**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

![](media/image1.wmf){width="0.85in" height="0.925in"}

> OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: July 10, 2008

**[MEMORANDUM]{.underline}**

  ----------------------------------- -----------------------------------
  **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    **Case No.:** N/A
  Chemical Aggregate                  

  T**XR 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

[1.0 Executive Summary 4](#__RefHeading___Toc203446689)

[2.0 Ingredient Profile 8](#__RefHeading___Toc203446690)

[2.1 Summary of Registered and Proposed Uses
8](#__RefHeading___Toc203446691)

[2.2 Structure and Nomenclature 10](#__RefHeading___Toc203446692)

[2.3 Physical and Chemical Properties 11](#__RefHeading___Toc203446693)

[3.0 Hazard Characterization/Assessment
11](#__RefHeading___Toc203446694)

[3.1 Hazard and Dose-Response Characterization
11](#__RefHeading___Toc203446695)

[3.1.1 Database Summary 11](#__RefHeading___Toc203446696)

[3.1.2 Mode of Action, Metabolism, and Toxicological Effects
11](#__RefHeading___Toc203446697)

[3.3 FQPA Considerations 12](#__RefHeading___Toc203446698)

[3.3.1 Adequacy of the Toxicity Database
12](#__RefHeading___Toc203446699)

[3.3.2 Evidence of Neurotoxicity 12](#__RefHeading___Toc203446700)

[3.3.3 Studies Assessing Offspring Sensitivity
13](#__RefHeading___Toc203446701)

[3.3.4 Degree of Concern Analysis for Pre and Postnatal Susceptibility
14](#__RefHeading___Toc203446702)

[3.4 FQPA Safety Factor for Infants and Children
15](#__RefHeading___Toc203446703)

[3.5 Hazard Identification and Toxicity Endpoint Selection
15](#__RefHeading___Toc203446704)

[3.5.1 Acute Reference Dose (aRfD) 15](#__RefHeading___Toc203446705)

[3.5.2 Chronic Reference Dose (cRfD) 16](#__RefHeading___Toc203446706)

[3.5.3 Dermal Absorption 17](#__RefHeading___Toc203446707)

[3.5.4 Dermal Exposure -- Liquid Formulations
18](#__RefHeading___Toc203446708)

[3.5.5 Dermal Exposure -- Granular Formulations
18](#__RefHeading___Toc203446709)

[3.5.6 Inhalation Exposure 19](#__RefHeading___Toc203446710)

[3.5.7 Level of Concern for Margin of Exposure
19](#__RefHeading___Toc203446711)

[3.5.8 Recommendation for Aggregate Exposure Risk Assessments
20](#__RefHeading___Toc203446712)

[3.5.9 Classification of Carcinogenic Potential
20](#__RefHeading___Toc203446713)

[3.5.10 Toxicological Doses and Endpoints
20](#__RefHeading___Toc203446714)

[3.6 Endocrine disruption 21](#__RefHeading___Toc203446715)

[4.0 Public Health and Pesticide Epidemiology Data
22](#__RefHeading___Toc203446716)

[5.0 Dietary Exposure/Risk Characterization
23](#__RefHeading___Toc203446717)

[5.1 Pesticide Metabolism and Environmental Degradation
23](#__RefHeading___Toc203446718)

[5.1.2 Drinking Water Residue Profile 24](#__RefHeading___Toc203446719)

[5.1.3 Food Residue Profile 25](#__RefHeading___Toc203446720)

[5.2 Dietary Exposure and Risk 25](#__RefHeading___Toc203446721)

[5.2.1 Acute Dietary Exposure/Risk 26](#__RefHeading___Toc203446722)

[5.2.2 Chronic Dietary Exposure/Risk 27](#__RefHeading___Toc203446723)

[5.2.3 Cancer Dietary Risk 30](#__RefHeading___Toc203446724)

[6.0 Residential (Non-Occupational) Exposure
31](#__RefHeading___Toc203446725)

[7.0 Aggregate Risk Assessments 31](#__RefHeading___Toc203446726)

[8.0 Cumulative Risk Characterization/Assessment
31](#__RefHeading___Toc203446727)

[9.0 Occupational Exposure and Risk 31](#__RefHeading___Toc203446728)

[9.1 Occupational Handler Exposure (PHED-based)
31](#__RefHeading___Toc203446729)

[9.1.1 Occupational Handler Risk (PHED-based)
33](#__RefHeading___Toc203446730)

[9.2 Occupational Handler Exposure (Biomonitoring-based)
36](#__RefHeading___Toc203446731)

[9.2.1 Occupational Handler Risk (Biomonitoring-based)
37](#__RefHeading___Toc203446732)

[9.3 Risk Characterization Comparing PHED and Biomonitoring Assessments
41](#__RefHeading___Toc203446733)

[9.4 Occupational Cancer Exposure 42](#__RefHeading___Toc203446734)

[9.4.1 Occupational Handler Cancer Risk
42](#__RefHeading___Toc203446735)

[9.5 Occupational Postapplication Exposure
44](#__RefHeading___Toc203446736)

[10.0 Data Needs 44](#__RefHeading___Toc203446737)

[11.0 References 45](#__RefHeading___Toc203446738)

[Appendix A: Toxicology Assessment 46](#__RefHeading___Toc203446739)

[A.1 Toxicology Data Requirements 46](#__RefHeading___Toc203446740)

[A.2 Toxicity Profiles 47](#__RefHeading___Toc203446741)

[A.3 Executive Summaries 53](#__RefHeading___Toc203446742)

[Appendix B: Tolerance Reassessment Summary
61](#__RefHeading___Toc203446743)

[Appendix C: Review of Human Research 62](#__RefHeading___Toc203446744)

[]{#__RefHeading___Toc203446689 .anchor}**1.0 Executive Summary**

[Background]{.underline}: 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]{.underline}: 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
Q~1~\*.

[Studies Assessing Offspring Sensitivity]{.underline} 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]{.underline}: 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]{.underline}: 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 BMDL~10~, 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]{.underline}: 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]{.underline}: 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 99.9^th^ 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]{.underline}: All exposure estimates are below the
level of concern for all population groups, using all estimated drinking
water concentrations.

[Cancer Dietary Risk]{.underline}: 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]{.underline}: 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)]{.underline}: 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)]{.underline}: 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]{.underline}: There were no risk concerns for
cancer for occupational workers identified at the proposed label
engineering controls.

[Occupational Postapplication Exposure]{.underline}: 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]{.underline} : 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]{.underline}: 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,\"
<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]{.underline}: 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]{.underline}: 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.

[]{#__RefHeading___Toc203446690 .anchor}**2.0 Ingredient Profile**

[]{#__RefHeading___Toc203446691 .anchor}**2.1 Summary of Registered and
Proposed Uses**

**Background on Currently Registered Use Pattern:** 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   | Motorized ground equipment only (groundboom/tractor  |
| Methods       | spreader)                                            |
+---------------+------------------------------------------------------+
| Application   | EC (mint & hops):                                    |
| Rates and     |                                                      |
| Intervals     | 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..."*

[]{#__RefHeading___Toc203446692 .anchor}**2.2 Structure and
Nomenclature**

+-------------------------+--------------------------------------------+
| **Table 2.2.            |                                            |
| Nomenclature of         |                                            |
| Ethoprop and its        |                                            |
| Metabolites of          |                                            |
| Concern.**              |                                            |
+=========================+============================================+
| Ethoprop or Ethoprophos | ![](medi                                   |
|                         | a/image2.wmf){width="2.1041666666666665in" |
| *                       | height="0.9270833333333334in"}             |
| O*-ethyl-*S,S*-dipropyl |                                            |
| phosphorodithioate      |                                            |
|                         |                                            |
| CAS: 13194-48-4         |                                            |
+-------------------------+--------------------------------------------+
| Metabolite II (S-Me)    | ![](medi                                   |
|                         | a/image3.wmf){width="2.1145833333333335in" |
| *O*-ethy                | height="0.9270833333333334in"}             |
| l-*S*-methyl-*S*-propyl |                                            |
| phosphorodithioate      |                                            |
+-------------------------+--------------------------------------------+
| Metabolite III (O-Me)   | ![](medi                                   |
|                         | a/image4.wmf){width="2.1145833333333335in" |
| *O*-ethy                | height="0.9166666666666666in"}             |
| l-*O*-methyl-*S*-propyl |                                            |
| phosphorodithioate      |                                            |
+-------------------------+--------------------------------------------+
| Metabolite IV (M-1)     | ![](medi                                   |
|                         | a/image5.wmf){width="2.1145833333333335in" |
| *O*-ethyl-*S*-propyl    | height="0.75in"}                           |
| phosphorodithioate      |                                            |
+-------------------------+--------------------------------------------+
| SSDP (S,S-dipropyl      | ![](media/image6.wmf)                      |
| degradate)              |                                            |
|                         |                                            |
| S,S-dip                 |                                            |
| ropylphosphorodithioate |                                            |
+-------------------------+--------------------------------------------+

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.

3.  []{#__RefHeading___Toc203446693 .anchor}**Physical and Chemical
    Properties**

Ethoprop (O-ethyl S,S-dipropyl phosphorodithioate) is a colorless to
yellow tinted liquid with a strong mercaptan odor and a boiling point of
86-91^o^ 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,      not available             
  pK~a~                                                 

  Octanol/water partition     3.59 at 21ºC              
  coefficient, Log(K~OW~)                               

  UV/visible absorption       not available             
  spectrum                                              
  -----------------------------------------------------------------------

[]{#__RefHeading___Toc203446694 .anchor}**3.0 Hazard
Characterization/Assessment**

[]{#__RefHeading___Toc203446695 .anchor}**3.1 Hazard and Dose-Response
Characterization**

[]{#__RefHeading___Toc203446696 .anchor}**3.1.1 Database Summary**

[Recent toxicity studies]{.underline} 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]{.underline} 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.

[]{#__RefHeading___Toc203446697 .anchor}**3.1.2 Mode of Action,
Metabolism, and Toxicological Effects**

[Mode of action]{.underline}: 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]{.underline}: 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]{.underline}: 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 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.

[]{#__RefHeading___Toc203446698 .anchor}**3.3 FQPA Considerations**

[]{#__RefHeading___Toc203446699 .anchor}**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.

[]{#__RefHeading___Toc203446700 .anchor}**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 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.

[]{#__RefHeading___Toc203446701 .anchor}**3.3.3 Studies Assessing
Offspring Sensitivity**

[Developmental toxicity]{.underline}: 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]{.underline}: 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]{.underline}: 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.

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]{.underline}: 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]{.underline}: 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.

4.  []{#__RefHeading___Toc203446702 .anchor}**Degree of Concern Analysis
    for Pre and Postnatal Susceptibility**

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.

[]{#__RefHeading___Toc203446703 .anchor}**3.4 FQPA 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 BMDL~10~ 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.

[]{#__RefHeading___Toc203446704 .anchor}**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.

[]{#__RefHeading___Toc203446705 .anchor}**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**

[Study Selected:]{.underline} Acute comparative cholinesterase study in
rats

[MRID No.:]{.underline} 46278701

[Executive Summary]{.underline}: See Appendix A.

[Point of Departure:]{.underline} BMDL~10~ = 0.76 mg/kg based on brain
ChE inhibition in pups. The BMDL~10~ is the lower 95% confidence limit
on the estimated mean 10% brain ChE inhibition.

[Uncertainty Factor]{.underline}: 100x (based on 10x for interspecies
extrapolation from rats to

> humans and 10x for variation in sensitivity between humans)

[FQPA Safety Factor]{.underline}: 1x

**aRfD** = [0.76 mg/kg]{.underline} = **0.0076 mg/kg** **aPAD** = [0.76
mg/kg]{.underline} = **0.0076 mg/kg**

100 100

[Comments about Study:]{.underline} 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.

[]{#__RefHeading___Toc203446706 .anchor}**3.5.2 Chronic Reference Dose
(cRfD)**

[Study Selected:]{.underline} Repeated dosing comparative cholinesterase
study in rats

[MRID No.:]{.underline} 46636401

[Executive Summary]{.underline}: See Appendix A.

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

[Uncertainty Factor]{.underline}: 100x (based on 10x for interspecies
extrapolation from rats to

> humans and 10x for variation in sensitivity between humans)

[FQPA Safety Factor]{.underline}: 1x

**cRfD** = [0.14 mg/kg/day]{.underline} = **0.0014 mg/kg** **cPAD** =
[0.14 mg/kg/day]{.underline} = **0.0014 mg/kg**

100 100

[Comments about Study:]{.underline} 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.[^1]

[]{#__RefHeading___Toc203446707 .anchor}**3.5.3 Dermal Absorption**

A dermal absorption study with ethoprop is not available. Dermal
absorption of [technical ethoprop]{.underline} 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]{.underline} 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.

4.  []{#__RefHeading___Toc203446708 .anchor}**Dermal Exposure --
    [Liquid]{.underline} Formulations**

**(Short- and Intermediate-Term)**

[Study Selected:]{.underline} 21-Day dermal toxicity study in rabbits

[MRID No.:]{.underline} 41304404

[Executive Summary]{.underline}: See Appendix A, Guideline 870.3200

[Point of Departure:]{.underline} NOAEL = 0.1 mg/kg/day based on brain
and

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

[Comments about Study:]{.underline} 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.

5.  []{#__RefHeading___Toc203446709 .anchor}**Dermal Exposure --
    [Granular]{.underline} Formulations**

**(Short- and Intermediate-Term)**

[Study Selected:]{.underline} 21-Day dermal toxicity study in rats

[MRID No.:]{.underline} 45034801

[Executive Summary]{.underline}: See Appendix A, Guideline 870.3200

[Point of Departure:]{.underline} NOAEL = 19 mg/kg/day based on brain
and

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

[Comments about Study:]{.underline} 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]{.underline} ethoprop (13 mg/kg/day) is less than the NOAEL
for ChE inhibition in the dermal study with the [granular]{.underline}
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.

6.  []{#__RefHeading___Toc203446710 .anchor}**Inhalation Exposure**

**(Short-, Intermediate-Term)**

[Study Selected:]{.underline} Repeated dosing comparative cholinesterase
study in rats

[MRID No.:]{.underline} 46636401

[Executive Summary]{.underline}: See Appendix A.

[Point of Departure:]{.underline} BMDL~10~ = 0.14 mg/kg/day based on
brain ChE inhibition in pups. The BMDL~10~ is the lower 95% confidence
limit on the estimated mean 10% brain ChE inhibition.

[Uncertainty Factor]{.underline}: 100x (based on 10x for interspecies
extrapolation from rats to

> humans and 10x for variation in sensitivity between humans)

[Comments about Study:]{.underline} 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.

[]{#__RefHeading___Toc203446711 .anchor}**3.5.7 Level of Concern for
Margin of Exposure**

The level of concern (MOEs ≥ 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           | Intermediate-Term       |
|                    |                      |                         |
|                    | (1 - 30 Days)        | (1 - 6 Months)          |
+--------------------+----------------------+-------------------------+
| **Occupational     |                      |                         |
| (Worker)           |                      |                         |
| Exposure**         |                      |                         |
+--------------------+----------------------+-------------------------+
| Dermal             | 100                  | 100                     |
+--------------------+----------------------+-------------------------+
| Inhalation         | 100                  | 100                     |
+--------------------+----------------------+-------------------------+
| **Residential      |                      |                         |
| Exposure**         |                      |                         |
+--------------------+----------------------+-------------------------+
| Not applicable.    |                      |                         |
| There are no       |                      |                         |
| residential uses   |                      |                         |
| for ethoprop.      |                      |                         |
+--------------------+----------------------+-------------------------+

[]{#__RefHeading___Toc203446712 .anchor}**3.5.8 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.

[]{#__RefHeading___Toc203446713 .anchor}**3.5.9 Classification of
Carcinogenic Potential**

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

[]{#__RefHeading___Toc203446714 .anchor}**3.5.10 Toxicological Doses and
Endpoints**

+----------+--------+-----------+----------+--------------------------+
| **Table  |        |           |          |                          |
| 3.5.10a. |        |           |          |                          |
| Doses    |        |           |          |                          |
| and      |        |           |          |                          |
| E        |        |           |          |                          |
| ndpoints |        |           |          |                          |
| for      |        |           |          |                          |
| Dietary  |        |           |          |                          |
| and      |        |           |          |                          |
| Non-Occu |        |           |          |                          |
| pational |        |           |          |                          |
| Asses    |        |           |          |                          |
| sments** |        |           |          |                          |
+==========+========+===========+==========+==========================+
| Exposure | Point  | Uncerta   | RfD, PAD | Study and Toxicological  |
| Scenario | of     | inty/FQPA |          | Effects                  |
|          | Dep    | Safety    |          |                          |
|          | arture | Factors   |          |                          |
+----------+--------+-----------+----------+--------------------------+
| Acute    | BM     | UF~A~=    | Acute    | NOAEL = 0.5 mg/kg        |
| Dietary  | DL~10~ | 10x       | RfD =    |                          |
| (General | = 0.76 |           | 0.0076   | LOAEL = 1.0 mg/kg based  |
| Pop      | mg/kg  | UF~H~ =   | m        | on brain ChEI in pups in |
| ulation, |        | 10x       | g/kg/day | the acute comparative    |
| i        |        |           |          | cholinesterase study in  |
| ncluding |        | FQPA SF=  | aPAD =   | rats.                    |
| Infants  |        | 1x        | 0.0076   |                          |
| and      |        |           | m        |                          |
| C        |        |           | g/kg/day |                          |
| hildren) |        |           |          |                          |
+----------+--------+-----------+----------+--------------------------+
| Acute    | There  |           |          |                          |
| Dietary  | is no  |           |          |                          |
|          | inc    |           |          |                          |
| (Females | reased |           |          |                          |
| 13-49    | su     |           |          |                          |
| years of | scepti |           |          |                          |
| age)     | bility |           |          |                          |
|          | for    |           |          |                          |
|          | f      |           |          |                          |
|          | emales |           |          |                          |
|          | of     |           |          |                          |
|          | c      |           |          |                          |
|          | hild-b |           |          |                          |
|          | earing |           |          |                          |
|          | age.   |           |          |                          |
|          |        |           |          |                          |
|          | The    |           |          |                          |
|          | aPAD   |           |          |                          |
|          | for    |           |          |                          |
|          | the    |           |          |                          |
|          | g      |           |          |                          |
|          | eneral |           |          |                          |
|          | popu   |           |          |                          |
|          | lation |           |          |                          |
|          | is     |           |          |                          |
|          | prot   |           |          |                          |
|          | ective |           |          |                          |
|          | of     |           |          |                          |
|          | this   |           |          |                          |
|          | popu   |           |          |                          |
|          | lation |           |          |                          |
|          | group. |           |          |                          |
+----------+--------+-----------+----------+--------------------------+
| Chronic  | BM     | UF~A~=    | Chronic  | NOAEL \< 0.25 mg/kg/day  |
| Dietary  | DL~10~ | 10x       | RfD =    |                          |
| (All     | = 0.14 |           | 0.0014   | LOAEL = 0.25 mg/kg/day   |
| Popu     | mg/    | UF~H~ =   |          | based on brain ChEI in   |
| lations) | kg/day | 10x       | m        | pups in the repeated     |
|          |        |           | g/kg/day | dose comparative         |
|          |        | FQPA SF=  |          | cholinesterase study in  |
|          |        | 1x        | cPAD =   | rats.                    |
|          |        |           | 0.0014   |                          |
|          |        |           | m        |                          |
|          |        |           | g/kg/day |                          |
+----------+--------+-----------+----------+--------------------------+
| In       | There  |           |          |                          |
| cidental | are no |           |          |                          |
| Oral     | resid  |           |          |                          |
| Exposure | ential |           |          |                          |
|          | uses   |           |          |                          |
|          | for    |           |          |                          |
|          | et     |           |          |                          |
|          | hoprop |           |          |                          |
|          | and    |           |          |                          |
|          | the    |           |          |                          |
|          | refore |           |          |                          |
|          | there  |           |          |                          |
|          | is no  |           |          |                          |
|          | ex     |           |          |                          |
|          | posure |           |          |                          |
|          | to     |           |          |                          |
|          | ch     |           |          |                          |
|          | ildren |           |          |                          |
|          | by the |           |          |                          |
|          | inci   |           |          |                          |
|          | dental |           |          |                          |
|          | oral   |           |          |                          |
|          | route  |           |          |                          |
|          | of     |           |          |                          |
|          | exp    |           |          |                          |
|          | osure. |           |          |                          |
+----------+--------+-----------+----------+--------------------------+
| Dermal   | There  |           |          |                          |
| Exposure | are no |           |          |                          |
|          | resid  |           |          |                          |
|          | ential |           |          |                          |
|          | uses   |           |          |                          |
|          | for    |           |          |                          |
|          | et     |           |          |                          |
|          | hoprop |           |          |                          |
|          | and    |           |          |                          |
|          | the    |           |          |                          |
|          | refore |           |          |                          |
|          | there  |           |          |                          |
|          | is no  |           |          |                          |
|          | dermal |           |          |                          |
|          | ex     |           |          |                          |
|          | posure |           |          |                          |
|          | in     |           |          |                          |
|          | non-   |           |          |                          |
|          | occupa |           |          |                          |
|          | tional |           |          |                          |
|          | set    |           |          |                          |
|          | tings. |           |          |                          |
+----------+--------+-----------+----------+--------------------------+
| In       | There  |           |          |                          |
| halation | are no |           |          |                          |
| Exposure | resid  |           |          |                          |
|          | ential |           |          |                          |
|          | uses   |           |          |                          |
|          | for    |           |          |                          |
|          | et     |           |          |                          |
|          | hoprop |           |          |                          |
|          | and    |           |          |                          |
|          | the    |           |          |                          |
|          | refore |           |          |                          |
|          | there  |           |          |                          |
|          | is no  |           |          |                          |
|          | inha   |           |          |                          |
|          | lation |           |          |                          |
|          | ex     |           |          |                          |
|          | posure |           |          |                          |
|          | in     |           |          |                          |
|          | non-   |           |          |                          |
|          | occupa |           |          |                          |
|          | tional |           |          |                          |
|          | set    |           |          |                          |
|          | tings. |           |          |                          |
+----------+--------+-----------+----------+--------------------------+
| Cancer   | Cla    |           |          |                          |
| (oral    | ssific |           |          |                          |
| route)   | ation: |           |          |                          |
|          | \"     |           |          |                          |
|          | Likely |           |          |                          |
|          | to be  |           |          |                          |
|          | carcin |           |          |                          |
|          | ogenic |           |          |                          |
|          | to     |           |          |                          |
|          | hum    |           |          |                          |
|          | ans.\" |           |          |                          |
|          |        |           |          |                          |
|          | Q1\* = |           |          |                          |
|          | 2.81 x |           |          |                          |
|          | 10^-2^ |           |          |                          |
|          | based  |           |          |                          |
|          | on     |           |          |                          |
|          | mal    |           |          |                          |
|          | ignant |           |          |                          |
|          | a      |           |          |                          |
|          | drenal |           |          |                          |
|          | pheoc  |           |          |                          |
|          | hromoc |           |          |                          |
|          | ytomas |           |          |                          |
|          | 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. BMDL~10~ = 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. UF~A~ =
extrapolation from animal to human (interspecies). UF~H~ = 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      |        |         |            |                          |
| E        |        |         |            |                          |
| ndpoints |        |         |            |                          |
| for      |        |         |            |                          |
| Occu     |        |         |            |                          |
| pational |        |         |            |                          |
| Human    |        |         |            |                          |
| Health   |        |         |            |                          |
| Risk     |        |         |            |                          |
| Asses    |        |         |            |                          |
| sments** |        |         |            |                          |
+==========+========+=========+============+==========================+
| E        | Point  | Unce    | Level of   | Study and Toxicological  |
| xposure/ | of     | rtainty | Concern    | Effects                  |
|          | Dep    | Factors |            |                          |
| Scenario | arture |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| Dermal   | NOAEL  | UF~A~=  | LOC for    | LOAEL = 1.0 mg/kg/day    |
| Short-   | = 0.1  | 10x     | MOE        | based on RBC and brain   |
| (1-30    | mg/    |         |            | ChEI in a 21-day dermal  |
| days)    | kg/day | UF~H~ = | = 100      | toxicity study in        |
| and      |        | 10x     |            | rabbits with technical   |
| I        |        |         |            | ingredient.              |
| ntermedi |        |         |            |                          |
| ate-Term |        |         |            |                          |
| (1-6     |        |         |            |                          |
| months): |        |         |            |                          |
| **       |        |         |            |                          |
| Liquid** |        |         |            |                          |
| Form     |        |         |            |                          |
| ulations |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| Dermal   | NOAEL  | UF~A~=  | LOC for    | LOAEL = 97 mg/kg/day     |
| Short-   | = 19   | 10x     | MOE        | based on RBC and brain   |
| (1-30    | mg/    |         |            | ChEI in a 28-day dermal  |
| days)    | kg/day | UF~H~ = | = 100      | toxicity study in rats   |
| and      |        | 10x     |            | with granular            |
| I        |        |         |            | formulation.             |
| ntermedi |        |         |            |                          |
| ate-Term |        |         |            |                          |
| (1-6     |        |         |            |                          |
| months): |        |         |            |                          |
| **Gr     |        |         |            |                          |
| anular** |        |         |            |                          |
| Form     |        |         |            |                          |
| ulations |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| In       | BM     | UF~A~=  | LOC for    | NOAEL \< 0.25 mg/kg/day  |
| halation | DL~10~ | 10x     | MOE        |                          |
| Short-   | = 0.14 |         |            | LOAEL = 0.25 mg/kg/day   |
| (1-30    | mg/    | UF~H~ = | = 100      | based on brain ChEI in   |
| days and | kg/day | 10x     |            | pups in the repeated     |
| Inte     |        |         |            | dose comparative         |
| rmediate |        |         |            | cholinesterase study in  |
| Term     |        |         |            | rats.                    |
| (1-6     |        |         |            |                          |
| months)  |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| Combined | BM     | UF~A~=  | LOC for    | NOAEL \< 0.25 mg/kg/day  |
| Dermal   | DL~10~ | 10x     | MOE        |                          |
| and      | = 0.14 |         |            | LOAEL = 0.25 mg/kg/day   |
| In       | mg/    | UF~H~ = | = 100      | based on brain ChEI in   |
| halation | kg/day | 10x     |            | pups in the repeated     |
| Exposure |        |         |            | dose comparative         |
| for use  |        |         |            | cholinesterase study in  |
| with     |        |         |            | rats.                    |
|          |        |         |            |                          |
| Biomo    |        |         |            |                          |
| nitoring |        |         |            |                          |
+----------+--------+---------+------------+--------------------------+
| Cancer   | Cla    |         |            |                          |
| (dermal, | ssific |         |            |                          |
| inh      | ation: |         |            |                          |
| alation) | \"     |         |            |                          |
|          | Likely |         |            |                          |
|          | to be  |         |            |                          |
|          | carcin |         |            |                          |
|          | ogenic |         |            |                          |
|          | to     |         |            |                          |
|          | hum    |         |            |                          |
|          | ans.\" |         |            |                          |
|          |        |         |            |                          |
|          | Q1\* = |         |            |                          |
|          | 2.81 x |         |            |                          |
|          | 10^-2^ |         |            |                          |
|          | based  |         |            |                          |
|          | on     |         |            |                          |
|          | mal    |         |            |                          |
|          | ignant |         |            |                          |
|          | a      |         |            |                          |
|          | drenal |         |            |                          |
|          | pheoc  |         |            |                          |
|          | hromoc |         |            |                          |
|          | ytomas |         |            |                          |
|          | 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.
UF~A~ = extrapolation from animal to human (interspecies). UF~H~ =
potential variation in sensitivity among members of the human population
(intraspecies). LOC = level of concern. MOE = margin of exposure.
BMDL~10~ = lower 95% confidence limit of the 10% benchmark response, in
this case the estimated dose resulting in 10% ChE inhibition. ChEI =
cholinesterase inhibition.

5.  []{#__RefHeading___Toc203446715 .anchor}**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.

4.  []{#__RefHeading___Toc203446716 .anchor}**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.

[]{#__RefHeading___Toc203446717 .anchor}**5.0 Dietary Exposure/Risk
Characterization**

[]{#__RefHeading___Toc203446718 .anchor}**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.

[]{#__RefHeading___Toc203446719 .anchor}**5.1.2 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**   | **Water          |
|                                  |               | Concentration    |
|                                  | *             | (ppb)**          |
|                                  | *Assessment** |                  |
+----------------------------------+---------------+------------------+
| **Modeling**                     |               |                  |
+----------------------------------+---------------+------------------+
| PRZM-EXAMS surface water         | Acute         | 138              |
| modeling                         |               |                  |
|                                  |               |                  |
| (LA sugarcane, upper 1-in-10     |               |                  |
| year peak conc)                  |               |                  |
+----------------------------------+---------------+------------------+
| PRZM-EXAMS surface water         | Chronic       | 18               |
| modeling                         |               |                  |
|                                  |               |                  |
| (LA Sugarcane upper 1-in-10 yr   |               |                  |
| mean conc)                       |               |                  |
+----------------------------------+---------------+------------------+
| Sci-Grow ground water modeling   | Cancer        | 10.1             |
+----------------------------------+---------------+------------------+
| **Monitoring**                   |               |                  |
+----------------------------------+---------------+------------------+
| Surface water monitoring of raw  | Acute and     | 0.23             |
| water **^a^**                    | Chronic       |                  |
+----------------------------------+---------------+------------------+
| Surface water monitoring of raw  | Cancer        | 0.23             |
| water **^b^**                    |               |                  |
+----------------------------------+---------------+------------------+

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)

[]{#__RefHeading___Toc203446720 .anchor}**5.1.3 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.

[]{#__RefHeading___Toc203446721 .anchor}**5.2 Dietary Exposure and
Risk**

Ethoprop acute and chronic dietary exposure assessments were conducted
using the Dietary Exposure Evaluation Model software with the Food
Commodity 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:
<http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf> ; or
see SOP 99.6 (8/20/-1999).

[]{#__RefHeading___Toc203446722 .anchor}**5.2.1 Acute Dietary
Exposure/Risk**

The results of the acute dietary exposure analysis 99.9^th^ 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 95^th^,
99^th^, and the 99.9^th^ 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 99.9^th^
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 99.9^th^ percentile of exposure,
and using an EDWC of 15 ppb, the total food and water exposure is at 99%
of the aPAD.

[]{#__RefHeading___Toc203446723 .anchor}**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   **aPAD          **Food Alone**           **Food and                **Food and               **Food and               **Food and      
  Subgroup**     (mg/kg/day)**                            Drinking Water            Drinking Water           Drinking Water           Drinking Water  
                                                          Using 138 ppb             Using 0.231 ppb          Using 0.52 ppb           Using 15 ppb    
                                                          Water Value**             Water Value**            Water Value**            Water Value**   

                                 **99.9^th^               **99.9^th^                **99.9^th^               **99.9^th^               **99.9^th^      
                                 Percentile**             Percentile**              Percentile**             Percentile**             Percentile**    

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[]{#__RefHeading___Toc203446724 .anchor}**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,         Estimated Cancer
                                      mg/kg/day         Risk

  Food Alone                          0.000009          3 x 10^-7^

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

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

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

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

[]{#__RefHeading___Toc203446725 .anchor}**6.0 Residential
(Non-Occupational) Exposure**

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

[]{#__RefHeading___Toc203446726 .anchor}**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.

[]{#__RefHeading___Toc203446727 .anchor}**8.0 Cumulative Risk
Characterization/Assessment**

Ethoprop has been evaluated in a cumulative assessment: Organophosphorus
Cumulative Risk Assessment -- 2006 Update
([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.

[]{#__RefHeading___Toc203446728 .anchor}**9.0 Occupational Exposure and
Risk**

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.

1.  []{#__RefHeading___Toc203446729 .anchor}**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:]{.underline}***

\(1\) M/L liquids for Groundboom Applications;

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

> ***[Applicators:]{.underline}***

\(3\) 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  Area Treated per
                                     Assessed (lb ai/A) Day

  Granular:          Mint            6                  80
  Broadcast Spreader                                    

  Granular:          Mint            3                  80
  Broadcast Spreader                                    

  Liquids:           Mint            4.2                80
  Groundboom                                            

  Liquids:           Mint & Hops     2.1                80
  Groundboom                                            
  ------------------ --------------- ------------------ -----------------

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.

1.  []{#__RefHeading___Toc203446730 .anchor}**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)**

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 20%" />
<col style="width: 10%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<thead>
<tr class="header">
<th rowspan="2"><strong>Exposure Scenario</strong></th>
<th rowspan="2"><strong>Crop or Target</strong></th>
<th rowspan="2"><p><strong>Application</strong></p>
<p><strong>Rate <sup>a</sup></strong></p></th>
<th rowspan="2"><strong>Area Treated Daily <sup>b</sup></strong></th>
<th colspan="8"><strong>Combined MOEs <sup>c</sup></strong></th>
</tr>
<tr class="odd">
<th><strong>Base line</strong></th>
<th><strong>G - NR</strong></th>
<th><strong>PPE-G, DL-NR</strong></th>
<th><strong>G - 80% R</strong></th>
<th><strong>G,DL - 80% R</strong></th>
<th><strong>G - 90% R</strong></th>
<th><strong>G,DL - 90% R</strong></th>
<th><strong>Eng Cont</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="12">Mixer/Loader</td>
</tr>
<tr class="even">
<td rowspan="2">Loading Granulars for Tractor Drawn Spreader
Applications (2)</td>
<td>Hops/Mint</td>
<td>4.2 lb ai/acre</td>
<td>80 acres</td>
<td>12</td>
<td>12</td>
<td>52</td>
<td>93</td>
<td>12</td>
<td>56</td>
<td>105</td>
<td>580</td>
</tr>
<tr class="odd">
<td>Hops/Mint</td>
<td>2.1 lb ai/acre</td>
<td>80 acres</td>
<td>23</td>
<td>23</td>
<td>105</td>
<td>185</td>
<td>24</td>
<td>112</td>
<td>210</td>
<td>1160</td>
</tr>
<tr class="even">
<td rowspan="2">M/L ECs for Groundboom Applications (1)</td>
<td>mint (nematodes)</td>
<td>6 lb ai/acre</td>
<td>80 acres</td>
<td>&lt;1</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>2</td>
<td>1</td>
<td><strong>2</strong></td>
</tr>
<tr class="odd">
<td>mint (symphylans)</td>
<td>3 lb ai/acre</td>
<td>80 acres</td>
<td>&lt;1</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td><strong>5</strong></td>
</tr>
<tr class="even">
<td colspan="12">Applicator</td>
</tr>
<tr class="odd">
<td rowspan="2">Applying Liquid Sprays via Groundboom Equipment (3)</td>
<td>Hops/mint</td>
<td>4.2 lb ai/acre</td>
<td>80 acres</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td><strong>4</strong></td>
</tr>
<tr class="even">
<td>Hops/mint</td>
<td>2.1 lb ai/acre</td>
<td>80 acres</td>
<td>3</td>
<td>3</td>
<td>4</td>
<td>3</td>
<td>4</td>
<td>4</td>
<td>4</td>
<td><strong>8</strong></td>
</tr>
<tr class="odd">
<td rowspan="2">Applying Granulars via Tractor Drawn Spreader (4)</td>
<td>Mint (nematodes)</td>
<td>6 lb ai/acre</td>
<td>80 acres</td>
<td>16</td>
<td>70</td>
<td>17</td>
<td>120</td>
<td>17</td>
<td>75</td>
<td>136</td>
<td>87</td>
</tr>
<tr class="even">
<td>Mint (symphylans)</td>
<td>3 lb ai/acre</td>
<td>80 acres</td>
<td>32</td>
<td>140</td>
<td>33</td>
<td>240</td>
<td>33</td>
<td>151</td>
<td>271</td>
<td>170</td>
</tr>
</tbody>
</table>

\* 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)**

+--------+----------+------+-----+-------+-------+------+------+------+
| Sc     | Repres   | App  | A   | D     | Inhal | De   | In   | Comb |
| enario | entative | lica | rea | ermal | ation | rmal | hala | ined |
|        | A        | tion | T   | Dose  | Dose  | MOE  | tion |      |
|        | pplicati | Rate | rea | (     | (     |      | MOE  | De   |
|        | on/Crops |      | ted | mg/kg | mg/kg |      |      | rmal |
|        |          |      | (   | /day) | /day) |      |      | and  |
|        |          |      | A/d |       |       |      |      | In   |
|        |          |      | ay) |       |       |      |      | hala |
|        |          |      |     |       |       |      |      | tion |
|        |          |      |     |       |       |      |      |      |
|        |          |      |     |       |       |      |      | MOE  |
+--------+----------+------+-----+-------+-------+------+------+------+
| M      |          |      |     |       |       |      |      |      |
| ixer/L |          |      |     |       |       |      |      |      |
| oaders |          |      |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| L      | H        | 4.2  | 80  | 0     | 0     | 1    | 600  | 580  |
| oading | ops/Mint | lb   | ac  | .0012 | .0002 | 6500 |      |      |
| Gra    |          | ai/  | res |       |       |      |      |      |
| nulars |          | acre |     |       |       |      |      |      |
| for    |          |      |     |       |       |      |      |      |
| t      |          |      |     |       |       |      |      |      |
| ractor |          |      |     |       |       |      |      |      |
| drawn  |          |      |     |       |       |      |      |      |
| sp     |          |      |     |       |       |      |      |      |
| reader |          |      |     |       |       |      |      |      |
| applic |          |      |     |       |       |      |      |      |
| ations |          |      |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| \" \"  | H        | 2.1  | 80  | 0     | 0     | 3    | 1200 | 1200 |
|        | ops/Mint | lb   | ac  | .0006 | .0001 | 3000 |      |      |
|        |          | ai/  | res |       |       |      |      |      |
|        |          | acre |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| M/L    | mint     | 6 lb | 80  | 0     | 0     | *    | 350  | *    |
|        | (ne      | ai/  | ac  | .0413 | .0004 | *2** |      | *2** |
| li     | matodes) | acre | res |       |       |      |      |      |
| quids: |          |      |     |       |       |      |      |      |
| Grou   |          |      |     |       |       |      |      |      |
| ndboom |          |      |     |       |       |      |      |      |
| Applic |          |      |     |       |       |      |      |      |
| ations |          |      |     |       |       |      |      |      |
| (1)    |          |      |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| \" \"  | mint     | 3 lb | 80  | 0.021 | 0     | *    | 700  | *    |
|        | (sym     | ai/  | ac  |       | .0002 | *5** |      | *5** |
|        | phylans) | acre | res |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| Appli  |          |      |     |       |       |      |      |      |
| cators |          |      |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| Ap     | H        | 4.2  | 80  | 0     | 0     | *    | 680  | *    |
| plying | ops/mint | lb   | ac  | .0245 | .0002 | *4** |      | *4** |
| Liquid |          | ai/  | res |       |       |      |      |      |
| Sprays |          | acre |     |       |       |      |      |      |
| via    |          |      |     |       |       |      |      |      |
| Grou   |          |      |     |       |       |      |      |      |
| ndboom |          |      |     |       |       |      |      |      |
| Equ    |          |      |     |       |       |      |      |      |
| ipment |          |      |     |       |       |      |      |      |
| (3)    |          |      |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| \" \"  | H        | 2.1  | 80  | 0     | 0     | *    | 1360 | *    |
|        | ops/mint | lb   | ac  | .0122 | .0001 | *8** |      | *8** |
|        |          | ai/  | res |       |       |      |      |      |
|        |          | acre |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| Ap     | Mint     | 6 lb | 80  | 0     | 0     | 1400 | **   | **   |
| plying | (ne      | ai/  | ac  | .0137 | .0015 |      | 93** | 87** |
| Gra    | matodes) | acre | res |       |       |      |      |      |
| nulars |          |      |     |       |       |      |      |      |
| via    |          |      |     |       |       |      |      |      |
| T      |          |      |     |       |       |      |      |      |
| ractor |          |      |     |       |       |      |      |      |
| Drawn  |          |      |     |       |       |      |      |      |
| Sp     |          |      |     |       |       |      |      |      |
| reader |          |      |     |       |       |      |      |      |
| (4)    |          |      |     |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+
| \" \"  | Mint     | 3 lb | 80  | 0     | 0     | 2800 | 190  | 170  |
|        | (sym     | ai/  | ac  | .0069 | .0008 |      |      |      |
|        | phylans) | acre | res |       |       |      |      |      |
+--------+----------+------+-----+-------+-------+------+------+------+

*\* 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.*

1.  []{#__RefHeading___Toc203446731 .anchor}**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:
<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.

1.  []{#__RefHeading___Toc203446732 .anchor}**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.

+------+------+------+--------+--------+---------+---------+---------+
| **T  |      |      |        |        |         |         |         |
| able |      |      |        |        |         |         |         |
| 9.2  |      |      |        |        |         |         |         |
| .1a. |      |      |        |        |         |         |         |
| Risk |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| stim |      |      |        |        |         |         |         |
| ates |      |      |        |        |         |         |         |
| For  |      |      |        |        |         |         |         |
| Etho |      |      |        |        |         |         |         |
| prop |      |      |        |        |         |         |         |
| Hand |      |      |        |        |         |         |         |
| lers |      |      |        |        |         |         |         |
| B    |      |      |        |        |         |         |         |
| ased |      |      |        |        |         |         |         |
| On   |      |      |        |        |         |         |         |
| D    |      |      |        |        |         |         |         |
| aily |      |      |        |        |         |         |         |
| And  |      |      |        |        |         |         |         |
| Cu   |      |      |        |        |         |         |         |
| mula |      |      |        |        |         |         |         |
| tive |      |      |        |        |         |         |         |
| Dose |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| stim |      |      |        |        |         |         |         |
| ates |      |      |        |        |         |         |         |
| From |      |      |        |        |         |         |         |
| MRID |      |      |        |        |         |         |         |
| 45   |      |      |        |        |         |         |         |
| 6215 |      |      |        |        |         |         |         |
| 01** |      |      |        |        |         |         |         |
|      |      |      |        |        |         |         |         |
| **(B |      |      |        |        |         |         |         |
| ased |      |      |        |        |         |         |         |
| on   |      |      |        |        |         |         |         |
| M    |      |      |        |        |         |         |         |
| OCAP |      |      |        |        |         |         |         |
| EC   |      |      |        |        |         |         |         |
| sc   |      |      |        |        |         |         |         |
| aled |      |      |        |        |         |         |         |
| to   |      |      |        |        |         |         |         |
| 2.1  |      |      |        |        |         |         |         |
| lbs  |      |      |        |        |         |         |         |
| ai/  |      |      |        |        |         |         |         |
| A)** |      |      |        |        |         |         |         |
+======+======+======+========+========+=========+=========+=========+
| Han  | Days | Body | M      |        |         |         |         |
| dler | of   | We   | argins |        |         |         |         |
|      | Expo | ight | Of     |        |         |         |         |
|      | sure |      | Ex     |        |         |         |         |
|      |      | (kg) | posure |        |         |         |         |
|      |      |      | (MOEs) |        |         |         |         |
|      |      |      | Based  |        |         |         |         |
|      |      |      | On     |        |         |         |         |
|      |      |      | Single |        |         |         |         |
|      |      |      | Day &  |        |         |         |         |
|      |      |      | Cumu   |        |         |         |         |
|      |      |      | lative |        |         |         |         |
|      |      |      | \[M1\] |        |         |         |         |
|      |      |      | In     |        |         |         |         |
|      |      |      | Urine  |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
|      |      |      | Day 1  | Day 2  | Day 3   | Day 4   | Cum     |
|      |      |      |        |        |         |         | ulative |
+------+------+------+--------+--------+---------+---------+---------+
| **Mi |      |      |        |        |         |         |         |
| xing |      |      |        |        |         |         |         |
| /Loa |      |      |        |        |         |         |         |
| ding |      |      |        |        |         |         |         |
| with |      |      |        |        |         |         |         |
| Cl   |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Sys  |      |      |        |        |         |         |         |
| tems |      |      |        |        |         |         |         |
| U    |      |      |        |        |         |         |         |
| sing |      |      |        |        |         |         |         |
| Hard |      |      |        |        |         |         |         |
| Coup |      |      |        |        |         |         |         |
| ling |      |      |        |        |         |         |         |
| Dev  |      |      |        |        |         |         |         |
| ices |      |      |        |        |         |         |         |
| (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     |
+------+------+------+--------+--------+---------+---------+---------+
| Ar   |      |      | 110    | 180    | 430     | 230     | 46      |
| ithm |      |      |        |        |         |         |         |
| etic |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| G    |      |      | 180    | 200    | 1000    | 470     | 52      |
| eome |      |      |        |        |         |         |         |
| tric |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| **   |      |      |        |        |         |         |         |
| Appl |      |      |        |        |         |         |         |
| ying |      |      |        |        |         |         |         |
| with |      |      |        |        |         |         |         |
| Gr   |      |      |        |        |         |         |         |
| ound |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| quip |      |      |        |        |         |         |         |
| ment |      |      |        |        |         |         |         |
| Equi |      |      |        |        |         |         |         |
| pped |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Encl |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Cab  |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Char |      |      |        |        |         |         |         |
| coal |      |      |        |        |         |         |         |
| Fi   |      |      |        |        |         |         |         |
| ltra |      |      |        |        |         |         |         |
| tion |      |      |        |        |         |         |         |
| (Ap  |      |      |        |        |         |         |         |
| p)** |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| AP6  | 2    | 95   | 3300   | 4300   | 4100    | 2100    | 790     |
+------+------+------+--------+--------+---------+---------+---------+
| AP12 | 1    | 77   | 2800   | 160    | 1400    | 2100    | 130     |
+------+------+------+--------+--------+---------+---------+---------+
| AP14 | 3    | 95   | 2000   | 1800   | 1400    | 1300    | 390     |
+------+------+------+--------+--------+---------+---------+---------+
| Ar   |      |      | 2600   | 420    | 1800    | 1700    | 250     |
| ithm |      |      |        |        |         |         |         |
| etic |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| G    |      |      | 2700   | 1100   | 2000    | 1800    | 340     |
| eome |      |      |        |        |         |         |         |
| tric |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| **Mi |      |      |        |        |         |         |         |
| xing |      |      |        |        |         |         |         |
| /Loa |      |      |        |        |         |         |         |
| ding |      |      |        |        |         |         |         |
| with |      |      |        |        |         |         |         |
| Cl   |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Sys  |      |      |        |        |         |         |         |
| tems |      |      |        |        |         |         |         |
| U    |      |      |        |        |         |         |         |
| sing |      |      |        |        |         |         |         |
| Hard |      |      |        |        |         |         |         |
| Coup |      |      |        |        |         |         |         |
| ling |      |      |        |        |         |         |         |
| Dev  |      |      |        |        |         |         |         |
| ices |      |      |        |        |         |         |         |
| and  |      |      |        |        |         |         |         |
| Appl |      |      |        |        |         |         |         |
| ying |      |      |        |        |         |         |         |
| Gr   |      |      |        |        |         |         |         |
| ound |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| quip |      |      |        |        |         |         |         |
| ment |      |      |        |        |         |         |         |
| Equi |      |      |        |        |         |         |         |
| pped |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Encl |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Cab  |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Char |      |      |        |        |         |         |         |
| coal |      |      |        |        |         |         |         |
| Fi   |      |      |        |        |         |         |         |
| ltra |      |      |        |        |         |         |         |
| tion |      |      |        |        |         |         |         |
| (    |      |      |        |        |         |         |         |
| 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       |
+------+------+------+--------+--------+---------+---------+---------+
| Ar   |      |      | 790    | 160    | 110     | 190     | 44      |
| ithm |      |      |        |        |         |         |         |
| etic |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| G    |      |      | 1400   | 560    | 790     | 740     | 160     |
| eome |      |      |        |        |         |         |         |
| tric |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| \    |      |      |        |        |         |         |         |
| *AP1 |      |      |        |        |         |         |         |
| Ur   |      |      |        |        |         |         |         |
| ines |      |      |        |        |         |         |         |
| were |      |      |        |        |         |         |         |
| also |      |      |        |        |         |         |         |
| c    |      |      |        |        |         |         |         |
| olle |      |      |        |        |         |         |         |
| cted |      |      |        |        |         |         |         |
| on   |      |      |        |        |         |         |         |
| days |      |      |        |        |         |         |         |
| 5 &  |      |      |        |        |         |         |         |
| 6;   |      |      |        |        |         |         |         |
| AP2  |      |      |        |        |         |         |         |
| u    |      |      |        |        |         |         |         |
| rine |      |      |        |        |         |         |         |
| was  |      |      |        |        |         |         |         |
| also |      |      |        |        |         |         |         |
| c    |      |      |        |        |         |         |         |
| olle |      |      |        |        |         |         |         |
| cted |      |      |        |        |         |         |         |
| on   |      |      |        |        |         |         |         |
| Day  |      |      |        |        |         |         |         |
| 5;   |      |      |        |        |         |         |         |
| MOEs |      |      |        |        |         |         |         |
| are  |      |      |        |        |         |         |         |
| not  |      |      |        |        |         |         |         |
| p    |      |      |        |        |         |         |         |
| rese |      |      |        |        |         |         |         |
| nted |      |      |        |        |         |         |         |
| h    |      |      |        |        |         |         |         |
| ere. |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+

+------+------+------+--------+--------+---------+---------+---------+
| **T  |      |      |        |        |         |         |         |
| able |      |      |        |        |         |         |         |
| 9.2  |      |      |        |        |         |         |         |
| .1b: |      |      |        |        |         |         |         |
| Risk |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| stim |      |      |        |        |         |         |         |
| ates |      |      |        |        |         |         |         |
| For  |      |      |        |        |         |         |         |
| Etho |      |      |        |        |         |         |         |
| prop |      |      |        |        |         |         |         |
| Hand |      |      |        |        |         |         |         |
| lers |      |      |        |        |         |         |         |
| B    |      |      |        |        |         |         |         |
| ased |      |      |        |        |         |         |         |
| On   |      |      |        |        |         |         |         |
| D    |      |      |        |        |         |         |         |
| aily |      |      |        |        |         |         |         |
| And  |      |      |        |        |         |         |         |
| Cu   |      |      |        |        |         |         |         |
| mula |      |      |        |        |         |         |         |
| tive |      |      |        |        |         |         |         |
| Dose |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| stim |      |      |        |        |         |         |         |
| ates |      |      |        |        |         |         |         |
| From |      |      |        |        |         |         |         |
| MRID |      |      |        |        |         |         |         |
| 45   |      |      |        |        |         |         |         |
| 6215 |      |      |        |        |         |         |         |
| 01** |      |      |        |        |         |         |         |
|      |      |      |        |        |         |         |         |
| **(B |      |      |        |        |         |         |         |
| ased |      |      |        |        |         |         |         |
| on   |      |      |        |        |         |         |         |
| M    |      |      |        |        |         |         |         |
| OCAP |      |      |        |        |         |         |         |
| EC   |      |      |        |        |         |         |         |
| sc   |      |      |        |        |         |         |         |
| aled |      |      |        |        |         |         |         |
| to   |      |      |        |        |         |         |         |
| 4.2  |      |      |        |        |         |         |         |
| lbs  |      |      |        |        |         |         |         |
| ai/  |      |      |        |        |         |         |         |
| A)** |      |      |        |        |         |         |         |
+======+======+======+========+========+=========+=========+=========+
| Han  | Days | Body | M      |        |         |         |         |
| dler | of   | We   | argins |        |         |         |         |
|      | Expo | ight | Of     |        |         |         |         |
|      | sure |      | Ex     |        |         |         |         |
|      |      | (kg) | posure |        |         |         |         |
|      |      |      | (MOEs) |        |         |         |         |
|      |      |      | Based  |        |         |         |         |
|      |      |      | On     |        |         |         |         |
|      |      |      | Single |        |         |         |         |
|      |      |      | Day &  |        |         |         |         |
|      |      |      | Cumu   |        |         |         |         |
|      |      |      | lative |        |         |         |         |
|      |      |      | \[M1\] |        |         |         |         |
|      |      |      | In     |        |         |         |         |
|      |      |      | Urine  |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
|      |      |      | Day 1  | Day 2  | Day 3   | Day 4   | Cum     |
|      |      |      |        |        |         |         | ulative |
+------+------+------+--------+--------+---------+---------+---------+
| **Mi |      |      |        |        |         |         |         |
| xing |      |      |        |        |         |         |         |
| /Loa |      |      |        |        |         |         |         |
| ding |      |      |        |        |         |         |         |
| with |      |      |        |        |         |         |         |
| Cl   |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Sys  |      |      |        |        |         |         |         |
| tems |      |      |        |        |         |         |         |
| U    |      |      |        |        |         |         |         |
| sing |      |      |        |        |         |         |         |
| Hard |      |      |        |        |         |         |         |
| Coup |      |      |        |        |         |         |         |
| ling |      |      |        |        |         |         |         |
| Dev  |      |      |        |        |         |         |         |
| ices |      |      |        |        |         |         |         |
| (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      |
+------+------+------+--------+--------+---------+---------+---------+
| Ar   |      |      | 54     | 89     | 220     | 120     | 23      |
| ithm |      |      |        |        |         |         |         |
| etic |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| G    |      |      | 92     | 100    | 520     | 230     | 26      |
| eome |      |      |        |        |         |         |         |
| tric |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| **   |      |      |        |        |         |         |         |
| Appl |      |      |        |        |         |         |         |
| ying |      |      |        |        |         |         |         |
| with |      |      |        |        |         |         |         |
| Gr   |      |      |        |        |         |         |         |
| ound |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| quip |      |      |        |        |         |         |         |
| ment |      |      |        |        |         |         |         |
| Equi |      |      |        |        |         |         |         |
| pped |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Encl |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Cab  |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Char |      |      |        |        |         |         |         |
| coal |      |      |        |        |         |         |         |
| Fi   |      |      |        |        |         |         |         |
| ltra |      |      |        |        |         |         |         |
| tion |      |      |        |        |         |         |         |
| (Ap  |      |      |        |        |         |         |         |
| p)** |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| AP6  | 2    | 95   | 1700   | 2100   | 2000    | 1000    | 390     |
+------+------+------+--------+--------+---------+---------+---------+
| AP12 | 1    | 77   | 1400   | 78     | 680     | 1100    | 63      |
+------+------+------+--------+--------+---------+---------+---------+
| AP14 | 3    | 95   | 1000   | 910    | 710     | 630     | 200     |
+------+------+------+--------+--------+---------+---------+---------+
| Ar   |      |      | 1300   | 210    | 890     | 860     | 130     |
| ithm |      |      |        |        |         |         |         |
| etic |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| G    |      |      | 1300   | 530    | 990     | 880     | 170     |
| eome |      |      |        |        |         |         |         |
| tric |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| **Mi |      |      |        |        |         |         |         |
| xing |      |      |        |        |         |         |         |
| /Loa |      |      |        |        |         |         |         |
| ding |      |      |        |        |         |         |         |
| with |      |      |        |        |         |         |         |
| Cl   |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Sys  |      |      |        |        |         |         |         |
| tems |      |      |        |        |         |         |         |
| U    |      |      |        |        |         |         |         |
| sing |      |      |        |        |         |         |         |
| Hard |      |      |        |        |         |         |         |
| Coup |      |      |        |        |         |         |         |
| ling |      |      |        |        |         |         |         |
| Dev  |      |      |        |        |         |         |         |
| ices |      |      |        |        |         |         |         |
| and  |      |      |        |        |         |         |         |
| Appl |      |      |        |        |         |         |         |
| ying |      |      |        |        |         |         |         |
| Gr   |      |      |        |        |         |         |         |
| ound |      |      |        |        |         |         |         |
| E    |      |      |        |        |         |         |         |
| quip |      |      |        |        |         |         |         |
| ment |      |      |        |        |         |         |         |
| Equi |      |      |        |        |         |         |         |
| pped |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Encl |      |      |        |        |         |         |         |
| osed |      |      |        |        |         |         |         |
| Cab  |      |      |        |        |         |         |         |
| With |      |      |        |        |         |         |         |
| Char |      |      |        |        |         |         |         |
| coal |      |      |        |        |         |         |         |
| Fi   |      |      |        |        |         |         |         |
| ltra |      |      |        |        |         |         |         |
| tion |      |      |        |        |         |         |         |
| (    |      |      |        |        |         |         |         |
| 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       |
+------+------+------+--------+--------+---------+---------+---------+
| Ar   |      |      | 390    | 82     | 54      | 94      | 22      |
| ithm |      |      |        |        |         |         |         |
| etic |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| G    |      |      | 710    | 280    | 400     | 370     | 79      |
| eome |      |      |        |        |         |         |         |
| tric |      |      |        |        |         |         |         |
| Mean |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+
| \    |      |      |        |        |         |         |         |
| *AP1 |      |      |        |        |         |         |         |
| Ur   |      |      |        |        |         |         |         |
| ines |      |      |        |        |         |         |         |
| were |      |      |        |        |         |         |         |
| also |      |      |        |        |         |         |         |
| c    |      |      |        |        |         |         |         |
| olle |      |      |        |        |         |         |         |
| cted |      |      |        |        |         |         |         |
| on   |      |      |        |        |         |         |         |
| days |      |      |        |        |         |         |         |
| 5 &  |      |      |        |        |         |         |         |
| 6;   |      |      |        |        |         |         |         |
| AP2  |      |      |        |        |         |         |         |
| u    |      |      |        |        |         |         |         |
| rine |      |      |        |        |         |         |         |
| was  |      |      |        |        |         |         |         |
| also |      |      |        |        |         |         |         |
| c    |      |      |        |        |         |         |         |
| olle |      |      |        |        |         |         |         |
| cted |      |      |        |        |         |         |         |
| on   |      |      |        |        |         |         |         |
| Day  |      |      |        |        |         |         |         |
| 5;   |      |      |        |        |         |         |         |
| MOEs |      |      |        |        |         |         |         |
| are  |      |      |        |        |         |         |         |
| not  |      |      |        |        |         |         |         |
| p    |      |      |        |        |         |         |         |
| rese |      |      |        |        |         |         |         |
| nted |      |      |        |        |         |         |         |
| h    |      |      |        |        |         |         |         |
| ere. |      |      |        |        |         |         |         |
+------+------+------+--------+--------+---------+---------+---------+

1.  []{#__RefHeading___Toc203446733 .anchor}**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.

2.  []{#__RefHeading___Toc203446734 .anchor}**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 Q~1~\* that has been calculated for ethoprop based on
dose response data (Q~1~\* = 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 Q~1~\* 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.

1.  []{#__RefHeading___Toc203446735 .anchor}**Occupational Handler
    Cancer Risk**

Estimated cancer risk calculations were completed by multiplying the
LADD values by the Q~1~\* for ethoprop (Q~1~\* = 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       **Crop or         **Application   **Area    **Cancer Risk                                                                        
  Scenario**       Target**          Rate ^a^**      Treated   Estimates                                                                            
                                                     Daily     ^c^**                                                                                
                                                     ^b^**                                                                                          

                                                               **Baseline**   **PPE-G-NR**   **PPE-G,   **PPE-G-   **PPE-G,   **PPE-G-   **PPE-G,   **Eng
                                                                                             DL-NR**    80% R**    DL- 80%    90% R**    DL- 90%    Control**
                                                                                                                   R**                   R**        

  Mixer/Loader                                                                                                                                      

  Mixing/Loading   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
  Emulsifiable                                                                                                                                      
  Concentrates for                                                                                                                                  
  Groundboom                                                                                                                                        
  Applications                                                                                                                                      

                   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   mint (nematodes)  6 lb ai/acre    80 acres  2E-03          2E-05          2E-05      2E-05      2E-05      1E-05      1E-05      7E-06
  Granular                                                                                                                                          
  Broadcast                                                                                                                                         
  Spreader                                                                                                                                          

                   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  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
  Sprays via                                                                                                                                        
  Groundboom                                                                                                                                        
  Equipment                                                                                                                                         

                   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         Mint (nematodes)  6 lb ai/acre    80 acres  2E-05          2E-05          9E-06      8E-06      1E-05      6E-06      5E-06      4E-06
  Granulars via                                                                                                                                     
  Tractor Drawn                                                                                                                                     
  Spreader                                                                                                                                          

                   Mint (symphylans) 3 lb ai/acre    80 acres  9E-06          8E-06          5E-06      4E-06      7E-06      3E-06      3E-06      2E-06
  -------------------------------------------------------------------------------------------------------------------------------------------------------------

1.  []{#__RefHeading___Toc203446736 .anchor}**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.**

[]{#__RefHeading___Toc203446737 .anchor}**10.0 Data Needs**

**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**

None.

**Occupational and Residential Exposure**

None.

11. []{#__RefHeading___Toc203446738 .anchor}**References**

**[Occupational/Residential Exposure]{.underline}**: 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]{.underline}**: 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]{.underline}: 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]{.underline}**: Ethoprop. HED Metabolism Committee Meeting
on 1/27/98. Kit Farwell. 2/6/98. Txr 012563.

**[IRED]{.underline}**: 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.
<http://www.epa.gov/pesticides/reregistration/REDs/ethoprop_red.pdf>

**[Cumulative]{.underline}**: Organophosphorus Cumulative Risk
Assessment -- 2006 Update. August 2006.

<http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf>

[]{#__RefHeading___Toc203446739 .anchor}**Appendix A: Toxicology
Assessment**

[]{#__RefHeading___Toc203446740 .anchor}**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            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | yes         | yes         |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | no          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | yes         | **no**      |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | yes         |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | no          | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | yes         |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | yes         |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity---Reverse         | yes         | yes         |
| Mutation - bacterial                    |             |             |
|                                         | yes         | yes         |
| 870.5375 Mutagenicity---Chromosomal     |             |             |
| Aberrations-mammalian                   | yes         | yes         |
|                                         |             |             |
| 870.5395 Mutagenicity---Mammalian       |             |             |
| Micronucleus                            |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | yes         | yes         |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | no^b^       |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | yes         | yes         |
| Battery (rat)                           |             |             |
|                                         | yes         | yes         |
| 870.6200b 90-Day Neuro. Screening       |             |             |
| Battery (rat)                           | yes         | yes         |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | no          | no          |
|                                         |             |             |
| 870.7800 Immunotoxicity                 | yes         | **no**      |
+-----------------------------------------+-------------+-------------+

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

[]{#__RefHeading___Toc203446741 .anchor}**A.2 Toxicity Profiles**

**Table A.2.1 Acute Toxicity of Technical Ethoprop**

+--------+---------------+----------+------------------+--------------+
| *      | **Study       | **MRID   | **Results**      | **Toxicity   |
| *Guide | Type**        | \#**     |                  | Category**   |
| line** |               |          |                  |              |
|        |               |          |                  |              |
| *      |               |          |                  |              |
| *No.** |               |          |                  |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Acute Oral    | 00078035 | M LD~50~ = 56.2  | I            |
| 0.1100 |               |          | mg/kg            |              |
|        | \- Rat. 1965  |          |                  |              |
|        |               |          | F LD~50~ = 30.2  |              |
|        |               |          | mg/kg            |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Acute Oral    | 44472501 | F LD~50~ = 56    | II           |
| 0.1100 |               |          | mg/kg            |              |
|        | \- Rat. 1998  |          |                  |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Acute Dermal  | 00078035 | LD~50~ = 25.74   | I            |
| 0.1200 |               |          | mg/kg            |              |
|        | \- Rabbit.    |          |                  |              |
|        | 1965          |          |                  |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Acute Dermal  | 42979502 | LD~50~ = 8.5     | I            |
| 0.1200 |               |          | mg/kg            |              |
|        | \- Rabbit.    |          |                  |              |
|        | 1987          |          |                  |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Acute Dermal  | 42979501 | M LD~50~ = 1280  | II           |
| 0.1200 |               |          | mg/kg            |              |
|        | \- Rat. 1987  |          |                  |              |
|        |               |          | F LD~50~ = 424   |              |
|        |               |          | mg/kg            |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Acute         | 070060   | LC~50~ = 0.123   | II           |
| 0.1300 | Inhalation -  |          | mg/L             |              |
|        |               |          |                  |              |
|        | Rat           |          |                  |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Primary Eye   | 00078036 | 0.1 mL resulted  | I            |
| 0.2400 | Irritation -  |          | in 100%          |              |
|        | Rabbit        |          | mortality        |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Primary Skin  | 00048774 | 0.5 mL resulted  | I            |
| 0.2500 | Irritation -  |          | in 100%          |              |
|        | Rabbit        |          | mortality        |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Dermal        | N/A^1^   | N/A              | N/A          |
| 0.2600 | Sensitization |          |                  |              |
+--------+---------------+----------+------------------+--------------+
| 87     | Delayed       | 40609401 | Negative         | N/A          |
| 0.6100 | Neuropathy -  |          |                  |              |
|        | Hen           | 47127001 |                  |              |
+--------+---------------+----------+------------------+--------------+

^1^Requirement 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**  | *  | **DOSE** | **END   | *    | **LOAEL**            |
|            | *S |          | POINT** | *NOA | (mg/kg/day)          |
|            | EX |          |         | EL** |                      |
|            | ** |          |         |      |                      |
+============+====+==========+=========+======+======================+
| **C        |    | *        | S       |      | Not reported         |
| OMPARATIVE |    | *ADULT** | ystemic |      |                      |
| ChE        |    |          |         |      |                      |
| ACUTE**    |    | 0, 0.5,  |         |      |                      |
| Study      |    | 1, 2, 4  |         |      |                      |
|            |    | mg/kg    |         |      |                      |
| 2004       |    |          |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 46278701   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | 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.          |
+------------+----+----------+---------+------+----------------------+
|            |    | **OFF    | S       |      | Not reported         |
|            |    | SPRING** | ystemic |      |                      |
|            |    |          |         |      |                      |
|            |    | **(11    |         |      |                      |
|            |    | days     |         |      |                      |
|            |    | old)**   |         |      |                      |
|            |    |          |         |      |                      |
|            |    | 0, 0.5,  |         |      |                      |
|            |    | 1, 2     |         |      |                      |
|            |    |          |         |      |                      |
|            |    | mg/kg    |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | 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    | M  | 0, 5,    | S       | 5    | 50 mg/kg (MA, FOB).  |
| RAT        |    | 50, 75   | ystemic | m    | Death at HDT.        |
| NEUROTOX** |    | mg/kg    |         | g/kg |                      |
| SD Crl:CD  |    |          |         |      |                      |
| BR         |    | tested   |         |      |                      |
| VAF/Plus   |    | blood    |         |      |                      |
|            |    | ChE on   |         |      |                      |
| 1994       |    | day 2,   |         |      |                      |
|            |    | brain on |         |      |                      |
| MRID       |    | day 15   |         |      |                      |
| 43197701   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \< 5 | 5 mg/kg              |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 5    | 50 mg/kg (-45%)      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | ≥ 75 | \> 75 mg/kg          |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 5,    | S       | 5    | 25 mg/kg (MA, FOB).  |
|            |    | 25, 50   | ystemic | m    | Death at HDT.        |
|            |    | mg/kg    |         | g/kg |                      |
|            |    |          |         |      |                      |
|            |    | tested   |         |      |                      |
|            |    | blood    |         |      |                      |
|            |    | ChE on   |         |      |                      |
|            |    | day 2,   |         |      |                      |
|            |    | brain on |         |      |                      |
|            |    | day 15   |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \< 5 | 5 mg/kg              |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | \< 5 | 5 mg/kg (-32%)       |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | ≥ 50 | \> 50 mg/kg          |
+------------+----+----------+---------+------+----------------------+
| **SPECIAL  | M  | 0, 24,   | S       | 24   | 52 mg/kg             |
| ACUTE RAT  |    | 52 mg/kg | ystemic | m    | (cholinergic signs)  |
| NEUROTOX** |    |          |         | g/kg |                      |
| SD Crl:CD  |    | tested   |         |      |                      |
| BR         |    | at 2 hr, |         |      |                      |
| VAF/Plus   |    | day 8    |         |      |                      |
|            |    | and day  |         |      |                      |
| 1994       |    | 15       |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 43442402.  |    |          |         |      |                      |
|            |    |          |         |      |                      |
| ChE        |    |          |         |      |                      |
| activity 2 |    |          |         |      |                      |
| hours      |    |          |         |      |                      |
| p          |    |          |         |      |                      |
| ost-dosing |    |          |         |      |                      |
| (and still |    |          |         |      |                      |
| inhibited  |    |          |         |      |                      |
| on day     |    |          |         |      |                      |
| 15).       |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \<   | 24 mg/kg             |
|            |    |          |         | 24   |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | \<   | 24 mg/kg (-43% at 2  |
|            |    |          |         | 24   | hr, -23% on day 15)  |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | \<   | 24 mg/kg (\~ -46 %   |
|            |    |          |         | 24   | in 3 brain regions   |
|            |    |          |         |      | at 2 hr, -27% in     |
|            |    |          |         |      | frontal cortex on    |
|            |    |          |         |      | day 15)              |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 16,   | S       | 16   | 33 mg/kg             |
|            |    | 33 mg/kg | ystemic |      | (cholinergic signs)  |
|            |    |          |         |      |                      |
|            |    | tested   |         |      |                      |
|            |    | at 2 hr, |         |      |                      |
|            |    | day 8    |         |      |                      |
|            |    | and day  |         |      |                      |
|            |    | 15       |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | 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)                  |
+------------+----+----------+---------+------+----------------------+

+------------+----+----------+---------+------+----------------------+
| **C        |    | *        | S       |      | no clinical signs    |
| OMPARATIVE |    | *ADULT** | ystemic |      | observed             |
| ChE        |    |          |         |      |                      |
| 11-day**   |    | 0, 0.5,  |         |      |                      |
| gavage     |    | 1, 2     |         |      |                      |
| study      |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
| 2004       |    |          |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 46278702   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | 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            |
+------------+----+----------+---------+------+----------------------+
|            |    | **OFF    | S       |      | no clinical signs    |
|            |    | SPRING** | ystemic |      | observed             |
|            |    |          |         |      |                      |
|            |    | **(11    |         |      |                      |
|            |    | days     |         |      |                      |
|            |    | old)**   |         |      |                      |
|            |    |          |         |      |                      |
|            |    | 0, 0.25, |         |      |                      |
|            |    | 0.5, 1   |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \<   | 0.25                 |
|            |    |          |         | 0.25 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.25 | 0.5 (-39% males)     |
|            |    |          |         |      |                      |
|            |    |          |         |      | BMDL20 = 0.28        |
|            |    |          |         |      | mg/kg/day            |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | \<   | 0.25 (-10% / -15%    |
|            |    |          |         | 0.25 | males/females)       |
|            |    |          |         |      |                      |
|            |    |          |         |      | BMDL10 = 0.14        |
|            |    |          |         |      | mg/kg/day            |
+------------+----+----------+---------+------+----------------------+
| **         | M  | 0, 4,    | S       | 2.6  | 27 (FOB, MA,         |
| SUBCHRONIC |    | 40, 400  | ystemic |      | cholinergic signs,   |
| RAT        |    | ppm      |         |      | BW, FC)              |
| NEUROTOX** |    |          |         |      |                      |
|            |    | 0, 0.26, |         |      |                      |
| feeding    |    | 2.6, 27  |         |      |                      |
| study      |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
| SD Crl:CD  |    |          |         |      |                      |
| BR         |    | tested   |         |      |                      |
| VAF/Plus   |    | weeks 4, |         |      |                      |
|            |    | 8, 14    |         |      |                      |
| 1994       |    |          |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 43424001   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.26 | 2.6                  |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.26 | 2.6 (-30% week 4)    |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | \<   | 2.6                  |
|            |    |          |         | 0.26 |                      |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 4,    | S       | 3    | 31 (FOB, MA, signs,  |
|            |    | 40, 400  | ystemic |      | BW, FC)              |
|            |    | ppm      |         |      |                      |
|            |    |          |         |      |                      |
|            |    | 0, 0.31, |         |      |                      |
|            |    | 3.0, 31  |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
|            |    |          |         |      |                      |
|            |    | tested   |         |      |                      |
|            |    | weeks 4, |         |      |                      |
|            |    | 8, 14    |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \<   | 0.31                 |
|            |    |          |         | 0.31 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.31 | 3.0 (large S.D., no  |
|            |    |          |         |      | statistical          |
|            |    |          |         |      | significance)        |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | \<   | 0.31                 |
|            |    |          |         | 0.31 |                      |
+------------+----+----------+---------+------+----------------------+
| **DNT**    | F  | **MA     | S       | 6.2  | 38.2 tremors,        |
|            |    | TERNAL** | ystemic |      | repetitive chewing,  |
| 2004       |    |          |         |      | muscle               |
|            |    | 0, 3,    |         |      | fasciculations,      |
| MRID       |    | 30, 180  |         |      | nasal stains, ↓BW    |
| 46364801   |    | ppm      |         |      |                      |
| 46364802   |    |          |         |      |                      |
|            |    | 0, 0.7,  |         |      |                      |
|            |    | 6.2,     |         |      |                      |
|            |    | 38.2     |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
|            |    | during   |         |      |                      |
|            |    | l        |         |      |                      |
|            |    | actation |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \<   | 0.7                  |
|            |    |          |         | 0.7  |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | \<   | 0.7 (-30%)           |
|            |    |          |         | 0.7  |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0.7  | 6.2 (-49%)           |
+------------+----+----------+---------+------+----------------------+
|            |    | **OFF    | S       | \<   | 0.7 ↑ MA (males on   |
|            |    | SPRING** | ystemic | 0.7  | PND 17)              |
|            |    |          |         |      |                      |
|            |    | **(21    |         |      | (at 38.2 mg/kg/day,  |
|            |    | days     |         |      | also effect on       |
|            |    | old)**   |         |      | 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   | M  | 0, 0.2,  | S       | \>   | \> 0.090             |
| FEEDING    | /F | 0.5, 1.0 | ystemic | 0    |                      |
| STUDY**    |    | ppm      |         | .090 |                      |
| Crl        |    |          |         |      |                      |
| :CD(SD)IGS |    | M        |         |      |                      |
| BR         |    | 0,0.018, |         |      |                      |
|            |    | 0.045,   |         |      |                      |
| 2001       |    | 0.090    |         |      |                      |
|            |    | m        |         |      |                      |
| MRID       |    | g/kg/day |         |      |                      |
| 45388501   |    |          |         |      |                      |
|            |    | F 0,     |         |      |                      |
|            |    | 0.021,   |         |      |                      |
|            |    | 0.052,   |         |      |                      |
|            |    | 0.099    |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | Not  | \-\-\--              |
|            |    |          |         | te   |                      |
|            |    |          |         | sted |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | \>   | \> 0.090             |
|            |    |          |         | 0    |                      |
|            |    |          |         | .090 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | Not  | \-\--                |
|            |    |          |         | te   |                      |
|            |    |          |         | sted |                      |
+------------+----+----------+---------+------+----------------------+
| **28-DAY   | M  | 0, 7.5,  | S       | \>   | \> 2.363             |
| FEEDING    |    | 15, 30   | ystemic | 2    |                      |
| STUDY**    |    | ppm      |         | .363 |                      |
| Crl        |    |          |         |      |                      |
| :CD(SD)IGS |    | 0,       |         |      |                      |
| BR         |    | 0.567,   |         |      |                      |
|            |    | 1.159,   |         |      |                      |
| 2001       |    | 2.363    |         |      |                      |
|            |    | m        |         |      |                      |
| MRID       |    | g/kg/day |         |      |                      |
| 45388502   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0    | 1.159                |
|            |    |          |         | .567 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | \<0  | 0.567 (-22%)         |
|            |    |          |         | .567 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | Not  | \-\--                |
|            |    |          |         | te   |                      |
|            |    |          |         | sted |                      |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 7.5,  | S       | \>   | \> 2.677             |
|            |    | 15, 30   | ystemic | 2    |                      |
|            |    | ppm      |         | .677 |                      |
|            |    |          |         |      |                      |
|            |    | 0,       |         |      |                      |
|            |    | 0.707,   |         |      |                      |
|            |    | 1.366,   |         |      |                      |
|            |    | 2.677    |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \<0  | 0.707                |
|            |    |          |         | .707 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 1    | 2.677 (-40%)         |
|            |    |          |         | .366 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | \    | \-\--                |
|            |    |          |         | -\-- |                      |
+------------+----+----------+---------+------+----------------------+
| **CH       | M  | 0, 1,    | S       | 2.44 | 18.38 (↓BW gain, FC, |
| RONIC/ONCO |    | 60,      | ystemic |      | anemia)              |
| RAT** 1992 |    | *        |         |      |                      |
| Crl:CD     |    | *600/400 |         |      |                      |
|            |    | ppm**    |         |      |                      |
| MRID       |    |          |         |      |                      |
| 42530201   |    | 0.04,    |         |      |                      |
|            |    | 2.44,    |         |      |                      |
| Doc 010775 |    | 18.38    |         |      |                      |
|            |    | mkd.     |         |      |                      |
|            |    | ↓dose:   |         |      |                      |
|            |    | signs,   |         |      |                      |
|            |    | death,   |         |      |                      |
|            |    | major    |         |      |                      |
|            |    | ↓BW in   |         |      |                      |
|            |    | 1st 2    |         |      |                      |
|            |    | wks.     |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.04 | 2.44                 |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.04 | 2.44 (-40% starting  |
|            |    |          |         |      | at week 14)          |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0.04 | 2.44 (-35%)          |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 1,    | S       | 3.56 | 23.98 (↓BW gain, FC, |
|            |    | 60,      | ystemic |      | anemia)              |
|            |    | 600/400  |         |      |                      |
|            |    | ppm      |         |      |                      |
|            |    |          |         |      |                      |
|            |    | 0, 0.06, |         |      |                      |
|            |    | 3.56,    |         |      |                      |
|            |    | 23.98    |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.06 | 3.56                 |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.06 | 3.56 (-41% starting  |
|            |    |          |         |      | at week 14)          |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0.06 | 3.56 (-28%)          |
+------------+----+----------+---------+------+----------------------+
| **MOUSE    | M  | 0, 0.2,  | S       | 0    | 3.96 (↓ BW)          |
| ONCO**     |    | 2, 30    | ystemic | .254 |                      |
|            |    | ppm      |         |      |                      |
| MRID       |    |          |         |      |                      |
| 40356301,  |    | 0,       |         |      |                      |
| 43326001   |    | 0.026,   |         |      |                      |
|            |    | 0.254,   |         |      |                      |
| Doc 006620 |    | 3.96     |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0    | 0.254                |
|            |    |          |         | .026 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0    | 0.254 (-12% starting |
|            |    |          |         | .026 | week 26)             |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0    | 3.96 (-36% at week   |
|            |    |          |         | .254 | 26)                  |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 0.2,  | S       | 0    | 4.91 (↓ BW)          |
|            |    | 2, 30    | ystemic | .318 |                      |
|            |    | ppm      |         |      |                      |
|            |    |          |         |      |                      |
|            |    | 0,       |         |      |                      |
|            |    | 0.032,   |         |      |                      |
|            |    | 0.318,   |         |      |                      |
|            |    | 4.9      |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0    | 0.318                |
|            |    |          |         | .032 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0    | 0.318 (-13% starting |
|            |    |          |         | .032 | week 26)             |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0    | 4.9 (-29% at week    |
|            |    |          |         | .318 | 26)                  |
+------------+----+----------+---------+------+----------------------+

+------------+----+----------+---------+------+----------------------+
| **90-DAY   |    | 0, 1, 3, | S       | 0    | 2.5 (emesis)         |
| DOG**      |    | 100 ppm  | ystemic | .075 |                      |
|            |    |          |         |      |                      |
| 1967       |    | 0,       |         |      |                      |
|            |    | 0.025,   |         |      |                      |
| MRID 75240 |    | 0.075,   |         |      |                      |
|            |    | 2.5      |         |      |                      |
| Doc 001789 |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0    | 0.075                |
|            |    |          |         | .025 |                      |
|            |    |          | M day 2 |      | 0.025                |
|            |    |          |         | \<0  |                      |
|            |    |          | M day   | .025 |                      |
|            |    |          | 65      |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0    | 2.5                  |
|            |    |          |         | .075 |                      |
|            |    |          | F day 4 |      | 0.075                |
|            |    |          |         | 0    |                      |
|            |    |          | F day   | .025 |                      |
|            |    |          | 65      |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | \    | \-\--                |
|            |    |          |         | -\-- |                      |
+------------+----+----------+---------+------+----------------------+
| **COMBINED | M  | 0, 0.01, | S       | 0    | 1.0 (anemia, liver   |
| 1-YEAR + 5 |    | 0.025,   | ystemic | .025 | tox)                 |
| MONTH      |    | 1.0,     |         |      |                      |
| DOG**      |    | 10.0     |         |      |                      |
|            |    | m        |         |      |                      |
| 1986, 1990 |    | g/kg/day |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| *          |    |          |         |      |                      |
| *160179**, |    |          |         |      |                      |
| 41498601   |    |          |         |      |                      |
|            |    |          |         |      |                      |
| Doc        |    |          |         |      |                      |
| 006353,    |    |          |         |      |                      |
| 011281     |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.01 | 0.025                |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0    | 1.0 (-21 to -48% at  |
|            |    |          |         | .025 | various time points) |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 1.0  | 10.0 (-44% at 1 year |
+------------+----+----------+---------+------+----------------------+
|            | F  | 0, 0.01, | S       | 0    | 1.0 (anemia)         |
|            |    | 0.025,   | ystemic | .025 |                      |
|            |    | 1.0,     |         |      |                      |
|            |    | 10.0     |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.01 | 0.025                |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0    | 1.0 (-11 to -45% at  |
|            |    |          |         | .025 | various time points) |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 1.0  | 10.0 (-35% at 1      |
|            |    |          |         |      | year)                |
+------------+----+----------+---------+------+----------------------+
| **[TECH    | M  | 0.03,    | S       | 1.0  | 1.0 (↓ BW, ↓kidney   |
| NICAL]{.un | /F | 0.1, 1   | ystemic |      | wt) - Females, only  |
| derline}** |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
| 21-DAY     |    |          |         |      |                      |
| **DERMAL** |    |          |         |      |                      |
| **[R       |    |          |         |      |                      |
| ABBIT]{.un |    |          |         |      |                      |
| derline}** |    |          |         |      |                      |
|            |    |          |         |      |                      |
| 1989       |    |          |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 41304404   |    |          |         |      |                      |
|            |    |          |         |      |                      |
| DOC 010143 |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.1  | 1.0                  |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.1  | 1.0 (-42%)           |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0.1  | 1.0 (-49%)           |
+------------+----+----------+---------+------+----------------------+
| **[TECH    | M  | 0.3, 1,  | S       | \>   | \> 10                |
| NICAL]{.un | /F | 10       | ystemic | 10   |                      |
| derline}** |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
| 21-DAY     |    |          |         |      |                      |
| **DERMAL** |    |          |         |      |                      |
| *          |    |          |         |      |                      |
| *[RAT]{.un |    |          |         |      |                      |
| derline}** |    |          |         |      |                      |
| 1990       |    |          |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 45074602   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.3  | 1                    |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 0.3  | 1 (-33%)             |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 1    | 10 (-70%)            |
+------------+----+----------+---------+------+----------------------+
| *          | M  | 0,       | S       | \>   | \> 387               |
| *[GRANULAR | /F | 19.34,   | ystemic | 387  |                      |
| FORMUL     |    | 96.7,    |         |      |                      |
| ATION]{.un |    | 387      |         |      |                      |
| derline}** |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
| **19.34%   |    | (c       |         |      |                      |
| granular** |    | orrected |         |      |                      |
|            |    | for %    |         |      |                      |
| 28-DAY     |    | a.i.)    |         |      |                      |
| **DERMAL   |    |          |         |      |                      |
| [RAT]{.un  |    |          |         |      |                      |
| derline}** |    |          |         |      |                      |
| Year 2000  |    |          |         |      |                      |
|            |    |          |         |      |                      |
| MRID       |    |          |         |      |                      |
| 45034801   |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | \<   | 19.34                |
|            |    |          |         | 1    |                      |
|            |    |          |         | 9.34 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | 1    | 96.7 (-40% to -80%)  |
|            |    |          |         | 9.34 |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 1    | 96.7 (-40%)          |
|            |    |          |         | 9.34 |                      |
+------------+----+----------+---------+------+----------------------+

+------------+----+----------+---------+------+----------------------+
| **RABBIT   | F  | **MA     | S       | ≥    | \> 2.5 No maternal   |
| DEVELOP**  |    | TERNAL** | ystemic | 2.5  | or offspring         |
|            |    |          |         |      | toxicity occurred.   |
| 1989       |    | 0.625,   |         |      | ChE was not          |
|            |    | 1.25,    |         |      | determined.          |
| MRID       |    | 2.5      |         |      |                      |
| 41304403   |    | m        |         |      |                      |
|            |    | g/kg/day |         |      |                      |
| DOC        |    |          |         |      |                      |
| 010143,    |    |          |         |      |                      |
| 011000     |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    | **OFF    |         | ≥    | \> 2.5               |
|            |    | SPRING** |         | 2.5  |                      |
+------------+----+----------+---------+------+----------------------+
| **RAT      | F  | **MA     | S       | 2    | 9 (↓ BW gain,        |
| DEVELOP**  |    | TERNAL** | ystemic |      |                      |
|            |    |          |         |      | ↑ soft stool)        |
| 1989       |    | 2, 9, 18 |         |      |                      |
|            |    | m        |         |      |                      |
| MRID       |    | g/kg/day |         |      |                      |
| 41304402   |    |          |         |      |                      |
|            |    |          |         |      |                      |
| Doc 010143 |    |          |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    | **OFF    |         | ≥ 18 | \> 18                |
|            |    | SPRING** |         |      |                      |
+------------+----+----------+---------+------+----------------------+
| **2-GEN    | MF | **PA     | S       | 2.3  | 13 (↓ BW gain)       |
| RAT        |    | RENTAL** | ystemic |      |                      |
| REPRO**    |    |          |         |      | At [24]{.underline}  |
|            |    | 0, 1,    |         |      | mkd there were       |
| 1991       |    | 30,      |         |      | tremors, loose       |
|            |    | 300/150  |         |      | stools.              |
| MRID       |    | ppm      |         |      |                      |
| 41921201   |    |          |         |      |                      |
|            |    | 0.08,    |         |      |                      |
| Doc 011282 |    | 2.3,     |         |      |                      |
|            |    | 24/13    |         |      |                      |
|            |    | mkd.     |         |      |                      |
|            |    | ↓dose:   |         |      |                      |
|            |    | excess   |         |      |                      |
|            |    | m        |         |      |                      |
|            |    | ortality |         |      |                      |
|            |    | in F1a   |         |      |                      |
|            |    | pups.    |         |      |                      |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Plasma  | 0.08 | 2.3                  |
+------------+----+----------+---------+------+----------------------+
|            |    |          | RBC     | ≥ 13 | \> 13                |
+------------+----+----------+---------+------+----------------------+
|            |    |          | Brain   | 0.08 | 2.3                  |
+------------+----+----------+---------+------+----------------------+
|            | MF | **OFF    | S       | 2.3  | 13 (↓ BW)            |
|            |    | SPRING** | ystemic |      |                      |
|            |    |          |         |      | 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.

[]{#__RefHeading___Toc203446742 .anchor}**A.3 Executive Summaries**

**Developmental Neurotoxicity**:

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]{.underline}, 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]{.underline} 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]{.underline}**:** In the [adult males]{.underline},
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]{.underline}, 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]{.underline}, 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]{.underline} \[assessment of ChE/AChE activity
performed at the selected peak-effect times of 24 hours (adult)/8 hours
(neonate)\]: [Adult]{.underline}: 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]{.underline}: 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]{.underline}: 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]{.underline}: 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    | **       | BMD20    | BMDL20   |
|       |      |          |          | BMDL10** |          |          |
+-------+------+----------+----------+----------+----------+----------+
| 8 hr  | **P  | Male -   | 0.9570   | **       | \- - -   | \- - -   |
|       | up** | Female   |          | 0.7592** |          |          |
+-------+------+----------+----------+----------+----------+----------+
| 24 hr | *    |          | Could    |          |          |          |
|       | *Adu |          | not      |          |          |          |
|       | lt** |          | c        |          |          |          |
|       |      |          | alculate |          |          |          |
|       |      |          | BMD for  |          |          |          |
|       |      |          | adults:  |          |          |          |
|       |      |          | insu     |          |          |          |
|       |      |          | fficient |          |          |          |
|       |      |          | ChE      |          |          |          |
|       |      |          | in       |          |          |          |
|       |      |          | hibition |          |          |          |
+-------+------+----------+----------+----------+----------+----------+
| **SEN |      | Could    |          |          |          |          |
| SITIV |      | not      |          |          |          |          |
| ITY** |      | c        |          |          |          |          |
|       |      | alculate |          |          |          |          |
| Pup : |      | sen      |          |          |          |          |
| Adult |      | sitivity |          |          |          |          |
|       |      | by       |          |          |          |          |
|       |      | c        |          |          |          |          |
|       |      | omparing |          |          |          |          |
|       |      | BMD      |          |          |          |          |
|       |      | values   |          |          |          |          |
|       |      | because  |          |          |          |          |
|       |      | of       |          |          |          |          |
|       |      | insu     |          |          |          |          |
|       |      | fficient |          |          |          |          |
|       |      | brain    |          |          |          |          |
|       |      | ChE      |          |          |          |          |
|       |      | in       |          |          |          |          |
|       |      | hibition |          |          |          |          |
|       |      | in       |          |          |          |          |
|       |      | adults.  |          |          |          |          |
+-------+------+----------+----------+----------+----------+----------+

Ethoprop RBC

+--------+-----+----------+----------+----------+----------+----------+
| Time   | Age | Sex      | BMD10    | BMDL10   | BMD20    | **       |
|        |     |          |          |          |          | BMDL20** |
+--------+-----+----------+----------+----------+----------+----------+
| 8 hr   | *   | Male -   | 0.9612   | 0.6160   | 1.528    | *        |
|        | *Pu | Female   |          |          |          | *1.226** |
|        | p** |          |          |          |          |          |
+--------+-----+----------+----------+----------+----------+----------+
| 24 hr  | **A | Male     | 1.062    | 0.5948   | 1.855    | *        |
|        | dul |          |          |          |          | *1.204** |
|        | t** |          |          |          |          |          |
+--------+-----+----------+----------+----------+----------+----------+
| 24 hr  | **A | Female   | 1.475    | 0.8902   | 2.575    | 1.880    |
|        | dul |          |          |          |          |          |
|        | t** |          |          |          |          |          |
+--------+-----+----------+----------+----------+----------+----------+
| **S    |     | MF : M   | 1.1      |          | 1.2      |          |
| ENSITI |     |          |          |          |          |          |
| VITY** |     |          |          |          |          |          |
|        |     |          |          |          |          |          |
| Pup :  |     |          |          |          |          |          |
| Adult  |     |          |          |          |          |          |
+--------+-----+----------+----------+----------+----------+----------+
| **S    |     | MF : F   | 1.5      |          | 1.7      |          |
| ENSITI |     |          |          |          |          |          |
| VITY** |     |          |          |          |          |          |
|        |     |          |          |          |          |          |
| Pup :  |     |          |          |          |          |          |
| Adult  |     |          |          |          |          |          |
+--------+-----+----------+----------+----------+----------+----------+

[Benchmark dose modeling for rat pups, acute study (MRID
46278701)]{.underline}:

![](media/image7.jpeg){width="6.495833333333334in"
height="4.142361111111111in"}

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]{.underline}**:** 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]{.underline}**:** 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.

Pups were shown to be 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]{.underline}: 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]{.underline}: 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   | **B     | BMD20   | BMDL20  |
|         |     |         |         | MDL10** |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| 11-day  | Pup | Male -  | 0.1760  | 0.1361  | \- - -  | \- - -  |
|         |     | Female  |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| 11-day  | Ad  | Male -  | 2.0417  | 1.759   | \- - -  | \- - -  |
|         | ult | Female  |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| *       |     | MF : MF | **12**  |         |         |         |
| *SENSIT |     |         |         |         |         |         |
| IVITY** |     |         |         |         |         |         |
|         |     |         |         |         |         |         |
| Pup :   |     |         |         |         |         |         |
| Adult   |     |         |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+

Ethoprop RBC

+---------+-----+---------+---------+---------+---------+---------+
| Time    | Age | Sex     | BMD10   | BMDL10  | BMD20   | **B     |
|         |     |         |         |         |         | MDL20** |
+---------+-----+---------+---------+---------+---------+---------+
| 11-day  | Pup | Male -  | 0.2687  | 0.1421  | 0.4248  | 0.2759  |
|         |     | Female  |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| 11-day  | Ad  | Male    | 0.2939  | 0.1840  | 0.5010  | 0.3442  |
|         | ult |         |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| 11-day  | Ad  | Female  | 0.4312  | 0.2860  | 0.7352  | 0.5480  |
|         | ult |         |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| *       |     | MF : M  | 1.1     |         | 1.2     |         |
| *SENSIT |     |         |         |         |         |         |
| IVITY** |     |         |         |         |         |         |
|         |     |         |         |         |         |         |
| Pup :   |     |         |         |         |         |         |
| Adult   |     |         |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+
| *       |     | MF : F  | 1.6     |         | 1.7     |         |
| *SENSIT |     |         |         |         |         |         |
| IVITY** |     |         |         |         |         |         |
|         |     |         |         |         |         |         |
| Pup :   |     |         |         |         |         |         |
| Adult   |     |         |         |         |         |         |
+---------+-----+---------+---------+---------+---------+---------+

[Benchmark dose modeling for rat pups, 11-day study (MRID
46636401)]{.underline}:

![](media/image8.jpeg){width="6.495833333333334in"
height="4.142361111111111in"}

[Benchmark dose modeling for adult rats, 11-day study (MRID
46636401)]{.underline}:

![](media/image9.jpeg){width="6.495833333333334in"
height="4.142361111111111in"}

[]{#__RefHeading___Toc203446743 .anchor}**Appendix B: Tolerance
Reassessment Summary**

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        0.02
  removed                                        

  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
  -----------------------------------------------------------------------

[]{#__RefHeading___Toc203446744 .anchor}**Appendix C: 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"

The PHED study has received the appropriate ethical review. The
biomonitoring study has received preliminary (but not final) ethical
review. The biomonitoring 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.

[^1]: 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, Acetylcholinesterase Inhibition.\"
    Office of Pesticide Programs. June 10, 2002.