  SEQ CHAPTER \h \r 1 FILE NAME:   company.wpt   (1/1/2005) (xml)

Dimethomorph IR-4 lima beans, ginseng, grape, raisin, turnip greens
October 2007	

ATTENTION: 

	All commodity terms must comply with the Food and Feed Commodity
Vocabulary database (http://www.epa.gov/pesticides/foodfeed/).

	All text in blue font (instructions for preparing the document), should
be removed prior to sending the document to the Federal Register Staff. 
Instructional text and prompts in green font should also be removed.

	

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2005)

EPA Registration Division contact: [Mary WallerSidney Jackson, (703)
3085-93761054]	

TEMPLATE:

[Interregional Research Project (IR-4])

[PP No. 8E7314Insert petition number]

		EPA has received a pesticide petition ([insert petition numberPP#
8E7314]) from [Interregional Research Project No. -4 Project
Headquarters, 500 College Road East, Suite 201 W. Princeton, NJ 08540,
Rutgers, The State University of New Jersey], [681, U.S. Highway No. 1
South, North Brunswick, NJ  08902-3390] proposing, pursuant to section
408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C.
346a(d), to amend 40 CFR part 180.493, 

 

Options (pick one)

	1. by  establishing a tolerance for residues of

	

[dimethomorph ,
[[(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-m
orpholine]] in or on  the raw agricultural commodity [Lima Bbeans, lima
at 0.6 parts per million (ppm);  Gginseng at 0.85 ppm,; Ggrape at 3.5
ppm; , Ggrape rRaisin at 6.0 ppm; and greens, turnip Turnip greens] at
[0.6, 0.85, 3.5, 6, 20 ppm.] 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.

A. Residue Chemistry  

                                    

		1. Plant metabolism. [Based upon the results of metabolism studies
conducted on potato, grape, and lettuce, the nature of the residues in
lima beans, ginseng, grape, raisin, and turnip greens 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.]

		2. Analytical method. [A reliable method for the determination of
dimethomorph residues in lima beans, ginseng, grape, raisin and turnip
greens exists; this method is the FDA Multi-Residue Method, Protocol D,
as published in the Pesticide Analytical Manual I.]

		3. Magnitude of residues. [The residue data for Ginseng submitted to
support this tolerance petition were collected from 4 ginseng studies
conducted in region 5 of the United States.  Trials were conducted using
multiple applications (7) of dimethomorph applied at 0.198 to 0.24 lb
ai/A with a maximum seasonal rate of 1.4 to 1.7 lb ai/A (1.4 to 1.7X the
proposed label rate).  Dimethomorph residues observed in these field
trials for ginseng ranged from 0.28 ppm to 0.62 ppm when harvested 13 to
15 days after the last application.

Therefore, a tolerance of 0.85 ppm in or on Ginseng is proposed.

The residue data for Lima Bean submitted to support this tolerance
petition were collected from 7 lima bean studies conducted in regions 2
and 5 of the United States.  Trials were conducted using multiple
applications (7 to 8) of dimethomorph applied at 0.2 lb ai/A with a
maximum seasonal rate of 1.4 to 1.6 lb ai/A (1.4 to 1.6X the proposed
label rate).  Dimethomorph residues observed in these field trials for
lima bean ranged from 0.03 ppm to 0.48 ppm when harvested 0 days after
the last application.

Therefore, a tolerance of 0.6 ppm in or on Lima Bean is proposed.

The residue data for Grape submitted to support this tolerance petition
were previously submitted to establish the current import tolerance for
grape and grape, raisin.  The residue data for grape were collected from
27 grape studies conducted in Europe.  Trials were conducted using
multiple applications (4 to 11) of dimethomorph applied at 0.11 to 0.36
lb ai/A with a maximum seasonal rate of 0.55 to 3.57 lb ai/A (0.55 to
3.57X the proposed label rate).  Dimethomorph residues observed in these
field trials for grape ranged from 0.05 ppm to 2.6 ppm when harvested 0
to 90 days after the last application.

Therefore, tolerances of 3.5 ppm in or on Grape and 6 ppm for Grape,
Raisin are proposed.

The residue data for Turnip Greens submitted to support this tolerance
petition were previously submitted to establish the current tolerance
for brassica leafy greens at 20 ppm.  The residue data for leafy
brassica greens were collected from eight (8) mustard green studies
conducted in mustard green producing regions of the United States. 
Trials were conducted using multiple applications (7) of dimethomorph
applied at 0.2 lb ai/A with a maximum seasonal rate of 1.4 lb ai/A. 
This exceeds the proposed label rate for dimethomorph on turnip greens
(1.0 lb ai/A).  Dimethomorph residues observed in these field trials
ranged from 0.65 to 18.1 ppm after last application on day of harvest.

Therefore, a tolerance of 20.0 ppm in or on Turnip Greens is proposed.]

B. Toxicological Profile

		1. Acute toxicity.  [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) ]

		2. Genotoxicty.  [ 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).]

		3. Reproductive and developmental toxicity.  [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.]

		4. Subchronic toxicity. [  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.]

		5. Chronic toxicity. [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.]

		6. Animal metabolism. [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.]

		7. Metabolite toxicology. [There were no metabolites identified in
plant or animal commodities which require regulation.]

		8. Endocrine disruption.  [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.]

C. Aggregate Exposure

		1. Dietary exposure. [An assessment was conducted to evaluate the
potential risk due to chronic dietary exposure of the U.S. population
and sub-populations to residues of dimethomorph.  This analysis included
all currently proposed tolerances listed in U.S. 40 CFR § 180.493 and
the proposed tolerances for lima beans, ginseng, grape, grape raisin,
and turnip greens.]

		i. Food.  [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 toxicological 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 16% 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	0.0075910	6.90

All infants (< 1 year)	0.0042140	3.83

Children 1-2	0.0168600	15.33

Children 3-5	0.0132540	12.05

Children 6-12	0.0078260	7.11

Youth 13-19	0.0058480	5.32

Adults 20-49	0.0071590	6.51

Adults 50+ yrs	0.0069390	6.31

Females 13 - 49 yrs	0.0067210	6.11

]

		ii. Drinking water. [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 1.  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	0.007591	0.000506	0.008097	7.36

All Infants (< 1 yr old)	0.11	0.004214	0.001658	0.005872	5.34

Children 1-2 years	0.11	0.01686	0.000751	0.017611	16.01

Children 3-5 years	0.11	0.013254	0.000703	0.013957	12.69

Children 6 – 12 years	0.11	0.007826	0.000485	0.008311	7.56

Youth 13-19 years	0.11	0.005848	0.000366	0.006214	5.65

Females 13-49 years	0.11	0.007159	0.000472	0.007631	6.94

Adults 20-49 years	0.11	0.006939	0.000497	0.007436	6.76

Adults + 50	0.11	0.006721	0.00047	0.007191	6.54



]

		2. Non-dietary exposure. [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.]

D. Cumulative Effects

		[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.]

E. Safety Determination

		1. U.S. population. [ 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.]

		2. Infants and children. [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.]

F. International Tolerances

		[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.]

