UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF PREVENTION,

PESTICIDES AND TOXIC SUBSTANCES

MEMORANDUM

Date:		6 November 2008

Subject:	Dimethomorph.  Human Health Risk Assessment for the Proposed
Food/Feed Use of the Fungicide (Associated with Section 3 Registration)
on Succulent Lima Beans, Ginseng, Grapes and Turnip Tops.  

PC Code:  268800	DP Barcode:  D349253

Decision Numbers:  388342	Registration Numbers:  241-410, 241-427

Petition Number:  8E7314	Regulatory Action:  Amended Section 3

Assessment Type:  Single Chemical, Aggregate	Case Number:  (None)

TXR Number:  (None)	CAS Number:  110488-70-5

MRID Numbers:  47317201 and -02	40CFR §180.493

Chemical Class:  Morpholine Fungicide	Trade Names:  Acrobat® 50WP,
Forum™



From:		William T. Drew, Chemist/Risk Assessor

		Suku Oonnithan, Biologist/ORE Assessor

		Anant Parmar, Biologist/Residue Chemistry and Dietary Exposure
Assessor

		Registration Action Branch 2 (RAB2)

		Health Effects Division (HED), 7509P

Through:	Douglas Dotson, PhD, Chemist

		Richard A. Loranger, PhD, Senior Scientist

		Karlyn J. Bailey, Toxicologist

		Christina Swartz, Branch Chief

		RAB2/HED, 7509P

To:		Sidney Jackson and Daniel Rosenblatt, RM Team 5

		Risk Integration Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD), 7505P

REQUESTED ACTION

	The Inter-regional Research Project #4 (IR-4) has proposed Section 3
registration for the use of dimethomorph to control downy mildew in
succulent lima beans, grapes and turnip tops, and to control foliar
blight/root rot in ginseng.  

Table of ContentS

  TOC \f  1.0	Executive Summary	4

2.0	Ingredient Profile	8

2.1	Summary of Proposed Uses	8

2.2	Structure and Nomenclature	9

2.3	Physical and Chemical Properties	10

3.0	Hazard Characterization/Assessment	11

3.1	Hazard and Dose-Response Characterization	11

3.1.1	Database Summary	11

3.2	Absorption, Distribution, Metabolism, Excretion	11

3.3	FQPA Considerations	12

3.3.1	Adequacy of the Toxicity Database	12

3.3.2	Evidence of Neurotoxicity	12

3.3.3	Developmental Toxicity Studies	12

3.3.4	Reproductive Toxicity Study	12

3.3.5	Additional Information from Literature Sources	13

3.3.6	Pre- and/or Post-Natal Toxicity	13

3.3.6.1	Determination of Susceptibility	13

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties	13

3.3.7	Recommendation for a Developmental Neurotoxicity Study	13

3.4	FQPA Safety Factor for Infants and Children	13

3.5	Hazard Identification and Toxicity Endpoint Selection	14

3.5.1	Acute Reference Dose - Females age 13-49	14

3.5.2	Acute Reference Dose - General Population	14

3.5.3	Chronic Reference Dose	14

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)	15

3.5.5	Dermal Absorption	15

3.5.6	Occupational Dermal Exposure (Short-, Intermediate- and Long-Term)
15

3.5.6.1	Occupational Dermal Exposure (Short-Term)	15

3.5.6.2	Occupational Dermal Exposure (Intermediate-Term)	15

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)	16

3.5.8	Level of Concern for Margin of Exposure	16

3.5.9	Recommendation for Aggregate Exposure Risk Assessments	17

3.5.10	Classification of Carcinogenic Potential	17

3.5.11	Summary of Toxicological Doses and Endpoints	17

3.6	Endocrine disruption	18

4.0	Public Health and Pesticide Epidemiology Data	19

4.1	Incident Reports	19

5.0	Dietary Exposure/Risk Characterization	19

5.1	Pesticide Metabolism and Environmental Degradation	19

5.1.1	Metabolism in Primary Crops	19

5.1.2	Metabolism in Rotational Crops	19

5.1.3	Metabolism in Livestock	19

5.1.4	Analytical Methodology	20

5.1.5	Environmental Degradation	20

5.1.6	Metabolic Profile in Rats	21

5.1.7	Toxicity Profile of Major Metabolites and Degradates	21

5.1.8	Pesticide Metabolites and Degradates of Concern	21

5.1.9	Drinking Water Residue Profile	21

5.1.10	Food Residue Profile	23

5.1.11	International Residue Limits	29

5.2	Dietary Exposure and Risk	29

5.2.1	Acute Dietary Exposure/Risk	29

5.2.2	Chronic Dietary Exposure/Risk	29

5.2.3	Cancer Dietary Risk	31

5.3 Anticipated Residue and Percent Crop Treated Information	31

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	31

6.1	Residential Handler Exposure	31

6.2	Residential Post-Application Exposure	31

6.3	Other (Spray Drift)	31

7.0	Aggregate Risk Assessments and Risk Characterization	32

7.1	Acute Aggregate Risk	32

7.2	Short-Term Aggregate Risk	32

7.3	Intermediate-Term Aggregate Risk	32

7.4	Long-Term Aggregate Risk	32

7.5	Cancer Aggregate Risk	33

8.0	Cumulative Risk Characterization/Assessment	33

9.0	Occupational Exposure/Risk Pathway	33

9.1	Short- and Intermediate-Term Handler Risk	33

9.2	Short- and Intermediate-Term Post-Application Risk	37

10.0	Data Needs and Regulatory Recommendations	38

10.1	Toxicology Data Needs	39

10.2	Residue Chemistry Data Needs	40

10.3	Occupational and Residential Exposure Data Needs	42

References:	43

Appendix A:	Toxicology Assessment	45

A.1	Toxicology Data Requirements	45

A.2	Toxicity Profiles	46

Appendix B:	Rationale for Toxicology Data Requirements	50

Appendix C:	Human Research Reference	52

 

1.0	Executive Summary  TC \l1 "1.0  Executive Summary 

	  SEQ CHAPTER \h \r 1 Dimethomorph, with IUPAC name
(E,Z)-4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine,
and CAS name
4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morpholin
e, is a systemic morpholine (Group 40) active ingredient (ai) having
fungicidal activity.  It is currently registered, under 40CFR
§180.493[a], for use on bulb vegetables, cucurbit vegetables, fruiting
vegetables, leafy Brassica greens, head and stem Brassica vegetables,
hops, lettuce (head and leaf), potatoes, taro, tobacco; tolerances have
also been established on imported grapes and raisins.  Its mode of
action is via inhibition of sterol (ergosterol) synthesis.  Dimethomorph
was developed for control of downy mildews, late blights, and crown and
root rots.  

	IR-4, on behalf of the Agricultural Experiment Stations of CO, DE, HI,
MI, NJ, NY, NC, OR and TN, is proposing to amend the labels for the 4.17
pounds ai per gallon (lb ai/gal) suspension concentrate formulation of
dimethomorph (Forum® Fungicide; EPA Registration #241-427), which is
equivalent to a flowable concentrate (FlC), and the 50% ai wettable
powder (WP) formulation of dimethomorph (Acrobat® 50WP Fungicide; EPA
Registration #241-410).  IR-4 has proposed the amendments to add new
uses on succulent lima beans, ginseng, grapes and turnip tops.  Up to 5
foliar applications, at single use rates of up to 0.20 pounds ai per
acre (lb ai/A), on these crops may be made (for a maximum seasonal use
rate of 1.0 lb ai/A), with minimum re-treatment intervals (RTIs) of 7
days, a 0-day pre-harvest interval (PHI) for lima beans and turnip tops,
a 14-day PHI for ginseng, and a 28-day PHI for grapes.  Applications to
all crops may be made using ground or aerial equipment.  This risk
assessment addresses these requested new uses.  

	Databases for toxicology, residue chemistry, and
occupational/residential exposure are complete for purposes of human
health risk assessment.  Some toxicological and residue chemistry data
are still needed to complete the database, and any registrations should
be made conditional upon receipt and review of those data (see Section
10).  In addition, there are label modifications, and tolerance
revisions that should be completed prior to registration or
establishment of tolerances.  

	Recent changes to 40CFR §158 make 21/28-day dermal testing (OPPTS
Guideline 870.3200), acute and subchronic neurotoxicity testing (OPPTS
Guideline 870.6200), and immunotoxicity testing (OPPTS Guideline
870.7800) required for pesticide registration.  The available data for
dimethomorph do not show potential for immunotoxic nor neurotoxic
effects.  However, the 870.3200 dermal, 870.6200 neurotoxicity, and
870.7800 immunotoxicity studies are required, and should be considered
confirmatory (see Appendix B).

	There is high confidence in the quality of the existing toxicological
studies, and the reliability of the toxicity endpoints identified for
use in risk assessment.  Based on the toxicity profile for dimethomorph,
a developmental neurotoxicity (DNT) study in rats is not required. 
Additionally, the existing dimethomorph data indicate that it possesses
relatively low toxicity.  

	The Health Effects Division (HED) has selected a no observed adverse
effect level (NOAEL) of 60 mg/kg/day for both short-term dermal and
inhalation exposures for assessing the occupational risk to handlers. 
The corresponding intermediate-term NOAELs are 15 mg/kg/day for both
routes of exposure.  The dose for short-term exposure is the maternal
NOAEL established in the rat developmental toxicity study, whereas the
dose for intermediate-term exposure is the NOAEL established in the
90-day dog feeding study.  A dermal absorption factor of 5 percent,
derived from the dermal absorption study, is included in the risk
assessment to account for the use of an oral endpoint for dermal
exposures.  Inhalation absorption is assumed to be 100 percent.  HED
selected a NOAEL of 11 mg/kg/day for chronic dietary exposures, which
was established in the rat carcinogenicity study, and was supported by
similar results in the rat chronic dietary feeding study.  There were
significant body weight decrements, and liver effects in female rats at
the LOAEL of 46.3 mg/kg/day.  Using an uncertainty factor of 100, the
chronic RfD was calculated to be 0.1 mg/kg/day.  At this time, there are
no residential uses for dimethomorph.  Therefore, discussion of dermal
and inhalation toxicity are unnecessary for this risk assessment with
respect to residential exposures.  

	No appropriate toxicological endpoints attributable to a single
exposure were identified in oral studies.  Consequently, it was
determined that there was no basis for selecting a dose and endpoint for
an acute RfD.  Because no acute toxicity endpoints were identified,
risks from acute exposure are not of concern to HED.  The RfD approach
adequately addresses chronic risk.  Dimethomorph has been classified as
showing no evidence of human carcinogenicity.  Therefore, cancer risk
from dimethomorph is not of concern to HED.  

	The toxicology data on dimethomorph provides no indication of enhanced
sensitivity of infants and children, based on the results from
developmental studies conducted with rats and rabbits, as well as a
two-generation reproduction study conducted with rats.  There were no
toxic effects observed in either the rat developmental toxicity, or the
rat two-generation reproductive toxicity studies, that were observed at
lower doses than those which produced toxic effects in the parents.  No
developmental toxicity was demonstrated in the rabbit developmental
toxicity study.  The risk assessment team concluded that the 10-fold
FQPA Safety Factor, to account for enhanced sensitivity of infants and
children, was unnecessary, and reduced it to 1.  

	The nature of the residues in plants has been adequately delineated
based on metabolism studies with grape, lettuce and potato.  In all
three studies, parent dimethomorph was the predominant residue.  No
metabolites were identified that require regulation.  With regard to the
subject petition considered herein, the only toxicologically significant
residue of concern (ROC), for tolerance setting and risk assessment
purposes, is dimethomorph per se.  

	There are no significant livestock feedstuffs associated with the
proposed uses on lima beans, ginseng, grapes and turnip tops. 
Therefore, no livestock metabolism data, enforcement methods, storage
stability data, or feeding studies are required to support this
petition.  

	For the proposed crop applications, the chronic estimated drinking
water concentration (EDWC) in ground water is 0.264 ppb, from Tier 1
Screening Concentration In GROund Water (SCI-GROW) modeling.  The
chronic EDWC in surface water, from Tier 1 FQPA Index Reservoir
Screening Tool (FIRST) modeling, is 24.7 ppb.  Another EDWC in surface
water, calculated for a previous drinking water assessment (DWA), was
28.5 ppb, from Tier 1 Generic Estimated Environmental Concentration
(GENEEC) modeling.  The 28.5 ppb EDWC was used in the current dietary
risk assessment to account for the most conservative water exposure
scenario.  

	The available European field trial data are adequate to support the
proposed use of the 50% ai WP and 4.17 lb ai/gal FlC formulations on
grapes grown east of the Rocky Mountains.  No change to the established
tolerance level in grape is necessary; however, the tolerance listing
for grape should be moved from 40CFR §180.493[a] to 40CFR §180.493[c],
the section for tolerances with regional registration.  

	No crop field trial data were submitted to support use of the 4.17 lb
ai/gal FlC formulation of dimethomorph on lima beans, ginseng, or turnip
tops.  On an interim basis, for the purposes of a conditional
registration, HED considers these uses to be supported by the European
grape field trials.  These trials compared residue levels arising from
the application of various dimethomorph formulations to grapes.  The
trials demonstrated that residues on grapes were comparable between the
WP and FlC formulations.  HED concludes that the existing dimethomorph
database and the European field trials support the conditional
registration of the 4.17 lb ai/gal FlC formulation for use on succulent
lima beans, ginseng, and turnip tops.  

	To support these conditional uses, results of at least two side-by-side
field trials should be submitted, comparing residues from the use of the
WP and FlC formulations, for both succulent lima beans, and turnip tops.
 These side-by-side trials should reflect application of the 4.17 lb
ai/gal FlC formulation at 1x the proposed maximum seasonal rate, and the
commodities should be harvested at the proposed PHI.  If these trials
demonstrate that the two different formulations result in comparable
residues, then side-by-side trials will not be required for ginseng. 
Otherwise, all commodities lacking adequate residue data for the 4.17 lb
ai/gal FlC formulation could require a full complement of field trials. 


	Adequate field trial data reflecting application of a 50% ai WP
formulation have been submitted to support the proposed uses of this
formulation on ginseng and lima beans; label amendments are required to
specify that the use on lima beans is restricted to areas east of the
Rocky Mountains.  The tolerance in succulent lima beans should be listed
in 40CFR §180.493[c], the section for tolerances with regional
registration.  The submitted crop field trial data were collected using
modified versions of the existing enforcement method, and are supported
by concurrent storage stability data.  The data indicate that the
proposed tolerance in lima beans is adequate.  For ginseng, the crop
field trial data indicate that the proposed tolerance of 0.85 ppm is
slightly low; a tolerance of 0.90 ppm in ginseng is recommended. 
Previously submitted data for mustard greens (a member of the leafy
Brassica greens subgroup 5B) are adequate to support the proposed use of
the 50% ai WP formulation on turnip tops.  The proposed tolerance in
turnip tops is adequate.  

	Previously submitted processing data for grapes indicate that
dimethomorph residues do not concentrate in juice.  The Chemistry
Science Advisory Council (ChemSAC) has concluded that residue data for
raisins are not required to support use of dimethomorph on grapes grown
east of the Rocky Mountains, as almost all raisins consumed in the US
come from California (minutes of 12 July 2006 ChemSAC meeting).  

	  SEQ CHAPTER \h \r 1 An adequate method is available to enforce
tolerances for dimethomorph residues in/on crops, Method FAMS 002-04,
which utilizes high-pressure liquid chromatography with ultraviolet
detection (HPLC/UV).  The limits of quantitation (LOQs) range from 0.010
ppm to 0.050 ppm, depending on the sample matrix.  In addition,
dimethomorph is recovered using FDA multiresidue method Section 302
(Protocol D).  

	In the chronic dietary exposure analysis, dimethomorph utilized a small
percentage of the chronic population adjusted dose (cPAD) for the
general US population, and all population subgroups.  Chronic dietary
(food + water) exposure estimates for dimethomorph are below the
Agency’s level of concern (LOC) for all population subgroups.  The
most highly exposed population subgroup is children 1 to 2 years old, at
20% of the cPAD.  The exposure estimate for the general US population is
9% of the cPAD.  In conducting this chronic dietary risk assessment, HED
made the following conservative assumptions:  

1. All commodities with dimethomorph tolerances contain residues of
dimethomorph, 

2. dimethomorph residues are at the level of the tolerance, and 

3. 100% of crops with dimethomorph tolerances are treated with
dimethomorph.  

This conservative treatment of the data results in an overestimate of
human dietary exposure.  Given the existing and proposed use patterns
for dimethomorph, as well as the health-protective assumptions
throughout this risk assessment, it is unlikely that any geographic,
ethnic or socioeconomic population will have increased exposure relative
to the standard population subgroups assessed by HED.  

	The chronic dietary risk assessment also serves as the long-term
aggregate risk assessment because, currently, there are no residential
uses for dimethomorph.  Short- and intermediate-term aggregate risk
assessments are not required.  

	HED has also assessed occupational exposures to dimethomorph.  These
assessments include scenarios for mixers, loaders, applicators and
flaggers, and for post-application exposure of workers arising from
scouting, harvesting, and other cultivation-related activities.  For all
of these scenarios, risk estimates are below HED’s LOC.  The 12-hour
re-entry interval (REI) mandated on the label is adequate.  

	HED is recommending in favor of the establishment of permanent
tolerances, as shown in Table 10 (and below).  HED also recommends in
favor of conditional registration of dimethomorph for the requested uses
of the 50% ai WP (Forum® Fungicide; EPA Registration #241-427), and the
4.17 lb ai/gal FlC (Acrobat® 50WP Fungicide; EPA Registration #241-410)
formulations of dimethomorph on lima beans, ginseng, grapes and turnip
tops, pending receipt and review of the data requested in Section 10. 
Prior to granting the registration or establishing new tolerances, HED
recommends that revisions to the proposed labels, and to the requested
tolerance levels, be completed.  These items are also described in
Section 10.  

		Tolerances to be listed under 40CFR §180.493[a]:

Ginseng 	0.90 ppm

Turnip, tops 	20.0 ppm

		Tolerances to be listed under 40CFR §180.493[c]:

Bean, lima, succulent 	0.60 ppm

Grape 	3.5 ppm

	Environmental Justice Considerations

	Potential areas of environmental justice concerns, to the extent
possible, were considered for this human health risk assessment, in
accordance with US Executive Order 12898, Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income Populations
(  HYPERLINK
"http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.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 USDA under the Continuing Survey of
Food Intakes 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 the associated risks for adult applicators, and
for toddlers, youths, and adults entering or playing on treated areas
post-application 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.  

	Review of Human Research

	This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  It has been determined that these studies (listed in Appendix
C), which comprise the Pesticide Handlers Exposure Database (PHED),
require a review of their ethical conduct.  They have received that
review, and have been determined to be appropriate (they were ethically
conducted) for use in human health risk assessments.  

2.0	Ingredient Profile tc \l2 "2.1	Summary of Registered/Proposed Uses 

	Dimethomorph is a systemic morpholine (Group 40) fungicide.  For use on
the requested crops, dimethomorph is formulated as either a 50% ai WP,
or as a 4.17 lb ai/gal FlC.  These end-use products (EPs) may be applied
by aerial, airblast or ground sprays, or via chemigation.  Up to five
foliar applications of the EPs, Acrobat® 50WP or Forum®, may be
applied at a rate of up to 0.20 lb ai/A at 7-day RTIs for a maximum
seasonal application rate of 1.0 lb ai/A with a 0-day PHI for lima beans
and turnip tops, a 14-day PHI for ginseng, and a 28-day PHI for grapes. 
The 12-hour REI that appears on the label is in compliance with the
Worker Protection Standard (WPS), based on dimethomorph's acute toxicity
ratings of category III for acute oral toxicity, and category IV for
acute dermal toxicity.  

	IR-4 included copies of an existing label, and an amended label for the
4.17 lb ai/gal FlC formulation (EPA Registration #241-427); the amended
label included use directions for succulent lima beans, ginseng, grapes
and turnip tops.  IR-4 also provided a description of the proposed uses
of the 50% ai WP formulation (EPA Registration #241-410) on succulent
lima beans, ginseng, grapes and turnip tops.  

2.1	Summary of Proposed Uses  TC \l2 "2.1  Summary of Proposed Uses 

	The proposed new use patterns are summarized in Table 2.1, below.  

Table 2.1	Summary of Directions for the Proposed Uses of Dimethomorph.

Use Timing; Type; Equipment	Formulation

[EPA Registration #]	Use Rate

(lb ai/A)	Max # of Uses per Season	Max Seasonal Use Rate

(lb ai/A)	PHI

(Days)	Use Directions and Limitations

Succulent Lima Beans

Post-emergence;

foliar; ground or aerial.	50% ai WP

[241-410]	0.20	5	1.0	0	Minimum RTI of 7 days.

Post-emergence;

inimum RTI of 7 days.  Ground applications to be made in ≥20 gal/A;
aerial applications to be made in ≥5 gal/A.

Ginseng

Post-emergence;

foliar; ground.	50% ai WP

[241-410]	0.20	5	1.0	14	Minimum RTI of 7 days.

Post-emergence;

foliar; ground.	4.17 lb ai/gal FlC [241-427]	0.20	5	1.0	14	Minimum RTI
of 7 days.  Applications to be made in ≥20 gal/A.

Grapes

Post-emergence;

foliar; ground or aerial.	50% ai WP

[241-410]	0.20	5	1.0	28	Minimum RTI of 7 days.

Post-emergence;

foliar; ground or aerial.	4.17 lb ai/gal FlC [241-427]	0.20	5	1.0	28
Minimum RTI of 7 days.  Use is restricted to grapes grown east of the
Rocky Mountains.  Applications to be made in ≥20 gal/A.

Turnip Tops

Post-emergence;

foliar; ground or aerial.	50% ai WP

[241-410]	0.20	5	1.0	0	Minimum RTI of 7 days.

Post-emergence;

foliar; ground or aerial.	4.17 lb ai/gal FlC [241-427]	0.20	5	1.0	0
Minimum RTI of 7 days.  Ground applications to be made in ≥20 gal/A;
aerial applications to be made in ≥5 gal/A.



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

	The chemical structure and nomenclature of dimethomorph are listed in
Table 2.2, below.  

Table 2.2	Dimethomorph Nomenclature.

Chemical structure	



Empirical formula	C21H22ClNO4

Molecular weight	387.86

Common name	  SEQ CHAPTER \h \r 1 Dimethomorph

Company experimental name	AC 336379

IUPAC name
(E,Z)-4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine

CAS name
4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morpholin
e

CAS registry number	110488-70-5

End-use product (EPs)	Acrobat 50WP; EPA Registration #241-410

Forum; EPA Registration #241-427



2.3	Physical and Chemical Properties  TC \l2 "2.3  Physical and Chemical
Properties 

	The physicochemical properties of technical grade dimethomorph are
listed in Table 2.3, below.  

Table 2.3	Physicochemical Properties of Dimethomorph.

Parameter	Value	Reference

Melting point/range (°C)	125-149; mixture of E and Z isomers.	D316328;
William Cutchin; 18 July 2005

pH	Not applicable; not soluble enough in water.

	Density (g/cm3 at 20ºC)	  SEQ CHAPTER \h \r 1 1.318 via the pycnometer
method.

	Water solubility (20ºC)	  SEQ CHAPTER \h \r 1 water, pH 5		19 mg/L

water, pH 7		18 mg/L

water, pH 9		16 mg/L

	Solvent solubility (20ºC)	  SEQ CHAPTER \h \r 1 n-hexane		0.11 mg/mL

methanol		39.0 mg/mL

toluene		49.5 mg/mL

acetone		100 mg/mL

dichloromethane		461 mg/mL

	Vapor pressure (Pa at 25ºC)	  SEQ CHAPTER \h \r 1 E-isomer:  9.7 x
10-7

Z-isomer:  1.0 x 10-6

	Dissociation constant (pKA)	Not determinable; the solubility of
dimethomorph is very low, and the ionized and non-ionized forms have
identical absorption coefficients.

	Octanol/water partition coefficient (Log [KOW] at 20ºC)	  SEQ CHAPTER
\h \r 1 E-isomer:  Kow = 430 (log Kow = 2.63)

Z-isomer:  Kow = 543 (log Kow = 2.73)

	UV/visible absorption spectrum	Not available.

	

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

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

	Table A.2.1 (in Appendix A) summarizes the acute toxicity of the
technical grade of dimethomorph.  As demonstrated, technical
dimethomorph is relatively non-toxic when administered acutely to
laboratory animals.  Table A.2.2 (in Appendix A) summarizes the
subchronic, chronic and other toxicity of the technical grade of
dimethomorph.  

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

Based on the proposed use pattern, the toxicology database for
dimethomorph is adequate for risk assessment.  The toxicity profile of
dimethomorph can be characterized for most effects, including potential
carcinogenic, mutagenic, developmental and neurotoxic effects.  The
doses and endpoints for use in human health risk assessments are
summarized in Table 3.5.11, below. As part of the new EPA guideline
requirements (40CFR §158), a 21/28 day dermal study is required to
eliminate the uncertainties associated with the use of an oral study and
dermal absorption factors.  Additionally, acute and subchronic
neurotoxicity studies, as well as an immunotoxicity study in rats and/or
mice are now required (see Appendix B).  The available data for
dimethomorph do not show evidence of immunotoxicity nor neurotoxicity,
and a developmental neurotoxicity study is not warranted at this time. 
HED does not believe that conducting immunotoxicity and neurotoxicity
studies will result in a NOAEL less than the NOAEL of 11 mg/kg/day
already set for dimethomorph.  Therefore, an additional 10x database
uncertainty factor (UFDB) is not needed to protect for potential
immunotoxic or neurotoxic effects.  

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

	Oral administration of dimethomorph results in rapid excretion into the
urine and feces of rats.  For all treatment protocols, most (80-90%) of
the radiolabel administered was excreted in the feces.  A considerably
smaller amount (6-16%) was excreted in the urine, and only minimal
levels (0.1-0.4%) were detected in the organs and tissues.  Rapid
absorption may be inferred by the rapid excretion of metabolites in the
urine and bile.  Saturation of absorption following single high doses
(500 mg/kg) was indicated by large amounts (roughly 50%) of
radioactivity in the feces being associated with parent compound.  For
low- or high-dose treatment, urinary excretion in female rats tended to
be greater (up to 2-fold in low-dose rats) than that of male rats. 
Retention of dimethomorph or [14C]-dimethomorph-derived radioactivity
was generally no more than 1% for most tissues, although the liver
exhibited slightly higher levels (1.4%).  Higher levels in the
gastrointestinal tract organs were caused by radioactivity in the
lumenal contents.  Urinary metabolites resulted from demethylation of
the dimethoxyphenyl ring, and oxidation of the morpholine ring.  Biliary
excretion exhibited first-order kinetics with a low-dose (10 mg/kg)
half-life of approximately 3 hours, and a high-dose (500 mg/kg)
half-life of 11 hours for males, and about 6 hours for females.  Biliary
metabolites accounted for most of the fecal excretion following low-dose
treatment.  The major biliary metabolites were glucuronides of one, and
possibly two, of the compounds produced by demethylation of the
dimethoxyphenyl ring.  

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

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

	The database is adequate to characterize potential pre- and/or
post-natal risk for infants and children.  Developmental toxicity
studies in rats and rabbits, and reproduction studies in rats were
available for FQPA assessment.  Based on the toxicity profile for
dimethomorph, a developmental neurotoxicity study in rats is not
required.  

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


	There are no Series 81-8 (acute, OPPTS Guideline 798.6050) nor 82-7
(subchronic, OPPTS Guideline 798.6200) neurotoxicity studies available. 
However, there was no evidence of neurotoxicity observed in the
submitted studies for dimethomorph.  

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies 

	In a developmental toxicity study in rats, reductions in body weight,
body weight gain, and food consumption were seen in maternal animals at
the LOAEL of 160 mg/kg/day (NOAEL = 60 mg/kg/day).  Increased
post-implantation loss was also seen at 160 mg/kg/day.  In a
developmental toxicity study in rabbits, increased incidence of abortion
was observed at the LOAEL of 650 mg/kg/day (NOAEL = 300 mg/kg/day).  No
effects were observed in pups at doses of up to 650 mg/kg/day.  

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study 

	In a multi-generation reproductive toxicity study, the P generation
animals were mated in a one-to-one ratio, and given the test material
for 15 weeks before they were mated.  Selection of the parents for the
F1 generation was made shortly after weaning on day 21 post-partum.  The
P1 animals were mated when they were approximately 21 weeks of age,
while the F1 generation was mated at about 15 weeks of age.  

	No clinical signs or necropsy findings which could be associated with
administration of the test material were noted at any dose level in
parental animals.  At 1000 ppm, P generation females weighed
consistently less than controls throughout the 15 week pre-mating period
(p<0.05).  Statistically significant reductions in food consumption were
also noted in 1000 ppm females during the pre-mating period.  In F1
females, body weights were slightly lower in all the dose groups but
differences were not statistically significant.  At the 1000 ppm level,
during several intervals of the pre-mating period, female weight gain
was reduced (p<0.05).  No effects were apparent in males of the P or F1
generations.  For parental systemic toxicity, the NOAEL was 300 ppm, and
the LOAEL was 1000 ppm, based upon decreased body weights and body
weight gains.  

	Reproductive indices were not affected by treatment at any dose level
or mating.  The percentage of pups with incisor eruption was noted at
the 1000 ppm dose level in the F1, F2a and F2b generations with
non-significant delays observed at the lower dose levels.  During the
second mating of the F1 generation to produce the F2b generation, a
large number of inseminated females failed to deliver.  This finding
appeared to occur in a dose-related manner at all dose levels but was
not apparent during other matings.  It should be noted that the prostate
gland was apparently affected by the test material in the dog chronic
feeding study, and the organ was not weighed in the chronic rat study. 
No organ weight data were presented for the prostate gland in this
reproduction study but no dose-related histopathology data were apparent
in this study.  For reproductive toxicity, the NOAEL was 300 ppm, and
the LOAEL was 1000 ppm, based upon decreased incisor eruption on day 10
postpartum.  

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

	There is no additional information available from the literature to
influence FQPA safety findings.  

3.3.6	Pre- and/or Post-Natal Toxicity  TC \l3 "3.3.6	Pre-and/or
Postnatal Toxicity 

3.3.6.1	Determination of Susceptibility  TC \l4 "3.3.6.1	Determination
of Susceptibility 

	The data available do not provide evidence of any increased
susceptibility in the offspring in either of the two developmental
toxicity studies, nor in the two-generation reproduction study.  In none
of these studies was any toxicity seen in the offspring which occurred
at doses lower than in the parents.  

3.3.6.2	Degree of Concern Analysis, and Residual Uncertainties  TC \l4
"3.3.6.2	Degree of Concern Analysis and Residual Uncertainties  for Pre-
and/or Post-Natal Susceptibility

	The purposes of the Degree of Concern analysis are to determine the
level of concern for the effects observed (when considered in the
context of all available toxicity data), and to identify any residual
uncertainties (after establishing toxicity endpoints, and traditional
uncertainty factors to be used in the risk assessment).  If residual
uncertainties are identified, then HED determines whether these residual
uncertainties can be addressed by an FQPA safety factor, and if so, the
size of the safety factor needed.  

	There are no residual uncertainties with regard to pre- and/or
post-natal toxicity following in utero exposure to rats or rabbits, and
pre and/or post-natal exposures to rats.  Therefore, it is recommended
that the FQPA safety factor be reduced to 1x; no additional safety
factors are needed (see Section 3.4, below).  

3.3.7	Recommendation for a Developmental Neurotoxicity Study  TC \l3
"3.3.7	Recommendation for a Developmental Neurotoxicity Study 

	None of the submitted studies indicate that dimethomorph is a
neurotoxic chemical.  Neither the subchronic nor chronic toxicity
studies in rats or dogs, nor the developmental toxicity studies
indicated that the nervous system was affected by treatment with
dimethomorph.  There is no indication that dimethomorph is a neurotoxic
chemical, and there are no residual uncertainties regarding pre- and/or
post-natal toxicity following dimethomorph exposure.  Therefore, a
developmental neurotoxicity study is not required, and there is no need
for additional uncertainty factors.  

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

	Initially (4 May 1998), HED determined that a safety factor was
necessary, based on the lack of environmental fate data required for the
drinking water exposure assessment of dimethomorph.  However, EFED
assured HED that, even assuming the worst possible model input
parameters for dimethomorph, risk levels for drinking water exposure are
not of concern.  Considering this inormation, on 8 June 1998, HED
recommended that the 10x Safety Factor be removed.  

	Additionally:  

1. The developmental and reproductive toxicity data did not indicate
increased susceptibility of rats or rabbits to in utero and/or
post-natal exposure to dimethomorph, 

2. there is no evidence of neurotoxicity, 

3. the dietary (food only) exposure assessment did not indicate a
concern for potential risk to infants and children, even though
unrefined field study data are used, resulting in an overestimate of
dietary exposure, and 

4. there are currently no registered residential uses for dimethomorph. 


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

3.5.1	Acute Reference Dose (aRfD) - Females Age 13-49

	No appropriate endpoint was identified.  

	Comments about Study/Endpoint/Uncertainty Factors:  TC \l3 "3.5.1	Acute
Reference Dose (aRfD) - Females age 13-49   The developmental toxicity
NOAEL of 60 mg/kg/day from a developmental toxicity study in rats, based
on post-implantation loss at 160 mg/kg/day, was considered for
establishing the acute RfD (females 13-49).  However, it was determined
that this endpoint was not appropriate for use in this risk assessment,
since the effect at the high dose was minimal, and was not supported by
a decrement in litter size (12.4 fetuses per dam in the control,
compared to 11.3 fetuses per dam at the high dose).  The maternal
effects (decreased body weight gain and food consumption) were not
considered to be attributable to a single exposure, and thus not
appropriate for this risk assessment.  No appropriate toxicological
endpoints attributable to a single exposure were identified in other
oral studies.  Consequently, it was determined that there was no basis
for selecting a dose and endpoint for an acute RfD.  

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

	No appropriate endpoint was identified.  

	Comments about Study/Endpoint/Uncertainty Factors:  TC \l3 "3.5.1	Acute
Reference Dose (aRfD) - Females age 13-49   No appropriate toxicological
endpoints attributable to a single exposure were identified in oral
studies.  Consequently, there was no basis for selecting a dose and
endpoint for an acute RfD.  An acute dietary risk assessment is not
required for any segment of the US population, including infants and
children.  

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

	Studies Selected:  Chronic Toxicity - Rat/Carcinogenicity - Rat

	MRID Numbers:  42233912 and 42233916		

	Dose and Endpoint for Risk Assessment:  NOAEL= 11 mg/kg/day 

	Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Chronic RfD = 11 mg/kg/day (NOAEL) = 0.1 mg/kg/day

				     100 (UF)





	Comments about Study/Endpoint/Uncertainty Factors:  The data evaluation
records (DERs) for the rat chronic, and rat carcinogenicity studies
(MRIDs #42233912 and #42233916) established comparable NOAELs (11.9
versus 11.3 mg/kg/day) and endpoints of increased incidences of
pigmented or hypertrophied hepatocytes, and “ground glass” foci in
livers of female rats.  Females appeared to be more sensitive in these
studies.  

	Dose and Endpoint for Establishing the RfD : NOAEL= 11 mg/kg/day based
on decreased body weight and statistically significant increases in
liver lesions in female rats at 46.3 mg/kg/day (LOAEL).  

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

	There are no residential uses for dimethomorph, so a toxicity endpoint
for incidental oral exposure is not necessary.  

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

	The total amount of dimethomorph absorbed (expressed as a percent of
the [14C]-dose) by rats at various times following dermal administration
of [14C]-dimethomorph at 7.73 (0.15 mg/cm2) or 79.62 mg/kg (1.58 mg/cm2)
is less than 5% of the dose, and it appears that the absorption is
concentration dependent.  Dermal absorption was 0.05%, 0.07% and 0.27%
of the administered dose in rats 4, 8 and 24 hours after dermal
treatment at 7.73 mg/kg, respectively.  Dermal absorption was 0.02%,
0.16% and 0.12% of the dose 4, 8 and 24 hours after dermal treatment at
79.62 mg/kg, respectively.  Dermal absorption was approximately 0.4 and
1 mg/kg in terms of weight equivalent at 7.73 and 79.62 mg/kg,
respectively.  Six days after dermal treatment, the percent total
absorption of the dose at 7.73 and 79.62 mg/kg was 4.76 and 1.20%,
respectively.  Mean percent recovery of 14C for dose levels of 7.73 and
79.62 mg/kg was 104.1% and 92.1%, respectively.  Majority of the
radioactivity was found in skin swabs and gauze wash (80.9 to 81.8%). 
The percent of the dose in the skin decreased with dose, being 17.5 % at
7.73 mg/kg, and 9.99% at 79.62 mg/kg.  

	The dermal absorption coefficient factor is 5%.  

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

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

	Study Selected:  Developmental Toxicity - Rat

	MRID Numbers:  42233919 and 44175302		

	Dose and Endpoint for Risk Assessment:  NOAEL= 60 mg/kg/day 

	Uncertainty Factor:  100x (10x interspecies extrapolation, 10x
intraspecies variability)

	Comments about Study/Endpoint/Uncertainty Factors:  No dermal toxicity
studies are available.  The maternal toxicity NOAEL is 60 mg/kg/day,
based on decreased body weight, decreased body weight gain, and
decreased food consumption at 160 mg/kg/day (LOAEL) in an oral
developmental toxicity study.  The effects seen in the dams during
gestation days 10-15 (after 4-5 dosings) are appropriate to use for
short-term exposure periods (1-30 days).  Since an oral NOAEL was
selected, a dermal absorption factor of 5% should be used in calculating
the risk from dermal exposure.  

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

	Study Selected:  Subchronic Toxicity - Dog

	MRID Number:  422339081		

	Dose and Endpoint for Risk Assessment:  NOAEL= 15 mg/kg/day 

	Uncertainty Factor:  100x (10x interspecies extrapolation, 10x
intraspecies variability)

	Comments about Study/Endpoint/Uncertainty Factors:  The NOAEL is 15
mg/kg/day, based on decreased absolute and relative prostate weight, and
possible threshold liver effects at the LOAEL of 43 mg/kg/day in a
subchronic oral feeding study in dogs.  A subchronic feeding study was
selected, so a dermal absorption factor of 5% should be chosen from the
dermal penetration study in performing intermediate-term (30 days to 6
months) risk assessments.  

	The current use pattern does not indicate a concern for long-term
exposure/risk, and no long-term uses are proposed.  

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

	There are no inhalation studies, except for the acute toxicity study
(MRID #43917246).  Therefore, the oral NOAELs described above for dermal
risk assessment were selected for short-and intermediate-term inhalation
risk assessments.  The use pattern does not indicate a concern for
long-term exposure/risk.  Since oral NOAELs were selected, appropriate
route-to-route extrapolation should be followed, as shown below:  

Step 1.	The inhalation exposure component (μg ai/day) using 100%
absorption rate should be converted to an equivalent oral dose
(mg/kg/day).  

Step 2.	The dermal exposure component (mg/kg/day) using a 100% dermal
absorption rate should be converted to an equivalent oral dose.  This
dose should then be combined with the oral dose in Step 1.  

Step 3. The combined dose from Step 2 should then be compared to the
oral NOAEL of 60 mg/kg/day for short-term, and 15 mg/kg/day for
intermediate-term risk assessments.  

3.5.8	Level of Concern (LOC) for Margin of Exposure  TC \l3 "3.5.8	Level
of Concern for Margin of Exposure  (MOE)

	Target MOEs are 100 for occupational dermal (short- and
intermediate-term) and inhalation (short- and intermediate-term)
exposures.  

Table 3.5.8	Summary of LOCs for Dimethomorph Risk Assessment.

Route of Exposure	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(>6 Months)

Occupational (Worker) Exposure

Dermal	100	100	NA*

Inhalation	100	100	NA

Residential Exposure

Dermal	NA	NA	NA

Inhalation	NA	NA	NA

Incidental Oral	NA	NA	NA

* NA = Not Applicable.  

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

	There are currently no registered residential uses, nor are any
proposed.  Therefore, at this time, dietary (food + water) exposure is
the only component of an aggregate exposure analysis and risk
assessment.  

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

	In a carcinogenicity study in rat, there was no evidence of increased
incidence of any neoplasms at the doses tested.  The chemical was tested
at adequate dosage, based on the high incidence of arteritis in males,
and the pronounced decrease in body weight in females at the mid- and
high-dose levels.  

	In a carcinogenicity study in mice, there was no dose-related decrease
in survival, or in any parameter examined on necropsy.  The LOAEL for
systemic toxicity was 1000 mg/kg/day, based on decreased body weight
gain in males.  The NOAEL was 100 mg/kg/day.  There was no evidence of
carcinogenicity.  The high dose tested (1000 mg/kg/day), while probably
not the maximum tolerated dose, especially in females, is the maximum
dose required by the test guidelines for a dietary oncogenicity study.  

	Dimethomorph has been classified as “not likely” to be a human
carcinogen.  

3.5.11	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments  TC \l3 "3.5.11	Summary of Toxicological Doses and
Endpoints for Use in Human Risk Assessments 

	The toxicity endpoints pertinent to an assessment of risk for
dimethomorph are summarized in Table 3.5.11, below.  

   Table Table 3.5.11	Summary of Toxicological Doses and Endpoints for
for Use in Dimethomorph Human 		Health Risk Assessments.

Exposure

Scenario	Point of Departure, Uncertainty/FQPA Safety Factors	LOC for
Risk Assessment	Study and Toxicological Effects

Acute Dietary

(Females 13-49)	No endpoint attributable to a single dose was
identified.	Not applicable.	No study selected.

Acute Dietary

(General Population)	No endpoint attributable to a single dose was
identified.	Not applicable.	No study selected.

Chronic Dietary

(All Populations)	NOAEL = 11 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1

UF = 100	cPAD = 

NOAEL ÷ UF = 0.1 mg/kg/day	Carcinogenicity study in rats.  LOAEL = 46.3
mg/kg/day, based on decreased body weight and increases in liver lesions
in female rats.

Dermal Short-Term

(1-30 Days)	Oral study NOAEL= 

60 mg/kg/day

(dermal absorption factor = 5%)	LOC for MOE <100 	Developmental toxicity
study in rats.  LOAEL = 160 mg/kg/day based on decreased body weight,
body weight gain, and food consumption.

Dermal Intermediate-Term (1-6 Months)	Oral study NOAEL= 

15 mg/kg/day

(dermal absorption factor = 5%)	LOC for MOE <100	Subchronic feeding
study in dogs.  LOAEL = 43 mg/kg/day based on decreased absolute and
relative prostate weight, and possible threshold liver effects.

Dermal Long-Term

(>6 Months)	No long-term exposure or risk.	Not applicable.	No study
selected.

Inhalation Short-Term

(1-30 Days)	Oral study NOAEL= 

60 mg/kg/day

(inhalation absorption factor = 100%)	LOC for MOE <100	Developmental
toxicity study in rats.  LOAEL = 160 mg/kg/day based on decreased body
weight, body weight gain, and food consumption.

Inhalation Intermediate-Term

(1-6 Months)	Oral study NOAEL= 

15 mg/kg/day

(inhalation absorption factor = 100%)	LOC for MOE <100	Subchronic
feeding study in dogs.  LOAEL = 43 mg/kg/day based on decreased absolute
and relative prostate weight, and possible threshold liver effects.

Inhalation Long-Term

(>6 Months)	No long-term exposure or risk.	Not applicable.	No study
selected.

Cancer (Oral, Dermal, Inhalation)	Classification: This chemical is
classified as “not likely” to be a human carcinogen.

Point of Departure (POD) = data point or estimated point, derived from
observed dose-response data, and used to mark the beginning of
extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  MOE = margin of exposure.  LOC
= level of concern.  

3.6	Endocrine disruption  TC \l2 "3.6	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 Screening 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 to 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, dimethomorph
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.  

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

4.1	Incident Reports  TC \l2 "4.1	Incident Reports 

	A review of the Incident Data System (1992 to August, 2005), California
(1982-2003), NIOSH state data (1998-2003), and the scientific literature
did not report any dimethomorph incidents.  

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

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

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

	No new plant metabolism studies were submitted.  Grape and potato
(D192776; Donna Davis; 13 March 1995, and D219530; Donna Davis; 31
October 1995), and lettuce (D237101; Yan Donovan; 4 May 2000) metabolism
studies have previously been submitted and reviewed.  In all three
studies, parent dimethomorph was the predominant residue.  No
metabolites were identified that require regulation.  For purposes of
this petition, the ROC, for tolerance setting and risk assessment
purposes, is considered to be the parent compound, dimethomorph
(comprised of E and Z isomers).  

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

	A study on dimethomorph in confined rotational crops was previously
submitted and reviewed (D251605, D252556; Douglas Dotson; 19 July 2000).
 As a result, the labeling contains rotational crop guidelines
indicating plant-back intervals (PBIs) ranging from “any time” to 12
months, depending on the crop to be rotated.  HED concluded that the ROC
in rotational crops is dimethomorph per se.  

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock 

	Based on the results of metabolism studies in ruminants and poultry,
and a cattle feeding study, tolerances are not required for residues in
meat, milk, poultry nor eggs as a result of ingestion of dimethomorph
residues in the rotational cereal grains (D251605, D252556; Douglas
Dotson; 19 July 2000).  Furthermore, there are no significant livestock
feedstuffs associated with the proposed uses on lima beans, ginseng,
grapes and turnip tops.  Therefore, a discussion of the nature of the
residues of dimethomorph in livestock is not germane to this action.  

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

	Enforcement method:  The HPLC/UV method, FAMS 002-04, has been
determined to be adequate for tolerance-enforcement purposes in
determining residues of dimethomorph per se.  Briefly, homogenized
samples are extracted with acetone, and the extract is mixed with sodium
chloride solution, and then partitioned with dichloromethane (DCM).  The
DCM phase is evaporated to dryness, and the residue is re-dissolved in
methanol for cleanup by gel permeation chromatography.  The extract is
then cleaned up on a silica gel column, using acetone/n-hexane (1:4,
v:v) to elute residues.  The eluate is evaporated to dryness, and
residue is re-dissolved in methanol for HPLC/UV analysis.  The reported
LOQs range from 0.010 to 0.050 ppm, depending on the sample matrix.  The
method has been successfully validated by BEAD’s Analytical Chemistry
Branch (ACB).  

	A confirmatory method is also available, Method M 2577, a
gas-chromatography method with nitrogen/phosphorus detection (GC/NPD).  

	Data collection methods:  Crop samples from the submitted lima bean and
ginseng field trial studies were analyzed for residues of dimethomorph
using GC with detection via mass spectrometry (GC/MS).  Briefly, samples
were extracted with acetone, and the extract was partitioned twice with
saturated sodium chloride solution and DCM.  The DCM phase was
evaporated to dryness, the residue was re-dissolved in acetonitrile
(ACN) and hexane, and the ACN phase was then evaporated to dryness and
the residue re-dissolved in DCM (ginseng), or 40% ethyl acetate in
hexane (lima beans).  The extract was cleaned up by solid phase
extraction (Florisil or silica gel column).  The eluate was concentrated
to dryness, and the residue was reconstituted in 0.1% corn oil in ethyl
acetate (ginseng), or 1% corn oil in acetone (lima beans) for GC/MS
analysis.  The lowest level of method validation (LLMV) was 0.050 ppm in
ginseng, and 0.010 ppm in lima beans.  

	The methods were adequately validated prior to, and in conjunction
with, analysis of the field trial samples.  Acceptable recoveries were
obtained from untreated ginseng samples fortified with dimethomorph at
0.050-5.0 ppm, and untreated lima bean samples fortified at 0.010-1.0
ppm.  The fortification levels used in method verification and
concurrent method recovery were adequate to bracket expected residue
levels in lima beans and ginseng.  

	Conclusions:  The GC/MS methods are adequate for collecting data on
residues of dimethomorph in lima beans and ginseng.  

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

	The ROC in drinking water is dimethomorph per se.  Based upon
information contained in EFED’s DWA (D349254; Jose Luis Melendez; 3
September 2008), dimethomorph is not expected to be affected by abiotic
degradation processes, such as hydrolysis and photolysis, in soil or
under aquatic conditions.  Biotic transformation appears to be the major
route of dissipation in the environment.  Dimethomorph was moderately
persistent in an aerobic soil (half-life = 117 days).  There are strong
indications that significantly more rapid dissipation may occur under
anaerobic conditions in soil and aquatic systems.  At this time,
deficiencies in the studies submitted prevent the reporting of
determined rates of dissipation in these important systems.  

	Laboratory studies on mobility of dimethomorph indicated low to medium
mobility in soil systems, in accordance with McCall et al (1981).  The
results of the field dissipation study appear to confirm the low to
medium mobility inferred from laboratory studies.  However, episodes of
high rainfall were shown to increase downward mobility in the field soil
profile.  

5.1.6	Metabolic Profile in Rats

	Oral administration of dimethomorph (10 mg/kg single dose; 10 mg/kg
14-day repeated dose; 10 mg/kg 7-day repeated dose; 500 mg/kg single
dose) results in rapid excretion into the urine and feces of rats.  For
all treatment protocols, most (80-90%) of the radiolabel administered
was excreted in the feces.  A considerably smaller amount (6-16%) was
excreted in the urine, and only minimal levels (0.1-0.4%) were detected
in the organs and tissues.  Rapid absorption may be inferred by the
rapid excretion of metabolites in the urine and bile.  Saturation of
absorption following single high doses (500 mg/kg) was indicated by
large amounts ((50%) of radioactivity in the feces being associated with
parent compound.  For low- and high-dose treatments, urinary excretion
in female rats tended to be up to 2-fold greater (in low-dose rats) than
that of males.  Retention of dimethomorph or [14C]-dimethomorph-derived
radioactivity was generally (1% for most tissues, although the liver
exhibited slightly higher levels (1.4%), and higher levels in the
gastrointestinal tract organs was owing to radioactivity in the lumenal
contents.  Urinary metabolites resulted from demethylation of the
dimethoxyphenyl ring, and oxidation of the morpholine ring.  Biliary
excretion exhibited first-order kinetics, with a low-dose half-life of
approximately 3 hours, and a high-dose half-life of 11 hours for males,
and about 6 hours for females.  Biliary metabolites accounted for most
of the fecal excretion following low-dose treatment.  The major biliary
metabolites were glucuronides of one, and possibly two, of the compounds
produced by demethylation of the dimethoxyphenyl ring.  

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates 

	As described above, in Sections 5.1.1, 5.1.2 and 5.1.5, the parent
compound dimethomorph is the only compound of toxicological interest in
primary crops, rotational crops, and drinking water.  

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

Table 5.1.8	Summary of Metabolites and Degradates to Be Included in Risk
Assessment and 	Tolerance Expression

Matrix	Residues Included in Risk Assessment	Residues Included in
Tolerance Expression

Plants	Primary crops	Dimethomorph per se	Dimethomorph per se

	Rotational crops



Livestock	Ruminants	NA*	NA

	Poultry



Drinking water	Dimethomorph per se	NA

* NA = Not Applicable.  

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

	The Agency lacks sufficient monitoring exposure data to complete a
comprehensive dietary exposure analysis and risk assessment for
dimethomorph in drinking water.  Because the Agency does not have
comprehensive monitoring data, drinking water concentration estimates
are made by reliance on simulation or modeling, taking into account data
on the physical characteristics of dimethomorph.  

	A revised DWA conducted by EFED for the proposed uses on lima beans,
ginseng, grapes and turnip tops (D349254; Jose Luis Melendez; 3
September 2008) recommended a groundwater value of 0.264 ppb, and a
surface water value of 24.7 ppb, for use in chronic risk assessments,
based on dimethomorph applications to broccoli (D328740; Jose Luis
Melendez; 26 April 2006).  For the proposed crop applications, the
chronic EDWC in ground water was 0.264 ppb, from Tier 1 SCI-GROW
modeling.  The chronic EDWC in surface water, from Tier 1 FIRST
modeling, was 24.7 ppb.  Another EDWC in surface water was estimated in
a previous DWA, based on the use of dimethomorph on hops (which appears
to represent the worst case scenario), from Tier 1 GENEEC modeling. 
This model simulates the transport of a pesticide off of an agricultural
field.  In this case, EFED calculated a Tier 1 chronic (56-day average
with 3X factor) EDWC of 28.5 ppb for dimethomorph (D278860; Jose Luis
Melendez; 8 August 2002).  The 28.5 ppb EDWC was used in the current
chronic dietary risk assessment to ensure safety under the most
conservative water exposure scenario.  

Table 5.1.9	Summary of EDWCs, Based on Aerial Application of
Dimethomorph.

Drinking Water Source [Model Used]	Crop Use [Rate Modeled]	EDWC (ppb)

Groundwater [SCI-GROW]	Broccoli  [1.4 lb ai/A]	Acute and Chronic	0.264

Surface Water [FIRST]	Broccoli  [1.4 lb ai/A]	Acute	81.1

	Broccoli  [1.4 lb ai/A]	Chronic	24.7

Surface Water [GENEEC]	Hops [1.2 lb ai/A]	Chronic	28.5*

* This EDWC was used in the current chronic dietary risk assessment.

	The GENEEC model was used to estimate concentrations that might occur
in vulnerable surface waters.  GENEEC is a screening model designed by
EFED to estimate the concentrations found in vulnerable surface waters
(a pond adjacent to fields treated with the pesticide in question). 
Spray drift over the pond is assumed to be 5% of an aerial application,
or 1% of a ground application.  The model is based on a single runoff
event 2 days after the last pesticide application.  If there are
multiple applications, spray drift from each application is included in
the simulation.  It is assumed the runoff event moves a maximum of 10%
of the applied pesticide into the pond.  This maximum is often
approached for highly persistent and mobile pesticides.  

	The FIRST screening model is designed to estimate the concentrations
found in drinking water from surface water sources.  As such, it
provides upper bound values on the concentrations that might be found in
drinking water due to the use of a pesticide.  FIRST is a single event
model (one runoff event), but can account for spray drift from multiple
applications.  Spray drift (resulting in direct deposition of the
pesticide into the reservoir) is assumed to be 16% of the applied ai for
aerial application, 6.3% for orchard air blast application, and 6.4% for
other ground spray application.  FIRST is hardwired to represent the
Index Reservoir, a standard water body used by OPP to assess drinking
water exposure (2002).  It is based on a real reservoir (albeit not
currently in active use as a drinking water supply), Shipman City Lake
in Illinois, that is known to be vulnerable to pesticide contamination. 
The single runoff event moves a maximum of 8% of the applied pesticide
into the reservoir.  This amount can be reduced, owing to degradation on
the field, and the effects of binding to soil in the field.  FIRST also
uses a Percent Cropped Area (PCA) factor to adjust for the area within
the watershed that is planted to the modeled crop.  The default
agricultural PCA is 0.87.  

	The SCI-GROW model was used to estimate concentrations that might occur
in vulnerable ground waters.  This model is based on maximum groundwater
concentrations from studies conducted at sites and under conditions
which are most likely to result in groundwater contamination.  The
groundwater concentrations generated by SCI-GROW are based on the
largest 90-day average concentration recorded during the sampling
period.  There may be circumstances under which groundwater
concentrations could exceed the SCI-GROW estimates.  

	None of these models include consideration of the impact that
processing (mixing, dilution or treatment) of raw water for distribution
as drinking water would likely have on the removal of pesticides from
the source water.  

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

	Crop samples from the submitted lima bean and ginseng field trial
studies were analyzed for residues of dimethomorph using GC/MS methods
(D349735; Anant Parmar; 21 October 2008).  The LLMV was 0.050 ppm in
ginseng, and 0.010 ppm in lima beans.  The methods were adequately
validated prior to, and in conjunction with, analysis of the field trial
samples.  Acceptable recoveries were obtained from untreated ginseng
samples fortified with dimethomorph at 0.050-5.0 ppm, and untreated lima
bean samples fortified at 0.010-1.0 ppm.  The fortification levels used
in method verification and concurrent method recovery were adequate to
bracket expected residue levels in lima beans and ginseng.  The GC/MS
methods are adequate for collecting data on residues of dimethomorph in
lima beans and ginseng.  

	Succulent lima beans:  Seven lima bean field trials were conducted in
Zones 2 (GA, MD, NJ; 6 trials) and 5 (WI; 1 trial) during the 2002 and
2003 growing seasons.  At each trial, seven foliar applications of the
50% ai WP formulation of dimethomorph were made at a target rate of 0.20
lb ai/A per application (1x the proposed maximum single application
rate), with 6- to 8-day RTIs, for total use rates of 1.41-1.43 lb ai/A
(roughly 1.4x the proposed maximum seasonal rate).  Applications were
made as foliar directed sprays at five of the sites, and as foliar
broadcast sprays at two of the sites.  At one GA trial, a total of eight
applications were made, owing to delayed crop maturity, yielding a total
application rate of 1.63 lb ai/A (1.6x the proposed maximum seasonal
rate).  In addition, at one MD trial, there was one 5-day RTI, and at
the other MD trial, there was one 11-day RTI.  Applications were made
using ground equipment, in 30-52 gallons per acre (GPA) spray volumes,
without an adjuvant.  Samples of mature lima beans (succulent seeds
without pod) were harvested on the day of the last application. 
Additional samples were collected from one trial site at 3, 5 and 11
days after the last application to evaluate residue decline.  Adequate
concurrent storage stability data were submitted to support sample
storage durations and conditions.  

	Maximum residues of dimethomorph were 0.48 ppm, and mean residues were
0.13 ppm, in succulent lima bean seeds (without pod) harvested on the
day of the last of 7-8 applications at total rates of 1.41-1.63 lb ai/A.
 It was noted that residues in samples from the trial in which 8
applications were made were low (0.03 ppm).  The residue decline data
indicate that residues of dimethomorph in lima beans decrease with
increasing sampling intervals.  

	Conclusions (succulent lima beans):  Provided the petitioner restricts
the proposed use to areas east of the Rocky Mountains, the submitted
lima bean field trial data are adequate.  The number and locations of
the field trials are not in accordance with OPPTS 860.1500 for lima
beans.  However, the petitioner has stated that the field trial data are
intended to support use on lima beans grown east of the Rocky Mountains.
 The number and location of the lima bean trials are adequate to support
use in areas east of the Rocky Mountains.  Although the trials reflected
both foliar directed and foliar broadcast applications, the petitioner
is proposing that dimethomorph applications be made to lima beans as
broadcast foliar applications.  

	Although the field trial data for lima beans represent seasonal rates
roughly 40-60% higher than the maximum proposed seasonal rate, the data
are acceptable to support the proposed use because the single
application rate used in the lima bean field trials was 1x the proposed
maximum single application rate.  

	No field trial data were submitted to support use of the 4.17 lb ai/gal
FlC formulation of dimethomorph on succulent lima beans.  On an interim
basis, for the purposes of a conditional registration, HED considers
this use to be supported by the European grape field trials.  These
trials compared residue levels arising from the application of various
formulations of dimethomorph to grapes.  The trials demonstrated that
residues on grape were comparable between the WP and FlC formulations.  

	To support this use, results of at least two side-by-side field trials
should be submitted, comparing residues from use of the WP and FlC
formulations, with succulent lima beans.  These side-by-side trials
should reflect application of the 4.17 lb ai/gal FlC formulation at 1x
the proposed maximum seasonal rate.  Lima beans should also be harvested
at the proposed PHI.  If these trials demonstrate that the two different
formulations do not result in comparable residues, then all commodities
lacking adequate residue data on the 4.17 lb ai/gal FlC formulation
could require a full complement of field trials.  

	The data support a tolerance, with regional registration, for residues
of dimethomorph in lima beans (succulent seed without pod) at 0.60 ppm. 
Because no field trial data for dry lima beans were submitted, use on
lima beans should be restricted to those varieties intended for harvest
as succulent seed.  

	Ginseng:  Four ginseng field trials were conducted in Zone 5 (MI and
WI) during the 2004 growing season.  At each trial, seven applications
of the 50% ai WP formulation of dimethomorph were made at a target rate
of 0.20 lb ai/A per application (1x the proposed maximum single
application rate) with 6- to 9-day RTIs.  At the three WI trials, foliar
broadcast applications were made using ground equipment in 159-202 GPA
spray volumes, without an adjuvant, for total rates of 1.40-1.44 lb ai/A
(roughly 1.4x the proposed maximum seasonal rate).  At the MI trial,
drip irrigation (chemigation) applications were made in 115 GPA volumes
without an adjuvant, for a total rate of 1.68 lb ai/A (roughly 1.7x the
proposed maximum seasonal rate).  The petitioner noted that individual
applications at the MI site were over-applied by approximately 20%. 
Samples of ginseng root were harvested 13-15 days after the last
application.  Adequate concurrent storage stability data were submitted
to support sample storage durations and conditions.  

	Maximum residues of dimethomorph were 0.62 ppm, and mean residues were
0.61 ppm,  in ginseng root harvested 14 days following the last of seven
drip irrigation (chemigation) applications of the 50% ai WP formulation
at a total rate of 1.68 lb ai/A.  

	Maximum residues of dimethomorph were 0.43 ppm, and mean residues were
0.33 ppm,  in ginseng root harvested 13-15 days following the last of
seven foliar broadcast applications of the 50% ai WP formulation at
total rates of 1.40-1.44 lb ai/A.  

	Conclusions (ginseng):  The submitted ginseng field trial data are
adequate.  The number and locations of the field trials are in
accordance with OPPTS 860.1500 for ginseng.  Although the field trial
data represent application rates roughly 40-70% higher than the maximum
proposed seasonal rate, the data are acceptable to support the proposed
use on ginseng because the single application rate used in the ginseng
field trials was 1x the proposed maximum single application rate.  

	No field trial data were submitted to support use of the 4.17 lb ai/gal
FlC formulation of dimethomorph on ginseng.  On an interim basis, for
the purposes of a conditional registration, HED considers this use to be
supported by the European grape field trials.  These trials compared
residue levels arising from the application of various formulations of
dimethomorph to grapes.  The trials demonstrated that residues on grape
were comparable between the WP and FlC formulations.  

	To support this use, results of at least two side-by-side field trials
should be submitted, comparing residues from use of the WP and FlC
formulations, with both succulent lima beans and turnip tops.  These
side-by-side trials should reflect application of the 4.17 lb ai/gal FlC
formulation at 1x the proposed maximum seasonal rate.  Lima beans and
turnip tops should also be harvested at the proposed PHIs.  If these
trials demonstrate that the two different formulations result in
comparable residues, then side-by-side trials in ginseng will not be
required.  Otherwise, all commodities lacking adequate residue data on
the 4.17 lb ai/gal FlC formulation could require a full complement of
field trials.  

	The data support a tolerance for residues of dimethomorph in ginseng at
0.90 ppm.  

	Grapes:  No new grape field trial data were submitted.  To support the
proposed use of dimethomorph on grapes in the US, IR-4 is relying on
European field trial data submitted to establish the current tolerance
for dimethomorph residues in imported grapes (PP#2E4054 and PP#7F4816). 
ChemSAC considered this request (see minutes of the 12 July 2006
meeting), and concluded that, because the available European data were
conducted in multiple countries and/or multiple years, the residue data
could be used to support application of dimethomorph to grapes grown
east of the Rocky Mountains, provided that the petitioner addresses the
following issues:  

1. Differences in formulation and inert ingredients between the
formulations used in the European trials, and those proposed for use in
the US, 

2. the US PHI and RTI should match those of the European trials, and 

3. the maximum US application rate should be equal to, or less than, the
maximum rate used in the European trials.  

	IR-4 is proposing the 50% ai WP and 4.17 lb ai/gal FlC formulations of
dimethomorph for up to five applications to grapes grown east of the
Rocky Mountains at 0.20 lb ai/A per application, for a maximum seasonal
rate of 1.0 lb ai/A, with a 7-day minimum RTI, and a 28-day PHI.  

	IR-4 has submitted (in Section G of the petition) summaries of the
European grape field trial data, reviewed in conjunction with PP#2E4054
and PP#7F4816 for imported grapes, as well as a description of the
products used in the field trials.  Based on the product summary
provided by IR-4, and the field trial residue summaries included in the
submission, six different products were used in the European field
trials:  9%, 10% and 50% ai WP formulations (two of which also contained
mancozeb), a 53 g ai/L oil-enhanced suspension concentrate formulation,
a 150 g ai/L dispersible concentrate (DC) formulation, and a 600 g ai/L
FlC formulation.  Information pertaining to inerts was provided for
three of the products (the 9% ai WP, 150 g ai/L DC, and 600 g ai/L FlC
formulations).  IR-4 stated that a 500 g ai/L FlC formulation equivalent
to the 4.17 lb ai/gal FlC formulation (proposed for use on grapes in the
US) was also used in the European field trials.  However, none of the
data submitted previously reflect application of this product, and no
summary data were submitted for field trials in which this product was
used.  

	A summary of the previously submitted grape residue data follows.

	Ten tests were conducted between 1988 and 1990 in various regions of
France.  The 10% or 50% ai WP formulation was foliarly applied to grape
plants 3-9 times, with 9- to 17-day RTIs, at 0.16-0.20 lb ai/A per
application, for total rates of 0.48-1.81 lb ai/A (0.5-1.8x the maximum
proposed seasonal rate in the current petition).  The 53 g ai/L
oil-enhanced suspension concentrate formulation, or 150 g ai/L DC
formulation, was foliarly applied to grape plants 4-11 times, with 9- to
17-day RTIs, at 0.18-0.27 lb ai/A per application, for total rates of
0.72-2.94 lb ai/A (0.7-2.9x).  Grapes were harvested 0-90 days following
the final application.  HED concluded that calculating the theoretical
residue values by prorating the application rates to 1x yielded residue
values well below 1.0 ppm, even when PHIs of 0, 7, 14 and 21 days were
used.  In field trials with a 28- or 33-day PHI, the highest theoretical
residue value obtained when the application rate was prorated to 1x was
0.64 ppm.  Residue levels did not decline substantially with increasing
harvest intervals (PP#2E4054).  

	In addition, 4 field trials were conducted in Spain, from which grapes
were harvested 30 days following the last of 5 applications of the 150 g
ai/L DC formulation at rates of roughly 0.16 or 0.20 lb ai/A per
application (0.8x and 1x).  Maximum residue levels were 2.55 ppm in
grape samples treated at the 1x rate, and 2.02 ppm in samples treated at
the 0.8x rate (PP#2E4054).  

	Two additional field trials were conducted in Spain, from which grapes
were harvested 28 days following the last of 6 applications, with 10-day
(approximately) RTIs, of the 9% ai WP formulation at rates of 0.15-0.23
lb ai/A per application, for total rates of 1.2 1b ai/A (1.2x).   The
maximum residues observed were 0.11 ppm (PP#7F4816).  

	Based on these data, including calculation of theoretical residue
levels at 1x treatment rates, HED recommended a tolerance of 3.5 ppm in
grapes.  

	IR-4 included field trial residue summary tables for European grape
data in the petition submission.  These summaries included information
on trial location, crop variety, application rate, number of
applications, PHI, and residues, but did not include information on
methods of analysis, and the summaries were not supported by any raw
data.  Several tables corresponded to the previously submitted data. 
However, summaries were also submitted for field trials that do not
appear to have been submitted to EPA previously.  Tables were submitted
for:  

1. Two tests in France in 1991, in which grapes were harvested 38 or 44
days following the last of 9 or 10 applications of the 150 g ai/L DC
formulation at 0.300 kg ai/ha per application (0.27 lb ai/A), for total
rates of 2.4 and 2.7 lb ai/A, 

2. 3 tests in France from 1992, in which grapes were harvested 31-45
days following the last of 9 or 10 applications of the 150 g ai/L DC,
50% ai WP, and 600 g ai/L FlC formulations (in separate tests) at 0.300
kg ai/ha per application (0.27 lb ai/A; DC) or 0.400 kg ai/ha per
application (0.36 lb ai/A; WP and FlC), for total rates of 2.4-3.6 lb
ai/A, 

3. 2 tests in France from 1993, in which grapes were harvested 0-27 days
following the last of 4 applications of the 9% ai WP formulation at
0.198 kg ai/ha per application (0.18 lb ai/A), for total rates of 0.71
lb ai/A, 

4. 2 tests in Germany from 1993, in which grapes were harvested 0-28
days following the last of 4 applications of the 9% ai WP formulation at
0.198 kg ai/ha per application (0.18 lb ai/A), for total rates of 0.71
lb ai/A, 

5. 3 tests in Germany from 1993, in which grapes were harvested 0-42
days following the last of 8 applications of the 150 g ai/L DC
formulation at 0.121-0.288 kg ai/ha per application (0.11-0.26 lb ai/A;
total rate not reported), and 

6. 3 tests in Germany from 1994, in which grapes were harvested 0-43
days following a single application of the 150 g ai/L DC formulation at
an unstated rate.  

	Residues of dimethomorph in grapes harvested 27-45 days post-treatment
were 0.09-1.7 ppm, with the lower residues found in samples receiving 4
applications.  

	Conclusions (grapes):  The available European grape field trial data
are adequate to support the proposed uses of the 50% ai WP formulation,
and the 4.17 lb ai/gal FlC formulation in the US on grapes grown east of
the Rocky Mountains.  The majority of the European data represent
application rates 1x or more of the proposed maximum seasonal rate use
in the US, and several studies are available at the proposed US PHI of
28 days.  

	The European data generally reflected applications using WP or DC
formulations.  Very few of the European studies were conducted using an
FlC formulation.  Only three tests were conducted (in France), and only
summary data for these tests were submitted.  However, at these three
sites, tests were conducted at the same time with three different
formulations, a WP, an FlC, and a DC formulation.  The resulting
residues at each site were very similar for the three formulations, even
though the DC formulation was applied at a lower rate (0.27 lb ai/A per
application for the DC, and 0.36 lb ai/A per application for the WP and
FlC).  These data indicate that use of the FlC formulation on grapes
yields residues at the same level or lower than use of a DC formulation.
 Therefore, HED concludes that the available European data may be
translated to support use of the WP and FlC formulations on grapes grown
east of the Rocky Mountains.  

	The available data support a tolerance, with regional registration, for
residues of dimethomorph in grapes at 3.5 ppm.  

	Turnip tops:  No field trial data have been submitted for turnip tops. 
The petitioner proposed to translate data on leafy Brassica greens
(subgroup 5B) to turnip tops.  HED has previously concluded that turnip
tops should be moved from leaves of root and tuber vegetables (group 2)
to Brassica leafy vegetables (group 5).  Turnip tops will also be a
member of the leafy Brassica greens subgroup.  Therefore, field trial
data for mustard greens, as the representative commodity of the leafy
Brassica greens subgroup, are sufficient to support the use on turnip
tops.  

	The use pattern proposed for the 50% ai WP and 4.17 lb ai/gal FlC on
turnip tops (a maximum of 5 foliar applications at 0.20 lb ai/A per
application, for a total rate of 1.0 lb ai/A, and a 0-day PHI) is the
same as that registered for leafy Brassica greens.  Adequate residue
data for mustard greens have previously been submitted and reviewed
(PP#3E6558).  The available data for mustard greens reflect use of the
50% ai WP formulation as multiple foliar applications, at a total rate
of 1.4 lb ai/A (1.4x the registered use rate on leafy Brassica greens,
and 1.4x the proposed use rate on turnip tops), with 6- to 8-day RTIs
and a 0-day PHI.  HED concluded that the mustard greens data supported
the use pattern proposed in the current petition, a maximum of 5
applications of the 50% ai WP formulation at 0.20 lb ai/A per
application, with a minimum RTI of 7 days, and a 0-day PHI.  HED also
concluded that a tolerance of 20.0 ppm would be appropriate for leafy
Brassica greens.  The petitioner did not propose the use of an FlC
formulation on mustard greens in PP#3E6558.  

	Conclusions (turnip tops):  Field trial data for mustard greens, as the
representative commodity of the leafy Brassica greens subgroup, are
sufficient to support the use on turnip tops.  

	No field trial data were submitted to support use of the 4.17 lb ai/gal
FlC formulation of dimethomorph on turnip tops.  On an interim basis,
for the purposes of a conditional registration, HED considers this use
to be supported by the European grape field trials.  These trials
compared residue levels arising from the application of various
formulations of dimethomorph to grapes.  The trials demonstrated that
residues on grape were comparable between the WP and FlC formulations.  

	To support this use, results of at least two side-by-side field trials
should be submitted, comparing residues from use of the WP and FlC
formulations, for turnip tops.  These side-by-side trials should reflect
application of the 4.17 lb ai/gal FlC formulation at 1x the proposed
maximum seasonal rate.  Turnip tops should also be harvested at the
proposed PHI.  If these trials demonstrate that the two different
formulations do not result in comparable residues, then all commodities
lacking adequate residue data on the 4.17 lb ai/gal FlC formulation
could require a full complement of field trials.  

	Until the regulations incorporating turnip tops into crop subgroup 5B
have been finalized in the Federal Register, a separate tolerance should
be established in turnip tops, at the same level as the leafy Brassica
greens tolerance.  The available data support a tolerance for
dimethomorph in turnip tops at 20 ppm.  The proposed use on turnip tops
should be amended to prohibit applications to turnip cultivars that are
grown for root production.  

	Processed food and feed:  HED does not require residue data for any
processed commodities of lima beans, ginseng or turnip tops.  Processing
study data for grapes were submitted previously in conjunction with the
tolerance petitions requesting use on imported grapes (PP#2E4054 and
PP#7F4816).  These data indicated that dimethomorph residues do not
concentrate in grape juice but do concentrate in raisins (average
processing factor of 1.8x).  ChemSAC has concluded that residue data for
raisins are not required to support use of dimethomorph on grapes grown
east of the Rocky Mountains, as almost all raisins consumed in the US
come from California (minutes of 12 July 2006 meeting).  Therefore, no
tolerances in grape processed commodities are required to support the
proposed domestic use of dimethomorph on grapes.  

	The existing tolerance for dimethomorph residues in raisins was
established to support use of dimethomorph on grapes grown outside the
US; therefore, the tolerance should remain in 40CFR §180.493[a].  

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue
Limits 

	There are no Canadian nor Mexican maximum residue limits (MRLs)
established for residues of dimethomorph in crops associated with this
review.  Codex MRLs have been finalized in grapes and raisins at 2 and 5
ppm, respectively.  The Codex MRLs are not harmonized with the
established US tolerances in grapes and raisins (3.5 and 6.0 ppm,
respectively), which are based on European residue data.  The Agency
cannot decrease the tolerance in grape to 2 ppm because, in Spanish
field trials conducted at a 1x application rate, maximum residues were
2.55 ppm.  

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

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

	An acute dietary risk assessment was not conducted because an acute
endpoint was not identified for any segment of the US population.  

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

	A chronic dietary risk assessment was conducted (D355935; Anant Parmar;
29 September 2008) using the Dietary Exposure Evaluation Model
(DEEM-FCID(, Version 2.03), which uses food consumption data from the
USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from
1994 to 1996, and 1998.  

	The unrefined chronic dietary analysis for dimethomorph is a
conservative estimate of dietary exposure, with tolerance level
residues, and 100% crop treated (CT).  The risk estimate from chronic
dietary exposure to dimethomorph, as represented by the %cPAD, is below
HED’s LOC for the general US population, and all population subgroups.
 The exposure estimate for the US population is 9% of the cPAD.  The
exposure estimate for the most highly exposed subpopulation (children
1-2 years old) is 20% of the cPAD.  

Table 5.2.2	Summary of Dietary Exposure and Risk for Dimethomorph

Population Subgroup	Acute Dietary	Chronic Dietary	Cancer Dietary



Dietary Exposure

(mg/kg/day)	% cPAD 2

	General US population	NA 1	0.008551	8.6	NA

All infants (< 1 year old)

0.007180	7.2

	Children 1-2 years old

0.019823	20

	Children 3-5 years old

0.015323	15

	Children 6-12 years old

0.008943	8.9

	Youth 13-19 years old

0.006528	6.5

	Adults 20-49 years old

0.007928	7.9

	Adults 50+ years old

0.007718	7.7

	Females 13-49 years old

0.007487	7.5

	1. NA = Not Applicable.  

2. Values for the population subgroup with the highest risk are in bold
type.  

	This chronic assessment was based on the assumption of tolerance-level
residues, and 100 %CT for all commodities with existing and proposed
tolerances.  The existing dimethomorph tolerances are listed in 40CFR
§180.493.  HED is currently recommending in favor of tolerances in the
raw agricultural commodities (RACs) listed below.  

Bean, lima, succulent	0.60 ppm

Ginseng	0.90 ppm

Grape	3.5 ppm

Grape, raisin	6.0 ppm

Turnip, tops	20.0 ppm

The tolerances for grape and raisin are based on the currently
established tolerances for these imported commodities, and the tolerance
for turnip tops is based on the established tolerance for Brassica leafy
greens (subgroup 5B).  

	The inadvertent tolerances for the cereal grains crop group were
removed because rotational studies submitted by the registrant
demonstrated that residues were not quantifiable in the grains of these
commodities (D323873; Debra Rate; 29 October 2008).  

	The forage, hay and straw of cereal grain commodities are cattle
feedstuffs.  HED has previously concluded (D251605, D252556; Douglas
Dotson; 19 July 2000) that tolerances are not required for residues in
cattle commodities as a result of ingestion of dimethomorph residues on
rotational cereal grain commodities, based on the results of a ruminant
metabolism study, and a cattle feeding study.  

	The processing factors for tomatoes were removed because the tolerance
for the fruiting vegetables crop group of 1.5 ppm covers the
concentration of residues expected in processed fractions (D288872;
Maxie Jo Nelson; 9 October 2003).  The processing factors for potato
processed fractions were removed because processing studies submitted by
the registrant demonstrate that residues do not concentrate in these
commodities (D242167; Douglas Dotson; 14 July 2000, and D237101; Douglas
Dotson; 4 May 2000).  DEEM default processing factors (from DEEM Version
7.81) were used for all remaining processed commodities that do not have
individual tolerances.  

	To account for exposure to dimethomorph residues in water under the
most conservative scenario, the EDWC of 28.5 ppb was used in the dietary
exposure assessment, rather than the value from the most recent DWA. 
Water residues were incorporated into DEEM-FCID in the food categories
“water, direct, all sources” and “water, indirect, all sources.”
  Details are provided in Section 5.1.9, above.  

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

	Dimethomorph has been classified by the Cancer Assessment Review
Committee (CARC) as “not likely” to be carcinogenic to humans;
therefore, cancer risk is not of concern.  

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "5.3 Anticipated Residue and Percent Crop Treated (%CT) Information 

	The chronic dietary exposure assessment was based on the assumption of
tolerance-level residues, and 100 %CT for all commodities with existing
and proposed tolerances.  

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

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure 

	There are no residential uses for dimethomorph at this time, nor are
any proposed.  Therefore, risks for non-occupational and/or residential
handler and post-application exposures are not of concern.  There are no
post-application residential uses for dimethomorph that result in
residential exposure to infants and children.

	Also, there are no registered or proposed uses of dimethomorph that
would result in treatment of recreational areas.  

6.2.	Residential Post-Application Exposure TC \l2 "6.2.	Residential
Postapplication Exposure 

	See Section 6.1, above.  

6.3	Other (Spray Drift) TC \l2 "6.3	Other (Spray Drift, etc.) 

	Spray drift is a potential source of exposure to residents near
spraying operations.  This is particularly the case with aerial
application but, to a lesser extent, could also be a potential source of
exposure from the ground application methods employed for dimethomorph. 
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices, various state lead agencies for pesticide regulation,
and other parties to develop the best spray drift management practices. 
On a chemical-by-chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that should be placed on
product labels.  The Agency has completed its evaluation of the new
database submitted by the Spray Drift Task Force (membership comprised
of US pesticide registrants), and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast, and ground
hydraulic methods.  After the policy is in place, the Agency might
impose further refinements in spray drift management practices to reduce
off-target drift and risks associated with aerial (as well as other)
application methods, where appropriate.   TC \l2 "6.3	Other (Spray
Drift, etc.) 

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

	In accordance with FQPA, EPA must consider and aggregate (add)
pesticide exposures and risks from three major sources:  food, drinking
water, and residential uses.  In an aggregate assessment, exposures from
relevant sources are added together and compared to quantitative
estimates of hazard (a NOAEL or PAD), or the risks themselves can be
aggregated.  When aggregating exposures and risks from various sources,
HED considers both the route and duration of exposure.  

	For most pesticide active ingredients, water monitoring data are
considered inadequate to determine surface and ground water drinking
water exposure estimates, so modeling results have been used to estimate
residues in drinking water (EDWCs).  In order to determine if aggregate
risks are of concern, HED incorporated EDWC values directly into the
dietary risk assessment.  Because there are no residential uses for
dimethomorph, the dietary risk assessment is equivalent to the aggregate
risk assessment, as well.  

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk 

	An acute oral endpoint was not identified for any segment of the US
population.  Therefore, acute aggregate risk is not of concern.  

7.2	Short-Term Aggregate Risk TC \l2 "7.2	Short-Term Aggregate Risk 

	There are no registered residential uses for dimethomorph.  Therefore,
short-term aggregate risk is not of concern.  

7.3	Intermediate-Term Aggregate Risk TC \l2 "7.3	Intermediate-Term
Aggregate Risk 

	There are no registered residential uses for dimethomorph.  Therefore,
intermediate-term aggregate risk is not of concern.  

7.4	Long-Term Aggregate Risk TC \l2 "7.4	Long-Term Aggregate Risk 

	Long-term aggregate risk for dimethomorph is assessed using chronic
dietary exposure from residues in food and drinking water.  This
assessment takes into account conservative estimates of average exposure
from dietary ingestion of dimethomorph (food and drinking water).  Since
there are no residential uses of dimethomorph, there are no other
contributors to long-term aggregate risk.  

	EFED and HED have agreed that chronic and cancer EDWCs can be used
directly in chronic and cancer dietary exposure assessments to calculate
aggregate dietary (food + water) risk.  This is done by using the
relevant modeled value as a residue in water (direct and indirect, all
sources) for the dietary exposure assessment.  The principal advantage
of this approach is that the actual individual body weight, and water
consumption data from the CSFII are used, rather than assumed weights,
and consumption for broad age groups.  This refinement has been used for
the dimethomorph chronic aggregate risk assessment.  

	There are no existing or proposed residential uses for dimethomorph at
this time, so the chronic dietary (food + water) risk is equivalent to
the long-term aggregate risk, as well.  Long-term aggregate risk is
summarized in Table 5.2.2, above.  

7.5	Cancer Aggregate Risk TC \l2 "7.5	Cancer Risk 

	Dimethomorph has been classified as “not likely” to be a human
carcinogen.  Therefore, cancer aggregate risk is not of concern.  

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

	Unlike other pesticides for which EPA has followed a cumulative risk
approach, based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding regarding dimethomorph and any
other substances.  Dimethomorph does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that dimethomorph has a
common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity, and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs (OPP) concerning common mechanism determinations, and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

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

9.1	Short- and Intermediate-Term Handler Risk  TC \l2 "9.1
Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk 

	The petitioner did not submit a product-specific exposure study with
this petition to estimate the occupational risks to handlers. 
Therefore, default values from the Agency's Pesticide Handler and Worker
Exposure Database (PHED), and Scientific Advisory Committee on Exposure
(ExpoSAC) Policy # 9 were used to calculate the occupational exposures
to mixers, loaders, applicators and flaggers (D350234; Suku Oonnithan;
24 October 2008).  

	Handler exposure:  The proposed use patterns on lima beans, ginseng,
grapes and turnip tops result in short- and intermediate-term exposures
to handlers, owing to repeated applications occurring over a period of
more than a month.  The estimated non-cancer short-term total MOEs to
handlers are 290 or more (the LOC is an MOE of less than 100),
indicating that the risks from the use of  dimethomorph on the proposed
crops are not of concern, provided that handlers wear baseline personal
protective equipment (PPE) consisting of long-sleeved shirt, long pants,
and shoes with socks (plus gloves for mixers and loaders of the 50% ai
WP formulation used in aerial and chemigation applications).  The
estimated intermediate-term MOEs to handlers also are 100 or more, and
therefore, are not of concern.  A cancer risk assessment for handlers is
not applicable because dimethomorph was classified as "not likely” to
be carcinogenic to humans.  

	Although more than 2 consecutive applications of dimethomorph are not
expected in the integrated pest management (IPM) setting, repeated
applications result in intermediate-term exposures to handlers.  The
exposure scenarios for mixers, loaders, applicators and flaggers
applying dimethomorph on the proposed crops are summarized in Table
9.1.1, below.  

Table 9.1.1	Short- and Intermediate-Term Exposure Scenarios Resulting
From the Proposed Use of 		Dimethomorph on Lima Beans, Ginseng, Grapes
and Turnip Tops.

Scenario Number	Scenarios	Formulation	Equipment  	Comments 

1	Mixing/loading	WP	Aerial	All crops except ginseng.

2	"	"	"	Ground boom	All crops.

3	"	"	"	Air blast	Grapes only.

4	"	"	"	Chemigation	All crops.

5	Mixing/loading	FlC	Aerial	All crops except ginseng.

6	"	"	"	Ground boom	All crops.

7	"	"	"	Air blast	Grapes only.

8	"	"	"	Chemigation	All crops.

9	Applying	WP and FlC	Aerial 	All crops except ginseng.

10	"       "	"	Ground boom	All crops.

11	"       " 	"	Air blast	Grapes only.

12	"       "	"	Chemigation	All crops.

13	Flagging	"	Aerial	All crops except ginseng.



	Because the dermal and inhalation endpoints selected for the short- and
intermediate-term durations, respectively, were the same, the resulting
dermal and inhalation doses were combined to calculate a total MOE for
each exposure duration.  The algorithms and inputs used to calculate the
daily exposure doses and MOEs are provided in the Table 9.1.2 (below)
and/or as foot-notes.  

	In a previous occupational risk assessment for dimethomorph, a handler
body weight of 60 kg was used for calculating the daily doses, since the
short-term endpoints were selected from a developmental toxicity study. 
However, for this assessment, a handler body weight of 70 kg was used,
because the endpoints were actually based on parental toxicity
(decreased body weight, body weight gain, and food consumption) rather
than developmental effects.  

	The estimated non-cancer short-term total MOEs for handlers ranged from
260 to 190,000, indicating the risks from the use of dimethomorph on
lima beans, ginseng, grapes and turnip tops are not of concern (the LOC
is an MOE of less than 100), provided that handlers wear baseline PPE
consisting of long-sleeved shirt, long pants, and shoes with socks
(Table 9.1.2).  The corresponding non-cancer intermediate-term total
MOEs for handlers ranged from 66 to 47,000, which are also not of
concern, except for the MOE of 66 for mixers and loaders of the 50% ai
WP formulation used in aerial and chemigation applications (scenarios 1
and 4).  Mixers and loaders in scenarios 1 and 4 require baseline PPE
plus gloves to be protective (the MOE is 290 with gloves).  The
submitted labels of both the 50% ai WP and 4.17 lb ai/gal FlC
formulations require the wearing of gloves along with baseline PPE;
therefore, no additional PPE is required.  



Table 9.1.2	Non-Cancer Short- and Intermediate-Term Risks to Handlers
from the Use of Dimethomorph on Lima Beans, Ginseng, Grapes and 		Turnip
Tops.

Handler Job	Exposure Scenario 1	Equipment Used and Area Treated/Day	PPE

[Engineering Controls] 2	Dermal 3	Inhalation 4	Total Exposure        
(mg kg/day) 5	Total MOE 6







	Short-Term	Intermediate-Term

Mixing/ Loading, [50% ai WP]

	1 and 4	Aerial and chemigation

350 acres	Baseline [open cab]	Unit exp.  3.7   Dose/day  0.185	Unit exp.
 0.04342    Dose/day  0.04342	0.2284	260	66



	Base line + Gloves [open cab]	Unit exp.  0.17   Dose/day  0.0085	Unit
exp.  0.04342   Dose/day  0.04342	0.0519	1,200	290

	2	Ground boom

80 acres	Baseline [open cab]	Unit exp.  3.7     Dose/day  0.04229	Unit
exp.  0.04342     Dose/day  0.00992	0.0522	1,100	290

	3	Air blast

40 acres	Baseline [open cab]	Unit exp.  3.7     Dose/day  0.02114	Unit
exp.  0.04342     Dose/day  0.00495	0.0261	2,300	570

Mixing/ Loading, [4.17 lb ai/gal FlC]

	5 and 8	Aerial and chemigation

350 acres	Baseline [open cab]	Unit exp.  2.9           Dose/day  0.145
Unit exp.  0.0012 Dose/day  0.0012	0.1462	410	100

	6	Ground boom

80 acres	Baseline [open cab]	Unit exp.  2.9            Dose/day  0.03314
Unit exp.  0.0012     Dose/day  0.00027	0.03342	1,800	450

	7	Air blast

40 acres	Baseline [open cab]	Unit exp.  2.9            Dose/day  0.01657
Unit exp.  0.0012     Dose/day  0.00014	0.01671	3,600	900

Applying	9	Aerial - fixed wing

350 acres	Base line [enclosed cockpit]	Unit exp.  0.005   Dose/day 
0.00025	Unit exp.  0.00007   Dose/day  0.00007	0.00032	190,000	47,000

	10	Ground boom

80 acres	Baseline [open cab]	Unit exp.  0.014 Dose/day  0.00016	Unit
exp.  0.00074   Dose/day  0.00017	0.00033	180,000	46,000

	11	Air blast          40 acres	Baseline [open cab]	Unit exp.  0.36     
       Dose/day  0.00206	Unit exp.  0.0045            Dose/day  0.00051
0.00257	23,000	5,800

	12	Chemigation	Not assessed because applicators are not involved in
chemigation applications.

Flagging	13	Aerial - fixed wing

350 acres	Baseline [none]	Unit exp.  0.011         Dose/day  0.00055
Unit exp.  0.00035   Dose/day  0.00035	0.0009	67,000	17,000

1. The scenario numbers were taken from Table 9.1.1 (scenarios 1 and 4,
and 5 and 8 were combined because of common inputs).  

2. PPE = Personal Protective Equipment; baseline PPE includes
long-sleeved shirt, long pants, and shoes with socks.  

3. Dermal dose (mg/kg/day) = [use rate (0.2 lb ai/A) x area treated
(A/day) x dermal unit exposure (mg/lb ai) x dermal absorption (5%)] ÷
body weight (70 kg).  	In a previous ORE assessment, a 60-kg body weight
for handlers was used.  But because the short-term dermal and inhalation
endpoints were based on 	parent toxicity, and not developmental effects,
a 70-kg body weight was used here.  

4. Inhalation dose (mg/kg/day) = [use rate (0.2 lb ai/A) x area treated
(A/day) x inhalation unit exposure (mg/lb ai) x inhalation absorption
(100%)] ÷ body 	weight (70 kg).  

5. Total exposure = dermal + inhalation exposures.  

6. Total short- and intermediate-term MOEs = short-term NOAEL (60
mg/kg/day) ÷ total exposure (mg/kg/day), and intermediate-term NOAEL
(15 mg/kg/day) 	÷ total exposure (mg/kg/day).  The MOE in boldface type
denotes risk above the LOC.  

9.2	Short- and Intermediate-Term Post-Application Risk  TC \l2 "9.2
Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication Risk 

	In the absence of chemical-specific dislodgeable foliar residue (DFR),
the post-application worker exposure to dimethomorph was calculated
using surrogate DFR values for day 0 after application.  In addition,
the activity-specific dermal transfer coefficients (TCs) were selected
for the proposed or similar crops from the Agency's ExpoSAC 3.1
database.  

	Post-application exposure:  According to the proposed use pattern on
lima beans, ginseng, grapes and turnip tops, workers would be subjected
to short- and intermediate-term exposures when they enter the treated
fields for irrigation, weeding, thinning, scouting, hand harvesting,
etc.  The estimated MOEs for short-term post-application exposure are
2,300 or more (Table 9.2, below), and those for intermediate-term
post-application exposure are 590 or more, and are not of concern (the
LOC is an MOE of less than 100).  The registered and proposed labels
have an REI of 12 hours.  This REI is adequate to protect the workers
who may enter the treated fields to engage in crop-related activities,
because dimethomorph (technical) has low acute toxicity properties.  

Table 9.2	Non-Cancer Short-and Intermediate-Term Risks to Workers
Entering Fields Treated with 		Dimethomorph.

Proposed Crops      	Post-app. Activity               [Surrogate Crop]
TC               (cm²/hr) 1	DFR              (µg/cm) 2	Dermal dose 
(mg/kg/day) 3	 Short-Term MOE              	Intermediate-Term MOE 4

Grapes	Hand harvesting, pruning [grapes].	5,000	0.4485	0.01282	4,700
1,200

	Girdling, turning, tying [grapes].	10,000	"	0.02563	2,300	590

Lima Beans	Hand harvesting [string beans].	2,500	"	0.00641	9,400	2,300

BW = Body Weight.  CF1, CF2 and CF3 = Conversion Factors.  DA = Dermal
Absorption.  DFR = Dislodgeable 	Foliar Residue.  ET = Exposure Time
(hours).  TC = Transfer Coefficient.  

1. TCs are from ExpoSAC Policy Number 3.1.  

2.  DFR (µg/cm2) = application rate (0.2 lb ai/A) x default amount of
residue (µg) at day 0 (20%) x CF1 for ug/lb ai 	(4.54 E+08) x CF2 for
A/cm2 (2.47 E-08).  

3. Dermal dose (mg/kg/day) = [TC (cm²/hr) x DFR (µg/cm2) x CF3 for
mg/ug (1.0 E-03) x DA (5%) x ET (8 hrs)] 	÷ BW (70 kg).  

4. Short- and intermediate-term MOEs = short- or intermediate-term NOAEL
(60 or 15 mg/kg/day) ÷ dermal dose   	(mg/kg/day).  

	Post-application exposure of workers to dimethomorph is likely even
after the REI period has passed, when they enter treated fields of lima
beans, ginseng, grapes and turnip tops to do scouting, harvesting and
other cultivation-related activities.  Due to the repeated applications
of dimethomorph, workers may be subjected to both dermal and inhalation
routes of exposures over short- and intermediate-term durations. 
Inhalation exposure after the REI period is not expected because of the
low volatility of dimethomorph, with vapor pressures of the E- and
Z-isomers being 9.7 x 10-7 Pa, and 1.0 x 10-6  Pa at 25°C, respectively
(Dimethomorph - Pesticide Fact Sheet; 1998).  

	The petitioner did not submit a post-application exposure study
providing chemical-specific DFR data, and crop- and activity-specific TC
values needed to estimate the daily exposure by workers.  Therefore, for
this assessment, a DFR value was estimated for day 0 after application,
and activity-specific TC values were selected from ExpoSAC Policy # 3.1,
for the proposed and/or surrogate crops.  Based on these inputs, a
dermal dose per day was calculated for each selected post-application
activity.  Table 9.2 (above) summarizes the risk to workers who may
enter the treated fields to conduct crop-related post-application
activities.  The estimated short- and intermediate-term dermal MOEs
ranged from 590 to 9400 (the LOC is an MOE of less than 100) and are,
therefore, not of concern.  

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

	Tolerances for residues of dimethomorph are established under 40CFR
§180.493, and are expressed in terms of dimethomorph per se.  IR-4 has
proposed the establishment of tolerances for the combined residues (free
and bound) of the fungicide dimethomorph.  The proposed tolerance
expression should be revised to remove reference to combined free and
bound residues.  Neither the enforcement nor the data collection methods
include any hydrolysis or other steps that would release bound residues.
 

	There are no Canadian nor Mexican MRLs established for residues of
dimethomorph in crops associated with this review.  Codex MRLs have been
finalized in grapes and raisins at 2 and 5 ppm, respectively.  The Codex
MRLs are not harmonized with the established US tolerances of 3.5 and
6.0 ppm in grapes and raisins, respectively, which are based on European
residue data.  The Agency cannot decrease the tolerance in grapes to 2
ppm because, in Spanish field trials conducted at a 1x application rate,
maximum residues were 2.55 ppm.  In the case of raisins, based on the
average concentration factor of 1.8x, and a highest average field trial
residue of about 3 ppm, HED concludes that the raisin tolerance needs to
remain higher than the 5 ppm Codex MRL.  Please refer to the review of
PP#7F4816 (D237101; Douglas Dotson; 4 May 2000).  

	The tolerances proposed by IR-4 are listed in Table 10, along with the
tolerance levels recommended by HED.  Provided the proposed uses are
amended as requested, adequate field trial data are available for lima
beans, ginseng, grapes and turnip tops.  

	The Agency’s Guidance for Setting Pesticide Tolerances Based on Field
Trial Data was utilized for determining appropriate tolerance levels in
lima beans and ginseng.  Based on these calculations, the proposed
tolerance in lima beans (0.60 ppm) is adequate, but the proposed
tolerance in ginseng is too low.  A revised tolerance of 0.90 ppm should
be proposed in ginseng.  Because use on lima beans is to be restricted
to areas east of the Rocky Mountains, the lima bean tolerance should be
established under 180.493[c], for tolerances with regional registration.
 

	The available European field trial data are adequate to support the
proposed use on grapes grown east of the Rocky Mountains.  No change to
the established tolerance level (3.5 ppm) in grapes is necessary;
however, the tolerance should be moved to 180.493[c], for tolerances
with regional registration.  

	The proposed tolerance in turnip tops (20 ppm) is adequate, as the
turnip tops tolerance is to be set at the same level as the existing
tolerance for dimethomorph residues in leafy Brassica greens.  

	The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in Table
10, below.  

Table 10	Tolerance Summary for Dimethomorph.

Commodity	Established Tolerance (ppm)	Proposed Tolerance (ppm)
Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Tolerances established or to be listed under 40CFR §180.493[a]

Ginseng	NA 1	0.85	0.90

	Grape	3.5 2	3.5	NA 3	Because use is to be restricted to areas east of
the Rocky Mountains, tolerance should be established with regional
registration in 40CFR §180.493[c], and deleted from 40CFR §180.493[a].
 Footnote on tolerance should be removed.

Grape, raisin	6.0 2	6	6.0 2	Footnote 1 to 40CFR §180.493[a] should be
amended to state “There are no US registrations, as of [insert date of
the FR notice], for the use of dimethomorph on grapes grown for raisin
production.”

Greens, turnip	NA 1	20	20.0	Turnip, tops

Tolerances to be listed under 40CFR §180.493[c]

Beans, lima	NA 1	0.6	0.60	Because use is to be restricted to areas east
of the Rocky Mountains, tolerance should be established with regional
registration in 40CFR §180.493[c].  Bean, lima, succulent

Grape	NA 4	3.5	3.5	Because use is to be restricted to areas east of the
Rocky Mountains, tolerance should be established with regional
registration in 40CFR §180.493[c].  

1. NA = Not Applicable.  These tolerances do not currently exist.  

2. These tolerances were established on imported grapes and raisins.  

3. NA = Not Applicable.  Move listing for tolerance in grape to
180.493[c].  

4. NA = Not Applicable.  This listing for tolerance in grape is
currently in 180.493[a].  

10.1	Toxicology Data Needs  TC \l2 "10.1	Toxicology 

	870-7800 Immunotoxicity Study

	870-6200 Acute and Subchronic Neurotoxicity Studies

	870-3200 21/28-Day Dermal Study

	The petitioner should submit, as a condition of registration, 870-3200
21/28-day dermal, 870.6200 neurotoxicity and 870.7800 immunotoxicity
studies.  With the exception of immunotoxicity, acute neurotoxicity,
subchronic neurotoxicity, and 21/28-day dermal studies, now mandatory
under the updated 40CFR §158 data requirements, the toxicological
database for dimethomorph is complete.  Recent changes to 40CFR §158
make 21/28-day dermal testing (OPPTS Guideline 870-3200), acute and
subchronic neurotoxicity testing (OPPTS Guideline 870.6200), and
immunotoxicity testing (OPPTS Guideline 870.7800) required for pesticide
registration.  The available data for dimethomorph do not show potential
for immunotoxic nor neurotoxic effects.  Therefore, HED does not believe
that conducting 870.6200 neurotoxicity and 870.7800 immunotoxicity
studies will result in a NOAEL less than the NOAEL of 11 mg/kg/day
already set for dimethomorph.  Consequently, an additional UFDB does not
need to be applied.  However, the studies are required, and should be
considered confirmatory (see Appendix B).  

10.2	Residue Chemistry Data Needs  TC \l2 "10.2	Residue Chemistry 

HED has examined the residue chemistry database for dimethomorph. 
Pending submission of a revised Section B (see requirements under
860.1200 Directions for Use, below), and a revised Section F (see
requirements under 860.1550 Proposed Tolerances, below), there are no
residue chemistry issues that would preclude granting conditional
Section 3 registration for the requested uses (of the 50% ai WP, and the
4.17 lb ai/gal FlC formulations of dimethomorph) on lima beans, ginseng,
grapes and turnip tops, or the establishment of tolerances for residues
of dimethomorph, as listed below.  

		Tolerances to be listed under 40CFR §180.493[a]:

Ginseng 	0.90 ppm

Turnip, tops 	20.0 ppm

		Tolerances to be listed under 40CFR §180.493[c]:

Bean, lima, succulent 	0.60 ppm

Grape 	3.5 ppm

	Notes to RD’s Risk Manager/Reviewer:  With the establishment of the
above tolerances, the tolerance listed for “Grape” under 40CFR
§180.493[a] should be deleted.  In addition, the text for footnote 1
should be changed from “There are no US registrations as of [insert
date of the FR notice], for the use of dimethomorph on the growing
crops, grape, hop, and raisins” to “There are no US registrations,
as of 25 August 2000, for the use of dimethomorph on grapes grown for
raisin production.”  Domestic registration of dimethomorph on hops was
addressed in the Federal Register Notice of 27 September 2002.  

	A tolerance is established in “Potato, wet peel” under 40CFR
§180.493[a], but there is no tolerance listed in “Potato.”  HED
recommended in favor of a permanent tolerance in potato at 0.05 ppm. 
The FR Notice dated 13 October 1998 established a permanent tolerance
in/on potato at 0.05 ppm.  This tolerance of 0.05 ppm in potato should
be listed under 40CFR §180.493[a].  

	860.1200 Directions for Use

1. The proposed use of the 50% ai WP and 4.17 lb ai/gal FlC formulations
on lima beans should be amended to specify that the product may only be
applied to lima beans grown east of the Rocky Mountains.  In addition,
the proposed use should be amended to specify that applications may only
be made to lima beans intended for harvest as succulent seed.  

2. The proposed use of the 50% ai WP and 4.17 lb ai/gal FlC formulations
on grapes should be amended to specify that applications may only be
made to grapes grown east of the Rocky Mountains.  In addition, a
minimum spray volume of 10 GPA should be specified for aerial
applications to grapes.  

3. The proposed use of the 50% ai WP and 4.17 lb ai/gal FlC formulations
on turnip tops should be amended to prohibit applications to turnip
cultivars that are grown for root production.  

4. The proposed uses of both the 50% ai WP and 4.17 lb ai/gal FlC
formulations on the four subject crops should be amended to prohibit the
addition of adjuvants to the spray mixture.   

	860.1550 Proposed Tolerances

1. The proposed tolerance expression should be revised to state,
“…the residues of the fungicide dimethomorph,
(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morp
holine in or on…” (remove the reference to combined free and bound
residues).  

2. The proposed tolerances should be revised to reflect the recommended
tolerance levels, and correct commodity definitions, as specified above
and in Table 10.  

	HED recommends that conversion of conditional registration to
unconditional registration for the requested uses may be considered upon
submission of the following outstanding residue chemistry data.  

	860.1500 Crop Field Trials

1. To support the conditional uses of the 4.17 lb ai/gal FlC
formulation, results from at least two side-by-side field trials should
be submitted, comparing residues from use of the 50% ai WP and 4.17 lb
ai/gal FlC formulations, for both lima beans (succulent) and turnip
tops.  These side-by-side trials should reflect application of the 4.17
lb ai/gal FlC formulation at 1x the proposed maximum seasonal rate. 
These commodities should also be harvested at the proposed PHI.  

2. If these trials demonstrate that the two different formulations
result in comparable residues (if the mean residues differ by a factor
of 1.5x or less), then side-by-side trials in ginseng will not be
required.  Otherwise, all commodities lacking adequate residue data on
the 4.17 lb ai/gal FlC formulation could require a full complement of
field trials.  

	  SEQ CHAPTER \h \r 1 860.1650 Analytical Reference Standards

	The standard for dimethomorph Z isomer at the National Pesticide
Standards Repository has expired (expiration date of 1 September 2008). 
For the expired standard, the registrant must either recertify the lot
in the repository, and send in an updated certificate of analysis (COA),
or submit a new standard (with a different lot number) if the previous
lot will not be recertified.  If a new COA is being submitted, it should
be faxed to the repository at (410)305-2999.  If a new standard is being
submitted, it should be sent to ACB, which is located at Fort Meade, to
the attention of Theresa Cole at the following address:  	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch

	701 Mapes Road

	Fort George G. Meade, MD   20755-5350

(Please note that the mail will be returned if the extended zip code is
not used.)

	860.1900 Field Rotational Crops

	As specified in D323873 (Debra Rate; 29 October 2008), two additional
field rotational crop studies each with a leafy vegetable, and a root
crop should be submitted.  

	

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

	None.  

REFERENCES

Risk Assessment Memoranda

	Dimethomorph: Human Health Risk Assessment for Proposed Uses on
Brassica Stem and Head Subgroup 5A.; D316328; J. R. Tomerlin; 7
September 2006.  

	Alternative Risk Integrated Assessment (AIRA) Human Health Risk
Assessment for DIMETHOMORPH Residues in/on the Fruiting Vegetables
(except Cucurbits) Crop Group, Leafy Brassica Greens Crop Group, Turnip
Greens, Taro Leaves, and Taro.; D315316; William G. Sproat, Jr; 15
August 2003.  

	DIMETHOMORPH: Human Health Risk Assessment for Residues in/on Domestic
and Imported Tomatoes, Imported Grapes, and Imported Hops; D265124,
D265126; Douglas Dotson; 28 July 2000.  

Residue Chemistry Summary Document Memoranda

	Dimethomorph.  Application for Amended Section 3 Registration to Add
Uses on Lima Beans, Ginseng, Grape, and Turnip Greens.  Summary of
Analytical Chemistry and Residue Data.; D349735; Anant Parmar; 21
October 2008.  

	Dimethomorph; Data Submitted to Fulfill Conditions of Registration for
Acrobat MZ® (EPA Reg. No. 241-383) and Acrobat® 50WP (EPA Reg. No.
241-410) for Requested Inadvertent Tolerances in/on Grain, Cereal Crop,
Fodder, Forage, Hay, and Straw.  Summary of Analytical Chemistry and
Residue Data for Rotated Crops.; D323873; Debra Rate; 29 October 2008.  

	Dimethomorph.  Head and Stem Brassica Vegetables (Crop Subgroup 5A). 
Summary of Analytical Chemistry and Residue Data.; D316328; William
Cutchin; 18 July 2005.  

	Dimethomorph.  Residue Chemistry Summary Document for:  PP#2E6483 
Fruiting Vegetables (except cucurbits), Crop Group 8 and PP# 3E6588 
Leafy Brassica Greens (Crop Subgroup 5B), Taro and Tanier.; D288872;
Maxie Jo Nelson; 9 October 2003.  

	Tolerance Petitions for the Use of Dimethomorph on Domestic and
Imported Tomatoes, Imported Grapes, and Imported Hops Evaluation of
Residue Chemistry and Analytical Methodology; PP#s: 7F4816 (Grapes) and
8F4946 (Tomatoes and Hops); D237101, D239372, D239899, D242381; Douglas
Dotson; 4 May 2000.  

	PP#2E4054.  Dimethomorph
(4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]
morpholine) in/on Grapes, Potatoes, Animal Tissues and Milk.  Review of
Plant and Animal Metabolism Data, Analytical Methods, Crop Field Trials,
Ruminant Feeding Study Data and Storage Stability Data to Support the
Establishment of an Import Tolerance for a New Chemical.; D192776; C.
Eiden; 13 March 1995.  

Occupational and Residential Exposure Assessment Memoranda

	Dimethomorph: Occupational and Residential Risk Assessment to Support
Registration of New Uses on Ginseng, Grape, Lima Bean, and Turnip
Greens.; D350234; Suku Oonnithan; 24 October 2008.  

	Dimethomorph: Exposure/Risk Assessment for the Proposed Use on Fruiting
Vegetables (Except Cucurbits, Crop Group 8), Leafy Brassica greens (Crop
Subgroup 5B, Taro and Tanier).; D293160; Mark I. Dow; 3 September 2003. 


Dietary Exposure Memorandum

	Dimethomorph.  Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action on
Lima Beans (succulent), Ginseng, Grape, and Turnip Greens.; D355935;
Anant Parmar; 29 September 2008.  

Drinking Water Assessments

	Drinking Water Assessment for the IR-4 Registration for the New Uses of
     Dimethomorph for New Uses on Ginseng, Lima Beans, Grapes and Turnip
Greens for Use in Human Health Risk Assessment; D349254; Jose Luis
Melendez; 3 September 2008.  

	Drinking Water Assessment for the IR-4 registration for the new uses of
        dimethomorph for use on brassica head and stem subgroup 5A.;
D328740; Jose Luis Melendez; 26 April 2006.  

	Tier I Estimated Environmental Concentrations of Dimethomorph in
Drinking Water for the Tolerance Petition for Minor Uses on Hops,
Lettuce, Endive, Radichio, and Bulb Vegetables; D278860, D279691,
D282423, D282423; Jose Luis Melendez; 8 August 2002.  

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

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

	The requirements (40CFR §158.340) for food use of dimethomorph are in
Table A.1, below.  Use of the new guideline numbers does not imply that
the new (1998) guideline protocols were used.  

Table A.1	Toxicology Data Requirements for Dimethomorph.

Test 

	Technical

	Required	Conducted

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization	yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (non-rodent)

870.3200    21/28-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation	yes

yes

yes

no

no	yes

yes

no 

no

no

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (non-rodent)

870.3800    Reproduction	yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (non-rodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity	no

yes

no

no

yes	yes

yes

yes

no

yes

870.5100    Mutagenicity—Gene Mutation (bacterial)

870.5300    Mutagenicity—Gene Mutation (mammalian)

870.5375    Mutagenicity—Structural Chromosomal Aberrations

870.5395    Mutagenicity—Other Genotoxic Effects	        870.5500   
Mutagenicity—Other Genotoxic Effects	yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.6100a  Acute Delayed Neurotoxicity (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotoxicity Screening Battery (rat)

870.6200b  90-Day Neurotoxicity Screening Battery (rat)

870.6300    Developmental Neurotoxicity	no

no

yes

yes

yes	no

no

no

no

no

870.7485    General Metabolism

870.7600    Dermal Penetration			        870.7800    Immunotoxicity		yes

no

yes	yes

yes

no



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

Table A.2.1	Acute Toxicity Profile for Dimethomorph.

Guideline Number	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral [Rat]	42233902	LD50 = 3900 (3300-4500) mg/kg (M,F)
III

870.1200	Acute dermal [Rat]	42233903	LD50 ≥ 5000  mg/kg	IV

870.1300	Acute inhalation [Rat]	42233904	LC50 ≥ 4.24 mg/L	III

870.2400	Acute eye irritation [Rabbit]	42233905	Conjunctival irritation
clearing in 4 days	III

870.2500	Acute dermal irritation [Rabbit]	42233907	No irritation
reported	IV

870.2600	Skin sensitization [Guinea pig]	42233906	Not a sensitizer



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

Guideline Number/ Study Type	MRID(s) [year]/ Classification/Doses
Results

870.3100

90-Day oral toxicity [dog]	42233908 [1991]

Acceptable/guideline

0, 150, 450, 1350 ppm

M: 0, 5, 15, 43 mg/kg/day

F: 0, 6, 15, 44 mg/kg/day	NOAEL = 15 mg/kg/day

LOAEL = 43 mg/kg/day based on decrease in the absolute and relative
weights of the prostate and possible threshold liver effects.

870.3150

90-Day oral toxicity [rat]	42233910 [1991]

Core minimum

0, 40, 200, 1000 ppm

M: 0, 2.9, 14.2, 73 mg/kg/day

F: 0, 3.2, 15.8, 82 mg/kg/day	NOAEL >73/82 [M/F] mg/kg/day

LOAEL was not established in this study, because the highest dose tested
produced no biologically significant effects.  

870.3700a

Prenatal developmental

[rabbit]	42233918 [1989]

Unacceptable/core 

supplemental [Initial rating]

0, 135, 300, 650 mg/kg/day	Maternal NOAEL = 300 mg/kg/day

LOAEL = 650 mg/kg/day based on an increased incidence of abortion
confirmed in a range-finding study.

Developmental NOAEL could not be determined.

LOAEL could not be determined.

870.3700b

Prenatal developmental [rabbit]	44175303

Acceptable

Information supplemental to MRID# 42233918	Maternal NOAEL = 300
mg/kg/day

LOAEL = 650 mg/kg/day based on an increased incidence of abortion
confirmed in a range-finding study.

Developmental NOAEL =650 mg/kg/day [highest dose tested].

LOAEL could not be determined - no effects observed at highest dose
tested.

870.3700c

Prenatal developmental

[rat]	42233919 [1989]

Unacceptable/core 

supplemental [Initial rating]

0, 20, 60, 160 mg/kg/day	Maternal NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body
weights and body weight gain.

Developmental NOAEL could not be determined

LOAEL = could not be determined.

870.3700d

Prenatal developmental

[rat]	44175302

Acceptable

Information supplemental to MRID# 42233919	Maternal NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body
weights and body weight gain.

Developmental NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on the incidence of post implantation loss

870.3800

Reproduction and fertility effects

[rat]	42233920 [1990]

Unacceptable/core supplemental

0, 100, 300, 1000 ppm	Parental/Systemic NOAEL = 300 ppm

LOAEL = 1000 ppm based on decreased body weights and body weight gains.

Reproductive NOAEL = 300 ppm

LOAEL = 1000 ppm based on decreased incisor eruption on day 10
postpartum.

Offspring NOAEL was not reported

LOAEL was not reported.

870.4100a

Chronic toxicity

[rat]	42233912 [1991]

Acceptable/guideline

0, 150, 450, 1350 ppm

M: 0, 9.4, 36.2, 99.9 mg/kg/day

F: 0, 11.9, 57.7, 157.8 mg/kg/day	NOAEL = 36.2/11.9 [M/F] mg/kg/day

LOAEL = 57.7/99.9 [M/F] mg/kg/day  based on decreased body weight and
increased incidence of arteritis in male rats and  decreased body weight
and significant increased incidence of "ground-glass" foci in the liver
in female rats.

870.4100b

Chronic toxicity [dog]

	42233911 [1991]

Acceptable/guideline

0, 150, 450, 1350 ppm

M: 0, 4.9, 14.7, 44.6 mg/kg/day

F: 0, 5.0, 15.7, 47.0 mg/kg/day	NOAEL = 14.7 mg/kg/day

LOAEL = 44.6mg/kg/day based on decreased prostate weight.

870.4200

Carcinogenicity

[rat]	42233916 [1991]

Acceptable/guideline

0, 200, 750, 20000 ppm

M: 0, 8.8, 33.9, 94.6 mg/kg/day

F: 0, 11.3, 46.3, 132.5 mg/kg/day	NOAEL [systemic] = 33.9/11.3 [M/F]
mg/kg/day

LOAEL [systemic] = 94.6/46.3 [M/F] mg/kg/day based on  decreased body
weight, gross and microscopic lesions in blood vessels, and liver
lesions in males and decreased body weight, gross and microscopic
lesions blood vessels, bone marrow hypercellularity, and liver lesions
in females.

There was no evidence of carcinogenicity

870.4300

Carcinogenicity

[mouse]	42233914 [1991]

Acceptable/guideline

0, 10, 100, 1000 mg/kg/day	NOAEL = 100 mg/kg/day

LOAEL [systemic] = 1000 mg/kg/day based on decreased body weight gain in
males.

There was no evidence of carcinogenicity

Gene Mutation

870.5100a	42233921 [1985]

Acceptable	Negative for inducing reverse gene mutation in either
Salmonella his-mutants or E. coli trp-cells exposed beyond precipitating
concentrations [500 ug/plate], up to the limit dose, 5000 ug/plate,
w/without metabolic activation.

Gene Mutation

870.5100b	42233926 [1989]

Acceptable	Negative for inducing reverse gene mutation in Salmonella TA
strains and E. coli WP2 uvr A exposed, with/without activation, up to
5000 ug/plate.

In vitro mammalian cell gene mutation test

870.5300a	42233923 [1987]

Acceptable	Negative for inducing forward mutation at the
hypoxanthine-guanine phosphoribosyl transferase locus in Chinese hamster
lung [V79] cells treated up to cytotoxic levels [230 ug/mL/-S9; 300
ug/mL/+S9].

In vitro mammalian cell gene mutation test

870.5300b	42233927 [1991]

Acceptable	Negative for inducing forward mutation at the
hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus in Chinese
hamster lung [V79] exposed, with/without activation, up to cytotoxic
concentrations [180 ug/mL/-S9; 333 ug/mL/+S9].

In vitro mammalian chromosome aberration test

870.5375a	42233924 [1986]

Unacceptable	Reportedly positive for chromosome aberrations at the
highest doses tested [160 ug/mL/-S9; 170 ug/mL/+S9].

In vitro mammalian chromosome aberration test

870.5375b	42233925 [1987]

Acceptable	[Confirmatory repeat of Study LMP-180 C, MRID 422339-24]. 
Positive for increased chromosome aberrations at high doses [160
ug/mL/-S9; 170 ug/mL/+S9].

In vitro mammalian chromosome aberration test

870.5375c	42233928 [1991]

Acceptable	Presumptively [weakly] positive, but only in activated
cultures treated at the HDT, in human lymphocyte cultures treated up to
the highly toxic dose, 422 ug/mL; negative in the absence of activation
at all doses.

Mammalian erythrocyte micronucleus test

870.5395a	42233930 [1991]

Acceptable	Negative for inducing micronuclei in bone marrow cells of
mice administered test article i.p.  up to severely toxic levels [200
mg/kg].

Mammalian erythrocyte micronucleus test

870.5395b	42233931 [1989]

Acceptable	Negative for inducing micronuclei in bone marrow cells of
mice treated orally at the limit dose, 5000 mg/kg.

Mutagenicity - DNA damage/repair in vitro

870.5500	42233922 [1986]

Unacceptable	Reportedly negative for inducing unscheduled DNA synthesis
[as measured by liquid scintillation counting] in rat hepatocytes
cultured [for only 3 hours] at doses up to 250 ug/mL, a weakly cytotoxic
level.

Other Effects - Morphologic transformation of cells in culture

870.8800	42233929 [1986]

Acceptable	Negative for transformation in Syrian hamster embryo cells
treated, in the presence and absence of activation,  up to cytotoxic
concentrations [265 ug/mL/+S9; 50 ug/mL/-S9]

870.7485

Metabolism and pharmacokinetics

[rat]	42233932 [1994]

Acceptable

10 mg/kg single dose; 10 mg/kg 14-day repeated dose; 10 mg/kg 7-day
repeated dose; 500 mg/kg single dose	Oral administration of dimethomorph
results in rapid excretion into the urine and feces of rats.  For all
treatment protocols, most [80-90%] of the radiolabel administered was
excreted in the feces.  A considerably smaller amount [6-16%] was
excreted in the urine and only minimal levels [0.1-0.4%] were detected
in the organs and tissues.  Rapid absorption may be inferred by the
rapid excretion of metabolites in the urine and bile.  Saturation of
absorption following single high doses [500 mg/kg] was indicated by
large amounts [(50%] of radioactivity in the feces being associated with
parent compound.  For low- or high-dose treatment, urinary excretion in
female rats tended to be greater [up to 2-fold in low-dose rats] than
that of male rats.  Retention of dimethomorph or
[14C]-dimethomorph-derived radioactivity was generally (1% for most
tissues although the liver exhibited slightly higher levels [1.4%] and
higher levels in the gastrointestinal tract organs was due to
radioactivity in the lumenal contents.  Urinary metabolites resulted
from demethylation of the dimethoxyphenyl ring and oxidation of the
morpholine ring.  Biliary excretion exhibited first-order kinetics with
a low-dose [10 mg/kg] half-life of approximately 3 hours and a high-dose
[500 mg/kg] half-life of 11 hours for males and about 6 hours for
females.  Biliary metabolites accounted for most of the fecal excretion
following low-dose treatment.  The major biliary metabolites were
glucuronides of one and possibly two of the compounds produced by
demethylation of the dimethoxyphenyl ring.  The report provided a
proposed metabolic pathway for dimethomorph.

870.7600

Dermal penetration

[rat]	43917221 [1995]

Acceptable/guideline

7.73 [2.5% w/v aqueous suspension] or 79.62 [25% w/v aqueous suspension]
mg/kg.	The total amount of dimethomorph absorbed [expressed as percent
of [14C]-dose] from rats at various times following dermal
administration of [14C]-dimethomorph at 7.73 [0.15 mg/cm2] or 79.62
mg/kg [1.58 mg/cm2] is less than 5% of the dose and it appears that the
absorption is concentration dependent.  Dermal absorption was 0.05%,
0.07% and 0.27% of the administered dose from rats 4, 8, and 24 hours
after dermal treatment at 7.73 mg/kg, respectively.  Dermal absorption
was 0.02%, 0.16% and 0.12% of the dose 4, 8, and 24 hours after dermal
treatment at 79.62 mg/kg, respectively.  Dermal absorption was
approximately 0.4 and 1 mg/kg in terms of weight equivalent at 7.73 and
79.62 mg/kg, respectively.  Six days after dermal treatment, the percent
total absorption of the dose in the 7.73 and 79.62 mg/kg was 4.76 and
1.20%, respectively.  Mean percent recovery of 14C for dose levels of
7.73 and 79.62 mg/kg was 104.1% and 92.1%, respectively.  Majority of
the radioactivity was found in skin swabs and gauze wash [80.9 to
81.8%].  The percent of the dose in the skin decreased with dose; at
7.73 mg/kg 17.5% and at 79.62 mg/kg 9.99%



Appendix B:  Rationale for Toxicology Data Requirements  TC \l1
"Appendix II – Rationale for Toxicology Data Requirements 

Guideline Number:  870.7800

Study Title:  Immunotoxicity 

Rationale for Requiring the Data

	The immunotoxicity study is a new data requirement under 40CFR §158 as
a part of the data requirements for registration of a pesticide (food
and non-food uses).  

	The Immunotoxicity Test Guideline (OPPTS Guideline 870.7800) prescribes
functional immunotoxicity testing, and is designed to evaluate the
potential of a repeated chemical exposure to produce adverse effects
(such as suppression) on the immune system.  Immunosuppression is a
deficit in the ability of the immune system to respond to a challenge of
bacterial or viral infections such as tuberculosis (TB), Severe Acquired
Respiratory Syndrome (SARS), or neoplasia.  Because the immune system is
highly complex, studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

	Immunotoxicity studies provide critical scientific information needed
to characterize potential hazard to the human population on the immune
system from pesticide exposure.  Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited, and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios, and are
considered a primary data source for reliable reference dose
calculation.  For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO),
based on observed immunotoxicity in animal studies (IRIS, 1997).  

How could the data impact the Agency's future decision-making? 

	If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.  

 	If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.  





Guideline Number:  870.6200

Study Title:  Acute and Subchronic Neurotoxicity

Rationale for Requiring the Data

	The acute and subchronic neurotoxicity studies are a new data
requirement under 40CFR §158 as a part of the data requirements for
registration of a pesticide (food and non-food uses).  

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ticide’s potential neurotoxicity.  While data on clinical signs of
toxicity or histopathology in routine chronic or subchronic toxicity
studies may offer useful information on potential neurotoxic effects,
these endpoints alone may be insufficient to detect more subtle
neurological effects.  

Practical Utility of the Data

How will the data be used?

	Neurotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the nervous
system from pesticide exposure.  Since epidemiologic data on the effects
of chemical exposures on neurological parameters are limited, and may be
inadequate to characterize a pesticide’s potential neurotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios, and are
considered a primary data source for reliable reference dose
calculation.  

How could the data impact the Agency's future decision-making? 

	If the neurotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.  

 	If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.  





AppendiX C:  Human Research REFERENCE

	The Pesticide Handlers Exposure Database, Version 1.1 (Electronic
Database); The PHED Task Force, 1995; (Task Force members: Health
Canada, US Environmental Protection Agency, and the National
Agricultural Chemicals Association); released February, 1995.  

Page   PAGE  4  of   NUMPAGES  52 

