EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Shaunta Hill, (703) 347-8961

 	1. by establishing a tolerance for residues of

	

dimethomorph
[(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-mo
rpholine] in or on the raw agricultural commodity Grape at 3.5 parts per
million (ppm). EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of the
FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition.  Additional data may be needed before EPA rules on the
petition.

                                      

. Based upon the results of metabolism studies conducted on potato,
grape, and lettuce, the nature of the residues in Grapes is considered
to be understood.  The results of the potato metabolism study show only
negligible residues in tubers, 0.01-0.02 parts per million (ppm) total
radioactive residues (TRR).  This is in contrast to the aerial portions
of the plant, which were found to have up to 23.5 ppm TRR, thus
demonstrating that translocation of dimethomorph downward within the
plant was not significant.  Almost all of the radioactive residue
(97.8%) was extractable from the plant at harvest.  In the aerial
portion of the plant, approximately 70% of the TRR was identified as
dimethomorph.  No metabolites were identified that require regulation.

The results of the grape metabolism study showed that the TRR in/on
grapes harvested 35 days following the last of four applications [0.8 lb
active ingredient per acre (ai/A) per application for four consecutive
weeks] for a total rate of 3.2 lb ai/A was 14.6 ppm.  Unmetabolized
dimethomorph accounted for 87.3% of the TRR (12.7 ppm).  No metabolites
were identified that require regulation.

	The results of the lettuce metabolism study showed that the TRR in/on
lettuce leaves harvested 4 days following the last of 4 applications
[approximately 1.0 lb ai/A per application with a 9 to 11 day spray
interval], for a total rate of 4.1 lb ai/A, was 102 ppm.  Of this total
residue, 98.5% was extractable and unmetabolized dimethomorph accounted
for greater than 93% of the extractable TRR.  No metabolites were
identified that require regulation. 

. A reliable method for the determination of dimethomorph residues in
Grapes exists; this method is the FDA Multi-Residue Method, Protocol D,
as published in the Pesticide Analytical Manual I. 

. Supervised field trials were carried out to determine the magnitude of
the residue in/on grapes;.  The number and locations of field trials are
in accordance with OPPTS Guideline 860.1500. Field trials were carried
out using the maximum label rates, the maximum number of applications,
and the minimum pre-harvest interval (PHI) for all the crops. Detected
residues of Dimethomorph in all crops support the proposed tolerances. 

.  i. Oral LD50 studies were conducted on dimethomorph technical:

a. An acute oral toxicity study in the Sprague-Dawley rat for
dimethomorph technical with a LD50 of 4,300 milligrams/kilogram body
weight (mg/kg b.w.) for males and 3,500 mg/kg b.w. for females.  Based
upon EPA toxicity criteria, the acute oral toxicity category for
dimethomorph technical is Category III or slightly toxic.

b. An acute toxicity study in the CD-1 mouse for dimethomorph technical
with a LD50 of greater than 5000 mg/kg b.w. for males and 3699
mg/kg/b.w. for females. Based on the EPA toxicity category criteria, the
acute oral toxicity category for dimethomorph technical is Category III
or slightly toxic.

ii. Oral LD50 studies were conducted on the two isomers (E and Z) alone:

An acute oral toxicity study in the Wistar rat for the E-isomer with a
LD50 greater than 5,000 mg/kg b.w. for males and approximately 5,000
mg/kg b.w. for females. 

   b. An acute oral toxicity study in the Wistar rat for the Z-isomer
with a LD50 greater than 5,000 mg/kg b.w. for both males and females.

An acute dermal toxicity study in the Wistar rat for dimethomorph
technical with a dermal LD50 greater than 5,000 mg/kg b.w. for both
males and females.  Based on the EPA toxicity category criteria, the
acute dermal toxicity category for dimethomorph is Category IV or
relatively non-toxic.

iv. A 4-hour inhalation study in Wistar rats for dimethomorph technical
with a LC50 greater than 4.2 mg/L for both males and females.  Based on
the EPA toxicity category criteria, the acute inhalation toxicity
category for dimethomorph technical is Category IV or relatively
non-toxic.

v. A skin irritation study was performed using New Zealand White
rabbits. Based on the EPA toxicity criteria, the skin irritation
toxicity category for dimethomorph technical in this study is Category
IV or non-to-slightly irritating.

vi. An eye irritation study using New Zealand White rabbits demonstrated
dimethomorph technical produced moderate conjunctival redness, slight to
moderate chemosis and slight discharge three hours after treatment.
Based on the EPA toxicity criteria, the eye toxicity category for
dimethomorph technical is Category III (slightly-to-moderately
irritating) 

.   i. Salmonella reverse gene mutation assays (2 studies) were negative
up to a limit dose of 5,000 (g/plate. Chinese hamster lung V79 cells
were negative for mutations at the HGPRT locus at up to toxic doses in
two studies.

Two Chinese hamster lung (V79 cells) structural chromosomal studies were
reportedly positive for chromosomal aberrations at the highest dose
tested (HDT) (160 (g/ml/-S9; 170 (g/ml/+S9).  However, dimethomorph
induced only a weak response in increasing chromosome aberrations in
this test system.  In addition, these results were not confirmed in two
micronucleus tests under in vivo conditions.

Structural Chromosomal Aberration studies were weakly positive in human
lymphocytic cultures, but only in S9 activated cultures treated at 422
(g/ml, the highest dose tested (HDT), which was strongly cytotoxic.  No
increase in chromosomal aberrations was observed in the absence of S9
activation at all doses.  Furthermore, the positive clastogenic response
observed under the in vitro conditions was not confirmed in two in vivo
micronucleus assays.

Micronucleus assay (2 studies) indicated that dimethomorph was negative
for inducing micronuclei in bone marrow cells of mice following i.p.
administration of doses up to 200 mg/kg or oral doses up to the limit
dose of 5,000 mg/kg.  Thus, dimethomorph was found to be negative in
these studies for causing cytogenic damage in vivo.

Dimethomorph was negative for inducing unscheduled DNA synthesis, in
cultured rat liver cells, at doses up to 250 (g/ml, a weakly cytotoxic
level.

Dimethomorph was negative for transformation in Syrian hamster embryo
cells treated, in the presence and absence of activation, up to
cytotoxic concentrations (265 (g/ml/+S9; 50 (g/ml/-S9). 

.  i. A rat developmental toxicity study with a Lowest-Observed-Effect
Level (LOEL) for maternal toxicity of 160 mg/kg/day and a
No-Observed-Effect Level (NOEL) for maternal toxicity of 60 mg/kg/day. 
The NOEL for developmental toxicity is 60 mg/kg/day.  Dimethomorph is
not teratogenic in the Sprague-Dawley rat.

ii. A rabbit development toxicity study with a LOEL for maternal
toxicity of 650 mg/kg/day and a NOEL for maternal toxicity of 300
mg/kg/day.  The NOEL for developmental toxicity is 650 mg/kg/day, the
highest dose tested.  Dimethomorph is not teratogenic in the New Zealand
white rabbit.

iii. A two-generation rat reproduction study with a LOEL for parental
systemic toxicity of 1000 ppm, or approximately 80 mg/kg/day, and a NOEL
for parental systemic toxicity of 300 ppm, or approximately 24
mg/kg/day.  The NOEL for fertility and reproductive function was 1000
ppm, the highest concentration tested, or approximately 80 mg/kg
b.w./day. 

 i. A 90-day dietary study in Sprague-Dawley rats with a NOEL of greater
than or equal to 1000 ppm, the highest concentration tested, or
approximately 73 mg/kg/day for males and 82 mg/kg/day for females.

ii.  A 90-day dog dietary study with a NOEL of 450 ppm, or approximately
15 mg/kg/day, and a LOEL of 1350 ppm, or approximately 43 mg/kg/day. 

. i. A 2-year chronic toxicity study in Sprague-Dawley rats with a NOEL
of 200 ppm or approximately 9 mg/kg/day for males and 12 mg/kg/day for
females.  The LOEL for systemic toxicity is 750 ppm, or approximately 36
mg/kg/day for males and 58 mg/kg/day for females.

ii. A 1-year chronic toxicity study in dogs with a NOEL of 450 ppm, or
approximately 14.7 mg/kg/day and a LOEL of 1350, or approximately 44.6
mg/kg/day.

iii. A 2-year oncogenicity study in Sprague-Dawley rats with a NOEL for
systemic toxicity of 200 ppm, or approximately 9 mg/kg/day for males and
11 mg/kg/day for females.  The LOEL for systemic toxicity was 750 ppm,
or approximately 34 mg/kg/day for males and 46 mg/kg/day for females. 
There was no evidence of increased incidence of neoplastic lesions in
treated animals.  The NOEL for oncogenicity is 2000 ppm, the highest
concentration tested, or approximately 95 mg/kg/day for males and 132
mg/kg/day for females.

iv. A 2-year oncogenicity study in CD-1 mice with a NOEL for systemic
toxicity of 100 mg/kg/day and a LOEL of 1,000 mg/kg/day.  There was no
evidence of increased incidence of neoplastic lesions in treated
animals.  The NOEL for oncogenicity is 1,000 mg/kg/day, the highest dose
tested. 

. Results from the livestock and rat metabolism studies show that orally
administered dimethomorph was rapidly excreted by the animals.  The
principal route of elimination is the feces. 

. There were no metabolites identified in plant or animal commodities
which require regulation. 

. Collective organ weights and histopathological findings from the
two-generation reproduction study in rats, as well as from the
subchronic and chronic toxicity studies in two or more animal species,
demonstrate no apparent estrogenic effects or effects on the endocrine
system.  There is no information available that suggests that
dimethomorph technical would be associated with endocrine effects. 

.  [Acute Dietary Exposure Assessment

An acute assessment was not needed since the U.S. EPA Toxicological
Endpoint Selection (TES) Committees had previously evaluated the
dimethomorph toxicity data, including developmental and maternal
toxicity in the developmental toxicity studies and determined there was
no toxicologic endpoints for acute dietary exposure and a quantitative
acute dietary exposure and risk assessment were not required.  

Chronic Dietary Exposure Assessment

A Tier 1 chronic dietary exposure assessment was conducted assuming
tolerance level residues and 100% crop treated factors for all
registered and proposed crops.  The EPA Food Commodity Ingredient
Database (FCID) was also used in Exponent's Dietary Exposure Evaluation
Module (DEEM-FCID) software.  Inadvertent residues in animal commodities
(i.e. meat, meat byproducts, milk, eggs) were not considered as a result
of grain forage since studies have shown dimethomorph does not
accumulate in animal tissues or milk and tolerance values for these
commodities are not required by the EPA.

Dietary exposure estimates were compared against the established
dimethomorph chronic Population Adjusted Dose (cPAD) of 0.11 mg/kg
b.w./day for all populations.  Results of the chronic dietary
assessments are listed in the table below.  The estimated chronic
dietary exposure from crops (both established and proposed tolerances)
was less than 25% of the cPAD for all subpopulations (Table 1). 
Additional refinements such as the use of anticipated residues would
further reduce the estimated chronic dietary exposure.  The results in
the Table below demonstrate that there are no safety concerns for any
subpopulation based on established and new uses, and that the results
clearly meet the FQPA standard of reasonable certainty of no harm.

Table 1.  Summary of Chronic Dietary Exposure Assessment considering
crops with established and proposed tolerances for Dimethomorph.

Population sub-group	Chronic Exposure (mg/kg bw/day)	%cPAD

US Population	0.0143730	13.5

All infants (< 1 year)	0.0083360	9.1

Children 1-2	0.0261150	24.4

Children 3-5	0.0217070	20.4

Children 6-12	0.0144150	13.5

Youth 13-19	0.0114830	10.8

Adults 20-49	0.0139690	13.1

Adults 50+ yrs	0.0137380	12.9

Females 13 - 49 yrs	0.0133010	12.5



. The chronic drinking water values used in this analysis were the
values proposed by EPA Federal Register Notice, September 29, 2003,
Volume 68, No. 188.  The chronic drinking water value used was 28.3
ug/L. 

Table 2.  Summary of Chronic Drinking Water Exposure Assessment
Considering the Maximum Estimated Chronic Drinking Water Concentration
for Dimethomorph.

Population sub-group	Chronic Exposure (mg/kg bw/day)	%cPAD

US Population	0.000506	0.46

All infants (< 1 year)	0.001658	1.51

Children 1-2	0.000751	0.68

Children 3-5	0.000703	0.64

Children 6-12	0.000485	0.44

Youth 13-19	0.000366	0.33

Adults 20-49	0.000472	0.43

Adults 50+ yrs	0.000497	0.45

Females 13 - 49 yrs	0.00047	0.43



Acute Aggregate Exposure and Risk (Food and water)

Since the U.S. EPA Toxicological Endpoint Selection (TES) Committees has
evaluated the dimethomorph toxicity data and determined there was no
toxicologic endpoints for acute dietary exposure, the determination of
an acute aggregate exposure and risk evaluation was not required.  

Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of dimethomorph from food
and water (Table 3). Exposures from residential uses are not included in
the chronic aggregate assessment.  The results demonstrate there are no
safety concerns for any subpopulation based on established and new uses,
and that the results clearly meet the FQPA standard of reasonable
certainty of no harm.

Table 3.  Estimated Chronic Aggregate Exposure and Risk for
Dimethomorph.

Population Subgroup	cPAD (mg/kg/day)	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	% cPAD

U.S. Population	0.11	0.014373	0.000506	0.014879	13.5

All Infants (< 1 yr old)	0.11	0.008336	0.001658	0.009994	9.1

Children 1-2 years	0.11	0.026115	0.000751	0.026866	24.4

Children 3-5 years	0.11	0.021707	0.000703	0.02241	20.4

Children 6 – 12 years	0.11	0.014415	0.000485	0.0149	13.5

Youth 13-19 years	0.11	0.011483	0.000366	0.011849	10.8

Females 13-49 years	0.11	0.013969	0.000472	0.014441	13.1

Adults 20-49 years	0.11	0.013738	0.000497	0.014235	12.9

Adults + 50	0.11	0.013301	0.00047	0.013771	12.5



. Dimethomorph is not registered for use on any sites that would result
in residential exposure.  Therefore, a residential exposure and risk
assessment was not conducted.

 

There is no information to indicate that any toxic effects produced by
dimethomorph would be cumulative with those of any other chemical.  The
fungicidal mode of action of dimethomorph is unique; dimethomorph
inhibits cell wall formation only in Oomycete fungi.  The result is
lysis of the cell wall that kills growing cells and inhibits spore
formation in mature hyphae.  This unique mode of action and limited pest
spectrum suggest that there is little or no potential for cumulative
toxic effects in mammals.  In addition, the toxicity studies submitted
to support this petition do not indicate that dimethomorph is a
particularly toxic compound.  No toxic end-points of potential concern
were identified.

 

. Based on this risk assessment, BASF concludes that there is a
reasonable certainty that no harm will result to the general population
from the aggregate exposure to dimethomorph residues.

. Based on this risk assessment, BASF concludes that there is a
reasonable certainty that no harm will result to infants or children
from the aggregate exposure to dimethomorph residues. 

There are no Canadian, Mexican, or Codex MRLs established for
dimethomorph for the commodities associated with this request;
consequently, a discussion of international harmonization is not
relevant. 

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