# I
EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: [ShajaJoyner,**P~-20,** 

### (703)-308-3194] INSTRUCTIONS: Please utilize this outline inpreparingthe pesticide petition. In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please donot change the margins, font, orformat in your pesticide petition. Simply replace the instructions that appearin 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) ofthe 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 550F) [(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) ofFDDCA; however. EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support., granting ofthe petition. Additional data may be needed before EPA rules on the petition. A. Re\idue Chemistry
I

. Plant metaholi\m. [Based upon the results ofmetabolism studies conducted on potato, grape, and lettuce, the nature ofthe 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 cont rast to the aerial portions ofthe plant, which were found to have up to 23.5 ppm TRR, thus demonstrating that translocation ofdimethomorph downward within the plant was not significant. Almost all ofthe radioactive residue (97.8%) was extractable from the plant at harvest. In the aerial portion ofthe plant, approximately 70% oftheTRR was identified as dimethomorph. No metabolites were identified that require regulation. The results ofthe grape metabolism st udy showed that the TRR inion grapes harvested 35 days following the last offour applications 

### l0.8 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% ofthe TRR (12.7 ppm). No



# ..2 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 w i th a 9 to I I day spray interva iJ , for a total rate of 4. 1 l b a i /A, was 102 ppm. Of this tota l r esidue, 98.5% was extractab l e a n d unmetaboliLed dime th omorph 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 metabo l ism 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 t he FDA Multi - Residue Method, Protocol D, as published in the Pesticide Analytical Manua l 1 . The determ i nation of the dimethomorph

residues in papaya was perfmmed according to the analytical BASF Method No. 535/1 (identical with Method No. 575/0). The fina l determination of BAS 550 F was performed by LC-MS/MS. The limit of quant i tation (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 I mported Commodities in the United States and Canada. which lists the number of field trai l s needed for a US Import Tolerance. Field trials were carried out using the maximum l abel rates, t he maximum number of applications. and the minimum pre-harvest interval (PHI) for all the crops. Detected residues of Dimethomorph in papaya support the proposed to l erance.] B. Toxicological Profile I. Amte to:-:il it.\. [i. Oral LD50 studies were conducted o n dimethomorph technica l : 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 fema l es. 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 di m ethomorph technical i s Category III or s l ight l y 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 LD 50 greater than 5,000 mglkg b.w. fo r 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 LD 50 greater than 5,000 mglkg b.w. for both males and fema l es.3
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 orrelatively 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 orrelatively 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. 

### li. Salmonella reverse gene mutation assays (2 studies) were negative up to a limit dose of5,000 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 ofS9 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 ofmice following i.p. administration of doses up to 200 mglkg or oral doses up to the limit dose of5,000 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 ofactivation, up to cytotoxic concentrations (265 J..Lg/rnlf+S9; 50 J..Lg/rnJJ-S9).]

3. Reproductil·e andde\·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 of60 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 of650
. mg/kg/day and a NOEL for maternal toxicity of300 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 parental4 systemic toxicity of 300 ppm, o r approximately 24 mglkg/day. The NOE L 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 h i ghest concentrat i on tested. or approximate l y 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 approximate l y 15 mglkg/day, and a L OE L of 1350 ppm, or approximate l y 43 mglkglday.] 5 ( lmmic toridt\ ( i . A 2-year ch r onic toxicity s tu dy 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 fema l es. The LOEL for systemic toxicity is 450 ppm, or approximate l y 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 ra t s with a NOEL for systemic toxicity of 200 ppm, or app r oximate l y 8.8 mglkg/day for ma l es and 1 1. 3 mg/kg/day for females. T h e LOEL for systemic toxicity was 750 ppm, or approximately 33.9 mglkg/ d ay for m a l es and 46.3 mg/kg/day for females. T here was no evidence of increased inc i dence of neoplastic l es i ons in treated animals. The NOEL for oncogenicity is 2000 ppm, the highest concentration tested, or approximately 94.6 mglkg/day for males and 1 32.5 mg/kg/da) for females. iv. A 2-year oncogenicity study in CO-l mice with a NOEL for systemic toxicity of 1 00 mglkg/day and a LOEL of 1,000 mglkg/day. There was no evidence of inc r eased incidence of neoplastic lesions in treated animals. The NOEL for oncogenicity i s 1 ,000 mglkg/day. the highest dose tested. v. A subch r onic neurotoxicity s t udy i n Wistar rats with a NOEL of 432.9 mglkg/day i n males or 5 1 0. 1 mg/kg/day in females. There was no evidence of neurotoxicity.

vi. A subchronic immunotox i c i ty study i n 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 l ivestock and rat metabolism studie s show that orally administered dimethomorph was rapidly excreted by the animals. The · principal route of e l imination is the feces.j 7 Mt'Wholite to\icologv. [ T here were no metabolites i dent if ied 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 anima l species. demonstrate no apparent estrogenic effects or effects on the endoc r ine system. There is no infonnation available5
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 ofthe U.S
. population and sub-populations t o 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. ChronicDietary Exposure Assessment A Tier 1chronic dietary exposure assessment was conducted assuming tolerance level residues and 100% crop t reated factors for all registered crops and the proposed impmt tolerance for papaya. The EPA Food Commodity I ngredient Database (FCID) was also used in Exponent's Dietary Exposure Evaluation Module (DEEM-FCID) software. Inadvertent residues in animal commodit ies (i
.e. meat, meat byproducts, milk, eggs) were not considered as a result ofgrain 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% ofthe 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 ofreasonable certainty ofno harm. 

### Table 1. 

### Summary of Chronic Dietar y 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::hildren 1-2 0.025248 23.0 k::hildren 3-5 0.021213 19.3 k::hildren 6-12 0.011995 10.9 

## IYouth 13- 19 0.008257 7.56 A dult s 20-49 0.011809 10.7 !Adults 50+ yrs 0.01209 3 11.0 !Females 1 3 - 49 yrs 0 . 011404 10.4 ii **DrinJ..in~ ~~oft**  r [ T h e chro n ic dri nking water values used in thb analysis were the va l ues p ro p osed b y E P A, S e pt e mb e r 1 5, 20 11 , " Di met h o m orph: H um an Hea l th Risk Assessment to Suppott Ameneded Use o n Grapes, B u l b Vegetables, Leafy B rassica Vegetab l e s and Leafy Vegetables". The c h ronic drinking water value used was 24.7 ug!L. Tabl e 2. Summar y of Chronic Drinking Water E xpo s ure A s sessment Con s id e rin g th e Maximum Es timated Chroni c Drinkin g Water C on ce ntration fo r Dim e thomorph . P opulation s ub - group Chroni c E xposur e ( mglk g bw / da y) %c PAD IUS Popula t ion 0 . 000517 0 . 47 IAII infan ts(< 1 y ear ) 0 . 001334 1.21

C hildr e n 1-2 0 . 000746 0 . 68 C hildren 3 -5 0 . 000629 0 . 57 K: bildren 6-12 0 . 00045 3 0.41 IY outb 13-19 0 . 000377 0.34 !Adults 20 - 49 0.000516 0 . 4 7 Adults 50+ y r s 0 . 00051 0 . 46 F e mal es 1 3 - 49 y r s 0.000514 0 . 47 Acute Aggregate Exposure and R isk (Food and water) Since the U.S. EPA Toxicological Endpoint Selection (TES) Committees has evalua t ed the d i methomorp h toxicity data and detennined there was no toxicologic endpoints for acute d i etary exposure, t h e determ in ation of an acute aggregate exposure a n d risk

eva l uation was not re q u i red. Chronic Aggregate Exposure and R isk (food and water) The aggregate chronic risk include!-. residues of dimethomorph from food and water {Table 3). Exposures f r om reside n tial uses are not included in the chronic aggregate assessment. The results demo n st r a t e there are no risk concerns fo r any subpopulation based on established and new uses, and that the results clearly mee t the FQPA standard of reasonable certainty of no h arm . T abl e 3. Es timated C hronic Aggregate E xpo s ur e and Ri s k for Dimethomorpb . Food Water Total Population cPAD Exposure E xpo s ur e Expo s ur e S ubgroup ( mg!kg!day ) { mglkg!day ) ( mg!kg!da y) { mglkg!da y) % cPAD U.S. Population 0 . 11 0.012279 0.000517 0.012796 11 . 6 All Infants ( < 1 y r 0.11 0.009332 0 . 001334 0.010666 9 .77
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 13-19years 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 0.01 2603 11.5 Adult s + 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 ofaction of

**dime~omorph** is unique; dimethomorph inhibits cell wall fmmation only in Oomycete fungi. The result is lysis ofthe cell wall that kills growing cells and inhibits spore formation in mature hyphae. This unique mode ofaction 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 onthis risk assessment, BASFconcludes that there is a reasonable certainty that no risk concems to the general population from the aggregate exposure to dimethomorph residues.] 2. 11 (£ ,. II' 1children [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 ofi ntemational hrumonization is not relevant]