I 

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Shaja Joyner, P~-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] 

[Inse11 petition number] 

EPA ha~ 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 (B)\S 550 F) [(E,Z)4-[3-(4-chlorophenyl)-3-(3,4-

dimethoxyphenyl)-l-oxo-2-propenyl]-morpholine] its metabolites and degradates I in or 

on the ra\\ agricultural commodity [papaya] at [1.51 part~ per million (ppm). EPA has 

deten11ined that the petition contains data or information regarding the elements set forth 

in section408 (<.1)(2) of FDDCA; however. EPA has not fully evaluated the sufficiency of 

the submitted data at this time or whether the data support., granting of the petition. 

Additional data may be needed before EPA rules on the petition. 

A. Re\idue Chemistry 

I . Plant metaholi\m. [Based upon the results of metabolism studies conducted on 

potato, grape, and lettuce, the nature of the residues in papaya is considered to be 

understood. The results of th~ 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 inion grapes 

harvested 35 days following the last of four applications l 0.8 lb active ingredient per acre 

(ail A) per application for four consecutive weeks] for a total rate of 3.2lb ai/A was 14.6 

ppm. Unmetabolized dimethomorph accounted for 87.3% of the TRR (12.7 ppm). No 

.. 
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metabolites were identified that require regulation. 

The results of the lettuce metabolism study showed that the TRR inion lettuce 

leaves harvested 4 days following the last of 4 applications f approximately 1.0 lb ail A per 

application with a 9 to II day spray intervaiJ, for a total rate of 4. 1 lb ai/A, was 102 ppm. 

Of this total residue, 98.5% was extractable and unmetaboliLed dimethomorph accmmted 

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 

studies are comidered to cover the metabolism of dimethomorph in papaya.) 

2 1 /"tico/1'1 tlwd. [A reliable method for the detennination of dimethomorph 

residues in Grapes exists; this method is the FDA Multi-Residue Method, Protocol D, as 

published in the Pesticide Analytical Manual 1. The determination of the dimethomorph 

residues in papaya was perfmmed according to the analytical BASF Method No. 535/1 

(identical with Method No. 575/0). The final determination of BAS 550 F was performed 

by LC-MS/MS. The limit of quantitation (LOQ) of the method for BAS 550 F is 0.01 

mglkg. The method has been validated in the context of this residue study.) 

3 \fr'nn: •. 4 I ( r rt\iduu. [Supervised field trials \\>ere caJ.Tied out to determine 

the magnitude of the residue inion papaya. The number and locations of field trials are in 

accordance with EPA's December 2005 NAFfA Guidance Document on Data 

Requirements for Tolerances on Imported Commodities in the United States and Canada. 

which lists the number of field trails needed for a US Import Tolerance. 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 papaya support the proposed tolerance.] 

B. Toxicological Profile 

I. Amte to:-:il it.\. 

[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 LDso of 4.300 milligrams/kilogram body weight (mglkg 

b.w.) for males and 3,500 mglkg 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 mglkg b.w. for males and 3699 mglkglb.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 LDso studies were conducted on the two isomers (E and Z) alone: 

c. An acute oral toxicity study in the Wistar rat for theE-isomer with a LD50 

greater than 5,000 mglkg b.w. for males and approximately 5,000 mglkg b.w. 

for females. 

d. An acute oral toxicity study in the Wistar rat for the Z-isomer with a LD50 

greater than 5,000 mglkg b.w. for both males and females. 
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iii. An acute dennaJ toxicity study in the Wistar rat for dimethomorph technical with 

a dermal LDso greater than 5.000 mglkg 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 dim~thomorph 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 initation toxicity category for dimethomorph 

technical in this study is Category IV or non-to-slightly initating. 

vi. An eye initation 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 initating).] 

2. Genotm"icty. 

l i. Salmonella reverse gene mutation assays (2 studies) were negative up to a limit 

dose of 5,000 J..Lg/plate. Chinese hamster lung V79 ceJls were negative for 

mutations at the HGPRT locus at up to toxic doses in two studies. 

ii. Stmctural Chromosomal AbeiTation studies were presumptively weakly positive in 

human lymphocytic cultures, but only in S9 activated cultures treated at 422 

J..Lg/ml, the highest dose tested (HDT). which was strongly cytotoxic. No increase 

in chromosomal abeiTations was observed in the absence of S9 activation at all 

doses. Fm'thennore. 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 mglkg or oral doses up to the limit dose of 5,000 mglkg. Thus, 

dimethomorph was found to be negative in these studies for causing cytogenic 

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 J..Lg/rnlf+S9; 50 J..Lg/rnJJ-S9).] 

3. Reproductil·e and de\·elopmental toxicity. 

fi. A rat developmental toxicity study with a Lowest-Observed-Effect Level (LOEL) 

for maternal toxicity of 160 mglkg/day and a No-Observed-Effect Level (NOEL) 

for maternal toxicity of 60 mglkg/day. The NOEL for developmental toxicity is 60 

mglkg/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 mglkg/day. The NOEL for 

developmental toxicity is 650 mglkg/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 mglkg/day, and a NOEL for parental 
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systemic toxicity of 300 ppm, or approximately 24 mglkg/day. The NOEL for 

fertility and reproductive function was I 000 ppm, the highest concentration tested, 

or approximately 80 mg/kg b.w./day. l 

4 \uhdmmic tmicity. 

I 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 

mglkg/day for males and 82 mglkg/day for females. 

ii. A 90-day dog dietary study '"'ith a NOEL of 450 ppm. or approximately 15 

mglkg/day, and a LOEL of 1350 ppm, or approximately 43 mglkglday.] 

5 ( lmmic toridt\ 

(i. A 2-year chronic toxicity study in Sprague-Dawley rats with a NOEL of 150 ppm 

or approximately 9.4 mglkg/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 mglkg/day for females. 

ii. A 1-year chronic toxicity study in dogs with a NOEL of 450 ppm, or 

approximately 14.7 mglkg/day and a LOEL of 1350 ppm. or approximately 44.6 

mglkg/day. 

iii. A 2-year oncogenicity study in Sprague-Dawley rats with a NOEL for systemic 

toxicity of 200 ppm, or approximately 8.8 mglkg/day for males and 11.3 

mg/kg/day for females. The LOEL for systemic toxicity was 750 ppm, or 

approximately 33.9 mglkg/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 mglkg/day for males and 132.5 mg/kg/da) for females. 

iv. A 2-year oncogenicity study in CO-l mice with a NOEL for systemic toxicity of 

100 mglkg/day and a LOEL of 1,000 mglkg/day. There was no evidence of 

increased incidence of neoplastic lesions in treated animals. The NOEL for 

oncogenicity is 1,000 mglkg/day. the highest dose tested. 

v. A subchronic neurotoxicity study in Wistar rats with a NOEL of 432.9 mglkg/day 

in males or 5 10. 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 mglkglday 432.9 mg/kg/day. There was no evidence of 

immunotoxicity.j 

6 Ani ' 11e ',ol\t>l. [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.j 

7 Mt'Wholite to\icologv. [There were no metabolites identified in plant or animal 

commodities which require regulation.] · 

8 l~lldocrille div~ -,ion. [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 infonnation available 
5 

that suggests that dimethomorph technical would be associated with endocrine effects.] 

C. Aggregllle E~pvsure 

l. Dietarv 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 import tolerance for papaya.] 

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 dete1mined 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 crops and the proposed impmt 

tolerance for papaya. 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 0.1 I mglkg 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 futther 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 papaya, 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. 

Chronic Exposure 

Population sub-group (mglkg bw/day) %cPAD 

US Population 0.012279 11.2 

All infants ( < 1 year) 0.009332 8.5 

k::hil dren 1-2 0.025248 23.0 

k::hildren 3-5 0.021213 19.3 

k::hildren 6-12 0.011995 10.9 

IY outh 13-19 0.008257 7.5 
6 

Adults 20-49 0.011809 10.7 

!Adults 50+ yrs 0.012093 11.0 

!Females 13 - 49 yrs 0.011404 10.4 

ii DrinJ..in~ ~~oft r [The chronic drinking water values used in thb analysis were 

the values proposed by EPA, September 15, 2011, "Dimethomorph: Human Health Risk 

Assessment to Suppott Ameneded Use on Grapes, Bulb Vegetables, Leafy Brassica 

Vegetables and Leafy Vegetables". The chronic drinking water value used was 24.7 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 (mglkg bw/day) %cPAD 

IUS Population 0.000517 0.47 

IAII infants(< 1 year) 0.001334 1.21 

Children 1-2 0.000746 0.68 

Children 3-5 0.000629 0.57 

K:bildren 6-12 0.000453 0.41 

IY outb 13-19 0.000377 0.34 

!Adults 20-49 0.000516 0.47 

Adults 50+ yrs 0.00051 0.46 

Females 13 - 49 yrs 0.000514 0.47 

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 detennined 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 include!-. 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 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. 

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

Food Water Total 

Population cPAD Exposure Exposure Exposure 

Subgroup (mg!kg!day) {mglkg!day) (mg!kg!day) {mglkg!day) % cPAD 

U.S. Population 0.11 0.012279 0.000517 0.012796 11.6 

All Infants ( < 1 yr 0.11 0.009332 0.001334 0.010666 9.7 
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old) 

Children 1-2 years 0.11 0.025248 0.000746 0.025994 23.6 

Children 3-5 years 0.11 0.021213 0.000629 0.021842 19.9 

Children 6 - 12 0.11 0.011995 0.000453 0.012448 11.3 

years 

Youth 13-19 years 0.11 0.008257 0.000377 0.008634 7.8 

Females 13-49 years 0.11 0.011809 0.000516 0.012325 11.2 

Adults 20-49 years 0.11 0.012093 0.00051 0.012603 11.5 

Adults + 50 0.11 0.011404 0.000514 0.011918 10.8 . 

2 Non die wn t \po.wre. [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. CumulatiH? E./lee'·' 

[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 dime~omorph is unique; dimethomorph inhibits cell wall fmmation 

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 dimcthomorph is a particularly toxic compound. No toxic end-points of 

potential concem were identified.] 

I U . f)(Jf>Ulati<m. [Based on this risk assessment, BASF concludes that there is a 

reasonable certainty that no risk concems to the general population from the aggregate 

exposure to dimethomorph residues.] 

2. 11 (£ ,. II' 1 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 expo~ure to dimethomorph residues.] 

f . lmematimwl tolerance' 

[There are no Canadian, Mexican, or Codex MRLs established for dimethomorph 

for papaya; consequently, a discussion of intemational hrumonization is not relevant]