Document ID: EPA-HQ-OPP-2007-0894-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-09-17T04:00Z

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. 

	Time-course study:  In the adult males, the magnitude of cholinesterase
inhibition was greatest at  8 hours post dose in plasma and at 24 hours
post dose in RBC and brain. In the adult females, the response in plasma
was flat (but greatest at 8 hours), and the magnitude of cholinesterase
inhibition was greatest at 24 hours in RBC and brain. In the pups, the
response in plasma was comparable at the 4- and 8-hour time points (both
sexes; 8-hour showed highest %) and lower at the 24-hour time point.
Similarly, the RBC response was comparable at the 8- and 24-hour time
points (both sexes; 8-hour showed highest %). The magnitude of the
acetylcholinesterase inhibition in brain was greatest at the 4-hour time
point in males and similar at the 4- and 8-hour time points in females
(8-hour slightly higher than 4-hour).

	Dose-response study [assessment of ChE/AChE activity performed at the
selected peak-effect times of 24 hours (adult)/8 hours (neonate)]: 
Adult: At the 1mg/kg dose level, the only effect observed was a
statistically-significant reduction (↓40%) in plasma cholinesterase
activity in the adult female rats. At 2 mg/kg, there was a
statistically-significant reduction in plasma cholinesterase activity in
both sexes (males ↓22%/females ↓65%) and a statistically-significant
reduction in RBC acetylcholinesterase activity in the males (males
↓22%). At 4 mg/kg, plasma (males ↓42%/females ↓74%) cholinesterase
and RBC (males ↓47%/females ↓30%) acetylcholinesterase activities
were statistically-significantly reduced in both sexes. Brain
acetylcholinesterase activity was not inhibited at any dose level in
either sex. Pups: There was a statistically-significant reduction in
plasma cholinesterase activity (males 25%/females 29%), RBC (↓17% in
males), and brain acetylcholinesterase activity (both sexes ↓10%) in
both sexes at 1 mg/kg. At 2 mg/kg, both sexes displayed reductions in
acetylcholinesterase activity in all compartments [plasma (males
↓51%/females ↓52%), RBC (males ↓31%/females ↓28%), and brain
(males ↓26%/females ↓23%).  

	BENCHMARK DOSE:  Following are the NOAEL/LOAEL values as well as
results of a benchmark dose (BMD) analysis conducted by HED.  The BMDL10
and BMDL20 results are the lower 95% confidence limit of the estimated
doses resulting in 10% brain cholinesterase inhibition and 20%
erythrocyte cholinesterase inhibition. 

	In adults, the BMDL20 for RBC cholinesterase inhibition was 1.2 mg/kg
in males and 1.9 mg/kg in females.  For pups, the BMDL20 for RBC
cholinesterase inhibition for male and female combined was 1.2 mg/kg.  

	In pups, the BMDL10 for brain cholinesterase inhibition was 0.8
mg/kg/day in combined males and females.  BMD values could not be
calculated for brain cholinesterase inhibition in adults because of
insufficient inhibition.  

	NOAELs and LOAELs:   In adults, the LOAEL for plasma cholinesterase
inhibition was 1 mg/kg (-40% inhibition in males), with a NOAEL of 0.5
mg/kg. In pups, the LOAEL for plasma cholinesterase inhibition was 0.5
mg/kg (-16% inhibition in males), with a NOAEL of <0.5 mg/kg. 

	In adults, the LOAEL for erythrocyte cholinesterase inhibition was 2
mg/kg (-22% inhibition in males), with a NOAEL of 1 mg/kg.  In pups, the
LOAEL for erythrocyte cholinesterase inhibition was 1 mg/kg (-17% in
males), with a NOAEL of 0.5 mg/kg.  

	In adults, the NOAEL for brain cholinesterase inhibition was 4 mg/kg,
the highest dose tested.  In pups, the LOAEL for brain cholinesterase
inhibition was 1 mg/kg (-10% in both males and females), with a NOAEL of
0.5 mg/kg. 

	The study is classified acceptable (non-guideline), and it does not
satisfy any guideline requirement.  However, it satisfies the
requirement for a comparative cholinesterase assay (acute exposure).

Ethoprop BRAIN

Time	Age	Sex	BMD10	BMDL10	BMD20	BMDL20

8 hr	Pup	Male - Female	0.9570	0.7592	- - -	- - -

24 hr	Adult

Could not calculate BMD for adults:  insufficient ChE inhibition

SENSITIVITY

Pup : Adult	Could not calculate sensitivity by comparing BMD values
because of insufficient brain ChE inhibition in adults. 

Ethoprop RBC

Time	Age	Sex	BMD10	BMDL10	BMD20	BMDL20

8 hr	Pup	Male - Female	0.9612	0.6160	1.528	1.226

24 hr	Adult	Male	1.062	0.5948	1.855	1.204

24 hr	Adult	Female	1.475	0.8902	2.575	1.880

SENSITIVITY  

Pup : Adult	MF : M	1.1

1.2

	SENSITIVITY  

Pup : Adult	MF : F	1.5

1.7

	

Benchmark dose modeling for rat pups, acute study (MRID 46278701):

	NOTE:   Could not calculate BMD in adult rats because of insufficient
ChE inhibition.  



Comparative Cholinesterase Study (11-day study):  

In a non-guideline comparative cholinesterase study (MRID 46636401),
ethoprop (93% a.i., Batch # OP 9950044) was administered to 6 young
adult Wistar rats (8-10 weeks old)/sex/group and to 10 Wistar
preweanling rat pups (11 days old)/sex/group for 11 consecutive days. 
Nominal doses for adults were 0, 0.25, 0.5, or 1 mg/kg/day and for pups
were 0, 0.25, 0.5, or 1 mg/kg/day.  Cholinesterase (ChE) and
acetylcholinesterase (AChE) activity was determined at peak effect times
of 24 hours after the final dose in adult rats and 8 hours after the
final dose in pups.

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

	Adult rats: There was a dose-related reduction in plasma ChE activity
in all treated female groups (↓44%, ↓57%, and ↓66% with increasing
dose) compared to the control. Males displayed a comparable reduction
(↓23%) at the mid- and high-dose levels. Erythrocyte AChE activity was
reduced in both sexes at the mid- (males ↓53%/females ↓28%) and
high- (males ↓73%/females ↓61%) dose levels. Brain AChE activity was
reduced only in the females at the high-dose level (↓12%).

	Rat pups: There was a similar, dose-related, reduction in plasma ChE
activity in both sexes (males ↓17%, ↓34%, and ↓49%/females ↓24%,
↓39% ↓47%, with increasing dose) compared to the control groups.
Erythrocyte AChE activity was reduced in males at the mid-dose level
(↓39%) and in both sexes at the high-dose level (males ↓65%/females
↓54%) compared to the control groups. Brain AChE activity was reduced
(dose-related) at all dose levels in both sexes (males ↓10%, ↓24%,
and ↓43%/females ↓15%, ↓27%, and ↓42%) compared to the control
groups. 

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6e more sensitive than the young adult rats, as evidenced by the
reduction observed in brain AChE activity at all dose levels (highest
dose was 1 mg/kg/day) in the preweanling animals (males
↓10%-43%/females ↓15%-42%) compared to the lack of an effect on
brain AChE activity in the young adult males and a 12% reduction in
brain AChE activity in young adult females only at the high-dose level
of 2 mg/kg/day. The reduction in erythrocyte AChE activity was
comparable between the age groups mainly at their respective high-dose
levels. 

	There are two common dose levels for the two age groups (0.5 and 1.0
mg/kg/day). The pups of both sexes displayed a greater reduction in both
erythrocyte (except 0.5 mg/kg/day females) and brain AChE activity at
both dose levels than the young adult animals. Preweanling animals of
both sexes displayed reductions in brain AChE activity at both dose
levels (males ↓ 24% and 43%/females; ↓27% and ↓42% at 0.5 and 1
mg/kg/day, respectively) compared to no reduction in the young adults at
these dose levels. Preweanling animals also displayed significant
reductions in brain AChE activity  (males ↓10%/females ↓15%) at the
lower dose of 0.25 mg/kg/day. At 1.0 mg/kg, preweanlings (males
↓65%/females ↓54%) displayed a greater reduction in erythrocyte AChE
activity than the young adults (males ↓53%/females ↓28%). 

	BENCHMARK DOSE:   A benchmark dose (BMD) analysis was conducted by HED
to estimate the doses resulting in 20% erythrocyte cholinesterase
inhibition and 10% brain cholinesterase inhibition.  In adults, the
BMDL20 for RBC cholinesterase inhibition was 0.3 mg/kg/day in males and
0.5 mg/kg/day in females.  In pups, the BMDL20 for RBC cholinesterase
inhibition was 0.3 mg/kg/day in combined males and females. 

	In adults, the BMDL10 for brain cholinesterase inhibition was 1.8
mg/kg/day in combined males and females.  In pups, the BMDL10 for brain
cholinesterase inhibition was 0.14 mg/kg/day for combined males and
females.  

	NOAELs and LOAELs:  In adults, the LOAEL for plasma cholinesterase
inhibition was 0.5 mg/kg/day (-44% in females), the lowest dose tested. 
The NOAEL in adults was <0.5 mg/kg/day.  In pups, the LOAEL for plasma
cholinesterase inhibition was 0.25 mg/kg/day (-24% in females), the
lowest dose tested. The NOAEL in pups was <0.25 mg/kg/day.

	 In adults, the LOAEL for erythrocyte cholinesterase inhibition was 1
mg/kg/day 

(-53% in males and -28% in females), with a NOAEL of 0.5 mg/kg/day.  In
pups, the LOAEL for erythrocyte cholinesterase inhibition was 0.5
mg/kg/day (-39% in males), with a NOAEL of 0.25 mg/kg/day.  

	In adults, the LOAEL for brain cholinesterase inhibition was 2
mg/kg/day (-12% in females), with a NOAEL of 1 mg/kg/day.  In pups, the
LOAEL for brain cholinesterase inhibition was 0.25 mg/kg/day (-10% in
males and -15% in females), the lowest dose tested. The NOAEL was <0.25
mg/kg/day.

	The study is classified acceptable (non-guideline), and it does not
satisfy any guideline requirement. However, it satisfies the requirement
for a comparative cholinesterase assay (repeat exposure).  

Ethoprop BRAIN

Time	Age	Sex	BMD10	BMDL10	BMD20	BMDL20

11-day	Pup	Male - Female	0.1760	0.1361	- - -	- - -

11-day	Adult	Male - Female	2.0417	1.759	- - -	- - -

SENSITIVITY  

Pup : Adult	MF : MF	12

	

Ethoprop RBC

Time	Age	Sex	BMD10	BMDL10	BMD20	BMDL20

11-day	Pup	Male - Female	0.2687	0.1421	0.4248	0.2759

11-day	Adult	Male	0.2939	0.1840	0.5010	0.3442

11-day	Adult	Female	0.4312	0.2860	0.7352	0.5480

SENSITIVITY  

Pup : Adult	MF : M	1.1

1.2

	SENSITIVITY  

Pup : Adult	MF : F	1.6

1.7

	

Benchmark dose modeling for rat pups, 11-day study (MRID 46636401):

	Benchmark dose modeling for adult rats, 11-day study (MRID 46636401):

Appendix B:  Tolerance Reassessment Summary  TC \l1 "Appendix C: 
Tolerance Reassessment Summary and Table 

Tolerances are currently established for numerous commodities in 40 CFR
180.262 for residues of the parent only and are listed below.  The
registrant has proposed uses on hops and mint and is proposing
tolerances be established in association with these uses at 0.02 ppm. 
The residue data have been reviewed and found acceptable (Olinger and
Fort, DP Barcodes: 352231 and 352233, 5/12/2008).  Although a tolerance
for peanuts has been established, the registrant has voluntarily
withdrawn all uses in association with the RED, and the Agency proposed
to revoke the peanut tolerance in a recent Federal Register Notice
(6/4/08 Volume 73, Number 108, pp. 31788-31807).

Tolerance Levels for Residues of Ethoprop

Commodity	Tolerance Level, ppm

Banana	0.02

Bean, lima	0.02

Bean, snap, succulent	0.02

Cabbage	0.02

Corn, forage	0.02

Corn, grain	0.02

Corn, stover	0.02

Corn, sweet, kernel plus cob with husks removed	0.02

Cucumber	0.02

Peanut	0.02

Peanut, hay	0.02

Pineapple	0.02

Potato	0.02

Sugarcane, cane	0.02

Sweet potato, roots	0.02

Appendix C:  Review of Human Research TC \l1 " Appendix D:  Review of
Human Research 

In the PHED study and biomonitoring study, adult human subjects were
intentionally exposed to a pesticide and it has been determined that a
review of their ethical conduct is required.  

The PHED Task Force, 1995.  The Pesticide Handler Exposure Database
(PHED), Version 1.1.  Task Force members Health Canada, U.S.
Environmental Protection Agency, and the National Agricultural Chemicals
Association, released February 1995.

MRID 45621501, “Determination of Exposure to Mixer-Loaders and
Applicators Who Handle Ethoprop During the Application of MOCAP EC
nematicide-Insecticide to Potatoes” 

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iomonitoring study.

 Reviewed in "Determination of the Appropriate FQPA Safety Factor(s) in
the Organophosphorus Pesticide Cumulative Risk Assessment.  Evaluation
of Sensitivity and Susceptibility to the Common Mechanism of Toxicity,
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