies along with data already reviewed by the Agency were included in this assessment.

Since the last version of this occupational risk assessment, the primary registrant for AZM has submitted additional exposure studies for handlers and post application activities. The new studies include one study assessing handler exposures and three studies assessing post application exposures based on biomonitoring. The handler study was designed to quantify worker exposure to AZM during mixing/ loading/ application of GUTHION ® 50 WP to orchard crops ( i. e., apples at 29 sites and apples plus stone fruit at 1 site) by open and closed cab airblast application. The post application studies were designed to quantify worker exposure to AZM after application of GUTHION ® 50 WP resulting from manual harvesting activities in apples, walnuts, and blueberries. Urine samples collected in these studies were used to estimate workers' internal doses of AZM based on measurement of the metabolite methylsulfonylbenzazimide ( MSMB) in their urine. MSMB serves as a biomarker for AZM. Results from a metabolism study with human volunteers were used to estimate the percentage of AZM that is represented by the biomarker MSMB in urine ( MRID 44785801). Blood samples were drawn from postapplication workers only and assayed for cholinesterase activity. However, the design of these biomonitoring studies reflects the intent to quantify worker exposure to AZM under controlled field conditions, not to monitor cholinesterase activity as a result of exposure.

Data from these biomonitoring studies and the pharmacokinetic study were used to refine the exposure estimates used in this risk assessment. Data from a metabolism study involving human volunteers were used to estimate the internal dose of AZM in workers based on the metabolite of AZM, MSMB, which was measured in the worker's urine. The metabolism and biomonitoring studies used in this assessment are listed below. Although not subject to review by the HSRB under EPA Human Subjects Protections Rule, 40 CFR Part 26, these studies do require a review of their ethical conduct. EPA is currently preparing these ethics reviews in accordance with EPA Human Subjects Protections Rule, 40 CFR Part 26.

MRID 447858 01. " Selim, S. Absorption, Excretion, Balance and Pharmacokinetics of 14 C Radioactivity After Single Dose Dermal Application of Three Dose Levels of 14 C Labeled Guthion to Healthy Volunteers." March 24, 1999.

MRID 463164 02. " Assessment of Pharmacokinetic Data to Identify A Biomarker for the Biological Monitoring of Azinphos Methyl". This MRID contains a summary of MRID 44785801.

MRID#: 463164 03, " GUTHION ® 50 WP  Biological Monitoring of Post Application Workers During Manual Thinning and Harvesting of Apples:.

MRID#: 463164 04: " GUTHION ® 50 WP  Biological Monitoring of Post Application Workers During Manual Harvesting of Blueberries MRID#: 463164 05: GUTHION ® 50 WP  Biological Monitoring of Post Application Workers During Manual Harvesting of Walnuts Page 4 of 42 MRID#: 463164 06, " Azinphos methyl  Biomonitoring of Applicators Following Airblast Treatment of Orchard Crops using Open and Closed Cab Equipment".

HSRB Recommendations:

This revision reflects the HSRB recommendation against the use of toxicological data from toxicity studies involving human volunteers exposed to AZM for assessing occupational handler and post application exposure and risk. The HSRB recommendations are discussed in more detail below. Consequently, this occupational risk assessment relies on data from toxicity studies using animals. Toxicity data from studies in which adult human subjects were intentionally exposed to AZM to elicit a toxic effect have not been used in this risk assessment.

Hazard Characterization The No Observed Adverse Effect Level ( NOAEL) of 0.56 mg/ kg/ day from a rat dermal absorption study in which the Lowest Observed Adverse Effect Level ( LOAEL) was 5.6 mg/ kg/ day for inhibition of red blood cell ( RBC) acetyl cholinesterase was selected as the endpoint for estimating risk from short term dermal exposures. This NOAEL from a routespecific study is appropriate for estimating risk based on external, dermal exposures as collected through passive dosimetry ( i. e., transfer coefficients from the Agricultural Reentry Task Force ( ARTF) and unit exposure estimates from the Pesticide Handlers Exposure Database ( PHED)). It is not appropriate for use with exposure estimates based on internal doses of AZM from biomonitoring studies. As this is a route specific study, dermal risk assessments based on this endpoint do not need modification by a dermal absorption factor.

The NOAEL from a chronic feeding study in the dog of 0.15 mg/ kg/ day in which the LOAEL was 0.69 mg/ kg/ day for inhibition of red blood cell ( RBC) acetyl cholinesterase ( AChE) was selected as the endpoint for estimating risk from intermediate term dermal exposures. This NOAEL from an oral dosing study is appropriate for estimating risk based on either external, dermal exposures as collected through passive dosimetry ( i. e., transfer coefficients from the Agricultural Reentry Task Force ( ARTF) and unit exposure available in the Pesticide Handlers Exposure Database ( PHED)) and/ or exposure estimates based on internal doses of AZM from biomonitoring studies. Internal doses estimated from biomonitoring studies capture all routes of exposure ( dermal, inhalation, and oral). This endpoint should be used to estimate risk from all routes of exposure wherever they are based on internal doses from biomonitoring studies, regardless of exposure duration.

A dermal absorption rate of 42% from a rat dermal absorption study was assumed for estimating exposure via the dermal route when using conventional exposure data ( from PHED and transfer coefficients) in conjunction with an oral endpoint.

The inhalation toxicity risk assessment endpoint is based on the NOAEL of 0.2 mg/ kg/ day from a 90 day inhalation study that is route specific for inhalation exposures. It is used when conventional exposure data ( e. g. from data collected through passive dosimetry and Page 5 of 42 available in PHED) are used rather than biomonitoring data. For inhalation risk assessments, 100% absorption of inhaled AZM is assumed.

Exposure and Risk Estimates Occupational risks have been estimated based on short term ( 1 to 30 days) and intermediate term ( 30 to 180 days) exposures. Occupational exposure for chronic durations ( more than 6 months) is not expected based on the registered use patterns. Based on an uncertainty factor of 100, a Margin of Exposure ( MOE) that is less than 100 is a risk concern. The Agency used biomonitoring data when available to estimate risk. These data were available for mixers/ loaders/ applicators for airblast applications and for all post application risks except those from activities involving parsley. All other risk estimates were estimated through the use of PHED and ARTF data.

MOEs calculated based on the biomonitoring study for mixer/ loader/ applicators using open and closed cab air blast sprayers for Group 3 crops ranged from 18 to 205, and for some crops/ activities resulted in risk estimates of concern.

In addition to collecting urine to measure internal AZM dose, breathing zone samples were also taken for mixer/ loader/ applicators. MOEs based on the breathing zone samples and the NOAEL of 0.2 mg/ kg/ day, ranged from 43 to 2390, are also a risk concern. This indicates that AZM exposures via inhalation and the dermal routes both have risk concerns.

MOEs for short term exposure based on PHED data for mixer/ loaders and applicators for Group 3 crops range from 7 to 623 and for some crop/ activities resulted in risk estimates of concern. These MOEs are based on the maximum application rate and assume area treated of 350 acres for aerial application, 80 acres for groundboom application and 40 acres for airblast application.

MOEs for intermediate term exposure based on PHED data for mixer/ loaders/ applicators for Group 3 crops range from 5 to 400 and for most crops resulted in risk estimates of concern. These MOEs are based on the maximum application rate and assume area treated of 350 acres for aerial application, 80 acres for groundboom application and 40 acres for airblast application.

Bayer submitted 2003 AZM biomonitoring data for blueberry, apple, and walnut postapplication activities at current restricted entry intervals ( REIs). Data from these studies were analyzed and used to estimate risk for all Group 3 uses except parsley. Post application activities associated with parsley ( hand harvesting) are very different from the types of harvesting activities represented in the submitted biomonitoring studies. MOEs based on internal doses from biomonitoring studies were estimated using the oral NOAEL of 0.15 mg/ kg/ day. Dislodgeable foliar residue ( DFR) data for AZM were used to extrapolate exposures on postapplication days beyond the Reentry Interval ( REI) in cases where MOEs were less than 100 at the current REI. For parsley, exposures were estimated using the same dermal transfer coefficient ( TC) method that was used in the 2001 AZM IRED. MOEs for short term dermal exposures from parsley were estimated using the dermal NOAEL of 0.56 mg/ kg/ day. The MOEs for intermediate term dermal exposures from parsley were estimated using the oral NOAEL of 0.15 mg/ kg/ day and a 42% dermal absorption factor. Page 6 of 42 REIs are not of concern when MOEs for post application workers reach 100. Walnuts and almonds are the only Group 3 crops with MOEs of at least 100 for current REIs ( 30 days). MOEs on day 30 for pistachios are greater than 100; however, the REI ( and PHI) is 21 days. An estimate of the day that MOEs would reach 100 for pistachios can not be calculated based on available data. The number of days for most of the crops to reach 100 is significantly longer than the current REIs specified on EPA labels ( e. g., the number of days for MOEs to reach 100 range from 18 days for nursery crops to 103 days for apples).

Risk Characterization HED believes these risk estimates for occupational activities are conservative and probably overestimate risks. These risk estimates are the result of a comparison of estimates of exposure to an endpoint for toxic effects, and there are conservative assumptions inherent in each of these risk components.

On the exposure side, the handler exposure scenarios for aerial and groundboom applications are based on conventional PHED data and assumptions likely to overestimate risk, such as maximum application rates and acreages treated. The airblast exposure estimates have been refined through the use of biomonitoring data and are considered less conservative. Available medical monitoring data ( Washington State) support the characterization of this risk assessment as conservative as it indicates that typical exposures of handlers to AZM may result in detectable cholinesterase inhibition, but only in a small number of handlers ( 2/ 580 in 2004 and 1/ 611 in 2005) or < 1% of the workers tested. The 2 cases in 2004 and 1 case in 2005 reported AZM use specifically. HED notes that the 580 and 611 workers tested in 2004 and 2005, respectively, were tested irrespective of the active ingredient handled. However, given that AZM is used on 73% of the apple crop, many of the workers tested in 2004 and 2005 likely applied AZM. The MOEs on which the REIs are based have been refined through biomonitoring data. REIs indicate the minimum amount of time between an AZM treatment and when a worker can reenter the field. The biomonitoring data for post application workers reflect reentry into a field at the minimum time specified ( the REI) and, therefore, worst case exposures. In practice, a post application worker may not reenter a treated field until several days after the REI by which time AZM residues may have dissipated. Although representative of only one day of exposure to AZM, available biomonitoring data show no firm evidence of cholinesterase inhibition in post application workers.

On the hazard side, HED recognizes that as regards cholinesterase inhibition, animals and humans probably are similar. Although the NOAELs for cholinesterase ( ChE) inhibition across species including humans are not very different, since the repeat dose study with humans is a NOAEL only study, there is no LOAEL for ChE inhibition in humans to compare with animal LOAELs. More importantly, the steep dose response that occurs in going from cholinesterase inhibition to more severe systemic effects is a caution to eliminating 10 fold safety factor for interspecies differences. In particular, HED notes the progression from moderate ChE inhibition to more severe systemic effects seen in the rat reproductive studies. In the rat reproduction study there was 25 47% RBC AChE inhibition during lactation at 0.55 mg/ kg/ day. Systemic effects are seen in pups ( decrease in viability index accompanied by a decrease in pup body weight during lactation) at the next higher dose of 1.5 mg/ kg/ day where there is 75 to 83% inhibition of RBC Page 7 of 42 AChE during lactation. There is only a 2 to 3 fold difference between the non systemic effect dose on RBC AChE inhibition and a systemic effect dose of AZM. As the dose level in the rats is increased to 4.8 mg/ kg/ day and RBC AChE inhibition reaches 89 to 91% there are convulsions and deaths in the dams further indicating the seriousness of the systemic toxicity of AZM.

Incident data indicate a 50% decline in poisoning incidents involving AZM over time. Medical monitoring data indicating that a small percentage of workers exhibit mild but detectable cholinesterase inhibition as a result of AZM exposure. Given this, HED believes that the majority of the time workers are using AZM safely. HED further believes the selection of the dog oral endpoint as the lowest NOAEL in the toxicity database on the most sensitive endpoint coupled with a 100 fold safety factor is adequately protective, and results in MOEs that are conservative and overestimate risk. However, HED remains concerned that on occasion a worker's accidental exposures to AZM at higher levels than may be typical may occur and result in serious health consequences regardless of all safeguards because of the steep dose response for more serious effects seen in the animal reproduction studies.

1.0 Hazard Characterization and Summary AZM is an organophosphate cholinesterase inhibitor. AZM inhibits the enzymes plasma cholinesterase and red blood cell and brain acetylcholinesterase by forming a covalent bond between the phosphate part of the AZM molecule and a free hydroxyl group of the enzyme. This bond renders the enzyme irreversibly inhibited and recovery of inhibition is slow. The toxicity database for AZM is robust and complete. It consists of the standard guideline acute, subchronic, chronic, carcinogenicity studies using rats, dogs, and mice, reproduction and developmental studies in rats and/ or rabbits, acute and subchronic neurotoxicity studies, a developmental neurotoxicity study, and mutagenicity studies. In addition, there is a special comparative cholinesterase study in neonatal and adult rats and both a single dose and repeat dose study using human volunteers. Inhibition of cholinesterase is the basis for the NOAEL or LOAEL for all of these species. In addition, there is a progression from moderate ChE inhibition to more severe systemic effects ( decreases in pup viability and weight, and convulsions and death in adults) seen in the rat reproductive studies that exhibits a steep dose response. Clinical signs of toxicity that are considered related to the effects of cholinesterase inhibition come at doses higher than the LOAEL except for certain gastrointestinal reactions in the dog. Table A in Appendix I gives the NOAEL ( when it was established) and the LOAEL for cholinesterase inhibition.

1.1 Human Studies Review Board ( HSRB)

HED presented an oral, repeat dose toxicity study using AZM and involving human volunteers to the HSRB at a meeting on April 3 6, 2006. The HSRB discussed the study during this meeting and has prepared a draft written report summarizing its discussions. HED has reviewed the HSRB's draft report of the April 2006 meeting. The following reference is for the oral, repeat dose study using AZM and human volunteers that was presented to the HSRB:

MRID 45476101. McFarlane, P. and Freestone, S. " A Randomized Double Blind Placebo Controlled Study with AZM to Determine the No Effect Level on Plasma and RBC Cholinesterase Activity After Repeat Doses. 13 August, 1999. Page 8 of 42 With regards to the single chemical occupational risk assessment for AZM, it is HED's understanding based on discussions held during the meeting that the results of the 28 day repeat dose study using human volunteers should not be used to develop a point of departure for extrapolation of risk to workers exposed to AZM via the dermal and inhalation routes. HED understands that the HSRB had little confidence in the study because only one dose level was used over the 28 day period, and that dose level could not be used to establish an effect level for cholinesterase inhibition in the human subjects. The HSRB expressed concerns that the laboratory conducting the cholinesterase assays may not have been able to detect cholinesterase inhibition at the one dose tested in the subjects. The HSRB's conclusion is consistent with the recommendation of the NAS committee ( NAS 2001) that the Agency should not consider data from No Observed Effect Level ( NOEL only) studies.

In an effort to respond to the HSRB's concerns related to the study, HED contacted the registrant and the laboratory in Scotland that conducted the assays on AZM. The registrant confirmed that the repeat dose study was only intended to establish a NOAEL. The laboratory confirmed that the study director and technicians were the same for a variety of chemicals for which changes in cholinesterase activity were measurable and cholinesterase inhibition was detected. Although this point was made to the HSRB during the April 2006 meeting, there remain residual uncertainties about the assay used for AZM and variables that may have resulted in the negative result for cholinesterase inhibition seen in the study. As a result, HED returned to the toxicity database to reconsider both animal and human data.

On balance, HED finds the repeat dose study with AZM using human volunteers to have been well conducted and well documented. The results of this study are well supported by the animal studies indicating little species differences regarding plasma and RBC cholinesterase inhibition. Although cholinesterase inhibition was not detected at 0.25 mg/ kg/ day in this study, the laboratory conducting the assay has experience conducting assays for cholinesterase inhibition with carbamates and other organophosphate chemicals in which they have detected cholinesterase inhibition. While HED does not completely agree with the HSRB's recommendation against relying upon the use of the human study, it is acknowledged that there are residual uncertainties associated with the use of a single dose study in which only a NOAEL was established. More importantly, HED is concerned about the steep dose response between the dose level for ChE inhibition without systemic effects and systemic effects seen in pups ( reduced viability and weight) and more severe neurotoxic effects ( convulsions and death) at higher doses in adults as seen in the rat reproduction studies. Consequently, HED selected endpoints ( NOAELs and LOAELs) from animal studies based on RBC cholinesterase inhibition for use in this risk assessment. Toxicity studies involving human volunteers and exposure to AZM to elicit a toxic response have not been used in this risk assessment.

1.2 Endpoint Selection for Occupational Risk Assessments The toxicity database was reviewed and toxic endpoints for use in risk assessments for workers were selected. They are as follows: Page 9 of 42 Dermal Risk Assessments The No Observed Adverse Effect Level ( NOAEL) of 0.56 mg/ kg/ day from a rat dermal absorption study ( MRID 42452701, 1992) in which the Lowest Observed Adverse Effect Level ( LOAEL) was 5.6 mg/ kg/ day for inhibition of red blood cell ( RBC) acetyl cholinesterase ( AChE) was selected as the endpoint for estimating risk from short term dermal exposures. This NOAEL from a route specific study is appropriate for estimating risk based on external, dermal exposures as collected through passive dosimetry ( i. e., transfer coefficients from ARTF and unit exposures from PHED. It is not appropriate for use with exposure estimates based on internal doses of AZM from biomonitoring studies. As this endpoint is from a route specific dermal study, no absorption factor is required for dermal risk assessment.

The study was not designed to meet the guideline requirements for a 21 or 90 day dermal toxicity study, but cholinesterase assessments were included in a study designed to meet the guidelines for a dermal absorption study. HED recognizes the limitations of this study in that only a single dose was applied, there were only four males assessed and females were not assessed. The extent of inhibition of RBC AChE was only about 17% and there were no indications of recovery as would be expected over the time frame of the study. However, the study demonstrated depression of RBC AChE consistent with other studies and the apparent inhibition was statistically significant on two successive assessment times ( 10 and 24 hours postdosing The selection of this study as the endpoint for short term occupational dermal risk assessment is considered conservative because of the relatively small effect on RBC AChE and the 10 fold difference between the NOAEL and the LOAEL. This 10 fold difference is considered protective for the cumulative effect of possible intermittent exposure during the shortterm ( 1 30 days) exposure period.

The NOAEL from a chronic feeding study in the dog ( MRID 41804901, 1990) of 0.15 mg/ kg/ day in which the LOAEL was 0.69 mg/ kg/ day for inhibition of red blood cell ( RBC) acetyl cholinesterase ( AChE) was selected as the endpoint for estimating risk from intermediateterm dermal exposures. This NOAEL from an oral dosing study is appropriate for estimating risk based on either external, dermal exposures as collected through passive dosimetry and available in the Pesticide Handlers Exposure Database ( PHED) and/ or exposure estimates based on internal doses of AZM from biomonitoring studies. This endpoint should be used to estimate risk from dermal exposures wherever they are based on internal doses from biomonitoring studies, regardless of exposure duration. The NOAEL of 0.15 mg/ kg/ day is the lowest and most protective demonstrated NOAEL on the most sensitive endpoint ( ChE inhibition) from all of the available animal studies.

Bench Mark Dose ( BMD) analysis of rat cholinesterase data resulted in BMD10 values ( doses at which cholinesterase activity is inhibited by 10%) and BMDL10 values ( the lower 95th percentile confidence limit on doses at which cholinesterase activity is inhibited by 10%) that bracket and support the NOAEL of 0.15 mg/ kg/ day ( see Table B in Appendix I). The BMDL10 value for RBC AChE inhibition in adult, male rats from a repeat dose comparative cholinesterase study was 0.16 mg/ kg/ day. Other BMD10 and BMDL10 values for adults were in the range of the 0.15 mg/ kg/ day dose selected based on the dog study. Page 10 of 42 In the chronic study in the dog, there was 20 to 43% inhibition of RBC AChE at 0.69 mg/ kg/ day ( the LOAEL) and 66 to 92 % inhibition at 3.8 mg/ kg/ day, the next higher dose. Results from two reproduction studies in the rat show systemic effects, such as reduced pup viability and body weights at doses approximating 1.7 mg/ kg/ day, and more severe effects including clinical signs of neurotoxicity ( convulsions and death) in adult female rats at doses approximating 4.8 mg/ kg/ day. The dose response curve in going from ChE inhibition to systemic effects to the more severe effects of convulsions and death is considered to be steep seen in the rat reproduction studies, as there is only a 2 to 3 fold increase in dose between these effects.

The dog chronic study also demonstrated a possible effect on the gastro intestinal system in the dogs at the LOAEL. There was increased incidence of dogs in both sexes with mucus containing feces at the LOAEL but the incidence was lower ( rather than higher) at the next higher dose. Dogs are prone to gastro intestinal disturbance and the significance of this relative to humans is uncertain. A factor that was considered in selecting this study for intermediate term dermal risk assessment is that the dermal absorption study selected for the short term scenarios is based on a single dose and cumulative effects of the intermittent exposure that may occur for exposure durations of one to six months may begin to be contribute to depression of ChE and this could be underestimated by the use of this study for longer term exposures.

Overall, as the lowest NOAEL in the database on the most sensitive endpoint, HED believes the 0.15 mg/ kg/ day is protective of all effects seen in the database.

Inhalation Risk Assessments The inhalation toxicity risk assessment endpoint was based on the NOAEL and LOAEL for the 90 day inhalation study ( MRID 00155011, 1976) and is route specific for risk assessments based on inhalation exposures. The NOAEL of 0.0012 mg/ L was converted to mg/ kg/ day by making slightly different assumptions concerning body weight and mean daily intake than was used in the previous risk assessment ( July 10, 2001). ( See Appendix I for assumptions and calculations.) Thus, a dose of 0.2 mg/ kg/ day, rather than 0.32 mg/ kg/ day, was used for this revised risk assessment. Inhalation exposure appears to be significant in a number of scenarios. For inhalation risk assessments, 100% absorption of inhaled AZM is assumed.

Dermal Absorption A dermal absorption factor of 42% was determined based on a weight of the evidence from both dermal absorption studies with human volunteers ( 1999, MRID No.: 44785801) and in rats ( 1992, MRID No.: 42452701). Although the study with human subjects was classified as unacceptable because only percentage data were provided in the report, HED determined that the results can be included in the WOE analysis to select the dermal absorption factor for AZM. In the study with humans, three groups of six male subjects were dosed for 8 hours on a 4 x 6 cm area of their forearms with 14C radiolabeled AZM at doses of 0.79, 3, or 1.49 gm/ kg. Urinary recovery following 5 to 8 days of collection, the key index of absorption, indicated a wide variety for the individual subjects with the range for the low dose being 12.7 to 45.18%, for the mid dose group being 10.2 to 39.44% and to be 9.91 to 34.56% for the high dose group. The ranges ( rather than the means) for the percent radioactivity in the urine values from this study Page 11 of 42 indicate that humans can vary widely in their ability to absorb AZM. As much as 45.18% was demonstrated to be absorbed.

In the dermal absorption study ( with rats, 14C labeled AZM in GUTHION 35WP was applied at doses of 0.056, 0.56 or 5.6 mg/ kg for a period of 10 hours. The rats were sacrificed at 1, 4, 10, 24, 72 and 168 hours post dosing. Total recovery was from 70.45 to 103% with the low dose group demonstrating the best recovery ( 96.8 to 103.21%). The mean total absorption ( blood, urine, feces, carcass and cage wash was 41.65%, 21.86% and 18.34% for the 0.056, 0.56 and 5.6 mg/ kg dose groups, respectively. Most of the radioactivity was in the urine ( 10.14 to 26.24%). Significant amounts remained on the skin after washing and this appears to be able to be absorbed after washing as indicated by the slow decline from 10 to 168 hours and increases in radioactivity in the urine for that same period. A dermal absorption factor of 42% based on total absorption is supported by this study when the percent absorption for the lowest test dose is considered. This factor was retained from the previous risk assessment document and was recommended by the HIARC ( April 20, 1998, HED Document No.: 012591). Thus, since similar values in the range of 40% were obtained in the rat and human studies, the 42% dermal absorption factor is considered appropriate.

The dermal absorption factor of 42% is used to modify the oral endpoint when it is used in conjunction with conventional exposure data from PHED and other HED occupational exposure databases for dermal risk assessment. It is not used in conjunction with the oral endpoint and internal doses from biomonitoring studies.

Metabolism Results from a study designed to determine the absorption, excretion, balance, and pharmacokinetics of radio labelled AZM in humans after a single dermal dose was used to estimate internal doses of AZM in workers ( MRID 447858 01). The volunteers received topical doses of AZM at either 0.79 ug/ kg or 3.0 ug/ kg in isopropyl alcohol, or 1.49 ug/ kg as the 25% a. i. wettable powder formulation. The distribution of the radioactivity was followed in all 3 dose groups for 120 hours after which 83.6% of the absorbed dose is excreted in the urine for the 1.49 ug/ kg dose of the 25% active ingredient ( a. i.) wettable powder ( WP) formulation. There was little difference between dose groups. Based on an analysis of pooled urine, MSMB was determined to represent 9.2% of the activity in the urine in the 0 to 120 hour pooled sample. Based on MSMB accounting for 9.2% of the urine activity and urine activity accounting for 83.6% of the absorbed dose, MSMB represents 7.7% of the absorbed dermal dose of AZM.

Safety Factors The following safety factors have been applied to all the occupational risk assessments for workers: a 10X for interspecies variations and a 10X for intraspecies variations. A total uncertainty factor of 100X has been applied to all risk assessments.

Table 1 summarizes toxicological endpoints of concern that were used to estimate shortand intermediate term risks for workers. Occupational exposure for chronic durations ( more than 6 months) is not expected based on the registered use patterns. Page 12 of 42 Table 1. Toxicity Endpoints Selected for Occupational Risk Assessments for AZM Exposure Route/ Scenario Study NOAEL Effect UF Short Term Dermal Dermal absorption in rat 0.56 mg/ kg/ day RBC ACHE 100 Intermediate Term Dermal* 1 year oral dog feeding study 0.15 mg/ kg/ day RBC ACHE 100 Inhalation** 90 day subchronic rat study 0.2 mg/ kg/ day RBC ACHE 100 All exposure scenarios based on Internal AZM Dose ( i. e. all exposure routes) from Biomonitoring Data 1 year oral dog feeding study 0.15 mg/ kg/ day RBC ACHE 100 * Dermal absorption rate was assumed to be 42% ** Inhalation absorption rate assumed to be 100%

Table 2 summarizes the acute toxicity categories for AZM Table 2. Acute Toxicity Categories for AZM Guideline No. Study Type MRID #( S). Results Toxicity Category 81 1 Acute Oral ( Rat) 00155002 LD50 = 4.6 mg/ kg_ 4.4 mg/ kg_ I 81 2 Acute Dermal ( Rabbit) 40280102 LD50 => 2000 mg/ kg III 81 2 Acute Dermal ( Rat) 00155003 LD50 = 200 250 mg/ kg_ 155 mg/ kg_ I 81 3 Acute Inhalation ( Rat) 40280103 LC50 = > 0.21mg/ L II 81 4 Primary Eye Irritation ( Rabbit) 43337501 No ocular effects at 48 hrs. III 81 5 Primary Skin Irritation ( Rabbit) 43337101 Non irritating IV 81 6 Dermal Sensitization ( Guinea Pig) 41064401 Sensitizer N/ A 2.0 Summary of Use Patterns and Formulations Page 13 of 42 AZM is formulated as a manufacturing product ( 88.1 percent active ingredient), and several wettable powder ( 35.0 to 50.0 percent active ingredient). All wettable powder formulations are contained in water soluble packaging. All liquid formulations have been cancelled.

Information regarding registered use sites, application rates and frequency of application in this assessment was based on the Benefits and Economic Analysis Division ( BEAD's) 3/ 25/ 05 use summary tables and was confirmed by SRRD.

Table 3 presents a summary of the Group 3 uses based on the crop grouping system developed by Markle, et. al. The grouping is based on cultural practices, leaf size, leaf shape and type of pests attracted to the plants. AZM can be applied to agricultural crops from early season up to harvest time. This assessment covers the maximum application rates and typical equipment used to apply AZM.

Table 3. Use Paztterns and Application Rate for AZM Crop Grouping Specific Crop Application rate lb a. i./ A Pome Fruits Apple, Pear, Crabapple 1.5 Stone Fruits Cherry 0.75 Berries Blueberry 0.75 Tree Nuts Almond, Walnut, pistachio 2.0 Brassica Leafy Vegetables Brussels Sprouts 0.75 Leafy Vegetables Parsley 0.5 Ornamental Plants Nursery Stock 1.0 The following use patterns are associated with the application equipment:

  Aerial ( spray) Equipment: foliar applications to fruit/ nut trees.   Chemigation Equipment: The exposure to the handlers using chemigation equipment is represented by the mixer/ loader and the amount handled is assumed to be equivalent to that of the aerial applicators.   Groundboom Equipment: fruit/ nut orchard floors and vegetable crops.   Airblast Equipment: fruit/ nut/ ornamental tree foliage. The use of hand held equipment voluntarily cancelled by the registrants.

3.0 Handler Exposure and Risk 3.1 Exposure Scenarios HED has determined that there are potential exposures to mixers, loaders, applicators, and other handlers during usual use patterns associated with AZM. Based on the use patterns and potential exposures described above, 7 major agricultural exposure scenarios are identified in this Page 14 of 42 document to represent the extent of AZM uses. The use of hand held equipment has been voluntarily cancelled by the registrants.

  Mixing/ loading wettable powders for aerial application/ chemigation irrigation;   Mixing/ loading wettable powders for groundboom application;   Applying sprays with fixed wing aircraft;   Aapplying sprays using a groundboom sprayer;   Applying sprays using an airblast sprayer;   Flagging during aerial application ( sprays).   Mixing/ loading/ applying wettable powders for airblast sprayer application;

For the occupational RED chapter process, HED has adopted a methodology to present the risks separately for some scenarios and combine others. For equipment such as fixed wingaircraft and groundboom tractors, the applicators are assessed separately from the individuals who mix and load the formulated product. HED assumes that the pilots are rarely involved in the mixing/ loading. By separating the two job functions, HED can determine the most appropriate PPE or engineering control without requiring the handler to wear PPE throughout the entire workday or engineering controls that are not needed. The biomonitoring airblast study submitted by the registrant monitored exposures during combined mixing, loading, and application activities; no separate measurement for exposures from specific, individual activities was made.

Typically, handler exposure assessments are completed by HED using a baseline exposure scenario and, if required, increasing levels of risk mitigation ( through PPE and up to engineering controls) to achieve an acceptable margin of exposure ( depending on the selected safety factor) for dermal and inhalation exposure. Products containing AZM are only marketed as wettable powder formulation and packaged in water soluble bags. Water soluble bags are considered to be a form of engineering control. Therefore, increasing the level of risk mitigation for mixer/ loaders from baseline is not considered to be applicable. The risk mitigation for the applicators is presented for both open and closed cab equipment.

Table 4 presents the exposure scenarios, application rates, and area ( i. e., acres) potentially treated that have been used in the exposure calculations. AZM labels include a multitude of uses and a wide range of application rates. Therefore, the rates presented in Table 4 are the maximum used to evaluate exposure associated with each scenario. Page 15 of 42 T able 4. Exposure Variables for Agricultural Uses of AZM Exposure Scenario Crop Group Crop Application Rates ( lb ai/ acre) Daily Acres Treated Mixer/ Loader Exposure ( source PHED)

Pome Fruits Apple, Pear, Crabapple ( SLN) 1.5 Mixing/ loading wettable powders for aerial application/ chemigation irrigation Berries Blueberry 0.75 350 Berries Blueberry 0.75 80 Brassica Leafy Vegetables Brussels Sprouts 0.75 Leafy Vegetables Parsley 0.5 80 Mixing/ loading wettable powders for groundboom application Ornamental Plants Nursery Stock 1.0 40 Applicator Exposure ( Source PHED)

Pome Fruits Apple, Pear, Crabapple ( SLN) 1.5 Applying Sprays with fixed wing aircraft Berries Blueberry 0.75 350 Berries Blueberry 0.75 80 Brassica Leafy Vegetables Brussels Sprouts 0.75 Leafy Vegetables Parsley 0.5 Applying sprays using a groundboom sprayer Ornamental Plants Nursery Stock 1.0 80 Flagger ( Source PHED)

Berries Blueberry 0.75 Flagging during aerial application ( sprays).

Pome Fruits Apple, Pear, Crabapple ( SLN) 1.5 350 Mixing/ loading/ Applying with Airblast ( open and Closed) using biomomitoring study ( source MRID # 46316406)

Pome Fruits Apple, Pear, Crabapple 1.5 Stone Fruits Cherry 0.75 Tree Nuts Almond, Pistachio, Walnut 2.0 Mixing/ loading/ Applying wettable powders for airblast sprayer application Ornamental Plants Nursery Stock 1.0 40 3.2 Handler Exposure Data 3.2.1 Biomonitoring Data A study titled " AZM  Biomonitoring of Applicators Following Airblast Treatment of Orchard Crops using Open and Closed Cab Equipment" ( MRID#: 463164 06) was submitted to the Agency for the purpose of assessing handler risk associated with orchard crops. Page 16 of 42 The purpose of this study was to quantify potential exposure from the use of AZM in the wettable powder formulation, while applying it to orchard crops ( primarily apple) using an open cab and closed cap airblast application equipment. The facilities for open cab trials were located in PA, MD and WA and for closed cab trials were located in NY, PA and WA. Guthion ®

wettable powder Insecticide was applied using open and closed cab airblast sprayer.

Fifteen experienced volunteer applicators for open cab and fifteen for closed cab were monitored via urinary and inhalation analyses. AZM exposure was quantified by measuring total MSMB in urine samples. Total 24 hour urine output was collected from each worker performing mixer/ loader/ applicator activities for the time period including the day before mixer/ loader/ applicator activities until 4 days after mixer/ loader/ applicator activities. Potential inhalation exposure was also measured using OVS tubes and a personal air sampling pump with the inlet positioned near the face of the worker. HED included the collection of this additional information on the inhalation route of exposure, alone, to determine the significance of inhalation as a route of exposure. The air sampling pumps were calibrated prior to use and the flow rate was approximately 2 L/ min. The workers were sequestered in a hotel during the test period, leaving only to perform application activities. Test subjects wore the following personal protective equipment ( PPE) during the application, as prescribed on the product label: longsleeved shirt and long pants underneath coveralls; waterproof gloves; chemical resistant footwear plus socks; protective eye wear; chemical headgear for overhead exposure; and dust/ mist filtering respirator ( MSHA/ NIOSH approval number prefix TC 21C). The raw data were corrected for a field recovery.

The average AZM doses for open cab and closed cab field trials, without background correction, are 0.0035 and 0.00080mg/ kg body weight, respectively. The total average AZM doses for open cab and closed cab field trials, with background correction, are 0.0027 and 0.00057mg/ kg body weight, respectively. AZM doses for open and closed cab field trials, based on pounds active ingredient handled, are 0.013 and 0.0023 mg/ lb ai handled ( without background correction) and 0.0095 and 0.0017 mg/ lb ai handled ( with background correction). Average potential inhalation exposures for open cab trials were calculated to be 166.8 µ g or 4.0 µ g/ lb ai handled and average exposures for enclosed cab trials were calculated to be 14.7 µ g or 0.2 µ g/ lb ai handled.

The study was in compliance with OPPTS Series 875 Occupational and Residential Exposure Test Guidelines and is considered to be of sufficient scientific quality to be used in determining handler exposure to AZM.

The AZM dose in the urine ( mg/ kg body weight) and the air concentration ( mg/ m3) were then analyzed to determine the data distribution type ( i. e., normal, lognormal, or other), using the XLSTAT program in Excel. This program uses the Kolmogorov Smirnov test and the Chisquare Goodness of Fit test to determine if the sample distribution is significantly different from a normal distribution. For the urine data sets and air concentration data sets, the distributions were not found to be significantly different from a normal distribution. Therefore, arithmetic mean values have been used for all calculations. Page 17 of 42 Risk estimates for handlers based on internal doses from biomonitoring studies are calculated with a NOAEL of 0.15 mg/ kg/ day, regardless of exposure duration or route; no dermal absorption factor is required.

3.2.2 PHED Data PHED data were used to estimate dermal and inhalation exposures for all handler scenarios, except the scenarios involving airblast applications to orchard crops ( i. e., apple, pear, crabapple, cherry, walnut, pistachio, almond, and nursery stock).

PHED was designed by a Task Force of representatives from the U. S. EPA, Health Canada, the California Department of Pesticide Regulation, and member companies of the American Crop Protection Association. PHED is a software system consisting of two parts  a database of measured exposure values for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. Currently, the database contains values for over 1,700 monitored individuals ( i. e., replicates).

Users select criteria to subset the PHED database to reflect the exposure scenario being evaluated. The sub setting algorithms in PHED are based on the central assumption that the magnitude of handler exposures to pesticides is primarily a function of activity ( e. g., mixing/ loading, applying), formulation type ( e. g., wettable powders), application method ( e. g., aerial, groundboom), and clothing scenarios ( e. g., gloves, double layer clothing). Once the data for a given exposure scenario have been selected, the data are normalized ( i. e., divided by) for the amount of pesticide handled, resulting in standard unit exposures ( milligrams of exposure per pound of active ingredient handled). Following normalization, the data are statistically summarized. The distribution of exposure values for each body part ( e. g., chest, upper arm) is categorized as normal, lognormal, or " other" ( i. e., neither normal nor lognormal). A central tendency value is then selected from the distribution of the exposure values for each body part. These values are the arithmetic mean for normal distributions, the geometric mean for lognormal distributions, and the median for all " other" distributions. Once selected, the central tendency values for each body part are composited into a " best fit" exposure value representing the entire body.

The data presented in this assessment are found in both the summary tables and the appendix tables. The summary tables provide total MOEs for baseline attire and engineering control at short and intermediate term duration.

For short term dermal exposures, risk estimates for handlers based on PHED data are calculated with a NOAEL of 0.56 mg/ kg/ day; no dermal absorption factor is required because this endpoint comes from a route specific dermal study. For intermediate term dermal exposures, risk estimates for handlers based on PHED data are calculated with a NOAEL of and 0.15 mg/ kg/ day and a dermal absorption factor of 42% is applied. For inhalation exposures of any duration, risk estimates for handlers based on PHED data are calculated with a NOAEL of 0.2 mg/ kg/ day. Since the inhalation endpoint is from a route specific study, 100% absorption is assumed. Page 18 of 42 3.3 Summary of Uncertainties The handler exposure assessments encompass all of the major uses of AZM throughout the country. It is difficult to assess all of the " typical" agricultural uses ( i. e., actual or predominant application rates and farm sizes), and, therefore, an assessment has been developed that is believed to be realistic and yet provides a reasonable certainty that the exposures are not underestimated. The assumptions and uncertainties are identified below to be used in risk management decisions:

  Application Rates: The application rates are the maximum allowable that were identified on the available product labels.   Amount Handled: The daily acres treated are HED standard values ( see Table 4).   Unit Exposures: The unit exposure values calculated by PHED generally range from the geometric mean to the median of the selected data set. To add consistency and quality control to the values produced from this system, the PHED Task Force has evaluated all data within the system and has developed a set of grading criteria to characterize the quality of the original study data. While data from PHED provide the best available information on handler exposures, it should be noted that some aspects of the included studies ( e. g., duration, acres treated, pounds of active ingredient handled) may not accurately represent labeled uses in all cases.

3.4 Exposure and Risk Calculations Potential daily dermal exposure is calculated using the following formula:

Potential daily inhalation exposure is calculated using the following formula:

Using the daily dermal exposure scenarios identified in the exposure section, EPA calculated the potential risk to persons from handler exposures to AZM.

The inhalation and dermal daily doses were calculated using the following formulas:

day A Treated Acres Daily x A ai lb Rate Use x g 1,000 1mg Factor Conversion x ai lb ai g Exposure Unit = day ai mg Exposure Inhalation Daily µ µ

Day Acres Treated Area . Acre ai lb Rate Appl. . ai lb ai mg Exposure Unit Dermal = Day ai mg Exposure Dermal Daily Max Max Page 19 of 42 The MOEs were calculated using the following formulas:

The MOE's derived for dermal and inhalation exposures may be combined to obtain a total MOE since a common toxicological endpoint ( i. e., cholinesterase inhibition) was observed in dermal and inhalation toxicity studies/ routes.

Total MOE = 1/ (( 1/ Dermal MOE) + ( 1/ Inhalation MOE)).

3.5 Risk From Handler Exposures ( based on biomonitoring and PHED data)

Typically, handler exposure assessments are completed by EPA using a baseline exposure scenario and, if required, increasing levels of risk mitigation ( through PPE and up to engineering controls) to achieve an acceptable margin of exposure ( depending on the selected safety factor) for dermal and inhalation exposure. Products containing AZM are only marketed as wettable powder formulations and packaged in water soluble bags. Water soluble bags are considered to be a form of engineering control. Therefore, increasing level of risk mitigation for mixer/ loaders from baseline is not considered to be applicable. The risk mitigation for the applicators is presented for both open and closed cab equipment. The total short term and intermediate term MOE calculations for baseline exposure and engineering controls using biomonitoring and surrogate data from PHED for the agricultural uses of AZM are presented in Appendix II.

HED calculated the total baseline MOE ( short term and intermediate term) for each of the exposure scenarios using the following baseline PPE assumptions: ( 100%) 1 * ( kg) Weight Body 1 x day ai mg Exposure Inhalation Daily = kg/ day ai mg Dose Inhalation Daily

%) ( 1 * ( kg) Weight Body 1 x day ai mg Exposure Dermal Daily = kg/ day ai mg Dose Dermal Daily 42

kg/ day mg Dose Daily Dermal kg/ day mg NOAEL = MOE

kg/ day mg Dose Daily Inhlation kg/ day mg NOAEL = MOE Page 20 of 42   all occupational handlers are wearing footwear ( socks plus shoes or boots).

  Occupational mixers and loaders using open mixing techniques are wearing longsleeved shirts, long pants, and no gloves.

  Occupational applicators who use open cab airblast or tractor driven application equipment and handlers flagging for aerial applications are wearing long sleeved shirts, long pants, and no gloves.

HED calculated the engineering control total short term or intermediate term MOE for each occupational exposure scenario using the following engineering control assumptions:

  all occupational handlers are wearing footwear ( socks plus shoes or boots).

  Occupational mixers and loaders handling wettable powders using a closed system ( water soluble packages) are wearing long sleeved shirts and long pants, and chemical resistant gloves.

  Occupational applicators who use aerial, airblast, or tractor driven application equipment and handlers flagging for aerial applications are located in enclosed cabs or cockpits and are wearing long sleeved shirts and long pants, and no gloves ( gloved value used for airblast).

Tables 5 and 6 summarize the MOE values for the total short term and intermediate term exposure durations. The comprehensive table of MOE values is presented in Appendix II.

Assessment of short term and intermediate term handler exposure for orchard crops using an open or closed cab airblast sprayer and data from biomonitoring studies resulted in MOEs ranging from 18 to 205. MOEs for mixer/ loader/ applicators using open cab airblast exceed EPA's level of concern. For mixer/ loader/ applicators using closed cab airblast equipment, MOEs ( with the exception of apple, pear, crabapple, nursery stock and cherry) are also less than100 and exceed EPA's level of concern.

In addition to collecting urine to measure internal AZM dose, breathing zone samples were also taken for mixer/ loader/ applicators. MOEs based on the breathing zone samples and the NOAEL of 0.2 mg/ kg/ day, ranged from 43 to 2390, are also a risk concern. This indicates that AZM exposures via inhalation and the dermal routes both have risk concerns. Page 21 of 42 The results of the total short term handler assessments using PHED data for remaining crops in Group 3 indicate that all potential exposure scenarios provide a total MOE( s) less than or equal to 100 ( except ground application of blueberry, Brussels sprouts and parsley). Table 5: Summary of Short  term Risk for Agricultural Handlers of AZM: Group 3 Crops Exposure Scenario ( Scenario #) Crop Application Rate lb ai/ A Daily Area Treated A/ Day Total Baseline MOE Total Eng. Control MOE Mixer/ Loader ( Source PHED)

Wettable Powders for Aerial application Apple, Pear, Crabapple 1.50 350 < 1 7 Wettable Powders for Aerial application Blueberry 0.75 350 < 1 14 Wettable Powders for Groundboom application Blueberry 0.75 80 < 1 62 Wettable Powders for Groundboom application Brussels Sprouts 0.75 80 < 1 62 Wettable Powders for Groundboom application Parsley 0.50 80 < 1 93 Wettable Powders for Groundboom application Nursery stock 1 80 < 1 46 Applicator ( Source PHED)

Sprays for Aerial application Apple, Pear, Crabapple 1.50 350 No Data 14 Sprays for Aerial application Blueberry 0.75 350 No Data 26 Sprays for Groundboom application Blueberry 0.75 80 40 127 Sprays for Groundboom application Brussels Sprouts 0.75 80 40 127 Sprays for Groundboom application Parsley 0.50 80 60 191 Sprays for Groundboom application Nursery stock 1 80 30 95 Flagger ( Source PHED)

Flagging for Sprays application Apple, Pear, Crabapple 1.50 350 6 311 Flagging for Sprays application Blueberry 0.75 350 12 623 Mixer/ Loader/ Applicator ( Source bimonitoring study MRID # 46316406)

Open Cab Closed Cab Mixing/ Loading/ Applying for Airblast Apple, Pear, Crabapple 1.5 40 18 102 Mixing/ Loading/ Applying for Airblast Cherry 0.75 40 36 205 Mixing/ Loading/ Applying for Airblast Almond, pistachio, walnut 2.0 40 14 80 Mixing/ Loading/ Applying for Airblast Nursery stock 1.0 40 28 155 Page 22 of 42 Table 6. Summary of Intermediate term Risk for Agricultural Handlers of AZM: Group 3 Crops Exposure Scenario ( Scenario #) Crop Application Rate lb ai/ A Daily Area Treated A/ Day Total Baseline MOE Total Eng. Control MOE Mixer/ Loader ( Source PHED)

Wettable Powders for Aerial application Apple, Pear, Crabapple 1.50 350 < 1 5 Wettable Powders for Aerial application Blueberry 0.75 350 < 1 9 Wettable Powders for Groundboom application Blueberry 0.75 80 < 1 40 Wettable Powders for Groundboom application Brussels Sprouts 0.75 80 < 1 40 Wettable Powders for Groundboom application Parsley 0.50 80 < 1 60 Wettable Powders for Groundboom application Nursery stock 1 80 < 1 30 Applicator ( Source PHED)

Sprys for Aerial application Apple, Pear, Crabapple 1.50 350 No Data 10 Sprays for Aerial application Blueberry 0.75 350 No Data 18 Sprays for Groundboom application Blueberry 0.75 80 25 80 Sprays for Groundboom application Brussels Sprouts 0.75 80 25 80 Sprays for Groundboom application Parsley 0.50 80 40 122 Sprays for Groundboom application Nursery stock 1 80 20 60 Flagger ( Source PHED)

Flagging for Sprays application Apple, Pear, Crabapple 1.50 350 25 200 Flagging for Sprays application Blueberry 0.75 350 8 400 Mixer/ Loader/ Applicator ( Source bimonitoring study MRID # 46316406)

Open Cab Closed Cab Mixing/ Loading/ Applying for Airblast Apple, Pear, Crabapple 1.5 40 18 102 Mixing/ Loading/ Applying for Airblast Cherry 0.75 40 36 205 Mixing/ Loading/ Applying for Airblast Almond, pistachio, walnut 2.0 40 14 80 Mixing/ Loading/ Applying for Airblast nursery stock 1.0 40 28 155 The results of the total intermediate term handler assessments using PHED data for remaining crops in Group 3 indicate that all potential exposure scenarios provide a total MOE( s) less than or equal to 100 ( except parsley).

4.0 Post application Exposure and Risk Bayer submitted 2003 AZM biomonitoring data for blueberry, apple, and walnut postapplication activities at current restricted entry intervals ( REIs). The biomonitoring studies were required as part of the 2001 Data Call In ( DCI) for AZM. Data from these studies were analyzed and used to estimate risk for all Group 3 uses except parsley. ( As mentioned previously, harvesting activities for parsley are very different from those used in the biomonitoring studies on other crops, i. e., blueberries, apples, and walnuts). MOEs based on internal doses from biomonitoring studies were estimated using the oral NOAEL of 0.15 mg/ kg/ day for both short and intermediate term exposures. Dislodgeable foliar residue ( DFR) Page 23 of 42 data for AZM were used to extrapolate exposures on post application days beyond the REI in cases where MOEs were less than 100 at the REI.

The data from the three biomonitoring studies were not appropriate for estimating high contact post application activities associated with parsley ( e. g. hand harvesting at 30 day REI). For parsley, exposures were estimated using the same dermal transfer coefficient ( TC) method that was used in the 2001 AZM IRED. MOEs for short term dermal exposures from parsley were estimated using the dermal NOAEL of 0.56 mg/ kg/ day. The MOEs for intermediate term dermal exposures from parsley were estimated using the oral NOAEL of 0.15 mg/ kg/ day and a 42% dermal absorption factor.

Inhalation exposures are not anticipated for post application workers and typically are not assessed.

HED considers the updated post application exposure estimates based on biomonitoring data to be more accurate than those based on TCs and DFR data only.

4.1 Biomonitoring Data Study protocols for the blueberry, apple, and walnut biomonitoring studies were submitted to the Agency and reviewed by HED in 2003 ( see 5/ 13/ 03 HED memo from S. Weiss/ HED to V. LaCapra/ SRRD, Review of DRAFT Protocols and Urinary Biomarker Data for AZM Occupational Exposure Studies, D288496).

MRID#: 463164 03, GUTHION ® 50 WP  Biological Monitoring of Postapplication Workers During Manual Thinning and Harvesting of Apples ( A review of this study is included in HED memo D307558)

This study measured worker exposure to AZM following thinning and harvesting of apples. Harvesting activity exposures took place at a New York test site 14 days following the last of 6 airblast applications. Exposure of harvesters was also studied in Oregon for workers reentering fields 14 days following the last of 3 applications. Exposures of workers thinning apple orchards 14 days following the first application at the Oregon test site were also studied. The application rates used in the trials were 0.275 lb ai/ A/ application in New York, and 0.47 lb ai/ A/ application in Oregon ( based on the tree row volume concept).

The Study Report stated that the workers wore clothing typical of what they would normally wear when performing agricultural work. The workers clothing is listed in Tables 10, 11 and 12 of the Study Report, and typically included long sleeve shirts and long pants. Three workers wore short sleeve or sleeveless shirts and seven workers wore a t shirt underneath their long sleeve shirt. Each worker wore a painter's hat provided by the Principle Field Investigator. No personal protective equipment, including gloves, was worn by the workers during any of the reentry activities.

MRID#: 463164 04, GUTHION ® 50 WP  Biological Monitoring of Post Application Workers During Manual Harvesting of Blueberries ( A review of this study is included in HED memo D307560) Page 24 of 42 This study measured worker exposure to AZM following harvesting of high bush blueberries, which had received two airblast applications of 0.749 lb ai/ A. Reentry activity was monitored in 10 male and 5 female workers at one Michigan field location. Harvesting activities took place 7 days following the final application.

The Study Report stated that the workers wore clothing typical of what they would normally wear when performing agricultural work. The workers' clothing was listed in Table 6 of the Study Report, and typically included long sleeve shirts or sweatshirts and jeans, sweatpants, or long work pants. Each worker wore a painter hat, supplied by the Principle Field Investigator.

MRID#: 463164 05, GUTHION ® 50 WP   Biological Monitoring of Post Application Workers During Manual Harvesting of Walnuts ( A review of this study is included in HED memo D307561)

This study measured worker exposure to AZM following harvesting of walnuts, which had received one application by airblast at 2.01 lb ai/ A. The reentry harvesting activities took place 30 days after the pesticide application. In this study, 15 male workers were monitored, including 2 shakers, 2 sweepers, and 11 rakers. The shakers operated a shaker machine within an enclosed cab, the sweepers operated a sweeper machine with an open cab, and the rakers used rakes and their hands to move walnuts and small tree limbs.

The Study Report states that the workers wore clothing typical of what they would normally wear when performing agricultural work. The workers clothing was listed in Table 6 of the Study Report, and typically included long sleeve shirts and long work pants. One worker wore a short sleeve shirt and two workers wore a short sleeve shirt underneath a long sleeve shirt. Each worker wore a hat, plastic hair cover, or bandana on the head, except for one worker who did not wear any head protection. Type N95 dust masks were made available to each worker just prior to beginning harvest and each worker was allowed to make their own decision regarding the use of a mask. All workers wore a dust mask; however, the mask was not necessarily worn for the entire exposure period.

4.2 Sampling Media Urine, blood, and breathing zone air sampling data were collected in each of the three studies.

Urine Samples ( MSMB as a urinary biomarker for AZM)

Total urine output was collected from each worker during each 24 hour period starting 1 day prior to reentry through 4 days after reentry. Day  1 samples were those collected starting after the first void of the bladder in the morning on the day prior to reentry and ending after the first void on the day of reentry. Day 0 samples were those collected during the 24 hour period starting when the workers began the reentry activities. Re entry activities occurred for 1 day only ( Day 0). No AZM exposure occurred during Day 1, 2, 3 and 4. Page 25 of 42 Data from a metabolism study in humans ( MRID 447858 01) were used to estimate internal doses of AZM in workers. Using the raw data provided in the Study Reports, AZM internal dose estimates in mg/ kg body weight were calculated for each worker and each worker type by sampling interval and as a cumulative total over the 4 sampling days ( 120 hours). The results were corrected for background ( day  1) residue. The measured residues were corrected to 100% recovery based on recoveries of the associated field fortification samples. Residues < LOD were set to 1/ 2 LOD for all calculations. The measured residues were adjusted for the volume of urine collected and the internal dose was calculated by adjusting the MSMB excreted during each sampling interval for the cumulative percent of the absorbed dose excreted 120 hours after exposure ( as determined from a previous study   83.6%) and the percent of the urine activity attributed to MSMB ( determined from a previous study  9.2%).

MSMB residue levels are presented in this report as µ g equivalents of parent AZM. Equivalents were calculated using a molecular weight conversion factor of 1.328. The total MSMB excreted by each worker over the 120 hour sampling period following exposure was used to arrive at an estimated internal dose of AZM for each worker. ( See equation below.)

Risk estimates included this risk assessment are based on the estimated AZM internal doses from these three biomonitoring studies. Internal dose estimates reflect exposure via all routes ( dermal, inhalation, and oral). The following equation was used to estimate AZM internal doses:

Mean AZM Equivalent Dose ( mg/ kg/ day) = [ Total MSMB excreted in urine ( mg) * 83.6% of abs dose excreted after 120 hrs/ 100 * 9.2% of total AZM dose represented by MSMB/ 100] / Body Weight ( kg)

Blood Samples Plasma and red blood cell cholinesterase levels were measured in the workers to determine changes in cholinesterase activity prior to exposure in the field, on their first day in the field, and on their 2nd day in the field, which was 4 days after their first exposure. These measurements were compared to estimate the percentage of change in ChE activity as a result of single day exposures 4 days apart.

For the three studies, the percent change of plasma and RBC ChE inhibition compared to pre exposure measurements of cholinesterase activity ranged from  7 to 19% and  10 to 20%, respectively, as a result of one day of exposure. The average percent change of plasma and RBC ChE inhibition after one day of exposure for the three studies was 6.3% and 1.7%, respectively.

For the three studies, the percent change of plasma and RBC ChE inhibition compared to pre exposure measurements ranged from  12 to 28% and  9 to 18%, respectively, as a result of a 2 single days of exposure that were 4 days apart. The average percent change of plasma and RBC ChE inhibition on day 4 for the three studies was  1.7% and 1.5%, respectively.

Based on these data, there is no firm evidence of ChE inhibition. The data on plasma ChE and RBC AChE activity are considered variable as would be expected from assessing human plasma and RBC AChE under field conditions. Values for apparent decreases in ChE activity are nearly as much as the values obtained for apparent increase in activity. A few subjects may Page 26 of 42 appear to be showing some slight inhibition, but this is not considered to be within the resolving power of the assay defining inhibition.

Breathing Zone Air Samples Although inhalation exposures are reflected in the internal doses estimated from MSMB in the workers' urine samples, HED included the collection of separate inhalation exposure data to determine the significance of inhalation exposures. Breathing zone air samples were taken using OVS tubes, containing XAD 2 sorbent, and a personal air sampling pump attached to the worker's belt. The data were used to estimate risk for AZM exposure via the inhalation route for post application activities monitored in the blueberry, walnut, and apple studies.

Dermal exposure is expected to be the major route of concern for the postapplication activities monitored in the three studies. Inhalation doses ( mg/ kg/ day) were calculated based on the air concentrations ( ug/ m3) measured in the breathing zones of the workers. A minute volume of 16.7 liters per minute, representing light activity was assumed ( based on the 1997 EPA Exposure Factors Handbook Volume III). Exposures were assumed to occur for 8 hours per day.

Inhalation MOEs for post application workers were based on an inhalation NOAEL of 0.2 mg/ kg/ day and uncertainty factor ( UF) of 100). Estimated inhalation MOEs ( ranged from 100 to 790) are not a risk concern.

4.3 Exposure and Risk Estimates for AZM's Group 3 Uses Postapplication exposures for all Group 3 crops, except parsley, were based on internal AZM doses from biomonitoring studies conducted for apples, blueberries, walnuts. Biomonitoring data from blueberry postapplication activities were used as a surrogate for nursery stock activities. Biomonitoring data for apples were used for crabapples, pears, and cherries. Biomonitoring data for walnuts were used for almonds and pistachios. It is assumed that the activities monitored in these biomonitoring studies are representative of high end postapplication exposures for which there are no biomonitoring data: crabapples, cherries, and pears, almonds and pistacios, and nursery stock. Risk for contact with treated foliage of Brussels sprouts was not evaluated since applications are soil directed at transplant only. All exposure estimates were calculated at maximum label rates provided by SRRD.

Walnuts and almonds are the only Group 3 crops with MOEs of at least 100 for current REI ( 30 days). MOEs on day 30 for pistachios are greater than 100; however, the REI ( and PHI) is 21 days. An estimate of the day that MOEs would reach 100 for pistachios can not be calculated based on available data.

DFR data for blueberries, nursery stock, apples, and cherries were used to extrapolate the number of days for MOEs to reach 100. This extrapolation is considered to be a conservative estimate of the DFR for crops for which we have no data. To determine the absorbed dose representing reentry on subsequent days, the initial dose was adjusted for the decline of DFR using predicted DFR values calculated from a linear regression analysis of DFR data. Page 27 of 42 AZM internal dose " x" DAT = AZM internal dose Initial DAT * ( DFR " x" DAT / DFR Initial DAT)

Where: AZM internal dose " x" DAT = AZM internal dose received from exposure to a pesticide in a given scenario for " x" days after treatment ( mg pesticide active ingredient/ kg body weight/ exposure) AZM internal dose Initial DAT = AZM internal dose received from exposure to a pesticide in a given scenario on the initial day which the postapplication activity was conducted in the biomonitoring study, adjusted for application rate ( mg/ kg/ exposure) DFR " x" DAT = DFR value in a given scenario for " x" days after treatment ( ug/ cm2), adjusted for application rate DFR Initial DAT = Predicted DFR value from DFR study on the initial day which the postapplication activity was conducted in the biomonitoring study ( ug/ cm2), adjusted for application rate MOE = oral NOAEL / AZM internal dose " x" DAT For both DFR and biomonitoring data, HED assumed a linear relationship with application rate. This assumption regarding a linear relationship between rate and DFR and biomonitoring data is considered to be conservative.

For parsley, transfer coefficients were based on HED's Science Advisory Council for Exposure, Policy Memo # 003.1 ' Agricultural Transfer Coefficients', August 17, 2000. Exposures for postapplication activities associated with parsley ( vegetable " leafy" transfer coefficient group) were estimated for:

* high exposure: hand harvesting, pruning, thinning mature plants ( 500 cm2/ hr) * medium exposure: irrigation, scouting of mature plants ( 1500 cm2/ hr). * low exposure: irrigation, scouting, thinning, weeding of immature plants ( 2500 cm2/ hr).

Table 7 contains a summary of the exposure and risk for post application activities associated with for all Group 3 uses. The number of days for most of the crops to reach a MOE of 100 is significantly longer than the current REIs specified on EPA labels. Page 28 of 42 Table 7. Summary of Risks for Short term and Intermediate term Exposures ( Group 3) Postapplication Activities DFR Data Biomonitoring Data Crop Max Application Rate ( lb ai/ A) Crop/ Location MRID# Dissipation Inputs Location Reentry Activity MOE at current REI ( Day where MOE is > 100) REI on label Blueberries, Low Bush 0.75 MI MOE = 30 at 7 days ( MOE = 100 at 42 days) 10 days for low bush,

7 for high bush Nursery Stock 1.0 Blueberry/

ME, MI 4637602 Slope:  0.0345 Initial: 1.82 ug/ cm2 Study Rate: 0.75 lb ai/ A MI High Bush Blueberry Harvesting MOE = 23 at day 7 ( MOE = 102 at 18 days) 4 days Apple/ CA 44685303 Avg for CA Initial %: 22.7 dissipation per day %: 3 Apple Harvesting MOE = 7 at day 14 ( MOE= 100 at 103 days)

Apple/ OR,

WA 44694901 44685301 46317601 Avg for OR and WA Initial %: 19.3 dissipation per day %: 4.5 Apple Harvesting MOE = 7 at day 14 ( MOE= 101 at 73 days)

Apples 1.5 Apple/ NY 44685303 46317601 Avg for NY Initial %: 15.7 dissipation per day %: 8.7 NY, OR Apple Harvesting MOE = 7 at day 14 ( MOE= 102 at 44 days) 14 days NY, OR Apple Harvesting MOE = 7 at 14 days ( MOE= 104 at 64 days) 14 days Apples, Crabapples,

Pears 1.5 OR Apple Thinning MOE= 24 at 14 days ( MOE= 102 at 41 days) 14 days Cherries 0.75 Apple/

CA, OR, NY,

WA 44685303 44685301 44694901 46317601 Avg for CA, OR, NY, WA Initial %: 19.2 dissipation per day %: 5.3 NY, OR Apple Harvesting MOE = 14 at 14 days ( MOE = 103 at 49 days) 15 days NA NA NA Walnut Shakers MOE = 790 at day 30 NA NA NA Walnut Sweepers MOE= 440 at day 30 Walnuts, Almonds,

Pistachios 2.0 NA NA NA CA Walnut Rakers MOE= 170 at day 30 30 days for walnuts and almonds,

21 days for pistachios Parsley 0.5 Potato 40899801 Slope:  0.0833 Initial: 1.03 ug/ cm2 Study Rate: 0.75 lb ai/ A no data no data Short term MOE = 100 at day 44 Intermediate term MOE =

100 at day 49 ( with potatoes DFR and ARTF TCs) 30 days Page 29 of 42 Incident Reports Historically, AZM has ranked as one of the top organophosphate pesticides associated with worker exposure incidents. The incident summary in the 2/ 18/ 99 IRED for AZM ( D252505) ranked AZM as 6th among the 28 chemicals on which the Poison Control Center ( PCC) collects data ( J. Blondell, 1994). This ranking considered data from the PCC and the State of California. An updated summary of incident data for AZM covering PCC data up through 1996 did not indicate much change in incidents reported as to number or severity ( J. Blondell, 1999 via email communication with M. Rice). Past incidents have been associated with re entry violations, spray drift, and tree crop use. The majority of the incidents reported resulted in systemic illnesses defined as a poisoning case including eye, skin, or respiratory effects. The data summaries indicate relatively few hospitalizations have been associated with workers' exposure to AZM. The most recent data indicate that there has been a decline in poisoning incidents with AZM. Overall, PCC data indicate that over the 10 year period 1993 2003 there has been a 54% decline in exposures reported and a 47% decline in poisoning incidents reported ( personal communication J. Blondell 2005). Some of this decline may be because of improved reporting requirements for workers in California, safer work practices, and mitigation measures implemented since the 2001 IRED, such as lengthened REIs and formulation changes to place wettable powders in water soluble bags, and voluntary cancellation of the liquid products by the registrant.

In addition to the summary incident data, Washington State is conducting medical monitoring of pesticide handlers. The program monitors mixing, loading, and application activities associated with handlers only; post application workers are not being monitored. Under the program, the workers are monitored for cholinesterase activity changes as a result of exposure to multiple pesticides. The study represents workers' exposures under uncontrolled field conditions, working at least 8 hours per day, in some cases wearing no protective clothing, using open mixing and open cabs, and treating large acreages. In 2004, 2 out of 580 workers tested were reported with AZM exposures, but no information was given regarding their exposures' impact on cholinesterase activity. In 2005, 1 worker out of 611 tested was reported to have had cholinesterase depression of RBC AChE from 8 to 21% over a 3 month period as a result of exposure to AZM.

Although the biomonitoring studies supplied by the registrant were not designed as medical monitoring studies, cholinesterase activity was monitored for the post application workers. However, the field conditions in these biomonitoring studies were much more controlled than those in the WA State medical monitoring program. Workers were exposed for 1 day and then removed from the field for urine collection over the next 4 days, and they were exposed to AZM only. The data were variable and there was no firm evidence of ChE inhibition.

Conclusions and Risk Characterization In summary, the majority of the handler MOEs are less than 100. Handlers and mixer/ loaders involved in activities to support aerial applications of AZM have the lowest MOEs and are of the most concern. In the case of activities that support airblast applications, biomonitoring data and engineering controls ( closed cabs) result in MOEs of 102 for apples, pear Page 30 of 42 and crabapples and 80 for nuts. MOEs for activities that support groundboom applications vary depending the type of handler activity ( mixer/ loader versus applicator), but most are less than 100 with engineering controls. For post application activities, the number of days for most of the crops to reach a MOE of 100 is significantly longer that the current REIs specified on EPA labels.

HED believes these risk estimates for occupation activities are conservative and probably overestimate risks. These risk estimates are the result of a comparison of estimates of exposure to an endpoint for toxic effects.

On the exposure side, the handler exposure scenarios for aerial and groundboom applications are based on conventional PHED data and assumptions likely to overestimate risk, such as maximum application rates and acreages treated. The airblast exposure estimates have been refined through the use of biomonitoring data and are less conservative. Available medical monitoring data ( Washington State) support the characterization of this risk assessment as conservative as it indicates that typical exposures of handlers to AZM may result in detectable cholinesterase inhibition, but only in a small number of handlers ( 2/ 580 in 2004 and 1/ 611 in 2005) or < 1% of the workers tested. The 2 cases in 2004 and 1 case in 2005 reported AZM use specifically. HED notes that the 580 and 611 workers tested in 2004 and 2005, respectively, were tested irrespective of the active ingredient handled. However, given that AZM is used on 73% of the apple crop, many of the workers tested in 2004 and 2005 likely applied AZM. The MOEs on which the REIs are based have been refined through biomonitoring data. REIs indicate the minimum amount time between an AZM treatment and when a worker can reenter the field. The biomonitoring data for post application workers reflect reentry into a field at the minimum of time specified ( the REI) and, therefore, worst case exposures. In practice, a post application worker may not reenter a treated field until several days after the REI by which time AZM residues may have dissipated. Although representative of only one day of exposure to AZM, available biomonitoring data show no firm evidence of cholinesterase inhibition in postapplication workers.

On the hazard side, HED recognizes that as regards cholinesterase inhibition, animals and humans probably are similar. Although the NOAELs for ChE inhibition across species including humans are not very different, since the repeat dose study with humans is a NOAEL only study, there is no LOAEL for ChE inhibition in humans to compare with animal LOAELs. More importantly, the steep dose response that occurs in going from cholinesterase inhibition to more severe systemic effects is a caution to eliminating 10 fold safety factor for interspecies differences. In particular, HED notes the progression from moderate ChE inhibition to more severe systemic effects seen in the rat reproductive studies. In the rat reproduction study there was 25 47% RBC AChE inhibition during lactation at 0.55 mg/ kg/ day. Systemic effects are seen in pups ( decrease in viability index accompanied by a decrease in pup body weight during lactation) at the next higher dose of 1.5 mg/ kg/ day where there is 75 to 83% inhibition of RBC AChE during lactation. There is only a 2 to 3 fold difference between the non systemic effect dose on RBC AChE inhibition and a systemic effect dose of AZM. As the dose level in the rats is increased to 4.8 mg/ kg/ day and RBC AChE inhibition reaches 89 to 91% there are convulsions and deaths in the dams further indicating the seriousness of the systemic toxicity of AZM. Page 31 of 42 Incident data indicate a 50% decline in poisoning incidents involving AZM over time. Medical monitoring data indicating that a small percentage of workers exhibit mild but detectable cholinesterase inhibition as a result of AZM exposure. Given this, HED believes that the majority of the time workers are using AZM safely. HED further believes the selection of the dog oral endpoint as the lowest NOAEL in the toxicity database on the most sensitive endpoint coupled with a 100 fold safety factor is adequately protective, and results in MOEs that are conservative and overestimate risk. However, HED remains concerned that on occasion a worker's accidental exposures to AZM at higher levels than may be typical may occur and result in serious health consequences regardless of all safeguards because of the steep dose response for more serious effects seen in the animal reproduction studies. Page 32 of 42 APPENDICES Page 33 of 42 APPENDIX I ADDITIONAL TOXICITY TABLES Page 34 of 42 Table A. Comparison of NOAELs and LOAELs for ChE inhibition across animal species Species Type MRID NOAEL ( mg/ kg/ day) LOAEL  effects ( mg/ kg/ day)

Single Dose Studies Rat CC Pups 46162101 0.49 1  plasma, RBC and brain Rat CC Adults 46162101 0.6 1.1  plasma, RBC or brain ( not always)

Rat ANT 43360301 Not established 1 plasma, RBC and brain and clinical signs.

Repeat Dose Studies Rat ( 2 years) Chronic feeding/ carcinogenicity 41119901 0.25 @ 0.75 plasma, RBC and brain inhibited Rat (~ 10 days) Prenatal developmental toxicity 40464801 * 0.5 @ 1.0 brain inhibited Rat ( 11 days) Comparative Cholinesterase Assay 46239001 < 0.24 @ 0.24 RBC AChE inhibited ( Pups)

Rat ( 11 days) Comparative Cholinesterase Assay 46239001 0.54 1 plasma, RBC or brain ( Adults)

Rat ( continuous) Multi generation reproduction 41916801 < 0.4 @ 0.4 inhibition of RBC Dog ( 1 year) Chronic feeding 41804801 0.15 @ 0.69 RBC inhibition Rabbit (~ 13 days) Prenatal developmental toxicity 40713901 * 1 @ 2.5 plasma and RBC inhibition Mouse ( 1 year) Chronic feeding/ carcinogenicity 46009101 < 0.71 @ 0.71 RBC and brain inhibition Rat  90 day Inhalation 00155011 0.20 @ 0.78 plasma and RBC inhibition Rat  single dose Dermal absorption 42452701 0.56 @ 5.6 plasma inhibition Page 35 of 42 Table B. Bench Mark Dose ( BMD) Analyses for AZM RBC AChE  Adults Only Chronic Feeding ( MRID No.: 41119901) Interval Males Females BMD BMDL BMD BMDL 30 days 0.4241* 0.3656* 0.6486* 0.6876 0.4997* 0.5032 90 days 0.5679* 0.4764* 0.866 0.6625 0.7974 0.5151 180 days 0.7042* 0.5641* 0.5613* 0.4881* 360 days 0.3514* 0.3042* 0.4375* 0.3959* 540 days 0.4204* 0.3688* 0.4369* 0.4065* 720 days 0.377* 0.2427 0.3278* 0.2083 0.5544* 0.4992*

* High value dropped and based on 3 doses included the control. Subchronic Neurotoxicity ( MRID No.: 43826601)  W. Sletzer 25 0.2205 0.1857 0.1627* 0.1316 0.1504* 0.1132 88 0.1451 0.1047 0.219 0.1499 Single Dose Comparative ChE ( MRID No.: 46162101) P. Villaneuva 1 0.23 0.17 0.37 0.26 Repeat Dose Comparative ChE ( MRID No.: 46239001) P. Villaneuva 11 0.21 0.16 0.09 0.08 Brain AChE Adults and Pups Single Dose ChE ( MRID No.: 46162101) Comparative ChE WS Adult 11 day old 1.14 0.252 1.04 0.0936 PV Adult 11 day old 0.88 0.63 0.70 0.43 1.84 0.44 1.10 0.35 Repeat dose ( MRID No.: 46239001) Comparative ChE PV Adult 11 day old 13.85 0.19 1.40 0.16 1.90 0.13 1.14 0.12 Plasma and RBC ChE  Adults and Pups Single Dose Comparative ChE ( MRID No.: 46162101) Plasma  PV Adult 11 day old 6.51 0.64 0.60 0.40 1.20 0.47 0.59 0.35 RBC  PV Adult 11 day old 0.23 0.26 0.17 0.19 0.37 0.25 0.26 0.19 Repeat Dose Comparative ChE ( MRID No.: 46239001) P. Villaneuva Plasma  PV Adult 11 day old 0.37 0.16 0.28 0.14 0.39 0.20 0.25 0.17 RBC  PV Adult 11 day old 0.21 0.06 0.16 0.05 0.09 0.07 0.08 0.06 Page 36 of 42 AZM Conversion of Inhalation Dose in mg/ L to mg/ kg/ day Basis Equation:

Mg/ L x RVa ( in hours) x hours of exposure x study days/ week = mg/ kg/ day Wa x 7 days/ week Where RVa ( in hours) = respiratory volume in liters is fixed for rat strain and sex. For the Wistar strain rat, the RVa is 15.4 and 10.8 L/ hr for males and females respectively.

Wa = Mean body weight for a rat for a typical inhalation study. For the Wistar strain rat, these are 0.4 Kg and 0.25 kg for males and females respectively.

Note: The original equation did not specifically include the number of hours per day that the animals breathed the test atmosphere.

Specifics for the AZM study ( 1976, MRID No.: 00155011).

For the 90 day study with AZM, the Wistar strain rat was used and exposure was for 6 hours per day, five days per week for a total of 90 days (~ 13 weeks) so it is assumed that there were 65 exposure days. The NOAEL was determined to be 0.0012 mg/ L.

Applying the Equation:

( 0.0012 mg/ L) X ( 15.4 L/ hr) X ( 6 hr/ day) X ( 5 days/ week) = 0.198 mg/ kg/ day ( 0.4 Kg) X ( 7 days/ week) ( For males)

Similarly, the dose for females would be 0.222 mg/ kg/ day. Page 37 of 42 APPENDIX II TOTAL SHORT TERM AND INTERMEDIATE TERM HANDLER EXPOSURE RISK Page 38 of 42 Table A1 Intermediate Term Baseline Risk for Agricultural Uses of AZM Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Applicati on Rate4 lb ai/ A Daily Area Treated5 A/ day Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Wettable Powders for Aerial application) 3.7 43 Apple, Pear, Crabapple 1.50 350 12 < 1 0.32 < 1 < 1 Wettable Powders for Aerial application 3.7 43 Blueberry 0.75 350 5.8 < 1 0.16 < 1 < 1 Wettable Powders for Groundboom application 3.7 43 Blueberry 0.75 80 1.3 < 1 0.037 5 < 1 Wettable Powders for Groundboom application 3.7 43 Brussels Sprouts 0.75 80 1.3 < 1 0.037 5 < 1 Wettable Powders for Groundboom application 3.7 43 Parsley 0.50 80 0.89 < 1 0.025 6 < 1 Wettable Powders for Groundboom application 3.7 43 Nursery stock 1 80 1.8 < 1 0.049 3 < 1 Applicator Sprays for Aerial application No Data No Data Apple, Pear, Crabapple 1.50 350 No Data No Data No Data No Data No Data Sprays for Aerial application No Data No Data Blueberry 0.75 350 No Data No Data No Data No Data No Data Sprays for Groundboom application 0.014 0.74 Blueberry 0.75 80 0.0050 30 0.00063 240 25 Sprays for Groundboom application 0.014 0.74 Brussels Sprouts 0.75 80 0.0050 30 0.00063 240 25 Sprays for Groundboom application 0.014 0.74 Parsley 0.50 80 0.0034 45 0.00042 360 40 Sprays for Groundboom application 0.014 0.74 Nursery stock 1 80 0.0067 23 0.00085 175 20 Flagger Flagging for Sprays application 0.011 0.35 Apple, Pear, Crabapple 1.50 350 0.035 42 0.0026 60 25 Flagging for Sprays application 0.011 0.35 Blueberry 0.75 350 0.017 8 0.0013 115 8 1Baseline dermal unit exposures represent long pants, long sleeved shirts, shoes, and socks. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 2Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 3Crops and use patterns are from AZM crops in groups 3 4Application rates are based on maximum values found in various sources including LUIS and labels.

5Amount treated is based on the area that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Dermal absorption ( 42%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres)] / Body weight ( 70 kg).

7Dermal MOE = NOAEL ( 0.15 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre) * Daily area treated ( acres)] / Body weight ( 70 kg).

9Inhalation MOE = NOAEL ( 0.2 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100. Page 39 of 42 Table A2: Intermediate Term Engineering Control Risk for Agricultural Uses of AZM Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Applicat ion Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Wettable Powders for Aerial application 0.0098 0.24 Apple, Pear, Crabapple 1.50 350 0.031 5 0.0018 110 5 Wettable Powders for Aerial application 0.0098 0.24 Blueberry 0.75 350 0.015 10 0.0009 165 9 Wettable Powders for Groundboom application 0.0098 0.24 Blueberry 0.75 80 0.0035 42 0.00021 715 40 Wettable Powders for Groundboom application 0.0098 0.24 Brussels Sprouts 0.75 80 0.0035 42 0.00021 715 40 Wettable Powders for Groundboom application 0.0098 0.24 Parsley 0.50 80 0.0024 63 0.00014 1070 60 Wettable Powders for Groundboom application 0.0098 0.24 Nursery stock 1 80 0.0047 32 0.00027 555 30 Applicator Sprays for Aerial application 0.005 0.068 Apple, Pear, Crabapple 1.50 350 0.016 10 0.00051 295 10 Sprays for Aerial application 0.005 0.068 Blueberry 0.75 350 0.0079 20 0.00026 575 18 Sprays for Groundboom application 0.005 0.043 Blueberry 0.75 80 0.0018 85 0.000037 4055 80 Sprays for Groundboom application 0.005 0.043 Brussels Sprouts 0.75 80 0.0018 85 0.000037 4055 80 Sprays for Groundboom application 0.005 0.043 Parsley 0.50 80 0.0012 125 0.000025 6000 122 Sprays for Groundboom application 0.005 0.043 Nursery stock 1 80 0.0024 63 0.000049 3060 60 Flagger Flagging for Sprays application 0.00022 0.007 Apple, Pear, Crabapple 1.50 350 0.00069 217 0.000053 2830 200 Flagging for Sprays application 0.00022 0.007 Blueberry 0.75 350 0.00035 430 0.000026 5770 400 1Engineering controls dermal unit exposures represent long pants and long sleeved shirts. For mixers and loaders, chemical resistant gloves are also included. Values are reported in the PHED Surrogate Exposure Guide dated August 1998.

2Engineering controls inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 3Crops and use patterns are from AZM crops in Group 3 4Application rates are based on maximum values found in various sources including LUIS and labels.

5Amount treated is based on the area that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Dermal absorption ( 42%) * Application rate ( lb ai/ acre) * Daily area treated ( acres] / Body weight ( 70 kg).

7Dermal MOE = NOAEL ( 0.15 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre) * Daily area treated ( acres )] / Body weight ( 70 kg).

9Inhalation MOE = NOAEL ( 0.2 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100.

Table A3 Short Term Baseline Risk for Agricultural Uses of AZM Page 40 of 42 Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Applicatio n Rate4 lb ai/ A Daily Area Treated5 A/ day Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Wettable Powders for Aerial application) 3.7 43 Apple, Pear, Crabapple 1.50 350 27.750 < 1 0.3225 < 1 < 1 Wettable Powders for Aerial application 3.7 43 Blueberry 0.75 350 13.875 < 1 0.1612 1 < 1 Wettable Powders for Groundboom application 3.7 43 Blueberry 0.75 80 3.171 < 1 0.0368 5 < 1 Wettable Powders for Groundboom application 3.7 43 Brussels Sprouts 0.75 80 3.171 < 1 0.0368 5 < 1 Wettable Powders for Groundboom application 3.7 43 Parsley 0.50 80 2.114 < 1 0.0246 8 < 1 Wettable Powders for Groundboom application 3.7 43 Nursery stock 1 80 4.228 < 1 0.0491 4 < 1 Applicator Sprays for Aerial application No Data No Data Apple, Pear, Crabapple 1.50 350 No Data No Data No Data No Data No Data Sprays for Aerial application No Data No Data Blueberry 0.75 350 No Data No Data No Data No Data No Data Sprays for Groundboom application 0.014 0.74 Blueberry 0.75 80 0.012 46 0.000634 315 40 Sprays for Groundboom application 0.014 0.74 Brussels Sprouts 0.75 80 0.012 46 0.000634 315 40 Sprays for Groundboom application 0.014 0.74 Parsley 0.50 80 0.008 70 0.000422 472 60 Sprays for Groundboom application 0.014 0.74 Nursery stock 1 80 0.016 35 0.000846 236 30 Flagger Flagging for Sprays application 0.011 0.35 Apple, Pear, Crabapple 1.50 350 0.0825 7 0.002625 76 6 Flagging for Sprays application 0.011 0.35 Blueberry 0.75 350 0.0412 13 0.00131 152 12 1Baseline dermal unit exposures represent long pants, long sleeved shirts, shoes, and socks. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 2Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 3Crops and use patterns are from AZM crops in groups 3 4Application rates are based on maximum values found in various sources including LUIS and labels.

5Amount treated is based on the area that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres )] / Body weight ( 70 kg).

7Dermal MOE = NOAEL ( 0.56 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre) * Daily area treated ( acres)] / Body weight ( 70 kg).

9Inhalation MOE = NOAEL ( 0.2 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100. Page 41 of 42 Table A4: Short  Term Engineering Control Risk for Agricultural Uses of AZM Exposure Scenario ( Scenario #) Dermal Unit Exposure ( mg/ lb ai) 1 Inhalation Unit Exposure ( Ug/ lb ai) 2 Crop3 Applicat ion Rate4 Daily Area Treated5 Dermal Dose ( mg/ kg/ day) 6 Dermal MOE 7 Inhalation Dose ( mg/ kg/ day) 8 Inhalation MOE9 Total MOE10 Mixer/ Loader Wettable Powders for Aerial application 0.0098 0.24 Apple, Pear, Crabapple 1.50 350 0.0735 7 0.0018 111 7 Wettable Powders for Aerial application 0.0098 0.24 Blueberry 0.75 350 0.03675 15 0.0009 222 14 Wettable Powders for Groundboom application 0.0098 0.24 Blueberry 0.75 80 0.0084 66 0.000206 972 62 Wettable Powders for Groundboom application 0.0098 0.24 Brussels Sprouts 0.75 80 0.0084 66 0.000206 972 62 Wettable Powders for Groundboom application 0.0098 0.24 Parsley 0.50 80 0.0056 100 0.000137 1458 93 Wettable Powders for Groundboom application 0.0098 0.24 Nursery stock 1 80 0.0112 50 0.000274 730 46 Applicator Sprays for Aerial application 0.005 0.068 Apple, Pear, Crabapple 1.50 350 0.0375 15 0.00051 392 14 Sprays for Aerial application 0.005 0.068 Blueberry 0.75 350 0.02036 27 0.000277 722 26 Sprays for Groundboom application 0.005 0.043 Blueberry 0.75 80 0.00429 130 0.0000368 5426 127 Sprays for Groundboom application 0.005 0.043 Brussels Sprouts 0.75 80 0.00429 130 0.0000368 5426 127 Sprays for Groundboom application 0.005 0.043 Parsley 0.50 80 0.00286 196 0.0000246 8139 191 Sprays for Groundboom application 0.005 0.043 Nursery stock 1 80 0.00571 98 0.0000492 4069 95 Flagger Flagging for Sprays application 0.00022 0.007 Apple, Pear, Crabapple 1.50 350 0.00165 340 0.0000525 3809 311 Flagging for Sprays application 0.00022 0.007 Blueberry 0.75 350 0.000825 680 0.00002625 7619 623 1Engineering controls dermal unit exposures represent long pants and long sleeved shirts. For mixers and loaders, chemical resistant gloves are also included. Values are reported in the PHED Surrogate Exposure Guide dated August 1998.

2Engineering controls inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 3Crops and use patterns are from AZM crops in Group 3 4Application rates are based on maximum values found in various sources including LUIS and labels.

5Amount treated is based on the area that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values).

6Dermal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Application rate ( lb ai/ acre ) * Daily area treated ( acres ] / Body weight ( 70 kg).

7Dermal MOE = NOAEL ( 0.56 mg/ kg/ day) / Daily Dermal Dose. Target Dermal MOE is 100.

8Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre) * Daily area treated ( acres )] /

Body weight ( 70 kg).

9Inhalation MOE = NOAEL ( 0.2 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100. Page 42 of 42 Table A5: Short and Intermediate Term Risk for Agricultural Uses of AZM ( Biomonitoring Study)

Exposure Scenario ( Scenario #) Internal Unit Exposure ( mg/ lb ai) 1 Crop2 Application Rate3 lb ai/ A Daily Area reated4 A/ day Total Dose ( mg/ kg/ day) 5 Total MOE 6 Mixer/ Loader/ applicator for Open Cab Airblast ( Data Source biomonitoring study 46316406)

Mixing/ Loading/ Applying for Airblast 0.0095 Apple, Pear, Crabapple 1.5 40 0.00814 18 Mixing/ Loading/ Applying for Airblast 0.0095 Cherry 0.75 40 0.00417 36 Mixing/ Loading/ Applying for Airblast 0.0095 Almond, pistachio, walnut 2.0 40 0.0109 14 Mixing/ Loading/ Applying for Airblast 0.0095 Nursery stock 1.0 40 0.00542 28 Mixer/ Loader/ applicator for Closed Cab Airblast ( Data Source biomonitoring study 46316406)

Mixing/ Loading/ Applying for Airblast 0.0017 Apple, Pear, Crabapple 1.5 40 0.00146 102 Mixing/ Loading/ Applying for Airblast 0.0017 Cherry 0.75 40 0.00073 205 Mixing/ Loading/ Applying for Airblast 0.0017 Almond, pistachio, walnut 2.0 40 0.00194 80 Mixing/ Loading/ Applying for Airblast 0.0017 Nursery stock 1.0 40 0.00097 155 1 Values are reported in the Biomonitoring study with MRID # 46316406 2. Crops and use patterns are from AZM Group 3 3 Application rates are based on maximum values found in various sources including LUIS and labels 4. Amount treated is based on the area that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values)

5Internal dose ( mg/ kg/ day) = [ unit exposure ( mg/ lb ai) * Gut absorption ( 100%) * Application rate ( lb ai/ acre) * Daily area treated ( acres] / Body weight ( 70 kg).

6 Total MOE = NOAEL ( 0.15 mg/ kg/ day) / Internal Dose. Target MOE is 100.