UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: July 10, 2008

MEMORANDUM

PC Code:  041101	DP Barcode:  D342754 and D342793

Decision No.: 382076, 299884	Registration No.:  7E7247, 5E4491

Petition No.: 5E4491 and 7E7247	Regulatory Action: New Registration/Tolerance

Risk Assessment Type: Single Chemical Aggregate	Case No.:  N/A

TXR No.:  N/A	CAS No.: 13194-48-4

MRID No.:  N/A	40 CFR:  180.262

FROM:	Kit Farwell, DVM, Risk Assessor

		Christine Olinger, Chemist

		Matthew Lloyd, Occupational Exposure Assessor

		Reregistration Branch 1

		Health Effects Division (7509P)

THROUGH:	Michael Metzger, Branch Chief

		Reregistration Branch 1

		Health Effects Division (7509P)

TO:		Susan Stanton, Product Manager

Risk Integration, Minor Use & Emergency Response Branch

		Registration Division (7505P)

Following is the human health risk assessment for ethoprop.

Table of Contents

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc203446689"  1.0	Executive Summary	  PAGEREF _Toc203446689 \h  4

  HYPERLINK \l "_Toc203446690"  2.0	Ingredient Profile	  PAGEREF _Toc203446690 \h  8

  HYPERLINK \l "_Toc203446691"  2.1	Summary of Registered and Proposed Uses	  PAGEREF _Toc203446691 \h  8

  HYPERLINK \l "_Toc203446692"  2.2	Structure and Nomenclature	  PAGEREF _Toc203446692 \h  10

  HYPERLINK \l "_Toc203446693"  2.3	Physical and Chemical Properties	  PAGEREF _Toc203446693 \h  11

  HYPERLINK \l "_Toc203446694"  3.0	Hazard Characterization/Assessment	  PAGEREF _Toc203446694 \h  11

  HYPERLINK \l "_Toc203446695"  3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc203446695 \h  11

  HYPERLINK \l "_Toc203446696"  3.1.1	Database Summary	  PAGEREF _Toc203446696 \h  11

  HYPERLINK \l "_Toc203446697"  3.1.2	Mode of Action, Metabolism, and Toxicological Effects	  PAGEREF _Toc203446697 \h  11

  HYPERLINK \l "_Toc203446698"  3.3	FQPA Considerations	  PAGEREF _Toc203446698 \h  12

  HYPERLINK \l "_Toc203446699"  3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc203446699 \h  12

  HYPERLINK \l "_Toc203446700"  3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc203446700 \h  12

  HYPERLINK \l "_Toc203446701"  3.3.3	Studies Assessing Offspring Sensitivity	  PAGEREF _Toc203446701 \h  13

  HYPERLINK \l "_Toc203446702"  3.3.4	Degree of Concern Analysis for Pre and Postnatal Susceptibility	  PAGEREF _Toc203446702 \h  14

  HYPERLINK \l "_Toc203446703"  3.4	FQPA Safety Factor for Infants and Children	  PAGEREF _Toc203446703 \h  15

  HYPERLINK \l "_Toc203446704"  3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF _Toc203446704 \h  15

  HYPERLINK \l "_Toc203446705"  3.5.1    Acute Reference Dose (aRfD)	  PAGEREF _Toc203446705 \h  15

  HYPERLINK \l "_Toc203446706"  3.5.2	Chronic Reference Dose (cRfD)	  PAGEREF _Toc203446706 \h  16

  HYPERLINK \l "_Toc203446707"  3.5.3	Dermal Absorption	  PAGEREF _Toc203446707 \h  17

  HYPERLINK \l "_Toc203446708"  3.5.4	Dermal Exposure – Liquid Formulations	  PAGEREF _Toc203446708 \h  18

  HYPERLINK \l "_Toc203446709"  3.5.5	Dermal Exposure – Granular Formulations	  PAGEREF _Toc203446709 \h  18

  HYPERLINK \l "_Toc203446710"  3.5.6	Inhalation Exposure	  PAGEREF _Toc203446710 \h  19

  HYPERLINK \l "_Toc203446711"  3.5.7	Level of Concern for Margin of Exposure	  PAGEREF _Toc203446711 \h  19

  HYPERLINK \l "_Toc203446712"  3.5.8	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF _Toc203446712 \h  20

  HYPERLINK \l "_Toc203446713"  3.5.9	Classification of Carcinogenic Potential	  PAGEREF _Toc203446713 \h  20

  HYPERLINK \l "_Toc203446714"  3.5.10	Toxicological Doses and Endpoints   PAGEREF _Toc203446714 \h  20

  HYPERLINK \l "_Toc203446715"  3.6	Endocrine disruption	  PAGEREF _Toc203446715 \h  21

  HYPERLINK \l "_Toc203446716"  4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF _Toc203446716 \h  22

  HYPERLINK \l "_Toc203446717"  5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc203446717 \h  23

  HYPERLINK \l "_Toc203446718"  5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF _Toc203446718 \h  23

  HYPERLINK \l "_Toc203446719"  5.1.2	Drinking Water Residue Profile	  PAGEREF _Toc203446719 \h  24

  HYPERLINK \l "_Toc203446720"  5.1.3	Food Residue Profile	  PAGEREF _Toc203446720 \h  25

  HYPERLINK \l "_Toc203446721"  5.2	Dietary Exposure and Risk	  PAGEREF _Toc203446721 \h  25

  HYPERLINK \l "_Toc203446722"  5.2.1	Acute Dietary Exposure/Risk	  PAGEREF _Toc203446722 \h  26

  HYPERLINK \l "_Toc203446723"  5.2.2	Chronic Dietary Exposure/Risk	  PAGEREF _Toc203446723 \h  27

  HYPERLINK \l "_Toc203446724"  5.2.3	Cancer Dietary Risk	  PAGEREF _Toc203446724 \h  30

  HYPERLINK \l "_Toc203446725"  6.0	Residential (Non-Occupational) Exposure	  PAGEREF _Toc203446725 \h  31

  HYPERLINK \l "_Toc203446726"  7.0	Aggregate Risk Assessments	  PAGEREF _Toc203446726 \h  31

  HYPERLINK \l "_Toc203446727"  8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc203446727 \h  31

  HYPERLINK \l "_Toc203446728"  9.0	Occupational Exposure and Risk	  PAGEREF _Toc203446728 \h  31

  HYPERLINK \l "_Toc203446729"  9.1	Occupational Handler Exposure (PHED-based)	  PAGEREF _Toc203446729 \h  31

  HYPERLINK \l "_Toc203446730"  9.1.1	Occupational Handler Risk (PHED-based)	  PAGEREF _Toc203446730 \h  33

  HYPERLINK \l "_Toc203446731"  9.2	Occupational Handler Exposure (Biomonitoring-based)	  PAGEREF _Toc203446731 \h  36

  HYPERLINK \l "_Toc203446732"  9.2.1	Occupational Handler Risk (Biomonitoring-based)	  PAGEREF _Toc203446732 \h  37

  HYPERLINK \l "_Toc203446733"  9.3	Risk Characterization Comparing PHED and Biomonitoring Assessments	  PAGEREF _Toc203446733 \h  41

  HYPERLINK \l "_Toc203446734"  9.4	Occupational Cancer Exposure	  PAGEREF _Toc203446734 \h  42

  HYPERLINK \l "_Toc203446735"  9.4.1	Occupational Handler Cancer Risk	  PAGEREF _Toc203446735 \h  42

  HYPERLINK \l "_Toc203446736"  9.5	Occupational Postapplication Exposure	  PAGEREF _Toc203446736 \h  44

  HYPERLINK \l "_Toc203446737"  10.0	Data Needs	  PAGEREF _Toc203446737 \h  44

  HYPERLINK \l "_Toc203446738"  11.0	References	  PAGEREF _Toc203446738 \h  45

  HYPERLINK \l "_Toc203446739"  Appendix A:  Toxicology Assessment	  PAGEREF _Toc203446739 \h  46

  HYPERLINK \l "_Toc203446740"  A.1	Toxicology Data Requirements	  PAGEREF _Toc203446740 \h  46

  HYPERLINK \l "_Toc203446741"  A.2	Toxicity Profiles	  PAGEREF _Toc203446741 \h  47

  HYPERLINK \l "_Toc203446742"  A.3	Executive Summaries	  PAGEREF _Toc203446742 \h  53

  HYPERLINK \l "_Toc203446743"  Appendix B:  Tolerance Reassessment Summary	  PAGEREF _Toc203446743 \h  61

  HYPERLINK \l "_Toc203446744"  Appendix C:  Review of Human Research	  PAGEREF _Toc203446744 \h  62

1.0	Executive Summary  TC \l1 "1.0	Executive Summary

Background:  Ethoprop or ethoprophos (O-ethyl S,S-dipropyl phosphorodithioate) is an organophosphate insecticide with tolerances on numerous crops.  There are no residential uses for ethoprop.  Since the last risk assessment was written, new toxicity studies have been reviewed including a developmental neurotoxicity study and comparative cholinesterase studies in adults and offspring.

In this risk assessment, new endpoints of brain cholinesterase inhibition from the comparative cholinesterase studies were selected for dietary exposure, replacing endpoints of plasma cholinesterase inhibition used in the previous risk assessment.  This risk assessment addresses the proposed new uses on hops and mint and the proposed tolerance for both commodities at 0.02 ppm, and includes new water monitoring data.  The dietary assessment includes all uses and results from the new water monitoring study.  The occupational assessment evaluates the new uses in hops and mints.

A cumulative assessment of organophosphate pesticides has been completed since the last risk assessment.  Dietary exposure to ethoprop from the proposed new uses in hops and mints is not expected to make a significant addition to dietary exposure and risk in the cumulative assessment.

Hazard:  The toxic mode of action in insects and humans is by phosphorylation of the acetylcholinesterase (referred to as cholinesterase or ChE in this document) enzyme in the brain and peripheral nervous systems.  The resulting enzyme inhibition causes accumulation of the neurotransmitter, acetylcholinesterase, and resulting signs of neurotoxicity.

Ethoprop is acutely toxic and is in toxicity category I by both oral and dermal routes.  In the longer term studies, the most sensitive indication of toxicity was inhibition of brain and red blood cell (RBC) ChE.   A slight anemia and liver toxicity (elevated liver enzymes and microscopic liver lesions) were also noted in dog studies.

Ethoprop is classified "likely to be carcinogenic to humans" based on malignant adrenal pheochromocytomas in male rats and is regulated with a Q1*.

Studies Assessing Offspring Sensitivity   TC \l3 "3.3.3	Developmental Toxicity Studies  No developmental toxicity was noted in rat and rabbit developmental studies.  In the 2-generation reproduction study, the high dose was reduced because of pup mortality.  Parental toxicity at this dose included clinical signs due to ChE inhibition (tremors and loose stools) and significant inhibition of brain ChE activity.  Reproductive parameters were unaffected by treatment in the 2-generation reproduction study.

In the developmental neurotoxicity study, an effect on learning (water maze) was noted in high-dose males.  Motor activity in all male treatment groups was increased on postnatal day 17 due to a lack of habituation (i.e., there was little or no decrease in activity over the course of the test session).  There was no indication of increased offspring sensitivity to ChE inhibition in this study.

The relative sensitivities of adult rats and 11-day old rat pups to ChE inhibition were compared in acute and 11-day comparative cholinesterase studies.  Pups were 8 times as sensitive as adults for brain ChE inhibition in the acute study and were 12 times as sensitive as adults in the 11-day study.  Pup sensitivity is believed to be due to their immature metabolic capacity.

FQPA Safety Factor:  The point of departure selected for dietary assessments is lower than the doses at which offspring toxicity occurred in the reproduction study and is protective of offspring toxicity occurring at higher doses.  There were no residual concerns and the FQPA safety factor was reduced to 1x.

Toxicity Endpoints:  The toxicity endpoint for acute and chronic dietary exposure was brain ChE inhibition in pups in the acute and 11-day comparative cholinesterase studies, respectively.  Benchmark dose (BMD) modeling was used to select a point of departure for dietary exposure.  The BMDL10, which is the lower 95% confidence limit on the estimated mean brain ChE inhibition 10% effect level, was used to evaluate risk.

Endpoints for dermal exposure were also based on brain ChE inhibition.  A separate dermal toxicity study was conducted using granular product to assess dermal exposure.  Dermal assessments used no observed adverse effect levels (NOAELs) as points of departure.  Dermal absorption was considered equivalent to oral absorption for cancer assessments by the dermal route.  Because an inhalation study was not available, inhalation exposure was assessed using an oral endpoint of brain ChE inhibition from the comparative cholinesterase study.

Drinking Water:  Dietary exposures calculated in this risk assessment incorporated updated modeling and recently conducted monitoring data.  The monitoring study targeted five watersheds with relatively high ethoprop usage believed vulnerable to contamination by pesticides.  The monitoring concentrations were much lower than modeling concentrations.  EFED characterized the modeled estimates as likely to be overestimates of exposure and the monitoring study as possibly an underestimate of peak exposure.  However, actual concentrations in water are expected to be closer to the monitoring results than to the modeling results.

Acute Dietary Risk  TC \l3 "5.2.1  Acute Dietary Exposure/Risk :  If the highest surface water monitoring value (0.23 ppb) is used as well as the value twice that (0.52 ppb), combined food and water exposures are well below the level of concern.  The highest exposed population sub-group is infants at 18% or 19% of the aPAD for when 0.23 or 0.52 ppb is used for the estimated drinking water concentration (EDWC) at the 99.9th percentile of exposure.  Combined food and water risk is below the level of concern at water concentrations up to 15 ppb.  When the PRZM-EXAMS modeled value is used for the drinking water concentration (138 ppb), the risk exceeds the level of concern; infants are the highest exposed population with exposure at 920% aPAD.

Chronic Dietary Risk:  All exposure estimates are below the level of concern for all population groups, using all estimated drinking water concentrations.

Cancer Dietary Risk  TC \l3 "5.2.3  Cancer Dietary Risk :  The estimated risk for food alone is below the level of concern.  Water was the greatest contributor to the aggregate cancer dietary exposure and analyses were conducted with varying levels of water concentrations.  If the maximum modeled estimate (10.1 ppb) is used as the drinking water concentration the estimated cancer risk is 6 x 10-6, which exceeds the level of concern.

As noted above, the modeled water concentration is believed to be an overestimate of exposure.  The combined cancer risk for food and water is below the level of concern if results from the water monitoring study (0.23 ppb) are used.  The combined risk for food and water is below the level of concern even at water concentrations (over a lifetime of exposure) up to 5 ppb.

Occupational Exposure:  Occupational exposure was evaluated both by following Exposure Science Advisory Council SOPs and data from the Pesticide Handlers Exposure Database (PHED) as well as data from a biomonitoring study using the granular product.  Data from adult human subjects in the PHED study has received ethical review and all regulatory requirements were met.  The human biomonitoring study has received preliminary ethical review and no ethical concerns were raised in this preliminary review.

Occupational Risk (PHED based):  For granular exposure scenarios, risks do not exceed HED’s level of concern for loading granulars with engineering controls.  For liquid exposure scenarios, risks exceed HED’s level of concern for mixer/loader and application scenarios with proposed label engineering controls/label PPE at both assessed application rates.

For applicator scenarios, risks exceed HED’s level of concern with proposed label engineering controls/label PPE.  For granular exposure scenarios, risks exceed HED’s level of concern for the higher application rates (6 lbs ai/A) but do not exceed HED’s level of concern for the lower application rate (3 lbs ai/A) with proposed engineering controls/label PPE.

Occupational Risk (Biomonitoring):  Following HED’s initial risk assessment of ethoprop, the registrant conducted a biological monitoring study of ethoprop.  The ethoprop biomonitoring study was performed with the sole purpose of quantifying professional applicator exposure during the use of ethoprop formulated as MOCAP® EC in Pacific Northwest potato fields. Because the proposed uses are similar in application profile and equipment, the results of the biological monitoring study on users in Washington State potato fields was applied to the new uses on hops and mint.

Individual MOEs varied widely, but in general the study showed low levels of exposure and associated risk when the required engineering controls are utilized and appropriate PPE are worn. Although in some cases, the workers used both engineering controls and various levels of PPE, the Agency believes that the low exposure are primarily attributed to the use of the engineering controls.

Occupational Cancer Risk:  There were no risk concerns for cancer for occupational workers identified at the proposed label engineering controls.

Occupational Postapplication Exposure:  Postapplication exposures to ethoprop were not assessed because the proposed label is for pre-plant/pre-bloom and post-emergent (to soil only) crop applications. Due to the method and timing of applications and typical agricultural practices for these crops, HED has determined that postapplication exposure is not likely to occur.

Data Needs   TC \l1 "10.0	Data Needs and Label Recommendations : An immunotoxicity study (870.7800) is required.  This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non-food uses).  A 90-Day inhalation toxicity study (870.3465) is also required.  This study is required for a route-specific assessment of inhalation toxicity which is presently assessed using an oral endpoint.

Environmental Justice:  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations,"   HYPERLINK "http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"  http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Human Studies:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies (listed in Appendix C), which comprise the Pesticide Handlers Exposure Database (PHED), have been determined to require a review of their ethical conduct, and have received that review.  A biomonitoring study has received a partial review.

Regulatory Recommendations:   HED has no objections to the establishment of tolerances for ethoprop of 0.02 ppm in hops and mint.  There are no concerns for aggregate exposure using the new water monitoring data and there are no concerns for occupational exposure using the biomonitoring data.

2.0	Ingredient Profile

2.1	Summary of Registered and Proposed Uses

Background on Currently Registered Use Pattern:     SEQ CHAPTER \h \r 1 Ethoprop [S,S-dipropyl O-ethyl phosphorodithioate] is an organophosphate  insecticide/nematicide registered for use on bananas/plantains, beans (lima and snap), cabbage, citrus (non-bearing), corn, cucumbers,  pineapples, potatoes, sugarcane, sweet potatoes, and tobacco.  The use on peanuts was voluntarily cancelled in association with the Reregistration Eligibility Decision (RED) and EPA proposed to revoke the peanut tolerances in a Federal Register notice dated 6/4/08.

Ethoprop is manufactured by Bayer CropScience under the trade name MOCAP® and is formulated as either an emulsifiable concentrate (EC), that can be applied at a rate of 4.2 lbs ai/A (EPA Reg. No. 264-458), or 15% granular nematicide-insecticide (EPA Reg. No. 264-457) that can be applied at 6 lbs ai/A for application to food/feed crops.  These products may be applied as broadcast or banded preplant to preemergence applications and as banded postemergence applications directed to the soil.  Use directions specify the exclusive use of ground equipment.

The proposed label is for application to hops and mint using motorized ground equipment. Air blast, aerial application and application through irrigation equipment are prohibited per the proposed labels. Table 2.1 contains a summary of the proposed use patterns.

IR-4 previously submitted a petition requesting the use of ethoprop (EC and granular) on mint in the U.S. (PP#5E4491).  The mint petition was originally submitted in 1995 and was reviewed by the Agency (DP# D214091, G. Otakie, 8/14/1995), but later with the inception of FQPA was rendered inactive pending completion of the OP cumulative risk assessment.  Now that the cumulative risk assessment has been completed, the petition has been reactivated.   Additionally, IR-4 has submitted a new petition (PP#7E7247) requesting the use of ethoprop (EC) on hops in the U.S.  In conjunction with these uses, IR-4 is proposing the establishment of permanent tolerances for ethoprop residues on mint and hops at 0.02 ppm.

Table 2.1.  Use Pattern Summary of Proposed New Use of Ethoprop on Hops and Mint

Formulations

Emulsifiable Concentrate [EC] (mint & hops):

Granular [G] (mint):

Pests

Hops:  Symphylans prionus (long-horned beetle)

Mint:  Symphylans, Nematodes, Mint Root Borer

Application Methods

Motorized ground equipment only (groundboom/tractor spreader)

Application Rates and Intervals

EC (mint & hops):

   4.2 lbs ai/A (max. app. rate) [hops]

   2.1 lbs ai/A  (max. app. rate) [mint]

G (mint):

   6 lbs ai/A [mint - nematodes]

   3 lbs ai/A [mint – symphylans]

Frequency

EC (mint & hops):

  Hops: Not more than 2 quarts MOCAP EC per acre per season

  Mint: Make one EC application per growing season.

G (mint):

  maximum one application per growing season

PHI

225 days (mint); 90 day (hops)

PPE	EC:  Long-sleeve shirt and long pants, shoes plus socks; M/L must also wear chemical resistant gloves/apron

G:  Long-sleeve shirt and long pants, shoes plus socks; M/L must also wear chemical resistant gloves/apron w/ non-powered air purifying respirator w/ N, R, or P, series filter*

REI

Not listed on proposed label

* additional PPE is required for when handlers  are “engaged in those activities for which use of an engineering control is not possible…”

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature

Table 2.2.	Nomenclature of Ethoprop and its Metabolites of Concern.

Ethoprop  or  Ethoprophos

O-ethyl-S,S-dipropyl phosphorodithioate

CAS:  13194-48-4

Metabolite II (S-Me)

O-ethyl-S-methyl-S-propyl phosphorodithioate

Metabolite III (O-Me)

O-ethyl-O-methyl-S-propyl phosphorodithioate

Metabolite IV (M-1)

O-ethyl-S-propyl phosphorodithioate

SSDP (S,S-dipropyl degradate)

S,S-dipropylphosphorodithioate

S-Me, O-Me, and M-1 are all plant and animal metabolites and are also environmental degradates detectable in water.  SSDP is an environmental degradate but is not a plant or animal metabolite.

S-Me and O-Me are ChE inhibitors and are therefore of concern for non-cancer risk assessments.  M-1 and SSDP are not ChE inhibitors and are not of concern for non-cancer risk assessments.  All four metabolite/degradates should be included in cancer risk assessments.

Physical and Chemical Properties

  SEQ CHAPTER \h \r 1 Ethoprop (O-ethyl S,S-dipropyl phosphorodithioate) is a colorless to yellow tinted liquid with a strong mercaptan odor and a boiling point of 86-91o C at 0.2 mm Hg.  Ethoprop is only slightly soluble in water (843 ppm at 21 C), but is soluble in most organic solvents (hexane, xylene, acetone, and ethanol).

Table 2.3	Physicochemical Properties of Technical Grade Ethoprop.

Parameter	Value	Reference

Boiling point	86-91ºC at 0.2 mmHg	Ethoprop Registration Standard (10/20/87)

pH	6.65 in saturated aqueous solution at 21ºC

	Density	1.097 g/mL at 15ºC

	Water solubility	843 ppm at 21ºC

	Solvent solubility	Completely miscible in hexane, xylene, acetone, and ethanol

	Vapor pressure	3.89 x 10-4 Torr at 24ºC

	Dissociation constant, pKa	not available

	Octanol/water partition coefficient, Log(KOW)	3.59 at 21ºC

	UV/visible absorption spectrum	not available

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary

Recent toxicity studies conducted since the last risk assessment include a developmental neurotoxicity study in rats, acute and 11-day comparative cholinesterase study in adults and rat pups, a 28-day delayed neurotoxicity study in hens, and two subchronic feeding studies in rats.

Toxicity studies evaluated in previous ethoprop risk assessments include acute and subchronic neurotoxicity studies in rats, combined toxicity/carcinogenicity studies in rats, carcinogenicity study in mice, developmental studies in rats and rabbits,  2-generation reproduction study in rats, 90-day feeding study in dogs, 5-month capsule study in dogs, dermal toxicity studies in rats and rabbits with technical ethoprop, dermal toxicity in rats with a granular formulation, in vitro and in vivo mutagenicity studies, metabolism in rats, and a battery of acute toxicity studies.

3.1.2	Mode of Action, Metabolism, and Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects

Mode of action:  Ethoprop is an organophosphate pesticide.  The toxic mode of action in insects and humans is by phosphorylation of the acetylcholinesterase enzyme in the brain and peripheral nervous systems.  The resulting enzyme inhibition causes accumulation of the neurotransmitter, acetylcholinesterase, and signs of neurotoxicity.

Metabolism in rats:  Oral absorption of ethoprop is rapid and essentially complete by 48 hours.  The principal route of excretion was in urine (>50% of dose).  Radioactivity was also found in feces (7-16%) and respiratory air (11-19%).  Terminal elimination half life in blood was 92-135 hours.  Metabolism was by dealkylation of one or both S-propyl groups, followed by hydroxylation and probably conjugation.  The TLC profiles of fecal metabolites were similar to the profiles for urinary metabolites.  The main urinary metabolites were SME, OME, and M1.  SME and OME are inhibitors of acetylcholinesterase, whereas the M1 metabolite is not a significant inhibitor.  (See Table 2.2 for structures.)

Toxicological effects:  Ethoprop is acutely toxic and is in toxicity category I by both oral and dermal routes.  In the longer term studies, the most sensitive indication of toxicity was inhibition of brain and RBC cholinesterase (ChE).  Signs of neurotoxicity related to inhibition of ChE by ethoprop include   SEQ CHAPTER \h \r 1 tremors, ataxia, muscle fasiculations, lacrimation, salivation, rapid/shallow respiration, repetitive chewing movements, nasal and perianal stains, vocalization, aggressive behavior, decreased grip strength, and decreased motor activity.  Although rabbits were more sensitive than rats to acute lethality, at lower doses ChE inhibition occurred at similar doses in rats and rabbits in the subchronic dermal studies.  A slight anemia occurred in the 1-year dog study and in the chronic rat study.  Liver toxicity in the 1-year dog study included elevated liver enzymes and microscopic liver lesions.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the Toxicity Database

The toxicity database is adequate for assessing potential sensitivity of infants and children.  The following acceptable studies were available:  developmental toxicity in rats and rabbits, 2-generation reproduction study, acute and subchronic neurotoxicity studies, acute comparative cholinesterase study in adult and rat pups, 11-day comparative cholinesterase study in adult and rat pups, and a developmental neurotoxicity study in rats.  No additional relevant information was found in a Medline literature search.

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

Ethoprop is an organophosphate pesticide.  As described above, members of this class are neurotoxicants which act by phosphorylation of the acetylcholinesterase enzyme in the brain and peripheral nervous systems.  This causes accumulation of the neurotransmitter, acetylcholinesterase, and resulting signs of neurotoxicity.

Brain and RBC ChE activity were consistently inhibited in acute, subchronic, and chronic studies in various species and were the most sensitive indications of toxicity in these studies.  Signs of neurotoxicity related to inhibition of ChE by ethoprop occurred at higher doses and included   SEQ CHAPTER \h \r 1 tremors, ataxia, muscle fasiculations, lacrimation, salivation, rapid/shallow respiration, repetitive chewing movements, nasal and perianal stains, vocalization, aggressive behavior, decreased grip strength, decreased motor activity.  Hen studies were negative for indications of organophosphate induced delayed neuropathy.

3.3.3	Studies Assessing Offspring Sensitivity   TC \l3 "3.3.3 Developmental Toxicity Studies

Developmental toxicity:  No developmental toxicity was noted in rat and rabbit developmental studies.  In the rat developmental toxicity study, maternal toxicity included decreased body weight gain and increased incidence of soft stool, the latter effect attributed to ChE inhibition.  No maternal toxicity occurred in the rabbit developmental study; however, dosing was considered adequate because the highest dose was close to a lethal dose.

Reproductive toxicity:  Reproductive parameters evaluated in the 2-generation reproduction study were unaffected by treatment.  The high dose was reduced from 300 ppm to 150 ppm dietary concentration for the 2nd generation because of significantly increased pup mortality which occurred at the high dose between days 21 and 28 after birth; there was also a slight increase in pup mortality between days 1-4.  Parental toxicity at this dose included clinical signs due to ChE inhibition (tremors and loose stools) and significant inhibition of brain ChE activity.

Developmental Neurotoxicity Study:     SEQ CHAPTER \h \r 1 There was no effect on reproduction parameters and pup survival was unaffected by treatment at the high dose of 180 ppm, which was similar to results at 150 ppm in the reproduction study described above.

  SEQ CHAPTER \h \r 1

Functional Observational Battery parameters, auditory startle reflex habituation, and learning and memory (passive avoidance) were comparable between treated and control offspring.  An effect on learning (water maze) in high-dose males was noted as an increase in the number of trials to criterion and a non-statistically significant increase in the trial 2 duration.  Mean absolute brain weight was unaffected by treatment.  No treatment-related findings were observed on gross or microscopic examination and morphometrics of the nervous system.

Motor activity in all male treatment groups was increased on postnatal day 17 due to a lack of habituation (i.e., there was little or no decrease in activity over the course of the test session).  Although this effect was considered toxicologically significant, the low dose may be close to a NOAEL because of the following considerations: 1) the increase was not statistically significant and  2) there was no increase in motor activity on postnatal days 13, 21, or 60.

ChE activity was determined in pups 4 days after birth and in adults and pups 21 days after birth.  There was no indication of increased offspring sensitivity to ChE inhibition in this study:  the NOAEL for brain ChE activity in pups was the same as for adults and the NOAEL for RBC ChE activity was greater in pups than for adults.  A comparison of fetal and maternal ChE activities were also made.  Fetuses were less sensitive to ChE inibition by ethoprop than were the adults.

Acute comparative cholinesterase study:  The relative sensitivity of adult rats and 11-day old rat pups to ChE inhibition after a single gavage dose of ethoprop was determined in this study.  ChE determinations were made in adults 24 hr after dosing and in pups 8 hr after dosing, which were the time points when maximal inhibition occurred in adults and pups respectively.  Benchmark dose (BMD) values were calculated for the doses estimated to result in 10% and 20% decreases in ChE activity compared to control values.

For RBC ChE activity, pups were 1.7 times as sensitive to inhibition compared to adult females and were of comparable sensitivity to adult males when benchmark doses were compared.  For brain ChE activity, pups were 8 times as sensitive as adults when NOAELs were compared.  (BMD values for brain ChE activity in adults could not be calculated because not enough brain inhibition occurred in adults.)  See Appendix A.3 for the executive summary for this study.

11-Day comparative cholinesterase study:  In this study, ChE activity in pups and adults was determined after 11 days of gavage dosing and BMD values were calculated.  For RBC ChE activity, similar to the acute comparative study above, pups were 1.7 times as sensitive when compared to adult females and were of comparable sensitivity to adults when benchmark doses were compared.  For brain ChE activity, pups were 12 times as sensitive as adults when BMD values were compared. See Appendix A.3 for the executive summary for this study.

Degree of Concern Analysis for Pre and Postnatal Susceptibility   TC \l3 "3.3.6	Pre-and/or Postnatal Toxicity

There are no concerns for developmental toxicity because no developmental toxicity occurred in the rat and rabbit developmental toxicity studies.

As noted above, pup mortality in the 2-generation reproduction study occurred at a high dietary concentration of 300 ppm, equivalent to 24 mg/kg/day, and was accompanied by significant maternal toxicity (clinical signs of tremors and loose stool and brain ChE inhibition).  The NOAEL for pup mortality was 13 mg/kg/day.  Because the point of departure for chronic dietary exposure (0.14 mg/kg/day) is much lower than the NOAEL for pup mortality and is protective of this endpoint, there are no residual concerns for sensitivity to infants and children from this study.

In the developmental neurotoxicity study, increased motor activity in pups occurred at the low dose of 0.7 mg/kg/day.  Maternal toxicity at this dose was limited to RBC ChE inhibition.

As noted above, the low dose is believed to be close to a NOAEL for motor activity.  The point of departure for chronic dietary exposure (0.14 mg/kg/day) is protective of this endpoint and therefore there are no residual concerns for sensitivity to infants and children from this study.

As noted above, in the acute comparative cholinesterase study, pups were 8 times as sensitive as adults for brain ChE inhibition when NOAEL values were compared (a BMD could not be calculated for adults because of insufficient ChE inhibition in adults).  This study was used to select a point of departure for acute dietary assessment.  Because the point of departure is protective of the population of concern, there are no residual concerns from this study.

As noted above, in the 11-day comparative cholinesterase study, pups were 12 times as sensitive as adults for brain ChE inhibition when BMD values were compared.  This study was used to select a point of departure for chronic dietary assessment.  Because the point of departure is protective of the population of concern, there are no residual concerns from this study.

3.4	FQPA Safety Factor for Infants and Children  TC \l2 "3.4	Safety Factor for Infants and Children

The points of departure for dietary assessment, based on brain ChE inhibition in pups, were selected from the comparative cholinesterase studies.  In comparison to other toxicity studies that had much wider dose spacing, the comparative cholinesterase studies had much closer dose spacing around the NOAEL and LOAEL doses and thus provided an accurate determination of BMDL10 values.  Furthermore, 1) the comparative cholinesterase studies provided an assessment of comparative sensitivity of adults and offspring; and 2) provided the lowest, most sensitive point of departure for the most vulnerable population which is protective of other effects described above.  For these reasons, the FQPA safety factor is reduced to 1x.

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5 Hazard Identification and Toxicity Endpoint Selection

Following are endpoints for dietary and occupational exposure.  There are no residential uses for ethoprop and consequently endpoints for dermal, inhalation, and incidental oral exposure were not selected for residential scenarios.

3.5.1    Acute Reference Dose (aRfD)

Acute Reference Dose (aRfD) - Females age 13-49

There is no increased susceptibility for females of child-bearing age.  The aPAD for the general population is protective of this population group.

Acute Reference Dose (aRfD) - General Population  TC \l3 "3.5.2	Acute Reference Dose (aRfD) - General Population

Study Selected:	Acute comparative cholinesterase study in rats

MRID No.:		46278701

Executive Summary:	See Appendix A.

Point of Departure: 	BMDL10 = 0.76  mg/kg based on brain ChE inhibition in pups.  The BMDL10 is the lower 95% confidence limit on the estimated mean 10% brain ChE inhibition.

Uncertainty Factor: 	100x (based on 10x for interspecies extrapolation from rats to

humans and 10x for variation in sensitivity between humans)

FQPA Safety Factor: 	1x

aRfD  =   0.76 mg/kg  =  0.0076 mg/kg          	aPAD  =   0.76 mg/kg  =  0.0076 mg/kg

                      100                                                                             100

Comments about Study:   This study provided a sensitive point of departure and compared the relative sensitivity of adults and offspring.  Pups were approximately 8x as sensitive as adults for brain ChE inhibition when NOAELs were compared.  BMD values for brain ChE activity could not be calculated for adults because not enough brain inhibition occurred in adults.

The endpoint of brain ChE inhibition in pups was selected because brain is the target tissue and pups were more sensitive than adults.  The close dose spacing in this study bracketed NOAEL and LOAEL values and allowed an accurate determination of BMD values in pups.

Other acute neurotoxicity  studies in adult rats (MRIDs 46278701, 43197701) used higher doses and did not provide a NOAEL value.  The developmental studies, reproduction study, and other longer term studies did not report toxicity attributable to a single dose.

3.5.2	Chronic Reference Dose (cRfD)   TC \l3 "3.5.3	Chronic Reference Dose (cRfD)

Study Selected:  	Repeated dosing comparative cholinesterase study in rats

MRID No.:   		46636401

Executive Summary:	See Appendix A.

Point of Departure: 	BMDL10 = 0.14 mg/kg/day based on brain ChE inhibition in pups.  The BMDL10 is the lower 95% confidence limit on the estimated mean 10% brain ChE inhibition.

Uncertainty Factor: 	100x (based on 10x for interspecies extrapolation from rats to

humans and 10x for variation in sensitivity between humans)

FQPA Safety Factor: 	1x

cRfD  =   0.14 mg/kg/day  =  0.0014 mg/kg          	cPAD  =   0.14 mg/kg/day  =  0.0014 mg/kg

                         100                                                                               100

Comments about Study:   This study provided a sensitive point of departure and had the advantage that the relative sensitivities of adults and offspring were directly compared.  In this study, pups were 12x as sensitive as adults when BMD values for brain ChE inhibition were compared.  The endpoint of brain ChE inhibition in pups was selected because brain is the target tissue and pups were more sensitive than adults.  The close dose spacing in this study bracketed NOAEL and LOAEL values and allowed an accurate determination of BMD values.

It was preferred to use a point of departure based on the target tissue, brain, rather than the more variable surrogate, RBC ChE.  Several studies were considered for use as the chronic dietary endpoint but were not used because these studies generally had wide dose spacing which would not have allowed for as accurate a point of departure (PoD) as in the comparative ChE study.

In the DNT study, pups did not have increased sensitivity relative to adults for brain ChE inhibition, as was noted in the comparative ChE study, because pups in the DNT study received gestational and lactational exposure, but did not receive gavage dosing as in the comparative cholinesterase study.  An endpoint based on brain or RBC ChE inhibition from the DNT study in either adults or pups was not used because it would have provided a higher PoD than from the comparative cholinesterase study.

An endpoint from the subchronic neurotoxicity study was not selected for this assessment because of the wide dose spread, larger standard deviations, and regional brain inhibition that showed inconsistent responses over time and between sexes.

The chronic/carcinogenicity rat study, mouse carcinogenicity study, and 5-month/1-year dog studies had low NOAELs for both RBC or brain ChE inhibition, however, there was wide dose spacing between the NOAEL and LOAEL which meant that the PoD would be comparable to, or greater than the PoD from the comparative cholinesterase study.  Inhibition at similar doses was generally similar to that in the comparative ChE study.

Although an 11-day study was used to assess chronic exposure, it is not believed that a longer study would provide a lower NOAEL.  This is because young rat pups are more sensitive than adult rats to ChE inhibition due to their immature metabolic capacity, especially for carboxylesterase and A-esterase enzymes.  As rat pups age, their metabolic capability increases, resulting in decreased susceptibility to OP pesticides.

3.5.3	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption

A dermal absorption study with ethoprop is not available.  Dermal absorption of technical ethoprop was estimated by comparing the NOAEL for brain ChE inhibition in the dermal rat study with the NOAEL from the comparative ChE study.  The NOAELs for brain ChE inhibition in both studies were 1.0 mg/kg/day.  The LOAEL in the oral study was 2 mg/kg/day based on

-12% brain ChE inhibition compared to controls and the LOAEL in the dermal toxicity study was 10 mg/kg/day based on -70% ChE inhibition.  Had there been a closer dose spread in the dermal study, the LOAEL values for the two studies would probably have been comparable.  It can therefore be concluded that ethoprop is readily absorbed by the dermal route and dermal absorption of technical ethoprop shall be assumed equivalent to oral absorption (100%).

Dermal absorption of the granular formulation is much less than for liquid formulations.  The NOAEL for brain ChE inhibition in the dermal toxicity study with granular formulation was 19 mg/kg/day and the NOAEL in the in the comparative ChE study was 1.0 mg/kg/day.  The LOAEL in the dermal toxicity study was 97 mg/kg/day based on -40% ChE inhibition and the LOAEL in the oral study was 2.0 mg/kg/day based on -12% ChE inhibition.  Had there been a closer dose spread in the dermal toxicity study, the LOAEL would have been lower.  Comparing LOAEL values results in an estimated dermal absorption factor of 2-5% for the granular formulation.

Dermal Exposure – Liquid Formulations

(Short- and Intermediate-Term)   TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected: 	21-Day dermal toxicity study in rabbits

MRID No.:		41304404

Executive Summary:	See Appendix A, Guideline 870.3200

Point of Departure: 	NOAEL = 0.1 mg/kg/day based on brain and

RBC ChE inhibition at LOAEL = 1.0 mg/kg/day.

Comments about Study:   This study is appropriate for the route of exposure for all non-granular formulations.  (See below for the endpoint for granular formulations.)  The rabbit study was used because it provided a lower NOAEL for RBC ChE inhibition than did a rat study with a NOAEL of 0.3 mg/kg/day, although it is possible that the NOAEL from the rabbit dermal study would have been the same as from the rat dermal study had identical doses been used.

Although developmental parameters were not assessed in the dermal rabbit study, there are no developmental concerns because no developmental toxicity occurred in the oral rat and rabbit developmental studies.  There was increased pup mortality in the reproduction study at 24 mg/kg/day; the NOAEL for this effect was 13 mg/kg/day.  There are no concerns for reproductive toxicity by the dermal route because:  1) the dermal NOAEL (0.1 mg/kg/day) is much lower than the NOAEL for pup mortality (13 mg/kg/day).  2) Also, the pup mortality was accompanied by maternal clinical signs (tremors), which were not evident in the dermal toxicity study.  There are therefore no concerns for developmental or reproductive toxicity by the dermal route for exposure to ethoprop liquid formulations.

Dermal Exposure – Granular Formulations

(Short- and Intermediate-Term)   TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected:   	21-Day dermal toxicity study in rats

MRID No.:	     	45034801

Executive Summary:	See Appendix A, Guideline 870.3200

Point of Departure:  	NOAEL = 19 mg/kg/day based on brain and

RBC ChE inhibition at LOAEL = 97 mg/kg/day.

Comments about Study:   This study is appropriate for risk assessments of granular formulations only.  Although rabbits are more sensitive to acute lethality from ethoprop, ChE inhibition, occurring at the lower doses assessed in the dermal toxicity studies, was comparable between rabbits (MRID413044004) and rats (MRID 45074602).  Therefore rats are considered an appropriate species to use for assessing dermal risk assessments.

Although developmental parameters were not assessed in the dermal study, there are no developmental concerns because no developmental toxicity occurred in the rat and rabbit developmental studies.

In the reproduction study, there was increased pup mortality at 24 mg/kg/day; the NOAEL for this effect was 13 mg/kg/day.  Although the NOAEL for pup mortality in the reproduction study with technical ethoprop (13 mg/kg/day) is less than the NOAEL for ChE inhibition in the dermal study with the granular formulation (19 mg/kg/day), there are no concerns for this effect by dermal exposure because:  1) There is poor dermal absorption with granular formulation in comparison to liquid technical ethoprop.  Using a 5% dermal absorption factor for granular ethoprop, as described above in the Dermal Absorption section, results in an estimated NOAEL for pup mortality of 380 mg/kg/day by the dermal route, which means that the NOAEL of ChE inhibition from the dermal granular study is protective of pup mortality from the granular product.  2)  Also, the pup mortality was accompanied by maternal clinical signs (tremors), which were not evident in the dermal toxicity study.  Therefore, there are therefore no concerns for developmental or reproductive toxicity by the dermal route.

Inhalation Exposure

(Short-, Intermediate-Term)

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)

Study Selected:  	Repeated dosing comparative cholinesterase study in rats

MRID No.:   		46636401

Executive Summary:	See Appendix A.

Point of Departure: 	BMDL10 = 0.14 mg/kg/day based on brain ChE inhibition in pups.  The BMDL10 is the lower 95% confidence limit on the estimated mean 10% brain ChE inhibition.

Uncertainty Factor: 	100x (based on 10x for interspecies extrapolation from rats to

humans and 10x for variation in sensitivity between humans)

Comments about Study:   An inhalation study with ethoprop is not available.  The comparative cholinesterase study provided the most sensitive point of departure and the close dose spacing in this study bracketed NOAEL and LOAEL values and allowed an accurate determination of BMD values.

≥ 100) are based on 10x for interspecies extrapolation from rats to humans and 10x for variation in sensitivity between humans.

Table 3.5.7.  Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)

Occupational (Worker) Exposure

Dermal	100	100

Inhalation	100	100

Residential Exposure

Not applicable.  There are no residential uses for ethoprop.

3.5.8	Recommendation for Aggregate Exposure Risk Assessments  TC \l3 "3.5.9	Recommendation for Aggregate Exposure Risk Assessments

Dermal and inhalation occupational exposures can be combined due to the presence of a common toxicity endpoint (brain ChE inhibition).  There are no residential uses for ethoprop so an aggregate assessment for the residential route includes only food and water exposure which can be combined.

3.5.9	Classification of Carcinogenic Potential  TC \l3 "3.5.10 Classification of Carcinogenic Potential

Ethoprop is classified "likely to be carcinogenic to humans" based on malignant adrenal pheochromocytomas in male rats.  The Q1* for ethoprop is 2.81x10-2 mg/kg/day-1.

3.5.10	Toxicological Doses and Endpoints

Table 3.5.10a.  Doses and Endpoints for Dietary and Non-Occupational Assessments

Exposure Scenario	Point of Departure	Uncertainty/FQPA Safety Factors RfD, PAD 	Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) BMDL10  = 0.76 mg/kg	UFA= 10x

UFH = 10x

FQPA SF= 1x	Acute RfD = 0.0076 mg/kg/day

aPAD = 0.0076 mg/kg/day	NOAEL = 0.5 mg/kg

LOAEL = 1.0 mg/kg based on brain ChEI in pups in the acute comparative cholinesterase study in rats.

Acute Dietary

(Females 13-49 years of age)	There is no increased susceptibility for females of child-bearing age.

The aPAD for the general population is protective of this population group.

Chronic Dietary (All Populations)	BMDL10  = 0.14 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF= 1x	Chronic RfD = 0.0014

mg/kg/day

cPAD = 0.0014 mg/kg/day	NOAEL < 0.25 mg/kg/day

LOAEL = 0.25 mg/kg/day based on brain ChEI in pups in the repeated dose comparative cholinesterase study in rats.

Incidental Oral Exposure	There are no residential uses for ethoprop and therefore there is no exposure to children by the incidental oral route of exposure.

Dermal Exposure	There are no residential uses for ethoprop and therefore there is no dermal exposure in non-occupational settings.

Inhalation  Exposure	There are no residential uses for ethoprop and therefore there is no inhalation exposure in non-occupational settings.

Cancer (oral route)	Classification:  "Likely to be carcinogenic to humans."

Q1* = 2.81 x 10-2 based on malignant adrenal pheochromocytomas in male rats.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.   BMDL10  = lower 95% confidence limit of the 10% benchmark response, in this case the estimated dose resulting in 10% ChEI.  ChEI = cholinesterase inhibition.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  RfD = reference dose (PoD ( combined UF).  PAD = population adjusted dose (RfD ( FQPA SF;  a = acute;  c = chronic).

Table 3.5.10b.  Doses and Endpoints for Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern 	Study and Toxicological Effects

Dermal Short- (1-30 days) and Intermediate-Term (1-6 months):  Liquid Formulations	NOAEL = 0.1 mg/kg/day	UFA= 10x

UFH = 10x	LOC for MOE

= 100	LOAEL = 1.0 mg/kg/day based on RBC and brain ChEI in a 21-day dermal toxicity study in rabbits with technical ingredient.

Dermal Short- (1-30 days) and Intermediate-Term (1-6 months):  Granular Formulations	NOAEL = 19 mg/kg/day	UFA= 10x

UFH = 10x	LOC for MOE

= 100	LOAEL = 97 mg/kg/day based on RBC and brain ChEI in a 28-day dermal toxicity study in rats with granular formulation.

Inhalation Short- (1-30 days and Intermediate Term (1-6 months)	BMDL10  = 0.14 mg/kg/day	UFA= 10x

UFH = 10x	LOC for MOE

= 100	NOAEL < 0.25 mg/kg/day

LOAEL = 0.25 mg/kg/day based on brain ChEI in pups in the repeated dose comparative cholinesterase study in rats.

Combined Dermal and Inhalation Exposure for use with

Biomonitoring 	BMDL10  = 0.14 mg/kg/day	UFA= 10x

UFH = 10x	LOC for MOE

= 100	NOAEL < 0.25 mg/kg/day

LOAEL = 0.25 mg/kg/day based on brain ChEI in pups in the repeated dose comparative cholinesterase study in rats.

Cancer (dermal, inhalation)	Classification:  "Likely to be carcinogenic to humans."

Q1* = 2.81 x 10-2 based on malignant adrenal pheochromocytomas in male rats.

Point of Departure (POD) = A data point or an estimated point derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  LOC = level of concern.  MOE = margin of exposure.  BMDL10  = lower 95% confidence limit of the 10% benchmark response, in this case the estimated dose resulting in 10% ChE inhibition.  ChEI = cholinesterase inhibition.

Endocrine disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.”  Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system.  EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife.  For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations.  As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).

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

  TC \l2 "3.6	Endocrine disruption

Public Health and Pesticide Epidemiology Data

An updated public health and epidemiology is presently being prepared.  An incident report was prepared for the previous risk assessment, however, mitigation measures have been implemented since that time that may result in changes from the previous incident report.

  TC \l1 "4.0	Public Health and Pesticide Epidemiology Data

  TC \l2 "4.4	Other Pesticide Epidemiology Published Literature

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1  Pesticide Metabolism and Environmental Degradation

The metabolism of ethoprop in plants and livestock was extensively discussed in the residue chemistry chapter of the ethoprop RED (DP# D239294, J. Abbotts, 3/27/1998).  The degradation of ethoprop in the environment is discussed in a memo by M. Barrett (DP Barcodes 323344; 335734; 295045; 295035, 12/18/07).

The residues of concern for the acute and chronic risk assessments in crops and water are parent and Metabolites II and III (S-ME and O-ME); for cancer dietary risk, the residues of concern are parent and Metabolites II through IV (S-ME, O-ME and M-1).  Metabolites II and III are ChE inhibitors, but Metabolite IV is not.  The environmental degradate SSDP is also of concern for non-cancer risk assessments. These metabolites are also rat metabolites.  Structures of the parent and metabolites may be found in Table 2.2.

Since field trial and PDP data on the metabolites are not available, metabolite ratios were estimated from metabolism and rotational crop studies.  Further information on the development of the ratios may be found in the anticipated residue memo (C. Olinger, DP Barcodes 352476 and 352477).

The drinking water assessment prepared by EFED (D323344) reported that ethoprop has high solubility, has moderately low sorption potential, is stable to hydrolysis, and does not readily undergo photodegradation in water or soil.  Ethoprop is mobile in soil and does have the potential to contaminate surface and ground water.

5.1.2	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water Residue Profile

Dietary exposures calculated in this risk assessment incorporated updated modeling and recently conducted monitoring data.  The monitoring study targeted five watersheds with relatively high ethoprop usage believed vulnerable to contamination by pesticides.  The monitoring study was required in the IRED because of high values for modeled water concentrations.  As shown below in Table 5.1.2., the monitoring concentrations were much lower than modeling concentrations.

EFED has characterized the modeled estimates as likely to be overestimates of exposure, particularly since it was assumed a large portion of the watershed was treated, but actual usage estimates are considerably lower.  The monitoring study may underestimate peak exposure, particularly acute exposure, because the study was limited in terms of samples, sites, and years.  However, EFED reported that actual concentrations would be expected to be closer to the monitoring results than to the modeling results (M. Barrett, 6/17/08, DP Barcodes D342755 and D342794).

The new usage sites are not expected to contribute substantially to the high-end exposure level of ethoprop because the proposed use sites are of minor acreage and the production regions do not correspond to areas at greatest risk for drinking water exposure.  Current water concentrations may have decreased since the water monitoring study was completed because the registrant has submitted sales data showing that ethoprop usage has declined nationwide since the time of the monitoring study.  Concentrations in drinking water may be lower than the monitored values because the results from monitoring data are for raw water and did not account for decreased concentrations that could occur as a result of water treatment.  Only a limited number of finished water samples were analyzed but there were no detections in that sample.

Table 5.1.2.  Summary of Water Concentrations Used in Dietary Assessments

Source of Data

	Dietary

Assessment	Water Concentration (ppb)

Modeling

PRZM-EXAMS surface water modeling

(LA sugarcane, upper 1-in-10 year peak conc)	Acute	138

PRZM-EXAMS surface water modeling

(LA Sugarcane upper 1-in-10 yr mean conc)	Chronic	18

Sci-Grow ground water modeling

	Cancer	10.1

Monitoring

Surface water monitoring of raw water a

	Acute and Chronic	0.23

Surface water monitoring of raw water b

	Cancer	0.23

a Sum of ethoprop (14 ppt) + SME (202 ppt) + Method Detection Limits (MDLs) for OME (6 ppt) + M1 (7 ppt)

b Sum of ethoprop (14 ppt) + SME (202 ppt) + MDLs for OME (6 ppt) + M1 (7 ppt) + SSDP (2 ppt)

5.1.3	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile

Field trial data are available for all crops for the parent compound; field trial data for the metabolite M-1 are available for a limited number of crops. USDA Pesticide Data Program data (PDP) are available for several commodities reflecting analysis for the parent only.  These data generally show very low or non-detectable residues.  Processing data generally show reduction of residues upon processing.

Anticipated residues estimates were revised to incorporate recent PDP data.  A detailed description may be found in a separate document (C. Olinger, DP Barcodes 352476 and 352477).  PDP monitoring data are available for bananas, snap beans (fresh and canned), corn syrup, sweet corn (canned), cucumber, pineapple, potato, and sweet potato.  Residues were non-detectable for all commodities with the exception of bananas (six detects), fresh snap beans (one detect), and sweet potatoes (four detects).  Field trial data were used for field corn, mint, hops, lima beans, and cabbage.

DEEM 7.81 default processing factors were used for dried bananas (plantains), dried pineapples, and dried potatoes.

The anticipated residues incorporate percent crop treated information for all crops except hops, mint, bananas, pineapple, and lima beans.  The percent crop treated estimates are from the Screening Level Usage Analysis (SLUA) dated 2/14/08 and are all generally 5% or less, with the exception of sweet potatoes with an estimated maximum at 15%.

Residue distribution files (RDF) were generated for bananas, snap beans, lima beans (succulent), cabbage, cucumbers, sweet potatoes, potatoes, sweet corn, corn syrup, and pineapple.  Water values and blended commodities were incorporated into the acute analysis as a point estimate.

5.2	Dietary Exposure and Risk TC \l2 "5.2  Dietary Exposure and Risk

ommodity Intake Database DEEM-FCID™, Version 2.03 which incorporates consumption data from USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98 data are based on the reported consumption of more than 20,000 individuals over two non-consecutive survey days.  Foods “as consumed” (e.g., apple pie) are linked to EPA-defined food commodities (e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using publicly available recipe translation files developed jointly by USDA/ARS and EPA.  For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups, but for acute exposure assessment are retained as individual consumption events.  Based on analysis of the 1994-96, 98 CSFII consumption data, which took into account dietary patterns and survey respondents, HED concluded that it is most appropriate to report risk for the following population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue level in each food or food-form (e.g., orange or orange juice) on the food commodity residue list is multiplied by the average daily consumption estimate for that food/food form to produce a residue intake estimate.  The resulting residue intake estimate for each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure.  Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD.  This procedure is performed for each population subgroup.

For acute exposure assessments, individual one-day food consumption data are used on an individual-by-individual basis.  The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic exposure assessment, or “matched” in multiple random pairings with residue values and then summed in a probabilistic assessment.  The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i.e., only those who reported eating relevant commodities/food forms) and a per-capita (i.e., those who reported eating the relevant commodities as well as those who did not) basis.  In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis.  However, for tiers 1 and 2, any significant differences in user vs. per capita exposure and risk are specifically identified and noted in the risk assessment.

Dietary risk assessment incorporates both exposure and toxicity of a given pesticide.  For acute and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects).  This dose is referred to as the population adjusted dose (PAD).  The PAD is equivalent to point of departure (POD, NOAEL, LOAEL, e.g.) divided by the required uncertainty or safety factors.

For acute and non-cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD.  HED is generally concerned when estimated cancer risk exceeds one in one million. References which discuss the acute and chronic risk assessments in more detail are available on the EPA/pesticides web site:  “Available Information on Assessing Exposure from Pesticides, A User’s Guide,” 21-JUN-2000, web link:      HYPERLINK "http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf"  http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf  ; or see SOP 99.6 (8/20/-1999).

5.2.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1  Acute Dietary Exposure/Risk

The results of the acute dietary exposure analysis 99.9th percentiles of exposure are reported in Table 5.2.1 for food alone and aggregate food and water, at various water concentrations.

When the PRZM-EXAMS modeled value is used for the drinking water concentration the risk exceeds the level of concern at the 95th, 99th, and the 99.9th percentiles of exposure.  Infants are the highest exposed population when the modeled value (138 ppb) is used, with exposure at 920% aPAD.

However, if the highest surface water monitoring value (0.231 ppb) is used as well as the value twice that (0.52 ppb), exposures are well below the level of concern.  The highest exposed population sub-group is infants at 18% or 19% of the aPAD for when 0.231 or 0.52 ppb is used for the estimated drinking water concentration (EDWC) at the 99.9th percentile of exposure.

HED conducted various scoping analyses to determine the water concentration at which the total food and water exposure is less than 100% of the aPAD.  For infants at the 99.9th percentile of exposure, and using an EDWC of 15 ppb, the total food and water exposure is at 99% of the aPAD.

5.2.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2  Chronic Dietary Exposure/Risk

The results of the aggregate chronic dietary exposure analysis are reported in Table 5.2.2 below.  All exposure estimates are below the level of concern for all population groups, using all estimated drinking water concentrations.  The maximum drinking water value used, the modeled estimate (18 ppb), is likely an overestimate because it assumes that most of the watershed is treated.

 Table 5.2.1.  Results of Ethoprop Acute Dietary (Food and Drinking Water) Exposure Analysis Using DEEM FCID

Population Subgroup	aPAD (mg/kg/day)	Food Alone	Food and Drinking Water Using 138 ppb Water Value	Food and Drinking Water Using 0.231 ppb Water Value	Food and Drinking Water Using 0.52 ppb Water Value	Food and Drinking Water Using 15 ppb Water Value

99.9th Percentile	99.9th Percentile	99.9th Percentile	99.9th Percentile 99.9th Percentile

Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	%     aPAD

General U.S. Population	0.0076	0.000668	8.8	0.0272	360	0.000673	8.9 0.000684	9.0	0.003	39

All Infants (< 1 year old)	0.0076	0.0014	18	0.0697	920	0.00141	18 0.00142	19	0.00753	99

Children 1-2 years old	0.0076	0.00127	17	0.0273	360	0.00127	17	0.00127 17	0.0031	41

Children 3-5 years old	0.0076	0.00103	14	0.0268	350	0.00105	14	0.00107 14	0.00304	40

Children 6-12 years old	0.0076	0.000632	8.3	0.0163	210	0.000608	8.0 0.000627	8.2	0.00188	25

Youth 13-19 years old	0.0076	0.000339	4.5	0.0178	230	0.000348	4.6 0.000353	4.6	0.002	26

Adults 20-49 years old	0.0076	0.00035	5.7	0.0203	270	0.000436	5.7 0.000441	5.8	0.0022	29

Adults 50+ years old	0.0076	0.000436	6.1	0.00141	180	0.000467	6.1 0.000472	6.2	0.00155	20

Females 13-49 years old 	0.0076	0.000426	5.6	0.0192	250	0.000434	5.7 0.000439	5.8	0.00209	28

Note:  the bolded population(s) indicate the highest dietary exposure to ethoprop residues.

Table 5.2.2  Results of Chronic Dietary (Food and Drinking Water) Exposure Analysis Using  DEEM FCID

Population Subgroup	cPAD (mg/kg/day)	Food Alone	Food and Drinking Water Using 18 ppb Water Value	Food and Drinking Water Using 0.231 ppb Water Value	Food and Drinking Water Using 0.52 ppb Water Value

Exposure (mg/kg/day)	% cPAD	Exposure (mg/kg/day)	% cPAD	Exposure (mg/kg/day)	% cPAD	Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.0014	0.000007	0.5	0.000387	28	0.000012	0.9 0.000018	1.3

All Infants (< 1 year old)	0.0014	0.000022	1.6	0.00127	90	0.000038	2.7 0.000058	4.2

Children 1-2 years old	0.0014	0.000031	2.2	0.000595	42	0.000038	2.7 0.000047	3.4

Children 3-5 years old	0.0014	0.000018	1.3	0.000545	39	0.000024	1.7 0.000033	2.3

Children 6-12 years old	0.0014	0.000008	0.6	0.000372	27	0.000013	0.9 0.000019	1.3

Youth 13-19 years old	0.0014	0.000003	0.2	0.000278	20	0.000007	0.5 0.000011	0.8

Adults 20-49 years old	0.0014	0.000005	0.3	0.000359	26	0.000009	0.7 0.000015	1.1

Adults 50+ years old	0.0014	0.000006	0.4	0.000379	27	0.000011	0.8 0.000017	1.2

Females 13-49 years old 	0.0014	0.000005	0.3	0.000357	26	0.000009	0.7 0.000015	1.1

Note:  the bolded population(s) indicate the highest dietary exposure to ethoprop residues.

5.2.3	Cancer Dietary Risk  TC \l3 "5.2.3  Cancer Dietary Risk

The estimated exposures of the general U.S. population to ethoprop as well as the corresponding cancer risk estimates are presented in Table 5.2.3.  HED conducted these analyses with varying levels of water concentrations.  Calculated risks ranging from approximately 3 x 10-7 to 3 x 10-6 are indistinguishable from 10-6.  Generally HED is concerned when the calculated risks exceed approximately 3 x 10-6.  The estimated risk for food alone is below the level of concern.  The combined risk for food and water is below the level of concern if the concentration of ethoprop in water (over a lifetime of exposure) is 5 ppb or lower.    The maximum water concentration observed in the target surface water monitoring study was 0.231 ppb.  If the maximum modeled estimate is used as the drinking water concentration the estimated cancer risk is 6 x 10-6, which exceeds the level of concern.  Water was the greatest contributor to the aggregate dietary exposure.  A commodity contribution analysis indicated that bananas are the food commodity leading to the greatest exposure to ethoprop in food.

Table 5.2.3.  Results of Cancer Dietary (Food and Drinking Water) Exposure Analysis Using  DEEM FCID at Varying Water Concentrations

Scenario	Exposure, mg/kg/day	Estimated Cancer Risk

Food Alone	0.000009	3 x 10-7

Food and Drinking Water Using 10.1 ppb Water Value	0.00022	6 x 10-6

Food and Drinking Water Using 0.231 ppb Water Value	0.000014	4 x 10-7

Food and Drinking Water Using 0.52 ppb Water Value	0.000020	6 x 10-7

Food and Drinking Water Using 5 ppb Water Value	0.000115	3 x 10-6

6.0	Residential (Non-Occupational) Exposure  TC \l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses for ethoprop and therefore no residential exposure assessment have been conducted.

7.0	Aggregate Risk Assessments

A typical aggregate risk assessment includes residential, food, and drinking water exposure.  Because there are no residential uses for ethoprop, the ethoprop aggregate assessment includes food and drinking water exposure.  See the Dietary section of this document for an evaluation of those risks.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative Risk Characterization/Assessment

Ethoprop has been evaluated in a cumulative assessment:    SEQ CHAPTER \h \r 1 Organophosphorus Cumulative Risk Assessment – 2006 Update (  HYPERLINK "http://www.regulations.gov"  http://www.regulations.gov ).  Dietary exposure to ethoprop from the proposed new uses in hops and mints is not expected to make significant additions to dietary exposure and risk in the cumulative assessment.

9.0	Occupational Exposure and Risk   TC \l1 "9.0	Occupational Exposure/Risk Pathway

This section describes the occupational exposure and risk assessments conducted to support ground applications of ethoprop (formulated as MOCAP® 15% granular product and MOCAP® EC) on hops and mint. Risks were evaluated for agricultural workers for mixing/loading of granular and liquid products for groundboom and broadcast spreader applications.  Exposure and risk were evaluated using the Pesticide Handlers Exposure Database (PHED) and by manipulation of the biomonitoring data when possible.

Occupational Handler Exposure (PHED-based)

In this exposure assessment, the use parameters were based on the label instructions and default exposure assumptions for quantity handled per day (ExpoSAC SOPs). The potential absorbed dose and margin of exposure (MOE) were calculated using standard EPA exposure algorithms and generic unit exposure values from the Pesticide Handlers Exposure Database (PHED) Version 1.1 (US EPA, 1998). The following exposure scenarios were assessed for agricultural workers:

Mixer/Loaders:

 (1) M/L liquids for Groundboom Applications;

 (2) M/L granulars for Tractor Drawn Spreader Applications ;

Applicators:

 (3) Groundboom Applications [closed cab];

 (4) Tractor Drawn Spreader Applications (Granulars) [closed cab];

Short- and intermediate-term dermal and inhalation exposures to agricultural workers were assessed as ethoprop is typically applied early in the growing season and chronic exposures to ethoprop are not be expected to occur.

Occupational workers may be exposed to ethoprop during the mixing/loading and/or application process for hops and mint. Based on the product labels, ethoprop can be applied at a maximum rate of 6 lbs ai/A for granular products and 4.2 lbs ai/A for liquid (EC) products. Maximum and typical application rates have been assessed in this document to more accurately inform risk management. Assumptions for the area treated per day were based on the EPA default values listed in ExpoSAC SOP #9.1. The work day was assumed to be 8 hours for all agricultural workers. For all use scenarios, the product application rates and amount handled per day are listed in Table 9.1.

Table 9.1.	Application Rates Assessed and Quantity Handled per Day

Use Scenario	Crop Group	Application Rates Assessed (lb ai/A)	Area Treated per Day

Granular:  Broadcast Spreader	Mint	6	80

Granular:  Broadcast Spreader	Mint	3	80

Liquids:  Groundboom	Mint	4.2	80

Liquids:  Groundboom	Mint & Hops	2.1	80

Non-cancer risks were calculated as a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint of concern to the daily dose.  Daily dose values were calculated by first calculating exposures by considering application parameters (i.e., rate and area treated) along with unit exposures.  Exposures were then normalized by body weight.

Occupational Handler Risk (PHED-based)

The proposed label indicates that applications are made pre-plant/pre-bloom applications (~1 application/yr. for private applicators) for the proposed uses. Commercial applicators may apply ethoprop more frequently. Therefore, this exposure assessment presents risks for short- and intermediate-term occupational handlers only. The proposed label instructions make long-term exposures improbable. Product label directions indicate “Lock ‘N Load” packaging (engineering controls) for mixer/loaders and closed cab motorized ground application equipment for applicators except “when handlers [are] engaged in those activities for which use of an engineering control is not possible”. Additional label information would help clarify what type of activities are included in this description.  See Tables 9.1.1a and 9.1.1b.

For mixer/loaders with engineering controls:

For granular exposure scenarios, risks do not exceed HED’s level of concern (i.e., the MOEs are greater than 100) with proposed engineering controls/label PPE.

At the maximum application rate (6 lbs ai/A) for mixer/loaders, the MOE is 580.

For liquid mixer/loader scenarios, risks exceed HED’s level of concern (i.e., the MOEs are less than 100) with proposed label engineering controls/label PPE.

At the maximum application rate (4.2 lbs ai/A) for mixer/loaders, the MOE is 2.

For applicators with engineering controls:

For liquid applicator scenarios, risks exceed HED’s level of concern (i.e., the MOEs are less than 100) with proposed label engineering controls/label PPE.

At the maximum application rate (4.2 lbs ai/A) for applicators, the MOE is 4.

For granular applicator scenarios, risks exceed HED’s level of concern (i.e., the MOEs are less than 100) for the higher application rates (6 lbs ai/A) but do not exceed HED’s level of concern (i.e., the MOEs are less than 100) for the lower application rate (3 lbs ai/A) with proposed engineering controls/label PPE.

At the maximum application rate (6 lbs ai/A) for applicators, the MOE is 87.

Table 9.1.1a. 	Short- and Intermediate-Term Ethoprop Occupational Handler Non-cancer Risk Estimates (using PHED data)

Exposure Scenario

Crop or Target

Application

Rate a

Area Treated Daily b

Combined MOEs c

Base line

G - NR

 PPE-G, DL-NR

G - 80% R

G,DL - 80% R

 G - 90% R

G,DL - 90% R

Eng Cont

Mixer/Loader

Loading Granulars for Tractor Drawn Spreader Applications (2)	Hops/Mint

4.2 lb ai/acre

80 acres	12	12	52	93	12	56	105	580

	Hops/Mint

2.1 lb ai/acre

80 acres	23	23	105	185	24	112	210	1160

M/L ECs for Groundboom Applications (1)	mint (nematodes)

6 lb ai/acre

80 acres	<1	1	1	1	1	2	1	2

	mint (symphylans)

3 lb ai/acre

80 acres	<1	2	2	2	2	2	2	5

Applicator

Applying Liquid Sprays via Groundboom Equipment (3)	Hops/mint

4.2 lb ai/acre

80 acres	2	2	2	2	2	2	2	4

	Hops/mint

2.1 lb ai/acre

80 acres	3	3	4	3	4	4	4	8

Applying Granulars via Tractor Drawn Spreader (4)	Mint (nematodes)

6 lb ai/acre

80 acres	16	70	17	120	17	75	136	87

	Mint (symphylans)

3 lb ai/acre

80 acres	32	140	33	240	33	151	271	170

* 	MOEs shown in bold indicate risks that exceed HED’s level of concern (i.e., MOEs <100)

a	Application rates are the maximum application rates determined from the proposed ethoprop labels as supplied by RD.

b	Amounts handled per day are HED estimates of acres, square feet, or cubic feet treated or gallons applied based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimates.

c                Baseline:  	Long-sleeve shirt, long pants, no gloves, and no respirator.

PPE-G-NR:  	Baseline plus chemical-resistant gloves, and no respirator.

PPE-G,DL-NR: 	Coveralls worn over long-sleeve shirt and long pants, chemical-resistant gloves, and no respirator.

PPE-G-80% R:	Baseline plus chemical-resistant gloves and an 80% PF  (quarter-face dust/mist) respirator.

PPE-G,DL-80% R: 	Coveralls worn over long-sleeve shirt and long pants, chemical-resistant gloves, and an 80% PF (quarter-face dust/mist) respirator.

PPE-G-90% R:	Baseline plus chemical-resistant gloves and a 90% PF (half-face dust/mist) respirator.

PPE-G,DL-90% R: 	Coveralls worn over long-sleeve shirt and long pants, chemical-resistant gloves, and a 90% PF (half-face dust/mist)  respirator.

Eng Controls: 	Closed mixing/loading system, enclosed cab, or enclosed cockpit.

                Table 9.1.1b Short/Intermediate Ethoprop Occupational Handler Non-cancer Risk Estimates (Eng. Cntrls, using PHED data)

Scenario	Representative Application/Crops	Application Rate	Area Treated (A/day)	Dermal Dose (mg/kg/day)	Inhalation Dose (mg/kg/day)	Dermal MOE Inhalation MOE	Combined

Dermal and Inhalation

MOE

Mixer/Loaders

Loading Granulars for tractor drawn spreader applications	Hops/Mint

4.2 lb ai/acre

80 acres	0.0012	0.0002	16500	600	580

" "	Hops/Mint

2.1 lb ai/acre

80 acres	0.0006	0.0001	33000	1200	1200

M/L

liquids: Groundboom Applications (1)	mint (nematodes)

6 lb ai/acre

80 acres	0.0413	0.0004	2	350	2

" "	mint (symphylans)

3 lb ai/acre

80 acres	0.021	0.0002	5	700	5

Applicators

Applying Liquid Sprays via Groundboom Equipment (3)	Hops/mint

4.2 lb ai/acre

80 acres	0.0245	0.0002	4	680	4

" "	Hops/mint

2.1 lb ai/acre

80 acres	0.0122	0.0001	8	1360	8

Applying Granulars via Tractor Drawn Spreader (4)	Mint (nematodes)

6 lb ai/acre

80 acres	0.0137	0.0015	1400	93	87

" "	Mint (symphylans)

3 lb ai/acre

80 acres	0.0069	0.0008	2800	190	170

	* This table expands on the final column in Table  9.1.1a “Eng Cont”; showing the individual dermal and inhalation daily doses and  MOEs along with the combined MOE.

Occupational Handler Exposure (Biomonitoring-based)

Bayer CropScience submitted a biological monitoring study in April, 2002 (MRID #456215-01) that quantified ethoprop exposure for mixer-loaders, applicators, and mixer-loader-applicators.  The study used the Mocap® 6EC formulation of ethoprop with mechanical ground application equipment to treat potato fields in the Central Basin of Washington State in the United States.

This study was used in a previous risk assessment (Dawson, 2005; D281648), which assessed exposure from the application of ethoprop on potatoes for handlers in the Northwest.  The Agency made its regulatory decision for the EC formulation of ethoprop in the “Addendum to the 2001 Ethoprop Interim Reregistration Eligibility Decision (IRED)” on 2/25/06. That document, along with additional information about the risk assessment for the EC formulation is available here:   HYPERLINK "http://www.epa.gov/oppsrrd1/REDs/ethoprop_ired_combined.pdf"  http://www.epa.gov/oppsrrd1/REDs/ethoprop_ired_combined.pdf

HED believes that this biomonitoring study is useful in evaluating the risks for the current proposed uses.  The study is relevant to the current uses because the product in the study is applied in a similar manner to the current uses (i.e., applied via pre-plant/pre-emergent soil incorporation) and the formulations and application equipment are similar. As seen in section 9.1.1, the PHED based exposure assessment indicates the liquid formulation as the risk driver. The risk estimates calculated in this document from the biomonitoring study results are not applicable to the ethoprop MOCAP® 15% granular product.

The biomonitoring study, conducted between March and April 2001, quantified ethoprop exposure using a biological monitoring technique. According to Bayer CropScience, the growers determined the application parameters with the commercial applicators based on the growers’ needs, such as the application rate in accordance with the registered label, and acreage treated. Bayer CropScience only monitored the planned activity, and did not determine any of the application parameters. The Agency believes that this study is observational in nature and did not involve intentional exposure of a human subject to ethoprop because the exposure to ethoprop would have occurred whether or not the study was conducted.

A typical biomonitoring study is designed to monitor the total absorbed dose resulting from a single exposure event and normally does not encompass exposure over several days. However, the intent of this study was quite different than a typical biomonitoring study in that it was focused on conducting monitoring of a specific, small population of professional applicators to define levels over the monitoring period for those involved in treating potato fields with ethoprop under actual working conditions. Under actual working conditions, workers may be exposed for more than one day at a time; therefore, urine was collected for 4 consecutive work days. For a few workers, urine was collected on day 5 and 6 as well. The urine samples represented 24 hour periods (2 twelve hour samples combined) and a sample was collected 24 hours prior to the first day of work in the study for each subject. In some cases the individual worked with ethoprop during each of the 4 days, while in other cases exposure only occurred on the first day. In most cases, individual handlers worked with ethoprop only on the first two days of the monitoring period.

The study was performed at 13 distinct test sites and 23 handlers participated in the study. Most of these individuals performed both loading and application tasks, while others only loaded or applied. Mocap® EC was applied to the potato fields 2 to 3 weeks prior to planting at an application rate ranging from 4 to 12 pounds of active ingredient per acre (lb ai/A). Most applications, however, were in the 9 to 12 lb ai/A range. In addition, the acres treated ranged from approximately 25 to 560. Loading was accomplished through closed loading systems that included a hard coupled mechanical transfer system from 55 gallon drums or closed 2.5 gallon containers. All applications were made either using large closed cab tractors coupled with deep injection equipment or large special groundboom field applicators. The test subjects wore several combinations of PPE, which varied by individual; however, most applicators wore full clothing (in some cases Tyvek suits), coveralls, gloves, rubber boots, and respirators.

Occupational Handler Risk (Biomonitoring-based)

HED analyzed the ethoprop biomonitoring data by scaling the calculated daily dose and cumulative dose (in mg/kg/day) from the application rate applied in the biomonitoring study based on the two possible proposed application rates (4.2 lbs ai/A and 2.1 lbs ai/A).  The results of the analysis based on the biological monitoring data scaled to 2.1 lbs ai/A are presented below in Table 9.2.1a and the results of the analysis based on the biological monitoring data scaled to 4.2 lbs ai/A are presented below in Table 9.2.1b.

One worker included in the original biomonitoring study was excluded from this reanalysis  - the worker that conducted mixing/loading using an open pour operation which is prohibited based on the label amendments in the 2001 IRED that require closed mixing and loading.  There were 185 post-exposure urine samples collected in the biomonitoring study. Of those, slightly over 50 percent (95 samples) were either below the level of detection (LOD) or below the level of quantification (LOQ), which were 1 ppb and 3 ppb respectively, or were at a non-detectable level. These results indicate that very low exposures (i.e., essentially no exposure) occurred in this population for more than half of the monitoring period.

Risk estimates were calculated using the biological monitoring data in two distinct manners: (1) a cumulative dose approach and (2) a daily dose approach. The cumulative approach calculates an MOE from the total residue (i.e., the addition of each day’s M1 residue) for each individual over the entire 4 day monitoring period, where the daily dose approach considered the single 24 hour urine output for each individual and did not account for additivity. Geometric and arithmetic means were used to calculate the cumulative and daily dose MOEs for each task performed [i.e., mixing/loading (ML) only, applying only, and mixing/loading/applying (M/L/A)].

It is important to note that biological monitoring data account for all routes of exposure for an individual.  A key factor to consider when interpreting the results is whether or not a cumulative or daily dose estimate should be used as the basis of the calculation.  The M1 metabolite of ethoprop has been determined to rapidly metabolize and be excreted from the body within 24 hours. Therefore, the Agency believes that the daily dose risk calculations for each task, and the respective MOEs based on the arithmetic mean daily doses for that task, are the most appropriate on which to base risk management conclusions.

The following paragraphs include discussion and risk characterization around the biomonitoring study. The text generally presents MOEs calculated from the arithmetic means of the daily doses for each of the three tasks (M/L, Applicator, M/L/A) for the 4.2 and 2.1 lb ai/A proposed application rates. Additional information is included is Tables 9.2.1a and 9.2.1b; specifically MOEs associated with each individual worker’s dose as well as MOEs calculated from the arithmetic and geometric means of the daily and cumulative doses for the task-specific exposure.

The MOEs calculated from the daily doses ranged widely among individual handlers. The Agency believes that these results are to be expected when considering the actual work practices of multiple individuals. The study screened for very low levels of exposure (i.e., low ppb); therefore, the smallest increase in exposure significantly affected (lowered) the MOE. The level of care with which an individual handles a pesticide greatly influences the overall exposure to the pesticide. Given this study monitored the actual work practices of 23 handlers, degrees of caution will differ. Therefore, the Agency also considered the MOEs calculated from the arithmetic mean daily dose with engineering controls.

For the 2.1 lb ai/A rate, these MOEs ranged from 110 to 2700, with all averages ≥100.

For the 4.2 lb ai/A rate, these MOEs ranged from 54 to 1300, with most averages ≥100.

For the 4.2 lb ai/A application rate, MOEs calculated from the arithmetic mean daily exposure for mixer/loaders exceed HED’s level of concern on Day 1 and Day 2 (MOEs of 54 and 89, respectively) but not the other two days of monitoring. On an individual basis, MOEs ranged widely (i.e., range = <28 to >3000). For applicators, the MOEs calculated from the arithmetic mean daily exposure do not exceed HED’s level of concern (i.e., MOEs ranged from 210 to 1300). For applicators only, nearly all individual daily MOEs were greater than 100.  For the mixer/loader/applicator job function, MOEs calculated from the arithmetic mean daily doses were above 100 on Day 1 and ranged from 54-94 on the other three monitoring days. Individual MOEs ranged widely from <10 to >6000.

For the 2.1 lb ai/A application rate, MOEs calculated from the arithmetic mean dose from each job category are >100 for all three handler tasks (M/L, Applicators, M/L/A) on individual days. On an individual basis, MOEs ranged widely (i.e., range = <20 to >2800).

For both application rates, MOEs calculated from the cumulative doses are of concern for mixer/loaders (i.e., MOEs < 100 for most subjects individually and all MOEs calculated from the arithmetic mean cumulative doses).  For both application rates, MOEs calculated from the cumulative doses exceed HED’s level of concern for mixer/loader/applicators (i.e., MOEs < 100 for all MOEs calculated from the arithmetic mean cumulative doses). MOEs calculated from the arithmetic mean cumulative doses do note exceed HED’s level of concern for applicators at either application rate. However, because of the rapid elimination of M1, it is believed that daily dose estimates probably more realistically reflect actual risks to ethoprop users as indicated above.

Table 9.2.1a.  Risk Estimates For Ethoprop Handlers Based On Daily And Cumulative Dose Estimates From MRID 45621501

(Based on MOCAP EC scaled to 2.1 lbs ai/A)

Handler

Days of Exposure

Body Weight

(kg)

Margins Of Exposure (MOEs) Based On Single Day & Cumulative [M1] In Urine

Day 1

Day 2

Day 3

Day 4

Cumulative

Mixing/Loading with Closed Systems Using Hard Coupling Devices (M/L)

ML1

2

132	55	110	910	120	27

ML2

1

77	69	480	3400	5900	59

ML3

3

132	260	160	130	160	42

AP11

1

70	1100	200	2800	420	110

Arithmetic Mean	110	180	430	230	46

Geometric Mean	180	200	1000	470	52

Applying with Ground Equipment Equipped With Enclosed Cab With Charcoal Filtration (App)

AP6

2

95	3300	4300	4100	2100	790

AP12

1

77	2800	160	1400	2100	130

AP14

3

95	2000	1800	1400	1300	390

Arithmetic Mean	2600	420	1800	1700	250

Geometric Mean	2700	1100	2000	1800	340

Mixing/Loading with Closed Systems Using Hard Coupling Devices and Applying Ground Equipment Equipped With Enclosed Cab With Charcoal Filtration (M/L/A)

AP1 *

3

68	860	160	140	36	18

AP2 *

4

66	2800	140	46	75	23

AP3

1

100	2400	3200	7000	1900	710

AP4

1

64	1500	4700	810	1500	360

AP5

1

89	1900	1700	890	1500	340

AP13

1

98	7700	1800	14000	5100	1100

AP15

2

91	150	31	82	240	18

AP16

2

55	720	170	570	650	96

AP17

2

95	3600	750	3600	6400	490

AP18

2

70	1700	2600	9500	3700	730

AP19

2

114	640	190	140	210	54

AP20

2

59	5100	1600	8500	3700	840

AP21

2

91	860	780	780	660	190

AP22

2

77	3400	1800	3900	2500	660

AP24

2

73	290	35	12	41	7

Arithmetic Mean	790	160	110	190	44

Geometric Mean	1400	560	790	740	160

*AP1 Urines were also collected on days 5 & 6;  AP2 urine was also collected on Day 5; MOEs are not presented here.

Table 9.2.1b: Risk Estimates For Ethoprop Handlers Based On Daily And Cumulative Dose Estimates From MRID 45621501

(Based on MOCAP EC scaled to 4.2 lbs ai/A)

Handler

Days of Exposure

Body Weight

(kg)

Margins Of Exposure (MOEs) Based On Single Day & Cumulative [M1] In Urine

Day 1

Day 2

Day 3

Day 4

Cumulative

Mixing/Loading with Closed Systems Using Hard Coupling Devices (M/L)

ML1

2

132	28	53	450	60	14

ML2

1

77	35	240	1700	3000	29

ML3

3

132	130	84	68	81	22

AP11

1

70	570	99	1400	210	57

Arithmetic Mean	54	89	220	120	23

Geometric Mean	92	100	520	230	26

Applying with Ground Equipment Equipped With Enclosed Cab With Charcoal Filtration (App)

AP6

2

95	1700	2100	2000	1000	390

AP12

1

77	1400	78	680	1100	63

AP14

3

95	1000	910	710	630	200

Arithmetic Mean	1300	210	890	860	130

Geometric Mean	1300	530	990	880	170

Mixing/Loading with Closed Systems Using Hard Coupling Devices and Applying Ground Equipment Equipped With Enclosed Cab With Charcoal Filtration (M/L/A)

AP1 *

3

68	430	79	70	18	9

AP2 *

4

66	1400	71	23	38	11

AP3

1

100	1200	1600	3500	960	360

AP4

1

64	750	2300	410	750	180

AP5

1

89	930	830	440	730	170

AP13

1

98	3900	910	6800	2500	530

AP15

2

91	73	15	41	120	9

AP16

2

55	360	87	290	320	48

AP17

2

95	1800	370	1800	3200	240

AP18

2

70	840	1300	4800	1900	370

AP19

2

114	320	96	71	100	27

AP20

2

59	2500	810	4300	1900	420

AP21

2

91	430	390	390	330	96

AP22

2

77	1700	890	1900	1300	330

AP24

2

73	150	18	6	21	4

Arithmetic Mean	390	82	54	94	22

Geometric Mean	710	280	400	370	79

*AP1 Urines were also collected on days 5 & 6;  AP2 urine was also collected on Day 5; MOEs are not presented here.

Risk Characterization Comparing PHED and Biomonitoring Assessments

The registrant conducted a biological monitoring study with ethoprop because risk estimates using PHED unit exposure values generally exceeded HED’s level of concern.  The biological monitoring study (MRID #456215-01) on users in Washington State potato fields can be applied to these new uses on hops and mint. The ethoprop biomonitoring study was performed with the sole purpose of quantifying professional applicator exposure during the use of ethoprop in Pacific Northwest potato fields. According to BEAD, hops are grown on a commercial basis almost exclusively in the Pacific Northwest. Mint is grown mostly in the Pacific Northwest, but small amounts are grown outside that region. It is unclear how different agricultural and climate conditions would affect the resulting handler exposure estimates.

The study generally showed low levels of exposure and associated risk when the required engineering controls are utilized and appropriate PPE are worn. Although in some cases, the workers used both engineering controls and various levels of PPE, the Agency believes that the low exposure primarily resulted from the use of the engineering controls.

The study protocol required that potential adverse effects of ethoprop be explained to each of the study participants. The study report provides detailed descriptions of observations by the study monitors of both the workers’ work practices and other observations. There is no mention of any worker exhibiting any adverse effects or anything that would be suggestive of cholinergic clinical signs in the original biomonitoring study. Application rates in the original study ranged from 4-12 lbs ai/A (i.e., the upper end of the proposed application rate for hops and mint to 3X the proposed application rate). Therefore, considering the MOEs for the majority of biomonitoring samples, as well as the MOEs calculated from the arithmetic mean daily doses, and the absence of observable adverse effects in the original biomonitoring study, the Agency believes when proper engineering controls are utilized for mixing, loading, and applying liquid ethoprop, occupational risk to ethoprop is low.

Occupational Cancer Exposure

Cancer risk estimates resulting from exposures to ethoprop were calculated using a linear low-dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q1*  that has been calculated for ethoprop based on dose response data (Q1*  = 2.8 x 10-2 (mg/kg/day)-1).  Absorbed average daily dose (ADD) levels were used as the basis for calculating the LADD values.  Dermal and inhalation ADD values were first added together to obtain combined ADD values.  LADD values were then calculated and multiplied by the Q1* to obtain cancer risk estimates.

To estimate the carcinogenic risk from absorbed average daily dose, the values must be amortized over the working lifetime of occupational handlers.  Current use patterns indicate that application can be made one time per growing season although commercial applicators may make multiple applications to crop land depending on the geographic area of the country and pest pressure.  As a result, HED considered commercial applicators for the cancer risk assessment. The proposed product labels indicate ~1 application per season; no information is currently available to indicate how many applications of ethoprop a commercial applicator makes per season. Therefore, cancer risk calculations assume commercial applicators apply ethoprop 30 days per calendar year for 35 years over a 70 year lifespan.

Occupational Handler Cancer Risk

Estimated cancer risk calculations were completed by multiplying the LADD values by the Q1* for ethoprop (Q1*  = 2.8 x 10-2 (mg/kg/day)-1).

HED has defined a level of concern range for cancer risk estimates based on a policy memorandum issued in 1996 by then Office of Pesticide Programs (OPP) director, Mr. Dan Barolo.  This memo refers to a predetermined quantified "level of concern" for occupational carcinogenic risk.  In summary, this policy memo indicates occupational carcinogenic risks that are 1 x 10-6 or lower require no risk management action.  For those chemicals subject to reregistration, HED is to carefully examine uses with estimated risks in the 10-6 to 10-4 range to seek ways of cost-effectively reducing risks.  If estimated cancer risks are in this range for occupational handlers, increased levels of personal protection would be warranted as is commonly applied with non-cancer risk estimates (e.g., engineering controls or additional PPE).  Cancer risk estimates that remain above 1.0 x 10-4 at the highest level of mitigation appropriate for that scenario remain a concern.

Estimated ethoprop cancer risks for occupational handlers are summarized below in Table 9.4.1.    Cancer risk estimates exceed HED’s level of concern for cancer risks (i.e., risks are below

1 x 10-4) with proposed label PPE (i.e., engineering controls).

NF – Not feasible (engineering controls assumed, therefore baseline – PPE-G, DL90%R is N/A)

Handler exposure was considered to be 30 days per year for 35 years over a 70 year lifetime.

a	Application rates are the maximum application rates provided by product labels for ethoprop in all cases.

b	Amount handled per day values are HED estimates of acreage treated or gallons applied based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” industry input, and HED estimates.

c                Baseline:  	Long-sleeve shirt, long pants, no gloves, and no respirator.

PPE-G-NR:  	Baseline plus chemical-resistant gloves, and no respirator.

PPE-G,DL-NR: 	Coveralls worn over long-sleeve shirt and long pants, chemical-resistant gloves, and no respirator.

PPE-G-80% R:	Baseline plus chemical-resistant gloves and an 80%PF (quarter-face dust/mist) respirator.

PPE-G,DL-80% R: 	Coveralls worn over long-sleeve shirt and long pants, chemical-resistant gloves, and an 80%PF (quarter-face dust/mist) respirator.

PPE-G-90% R:	Baseline plus chemical-resistant gloves and a 90% PF (half-face dust/mist) respirator.

PPE-G,DL-90% R: 	Coveralls worn over long-sleeve shirt and long pants, chemical-resistant gloves, and a 90% PF (half-face dust/mist) respirator.

Eng Controls: 	Closed mixing/loading system, enclosed cab, or enclosed cockpit.

Table 9.4.1. Summary of Ethoprop Occupational Handler Cancer Risk Estimates

Exposure Scenario

Crop or Target

Application Rate a

Area Treated Daily b

Cancer Risk Estimates c

Baseline

PPE-G-NR

PPE-G, DL-NR

PPE-G- 80% R

PPE-G, DL- 80% R

 PPE-G- 90% R

 PPE-G, DL- 90% R

Eng Control

Mixer/Loader

Mixing/Loading Emulsifiable Concentrates for Groundboom Applications  Hops/Mint

4.2 lb ai/acre

80 acres	2E-05	2E-05	9E-06	8E-06	2E-05	6E-06	4.7E-06	4E-07

	Hops/Mint

2.1 lb ai/acre

80 acres	1E-05	1E-05	5E-06	4E-06	8E-06	3E-06	2E-06	2E-07

Mixing/Loading Granular Broadcast Spreader	mint (nematodes)

6 lb ai/acre

80 acres	2E-03	2E-05	2E-05	2E-05	2E-05	1E-05	1E-05	7E-06

	mint (symphylans)

3 lb ai/acre

80 acres	1E-03	1E-05	9E-06	8E-06	9E-06	7E-06	6E-06	3E-06

Applicator

Applying Liquid Sprays via Groundboom Equipment 	Hops/mint

4.2 lb ai/acre

80 acres	1E-05	1E-05	1E-05	1E-05	1E-05	9E-06	8E-06	4E-06

	Hops/mint

2.1 lb ai/acre

80 acres	7E-06	7E-06	5E-06	5E-06	6E-06	4E-06	4E-06	2E-06

Applying Granulars via Tractor Drawn Spreader 	Mint (nematodes)

6 lb ai/acre

80 acres	2E-05	2E-05	9E-06	8E-06	1E-05	6E-06	5E-06	4E-06

	Mint (symphylans)

3 lb ai/acre

80 acres	9E-06	8E-06	5E-06	4E-06	7E-06	3E-06	3E-06	2E-06

Occupational Postapplication Exposure

Postapplication exposures to ethoprop have not been assessed in this document as the proposed label is for pre-plant/pre-bloom and post-emergent (to soil only) crop applications. Due to the method and timing of applications and typical agricultural practices for these crops, HED has determined that a specific postapplication exposure assessment is not necessary for these scenarios. This determination is based on the following: (1) routine hand labor activities that involve significant contact with the treated soil/planting medium are not required, or are not required for several weeks or months after the application, and (2) reentry activities that may be necessary are likely to result in relatively low levels of dermal exposure because contact with the treated medium is minimal or infrequent.

Therefore, in lieu of estimating a specific re-entry interval (REI), HED recommends that the default WPS REI, based on the acute toxicity of the active ingredient, be used for these scenarios. This will provide some measure of protection to workers who reenter treated areas for non-routine activities which may result in contact with treated surfaces.

10.0	Data Needs   TC \l1 "10.0	Data Needs and Label Recommendations

Toxicology

870.7800.  Immunotoxicity study.  This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non-food uses).

870.3465.  90-Day inhalation toxicity study.  This study is required for a route-specific assessment of inhalation toxicity which is presently assessed using an oral endpoint.

Residue Chemistry  TC \l2 "10.2	Residue Chemistry

	None.

Occupational and Residential Exposure  TC \l2 "10.3	Occupational and Residential Exposure

	None.

References

Occupational/Residential Exposure:  Ethoprop. Exposure/Risk Assessment for Pesticide Handlers and Agricultural Workers from the Proposed Uses on Hops and Mint.  Matthew Lloyd.  5/16/08.  D352634 and D352636

ETHOPROP: Risk Assessment For Handlers In The Northwest On Potatoes Based On Biomonitoring Study (MRID 456215-01).  Jeffrey L. Dawson .  3/1/05.  D281648.

Dietary:  Ethoprop. Acute (Probabilistic), Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Proposed New Uses on Hops and Mint.  Christine Olinger.   7/3/08.  D352232 and D352234.

Ethoprop . Anticipated Residues to Support New Uses on Hops and Mint.  Christine Olinger.  7/3/08.  D352476 and D352477.

Ethoprop (041101).  Reregistration Case No. 0106.  Product and Residue Chemistry Chapters for the Reregistration Eligibility Decision (RED).  John Abbots.  3/27/98.  3/27/98.

Water:  Drinking Water Exposure Assessment for the IR-4 New Use Registration.  Michael R. Barrett.  6/17/08.  D342755 and D342794.

Ethoprophos Drinking Water Assessment; Including Evaluation of Submitted Ground and Surface Water Monitoring Studies (Revised from 6/28/07 assessment).  Michael R. Barrett.  12/18/07.  D323344.

Metabolism:     SEQ CHAPTER \h \r 1 Ethoprop.  HED Metabolism Committee Meeting on 1/27/98.  Kit Farwell.  2/6/98.    SEQ CHAPTER \h \r 1 Txr 012563.

IRED:  Interim Reregistration Eligibility Decision for Ethoprop CASE 0106, Lois Rossi.  September, 2001,  and  Addendum to the 2001 Ethoprop Interim Reregistration Eligibility Decision (IRED), Debra Edwards, 7/31/06.    HYPERLINK "http://www.epa.gov/pesticides/reregistration/REDs/ethoprop_red.pdf"  http://www.epa.gov/pesticides/reregistration/REDs/ethoprop_red.pdf

Cumulative:  Organophosphorus Cumulative Risk Assessment – 2006 Update.  August 2006.

  HYPERLINK "http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf"  http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology Assessment

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for ethoprop are listed below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

yes

no

yes	yes

yes

yes

no

no

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

no

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Reverse Mutation - bacterial

870.5375    Mutagenicity—Chromosomal Aberrations-mammalian

870.5395    Mutagenicity—Mammalian Micronucleus		yes

yes

yes	yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

870.6200b  90-Day Neuro. Screening Battery (rat)

870.6300    Develop. Neuro		yes

no

yes

yes

yes	yes

nob

yes

yes

yes

870.7485    General Metabolism

870.7600    Dermal Penetration

870.7800    Immunotoxicity		yes

no

yes	yes

no

no

a An acceptable 28-day neurotoxicity study in hens is available.

A.2	Toxicity Profiles TC \l2 "A.2  Toxicity Profiles

  SEQ CHAPTER \h \r 1 Table A.2.1   Acute Toxicity of Technical Ethoprop

Guideline

 No.

Study Type

MRID #

Results

Toxicity Category

870.1100	Acute Oral

- Rat.  1965	00078035	M LD50 = 56.2 mg/kg

F LD50 = 30.2 mg/kg	I

870.1100	Acute Oral

- Rat.  1998	44472501	F LD50 = 56 mg/kg  	II

870.1200	Acute Dermal

- Rabbit.  1965	00078035	LD50 = 25.74 mg/kg	I

870.1200	Acute Dermal

- Rabbit.  1987	42979502	LD50 = 8.5 mg/kg	I

870.1200	Acute Dermal

- Rat.  1987	42979501	M LD50 = 1280 mg/kg

F LD50  =   424 mg/kg	II

870.1300	Acute Inhalation -

Rat	070060	LC50 = 0.123 mg/L	II

870.2400	Primary Eye Irritation - Rabbit	00078036	0.1 mL resulted in 100% mortality	I

870.2500	Primary Skin Irritation - Rabbit	00048774	0.5 mL resulted in 100% mortality	I

870.2600	Dermal Sensitization

	N/A1	N/A	N/A

870.6100	Delayed Neuropathy - Hen	40609401

47127001	Negative	N/A

1Requirement for dermal sensitization study waived in 1987 Registration Standard due to high acute dermal toxicity.

Table A.2.2	Subchronic, Chronic, and Other Toxicity Profile

STUDY	SEX	DOSE	ENDPOINT	NOAEL	LOAEL (mg/kg/day)

COMPARATIVE  ChE   ACUTE  Study

2004

MRID 46278701

	ADULT

0, 0.5, 1, 2, 4  mg/kg

	Systemic

Not reported

	Plasma	0.5	1.0

	RBC	1	2 (-22% males)

BMDL20 = 1.2 mg/kg

	Brain	4	> 4

BMD could not be calculated because of insufficient ChE inhibition.

OFFSPRING

(11 days old)

0, 0.5, 1, 2

mg/kg	Systemic

Not reported

	Plasma	< 0.5	0.5

	RBC	0.5	1 (-17% in males)

BMDL20 = 1.2 mg/kg

	Brain	0.5	1 (-10% males and females)

BMDL10 = 0.76 mg/kg

ACUTE RAT NEUROTOX SD Crl:CD BR VAF/Plus

1994

MRID 43197701

M

0, 5, 50, 75 mg/kg

≥ 75	> 75 mg/kg

F

0, 5, 25, 50 mg/kg

tested blood ChE on day 2, brain on day 15	Systemic	5 mg/kg	25 mg/kg (MA, FOB). Death at HDT.

	Plasma	< 5	5 mg/kg

	RBC	< 5	5 mg/kg (-32%)

	Brain	≥ 50	> 50 mg/kg

SPECIAL ACUTE RAT NEUROTOX SD Crl:CD BR VAF/Plus

1994

MRID 43442402.

ChE activity  2 hours post-dosing (and still inhibited on day 15).

M	0, 24, 52 mg/kg

tested at 2 hr, day 8 and day 15	Systemic	24 mg/kg	52 mg/kg (cholinergic signs)

	Plasma	< 24	24 mg/kg

	RBC	< 24	24 mg/kg (-43% at 2 hr,  -23% on day 15)

	Brain	< 24	24 mg/kg (~  -46 % in 3 brain regions at 2 hr,  -27% in frontal cortex on day 15)

F	0, 16, 33 mg/kg

tested at 2 hr, day 8 and day 15

	Systemic	16	33 mg/kg (cholinergic signs)

	Plasma	<16	16 mg/kg

	RBC	<16	16 mg/kg (-44% at 2 hr, -29% on day 8)

	Brain	<16	16 mg/kg (~  -55% in 3 brain regions at 2 hr,  -17% in hippocampus on day 15)

COMPARATIVE  ChE  11-day gavage study

2004

MRID 46278702

	ADULT

0, 0.5, 1, 2  mg/kg/day

	Systemic

no clinical signs observed

	Plasma	< 0.5	0.5

	RBC	0.5	1 (-53% / - 28% male/female)

BMDL 20 = 0.34 mg/kg/day

	Brain	1	2 (-12% females)

BMDL10 = 1.8 mg/kg/day

OFFSPRING

(11 days old)

0, 0.25, 0.5, 1 mg/kg/day	Systemic

no clinical signs observed

	Plasma	< 0.25	0.25

	RBC	0.25	0.5 (-39% males)

BMDL20 = 0.28 mg/kg/day

	Brain	< 0.25	0.25 (-10% / -15% males/females)

BMDL10 = 0.14 mg/kg/day

SUBCHRONIC RAT NEUROTOX

feeding study

SD Crl:CD BR VAF/Plus

1994

MRID 43424001

M	0, 4, 40, 400 ppm

0, 0.26, 2.6, 27 mg/kg/day

tested weeks 4, 8, 14	Systemic	2.6	27 (FOB, MA, cholinergic signs, BW, FC)

	Plasma	0.26	2.6

	RBC	0.26	2.6 (-30% week 4)

	Brain	< 0.26	2.6

F	0, 4, 40, 400 ppm

0, 0.31, 3.0, 31 mg/kg/day

tested weeks 4, 8, 14	Systemic	3	31 (FOB, MA, signs, BW, FC)

	Plasma	< 0.31	0.31

	RBC	0.31	3.0 (large S.D., no statistical significance)

	Brain	 <0.31	0.31

DNT

2004

MRID 46364801 46364802

F	MATERNAL

0, 3, 30, 180 ppm

0, 0.7, 6.2, 38.2 mg/kg/day during lactation

↓BW

	Plasma	< 0.7	0.7

	RBC	< 0.7	0.7 (-30%)

	Brain	0.7	6.2 (-49%)

OFFSPRING

(21 days old)	Systemic	< 0.7	0.7    ↑ MA (males on PND 17)

(at 38.2 mg/kg/day, also effect on learning in water maze)

	Plasma	0.7	6.2

	RBC	6.2 	38.2 (-62 / -76% male/female)

	Brain	0.7	6.2 (-10% / -7% male/female)

28-DAY FEEDING STUDY  Crl:CD(SD)IGS BR

2001

MRID 45388501

M/F	0, 0.2, 0.5, 1.0 ppm

M  0,0.018, 0.045, 0.090 mg/kg/day

F   0, 0.021, 0.052, 0.099 mg/kg/day	Systemic	> 0.090	> 0.090

	Plasma	Not tested	----

	RBC	> 0.090	> 0.090

	Brain	Not tested	---

28-DAY FEEDING STUDY  Crl:CD(SD)IGS BR

2001

MRID 45388502

M	0, 7.5, 15, 30 ppm

0, 0.567, 1.159, 2.363 mg/kg/day	Systemic	> 2.363	> 2.363

	Plasma	0.567	1.159

	RBC	<0.567	0.567 (-22%)

	Brain	Not tested	---

F	0, 7.5, 15, 30 ppm

0, 0.707, 1.366, 2.677 mg/kg/day

	Systemic	> 2.677	> 2.677

	Plasma	<0.707	0.707

	RBC	1.366	2.677 (-40%)

	Brain	---	---

CHRONIC/ONCO RAT 1992 Crl:CD

MRID 42530201

Doc 010775

↓dose: signs, death, major ↓BW in 1st 2 wks.	Systemic	2.44	18.38 (↓BW gain, FC, anemia)

	Plasma	0.04 	2.44

	RBC	0.04	2.44  (-40% starting at week 14)

	Brain	0.04	2.44  (-35%)

F	0, 1, 60, 600/400 ppm

0, 0.06, 3.56, 23.98 	Systemic	3.56	23.98 (↓BW gain, FC, anemia)

	Plasma	0.06	3.56

	RBC	0.06	3.56 (-41% starting at week 14)

	Brain	0.06	3.56 (-28%)

MOUSE ONCO

MRID 40356301, 43326001

Doc 006620

M	0, 0.2, 2, 30 ppm

0, 0.026, 0.254, 3.96 mg/kg/day 	Systemic	0.254	3.96 (↓ BW)

	Plasma	0.026	0.254

	RBC	0.026	0.254 (-12% starting week 26)

	Brain	0.254	3.96 (-36% at week 26)

F	0, 0.2, 2, 30 ppm

0, 0.032, 0.318, 4.9 mg/kg/day 	Systemic	0.318	4.91 (↓ BW)

	Plasma	0.032	0.318

	RBC	0.032	0.318 (-13% starting week 26)

	Brain	0.318	4.9 (-29% at week 26)

90-DAY DOG

1967

MRID 75240

Doc 001789

0, 1, 3, 100 ppm

0, 0.025, 0.075, 2.5 mg/kg/day	Systemic	0.075	2.5  (emesis)

	Plasma

M day 2

M day 65

0.025

<0.025

0.075

0.025

	RBC

F day 4

F day 65

0.075

0.025

2.5

0.075

	Brain	---	---

COMBINED 1-YEAR + 5 MONTH DOG

1986, 1990

MRID 160179, 41498601

Doc 006353, 011281	M	0, 0.01, 0.025, 1.0, 10.0 mg/kg/day 	Systemic	0.025 1.0 (anemia, liver tox)

	Plasma	0.01	0.025

	RBC	0.025	1.0   (-21 to -48% at various time points)

	Brain	1.0 	10.0   (-44% at 1 year

	F	0, 0.01, 0.025, 1.0, 10.0  mg/kg/day 	Systemic	0.025	1.0 (anemia)

	Plasma	0.01	0.025

	RBC	0.025	1.0   (-11 to -45% at various time points)

	Brain	1.0	10.0   (-35% at 1 year)

TECHNICAL

21-DAY DERMAL RABBIT

1989

MRID 41304404

DOC 010143

M/F

↓ BW, ↓kidney wt) - Females, only

	Plasma	0.1	1.0

	RBC	0.1	1.0  (-42%)

	Brain	0.1	1.0  (-49%)

TECHNICAL

21-DAY DERMAL RAT  1990

MRID 45074602

M/F

0.3, 1, 10 mg/kg/day	Systemic	> 10	> 10

	Plasma	0.3	1

	RBC	0.3	1  (-33%)

	Brain	1	10  (-70%)

GRANULAR FORMULATION

19.34% granular

28-DAY DERMAL RAT  Year 2000

MRID 45034801	M/F	0, 19.34, 96.7, 387 mg/kg/day (corrected for % a.i.) Systemic	> 387	> 387

	Plasma	< 19.34	19.34

	RBC	19.34	96.7   (-40% to -80%)

	Brain	19.34	96.7  (-40%)

RABBIT DEVELOP

1989

MRID 41304403

DOC 010143, 011000	F	MATERNAL

≥ 2.5	> 2.5      No maternal or offspring toxicity occurred.  ChE was not determined.

	OFFSPRING

≥ 2.5	> 2.5

RAT DEVELOP

1989

MRID 41304402

Doc 010143	F	MATERNAL

2, 9, 18 mg/kg/day 	Systemic	2	9 (↓ BW gain,

↑ soft stool)

OFFSPRING

≥ 18	> 18

2-GEN RAT REPRO

1991

MRID 41921201

Doc 011282

MF

	PARENTAL

0, 1, 30, 300/150 ppm

0.08, 2.3, 24/13 mkd.  ↓dose:  excess mortality in F1a pups.	Systemic 2.3	13 (↓ BW gain)

At 24 mkd there were tremors, loose stools.

	Plasma	0.08	2.3

	RBC	≥ 13	> 13

	Brain	0.08	2.3

	MF	OFFSPRING	Systemic	2.3	13 (↓ BW)

at 24 mkd, also ↑ mortality

Plasma, RBC, and Brain refers to cholinesterase activity.

BW = body weight, FC = food consumption, MA = motor activity, FOB = functional observational battery of neurotoxicity testing, HDT = highest dose tested, mkd = mg/kg/day.

A.3	Executive Summaries TC \l2 "A.3  Executive Summaries

Developmental Neurotoxicity:

	  SEQ CHAPTER \h \r 1 In a developmental neurotoxicity study (MRID 46364801), Ethoprop (93.6% a.i., batch # OP 9950044) was administered in the diet to 30 female mated Wistar Hannover Crl:WI (Glx/BRL/Han) IGS BR rats/dose at nominal concentrations of 0, 3, 30 and 180 ppm from gestation day (GD) 6 through lactation day (LD) 21.  Average doses to the animals were 0, 0.3, 2.8 and 16.6 mg/kg/day during gestation and 0, 0.7, 6.2 and 38.2 mg/kg/day during lactation for the 0, 3, 30 and 180 ppm groups, respectively.

	A Functional Operational Battery (FOB) was performed on 30 dams/dose on GDs 13 and 20, and on 10 dams/dose on LDs 11 and 21.  On postnatal day (PND) 4, litters were culled to yield four males and four females (as closely as possible).  Offspring were allocated for detailed clinical observations (FOB) and assessment of motor activity, auditory startle reflex habituation, learning and memory (passive avoidance and watermaze testing), and neuropathology at study termination (day 75±5 of age).  On PND 21, the whole brain was collected from 10 pups/sex/dose group for micropathologic examination and morphometric analysis.  Brain and erythrocyte (RBC) acetylcholinesterase (AChE) and plasma cholinesterase (ChE) activities were measured in offspring (10/dose group) on PNDs 4 and 21 and in dams (10/dose group) on LD 21.  Pup physical development was evaluated by body weight.  The age of sexual maturation (vaginal opening in females and preputial separation in males) was assessed.

	No parental animals died during gestation or lactation.  No treatment-related clinical signs of toxicity were observed during gestation.  During lactation, females at 180 ppm had an increased incidence of coarse tremors (7), repetitive chewing movements (7), muscle fasciculations (1), and nasal stains (2), none of which were observed in the control or other treated groups.  During the FOB, the dams at 180 ppm had an increased incidence of tremors (2) and red nasal stains (1) on LD 11 and tremors (4), repetitive chewing (2), and brown perianal stains (1) on LD 21 compared with no abnormal findings in the controls.  Mean body weight and food consumption were not affected by treatment during gestation.  Mean body weight gain in females at 180 ppm was non-significantly decreased (90% of control value) for GDs 6-20.  During lactation mean body weight for the high-dose dams was non-significantly decreased (94% of control value) on LD 4 and significantly decreased on LDs 7 through 21 (90-92% of control value).  Body weight gain in females at 180 ppm was decreased (45% of control value) during the lactation period.  Food consumption in high-dose females was non-significantly decreased (92-94% of control value) during the second and third weeks of lactation.

	No treatment-related effects were observed on reproduction parameters.  There was no treatment-related effect on the mean number of delivered pups per dam and survival during lactation and post-weaning was comparable between control and treated groups.

	Mean body weight of offspring in treated and control groups was similar at parturition but was significantly decreased in males (82-84% of control value) and females (81-85% of control value) at 180 ppm beginning on PND 11.  Mean body weight gain was significantly decreased in males (79-85% of control value) and females (78-84% of control value) at 180 ppm throughout lactation.  Post-weaning (PNDs 28-70) body weight was significantly decreased in males (87-94% of control value) and females (89-94% of control value) at 180 ppm.  The mean age at sexual maturation was not affected in either sex by treatment.

	FOB parameters, auditory startle reflex habituation, and learning and memory (passive avoidance) were comparable between treated and control offspring.  An effect on learning (water maze) in high-dose males was noted as an increase in the number of trials to criterion and a non-statistically significant increase in the trial 2 duration.  Motor activity in all male treatment groups was increased on PND 17 due to a lack of habituation.  Mean absolute brain weight was unaffected by treatment.  No treatment-related findings were observed on gross or microscopic examination and morphometrics of the nervous system.

	The maternal LOAEL for Ethoprop in rats is 180 ppm (38.2 mg/kg/day during lactation) based on clinical signs (coarse tremors, repetitive chewing, muscle fasciculations, and nasal stains) and decreased body weight and body weight gain during lactation.  The maternal NOAEL is 30 ppm (6.2 mg/kg/day during lactation).

	The offspring LOAEL for Ethoprop in rats is 3 ppm (0.7mg/kg/day), the lowest dose tested, based on increased motor activity in male pups on PND 17.  The offspring NOAEL is not established.

	On LD 21, dams treated with 180 ppm had marked inhibition of plasma ChE (89%), RBC AChE (90%) and brain AChE (85%) activities in relation to control values.  At 30 ppm, plasma ChE (77%), RBC AChE (85%) and brain AChE (49%) activity inhibition were reported.  Inhibition of plasma ChE (34%) and RBC AChE (30%) activity occurred at 3 ppm; no inhibition was seen in brain AChE activity.

	Pooled male and female offspring blood samples were tested on PND 4.  In offspring, only plasma ChE (22%) activity was significantly inhibited at 180 ppm.  RBC AChE was non-significantly decreased (12%) at 180 ppm.  On PND 21 in male and female offspring, plasma ChE (68-71%), RBC AChE (62-76%) and brain AChE (50-62%) activities were significantly inhibited at 180 ppm. At 30 ppm, plasma ChE (32-40%) and brain AChE (7-10%) activities were significantly inhibited in both sexes.

	The maternal LOAEL for plasma ChE and RBC AChE inhibition for Ethoprop in rats is 3 ppm (0.7 mg/kg/day during lactation), the lowest dose tested, based on enzyme inhibition on LD 21.  The maternal NOAEL for plasma ChE and RBC AChE inhibition is not established.

	The maternal LOAEL for brain AChE inhibition for Ethoprop is 30 ppm (6.2 mg/kg/day during lactation) based on enzyme inhibition on LD 21.  The maternal NOAEL for brain AChE inhibition is 3 ppm (0.7 mg/kg/day during lactation).

	The offspring LOAEL for RBC AChE inhibition for Ethoprop in rats is 180 ppm (38.2 mg/kg/day during lactation, respectively) based on enzyme inhibition on PND 21.  The offspring NOAEL for RBC AChE inhibition is 30 ppm (6.2 mg/kg/day during lactation).

	The offspring LOAEL for plasma ChE and brain AChE inhibition for Ethoprop in rats is 30 ppm (6.2 mg/kg/day during lactation) based on enzyme inhibition on PND 21.  The offspring NOAEL for plasma ChE and brain AChE inhibition is 3 ppm (0.7 mg/kg/day during lactation).

	Doses during lactation were selected for the NOAEL and LOAEL, rather than lower doses during gestation, because effects were seen during lactation and not during gestation.  It should be noted that several specifications of the DCI are not adequately addressed in the current protocol.  The major inadequacy is a lack of information regarding duration of exposure and dose to the pups.

	This study is classified Acceptable/Non Guideline and may be used for regulatory purposes. It does not, however, satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft) pending comprehensive review of the positive control data.

Comparative Cholinesterase Study (acute):

This comparative cholinesterase study (MRID 46278701) consisted  of a time-to-peak-effect phase and a dose-response phase.  In the time-to-peak-effect phase, ethoprop (93.6% a.i., Batch # OP 9950044) was administered to 30 young adult (8-10 weeks old) Wistar Hannover Crl:WI[Glx/BRl/Han] IGS BR rats/sex/group via gavage  as a single dose (0 or 20 mg/kg) in corn oil (dose volume 5 mL/kg), and blood and brain samples were collected from sets of 6 rats/sex/dose group/time point at 2, 4, 8, and 24 hours (at 4 hours for controls) following treatment in order to determine the peak-effect time of maximum plasma cholinesterase (ChE) and erythrocyte and brain acetylcholinesterase (AChE) inhibition (Ellman method).

Similarly, 40  Wistar Hannover Crl:WI[Glx/BRl/Han] IGS BR neonatal rat pups/sex/group (11 days old) were administered ethoprop (93.6% a.i., Batch # OP 9950044) via gavage as a single dose (0 or 3.0 mg/kg) in corn oil (dose volume 5 mL/kg), and samples were collected from 10 neonatal rats/sex/dose group/time point at 4, 8, and 24 hours post dose (at 4 hours for controls) in order to determine the peak-effect time of maximum plasma ChE and erythrocyte and brain AChE inhibition.

	In the dose-response phase of the study, ethoprop was administered to 6 adult rats/sex/dose at dose levels of 0, 0.5, 1, 2, and 4 mg/kg and to 10 rat pups/sex/dose at dose levels of 0, 0.5, 1, and 2 mg/kg. AChE/ChE activities were determined in all of the rats/sex/dose for each age group, for plasma (ChE), erythrocytes (AChE), and brain (AChE) at their respective peak-effect times (adult; 24 hours ± 30 minutes) or (neonate; 8 hours ± 15 minutes).  No other assessments were performed.

	There were no clinical signs of toxicity and no treatment-related deaths in either age group.