Document ID: EPA-HQ-OPP-2014-0531-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-12-17T05:00Z

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

EPA Registration Division contact: [Shaja Joyner, PM-20, (703)-308-3194]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition. In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.

TEMPLATE:

[BASF Corporation]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
[BASF Corporation], [P.O. Box 13528, Research Triangle Park, North
Carolina, 27709] requesting, 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 by establishing a tolerance for residues of [Dimethomorph (BAS
550 F)
[(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-mo
rpholine] its metabolites and degradates] in or on the raw agricultural
commodity [strawberry] at [1.0] parts per million (ppm) and to amend 40
CFR part 180 b [replacing] a tolerance for residues of [Dimethomorph
(BAS 550 F)
[(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]-mo
rpholine] its metabolites and degradates] in or on the raw agricultural
commodity [lettuce, head] from [10] ppm and [lettuce, leaf] at [10] ppm
[to 30 ppm].  EPA has determined that the petition contains data or
information regarding the elements set forth in section 408 (d)(2) of
FDDCA; 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
strawberry is considered to be understood. The results of the potato
metabolism study demonstrated that only negligible total radioactive
residues (TRR) were found in tubers, 0.01-0.02 parts per million (ppm.
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.

Since the metabolism between the three representative crops is not
different, these metabolism studies are considered to be adequate to
understand the nature of the residue in diverse crop groups and as such,
an additional metabolism study in strawberries is not required.]

	2. Analytical method. [A reliable method for the determination of
dimethomorph residues in plant matrices exists. The determination of the
dimethomorph residues in strawberries was performed according to the
analytical BASF Method No. L0013, Method for the determination of
geometric isomers of BAS 550 F. The final determination of BAS 550 F was
performed by LC-MS/MS at a LOQ of 0.005 mg/kg. The method has been
validated in the context of this residue study.]

	3. Magnitude of residues. [Supervised field trials were carried out to
determine the magnitude of the residue in/on strawberries. The number
and locations of field trials are in accordance with OCSPP Guideline
860.1500 and Directive 98-02, Section 9. Eight field trials were
conducted encompassing Regions 1 (PA; 1 trial), 2 (AL; 1 trial), 3 (FL;
1 trial), 5 (WI; 1 trial), 10 (CA; 3 trials) and 12 (OR; 1 trial) during
the 2013 growing season. The treated plot at each site received 3
applications of dimethomorph at a rate of 0.2 lb ai/A for a total
seasonal rate of 0.6 lb ai/A with a PHI of 0 days after the last
application. Detected residues of Dimethomorph in strawberries support
the proposed tolerance.]

B. Toxicological Profile

Acute toxicity. 

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

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.

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. 

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.

iii. 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 irritation 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 cytotoxic doses in
two studies.

ii. Structural Chromosomal Aberration studies were presumptively 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.

iii. 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 cytogenetic damage in vivo.

iv. 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 150 ppm or approximately 9.4 mg/kg/day for males and 11.9 mg/kg/day
for females. The LOEL for systemic toxicity is 450 ppm, or approximately
36.2 mg/kg/day for males and 57.7 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 ppm, 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 8.8 mg/kg/day for males
and 11.3 mg/kg/day for females. The LOEL for systemic toxicity was 750
ppm, or approximately 33.9 mg/kg/day for males and 46.3 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 94.6 mg/kg/day for males
and 132.5 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.

v. A subchronic neurotoxicity study in Wistar rats with a NOEL of 432.9
mg/kg/day in males or 510.1 mg/kg/day in females. There was no evidence
of neurotoxicity.

vi. A subchronic immunotoxicity study in male Wistar rats with a NOEL of
2400 ppm, equivalent to 184 mg/kg/day 432.9 mg/kg/day. There was no
evidence of an immunotoxic potential.]

	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 via 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 tolerance for strawberry at 1.0 ppm.]

	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, and determined there was no toxicological
endpoint attributable to a single dose and a quantitative acute dietary
exposure and risk assessment are 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 crops and the proposed new use for strawberry. The EPA Food
Commodity Ingredient Database (FCID) was also used in Exponent's Dietary
Exposure Evaluation Module (DEEM-FCID) software. Tolerances for animal
commodities (i.e. meat, meat byproducts, milk, eggs) are not required
since metabolism studies have shown dimethomorph residues will not occur
in animal commodities from the consumption of dimethomorph residues in
livestock feed. Furthermore, there are no livestock feedstuffs
associated with strawberry. Therefore, dimethomorph tolerances for
residues in animal commodities do not need to be established.

Dietary exposure estimates (food + drinking water) 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 and crop treatment
factors would further reduce the estimated chronic dietary exposure. The
results in the Table below demonstrate that there are no risk concerns
for any subpopulation based on established and new strawberry, 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 and
drinking water.

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

US Population	0.012933	11.8

All infants (< 1 year)	0.010746	9.8

Children 1-2	0.026544	24.1

Children 3-5	0.022276	20.3

Children 6-12	0.012695	11.5

Youth 13-19	0.008745	8.0

Adults 20-49	0.012406	11.3

Adults 50+ yrs	0.012718	11.6

Females 13 - 49 yrs	0.01202	10.9

]

	ii. Drinking water. [The chronic drinking water values used in this
analysis were the values proposed by EPA, September 15, 2011,
“Dimethomorph: Human Health Risk Assessment to Support Amended Use on
Grapes, Bulb Vegetables, Leafy Brassica Vegetables and Leafy
Vegetables”. The chronic drinking water value used was 24.7 ug/L. 

Acute Aggregate Exposure and Risk (Food and water)

The U.S. EPA Toxicological Endpoint Selection (TES) Committees has
evaluated the dimethomorph toxicity data and determined there was no
endpoint attributable to a single dose, therefore an acute aggregate
exposure and risk evaluation is not required. 

Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of dimethomorph from food
and water. The results in Table 1 demonstrate there are no risk 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.]

	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. Also, a
short-term aggregate risk assessment is not required. ]

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 risk concerns 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 risk concerns 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 strawberry; consequently, a discussion of international
harmonization is not relevant.]

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