EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Shaunta Hill , (703) 3 47 - 8961 0F7751 EPA has received a pesticide petition ( 0F 7751 ) from BASF Corporatio n, 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 dim ethomorph [(E,Z)4 - [3 - (4 - chlorophenyl) - 3 - (3,4 - dimethoxy phen yl ) - 1 - oxo - 2 - propenyl] - morpholine] 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. 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 o f the potato metabolism study show onl y 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 identifie d 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 day s following the last of four applications [0.8 lb active ingredient per acre (ai/A) per a pplication 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 Analy

tical Manual I .3. Magnitude of residues . Supervised field trials were carried out to determine the

magnitude of the residue in/on grapes ;. The numbe r 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 residue s of Dimethomorph in all crops support the proposed 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 t echnical 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

I II or slightly toxic. b. An a cute 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 LD 50 studies 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 gre ater 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 relativel y non - toxic. iv. A 4 - hour inhalation study in Wistar rats for dimethomorph t echnical with a L C 50 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 relativel y non - toxic. v. A skin irritation study

was pe rformed 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 - slightl y irritating. vi. An eye irritation study using New Zealand White ra bbits 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 Cate gory III (slightly - to - moderately irritating) 2. Genotoxicty . 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 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 increasingchromosome aberrations in this test sy stem. 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 lymphocyti c cultures, but only

in S9 activated cultures treated at 422  g/ml, the highest dose tested (HDT), which was strongly cy totoxic. No increase in chromosomal aberrations was observed in the absence of S9 activation at all doses. Furthermore, the positive c lastogenic response observed under the in vitro conditions was 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 the 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, i n cultured rat liver cells, at doses up to 250  g/ml, a weakl y cy totoxic level. 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; 5 0  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 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 of 1000 ppm, or a pproximately

80 mg/kg/day , and a NOEL for parental s ys temic 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. Sub chronic 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 w ith 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 s ys temic 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 LOEL of 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 forfemales. 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/k g/day

for males and 132 mg/kg/day for females. iv. A 2 - ye ar oncogenicit y 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 ani mals. The NOEL for oncogenicit y 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 rapidl y excreted b y the animals. The principal ro ute 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 s ys tem. There is no information available that sugges ts 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 - populati ons to residues of 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 treat ed factors for all registered and proposed crops. The EPA Food Commodity In gredient Database (FCID) was also used in Exponent's Dietary Exposure Evaluation Module (DEEM - FCID) software. Inadvertent residues in animal commodities (i.e. meat, meat by product s, 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 comp ared 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 wouldfurther reduce the estimated chronic dietary exposure. The results in the Table be low demonstrate that 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 no harm. Table 1. S ummary of Chronic Dietary Exposure Assessment con sidering crops with established and proposed tolerances for Dimethomorph.

Population sub - group Chronic Exposure (m g/kg bw/day) %cPAD US Population 0.0143730 13.5 All infants (< 1 year) 0.00 8336 0 9.1 Children 1 - 2 0.0261150 24.4 Children 3 - 5 0.0 21707 0 2 0.4 Children 6 - 12 0.0 14415 0 13.5 Youth 13 - 19 0.0 11483 0 10.8 Adults 20 - 49 0.0 13969 0 13.1 Adults 50+ yrs 0.013738 0 12.9 Females 13 - 49 yrs 0.0 13301 0 12.5 ii. Drinking water . The chronic drinking water values used in this analysis were the values proposed b y EPA 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 Wate r Concentration for Dimethomorph.

Population sub - group Chronic Exposure (m g/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 dimeth omorph 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 an y subpopulation based on establi shed and new uses, and that the results clearl y meet the FQPA standard of reasonable certainty of no harm. Table 3. Estimated Chronic Aggregate Exposure and Risk for Dimethomorph. Population Subgroup cPAD (m g/kg/day) Food Exposure

(m g/kg/day) Water Expo sure

(m g/kg/day) Total Exposure

(m g/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 0.02170 7 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 2. Non - dietary exposure . Dimethomorph is not registered for use on an y sites that would result in residential exposure. Therefore, a residential exposure and risk assessment was not conducted . D. Cumu lative Effects There is no information to indicate that any toxic effects produced b y dimethomorph would be cumulative with those of an y other chemical. The fungicidal mode of action of dimethomorph is unique; dimethomorph inhibits cell wall formation only in Oomycete fungi. The result is ly sis of the cell wall that kills growing cells and inhibits spore formation in mature hy phae. This unique mode of action and limited pest spectrum suggest that there is little or no potential for cumulative toxic ef fects in mammals. In addition, the toxicity studies submitted to support this petition do not indicate that dimethomorph is a particularl y toxic compound. No toxic end - points of potential concern were identified. E. Safety Determination 1. U.S. po pulation . 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 dim ethomorph for the commodities associated with this request; consequently , a discussion of international harmonization is not relevant.