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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: [insert name and telephone number with area code] 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 instr uctions 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 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. 1. by establishing a tolerance for residues of D imethomorp h [(E,Z)4
- [3
- (4
- chlorophenyl)
- 3
- (3,4
- dimethoxy phenyl )
- 1
- oxo - 2
- propenyl ]
- morpholine] in or on the raw agricultural commodity Leafy Vegetables at 16 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 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 Grapes is considered to be understood. The results of the potato metabolism study show onl y ne gligible 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 do wnward 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 was2

identified as dimethomorph. No metabolites were id entified that require regulation. The results of the grape metabolism study showed that the TRR in/on grapes harvested 35 day s 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 day s 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 Grapes exists; this method is the FDA Multi
- Residue Method, Protocol D, as published in the Pesticide Anal ytical Manual I
. 3. Magnitude of residues. 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 propose d tolerances. 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 LD 50 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

I II or slightly toxic. ii. Oral LD 50 studi es were conducted on the two isomers (E and Z) alone: a. An acute oral toxicity study in the Wistar rat for the E
- isomer with a LD 50 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 LD 50 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 LD 50 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 IVor relatively non - toxic. iv. A 4
- hour inhalation study in Wistar rats for dimethomorph technical with a L C 50 greater than 4.2 mg/Lfor both mal es and females. Based on the EPA toxicity category3

criteria, the acute inhalation toxicity category for dimethomorph technical is Category IV or relativel y non - toxic. v. A skin irritation study

was performed using New Zealand White rabbits. Based on the E PA 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 mode rate 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 I II (slightl y- to moderatel y irritating). 2. Geno toxicty. i. Salmonella reverse gene mutation assay s (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. ii. Two Chinese hamster lung (V79 cells) structural chromosomal studies were reportedl y 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 thi s test system. In addition, these results were not confirmed in two micronucleus tests under in vivo conditions. iii. Structural Chromosomal Aberration studies were weakl y positive in human ly mphocy tic cultures, but only

in S9 activated cultures treated at 422  g/ml, the highest dose tested (HDT), which was strongl y c yt otoxic. 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 w as not confirmed in two in vivo micronucleus assay s. iv. 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 th e limit dose of 5,000 mg/kg. Thus, dimethomorph was found to be negative in these studies for causing cy togenic damage in vivo. v. Dimethomorph was negative for inducing unscheduled DNA s ynthesis, in cultured rat liver cells, at doses up to 250  g/ml, a weakly cy totoxic level. vi. Dimethomorph was negative for transformation in Sy rian hamster embryo cells treated, in the presence and absence of activation, up to cy totoxic concentrations (265  g/ml/+S9; 50  g/ml/
- S9). 3. Reproductive and developmental toxicity

. i. A rat developmental toxicity study with a L owest - 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. Dime thomorph is not teratogenic in the Sprague
- Dawley

rat. ii. A rabbit development toxicity study with a LOELfor 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 of4

1000 ppm, or approximately 80 mg/kg/day , and a NOEL for parental s ys temic toxi city of 300 ppm, or approximately 24 mg/kg/day . The NOELfor 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
- ye ar 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 sy stemic toxicity is 750 ppm , or approximately 36 mg/kg/day

for males and 58 mg/kg/day

for females. ii. A 1
- ye ar chronic toxicity study in dogs with a NOEL of 450 ppm, or approximately 14.7 mg/kg/day

and a LOELof 1350, or approximately 44.6 mg/kg/day
. iii. A 2
- ye ar oncogenicity study in Sprague
- Dawley rats with a NOEL for sy stemic toxicity of 200 ppm, or approximately 9 mg/kg/day

for males and 11 mg/kg/day for females. The LOEL for sy stemic 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
- ye ar oncogenicity study in CD
- 1 mice with a NOEL for s ys temic 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 t ested. 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 sy stem. There is no information available that suggests that dimethomorph technical would be associated with endocrine effects. C. A ggregate 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 of5

dimethomorph. This analy sis included all currently proposed tolerances listed in U.S. 40 CFR § 180.493 and the proposed tolerances for grapes. 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 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 Databa se (FCID) was also used in Exponent's Dietary Exposure Evaluation Module (DEEM
- FCID) software. Inadvertent residues in animal commodities (i.e. meat, meat by products, milk, eggs) were not considered as a result of grain forage since studies have shown dim ethomorph does not accumulate in animal tissues or milk and tolerance values for these commodities are not required by the EPA. Dietary e xposure estimates were compared against the established dimethomorph chronic Population Adjusted Dose (cPAD) of 0.11 m g/kg b.w./day f or all populations. Results of the chronic dietary

a ssessments are listed in the table below. The estimated chronic dietary e xposure from crops (both established and proposed tolerances) was less than 25% of the cPAD for all subpopulations (Table 1). A dditional refinements such as the use of anticipated residues would further reduce the estimated chronic dietary e xposure. The results in the Table below demonstrate that there are no safety concerns for any subpopulation based on establishe d and new uses, and that the results clearl y 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 0.008577 7.8 All infants (< 1 year) 0.005436 4.9 Children 1
- 2 0.0162585 14.8 Children 3
- 5 0.013308 12.1 Children 6
- 12 0.0084945 7.7 Youth 13
- 19 0.0064905 5.9 Adults 20
- 49 0.00818175 7.4 Adul ts 50+ y

rs 0.00847875 7.7 Females 13
- 49 y

rs 0.007917 7.26 ii. Drinking water
. The chronic drinking water values used in this anal ys is were the values proposed by

E PA Federal Register Notice, September 29, 2003, Volume 68, No. 188. The chronic drinking water value used was 28.3 ug/L. Table 2. S ummary 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 P opulation 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+ y

rs 0.000497 0.45 Females 13
- 49 y

rs 0.0 0047 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 clearl y meet the FQPA standard of reasonable certainty

of n o 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 0.008577 0.000506 0.009083 8.3 All Infants (< 1 yrold) 0.11 0.005436 0.001658 0.007094 6.4 Children 1
- 2 years 0.11 0.0162585 0.000751 0.0170095 15.5 Children 3
- 5 years 0.11 0.013308 0.000703 0.014011 12.7 Children 6

– 12 years 0.11 0.0084945 0.000485 0.0089795 8.2 Youth 13
- 19 ye ars 0.11 0.0064905 0.000366 0.0068565 6.2 Females 13
- 49 years 0.11 0.00818175 0.000472 0.00865375 7.97

Adults 20
- 49 years 0.11 0.00847875 0.000497 0.00897575 8.2 Adults + 50 0.11 0.007917 0.00047 0.008387 7.6
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 b y dime thomorph 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 Oom ycet e fungi. The result is ly sis 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 no t indicate that dimethomorph is a particularl y 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.