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# a**~** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

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### D.C. 20460**~** -<:-0 -4t PAO'Tf-C

MEMORANDUM

DATE: January 3 1 ,2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Dim.ethomorph: Hum an Health Assessment Seeping Document in Support of Registration Review.

PC Code: 268800 Decision Nos.: 47 1 598 Petition Nos.: NA Risk Assessment Type: Single Chemica l Aggrega te TXRNo.: NA MRIDNo.: NA DP Barcodes: D4066 61 Registration No.: 241-427 Regulatory Action: Re g i stration Review Case No.: NA

CAS No.: 110488-70-5 40 CFR: 180.493

FROM: SheilaPiper,Chemist

# ~~Jv~**·** .

# ~ Yung Yang, Ph.D., Toxicolo g i st 

# 6-- hti

. " Monica Hawkins, Ph.D.

, M.P.H.

, E v ironme al Health Scie nti st

## ~"'**~~** Risk Assessment Branch VI Health Effec t s Di v ision (7509P)



### THROUGH: Christine Olinger, Acting Branch C hief

# ~ / 

# L_</ /

Risk Assessment Branch VI

### ~ C7 

# 7'(--

Health Effects Division (7509P)

TO: Monica Wait, Chemical Review Manager Avivah Jak ob, Team Leader Pe sticide Re-Evaluation Division (7505P) Risk Management & Implementati on Branch 3 (RMIB3)

Executive Summary

The Health Effects Division Dimethom orph Risk Assessment Team h as eva luated the databa se and the most recent hum an health risk assessment for the fungicide dimethomorph. HED performed thi s evaluation in order to determine the sco p e of work necessary to s upport th e established tolerances and existing regi strations. The primary so urc e of information for this

eva lua t ion was the most recent human health risk assessment written for dimethomorph (Memo, D387381, S. Piper

, 09 / 15 / 20 11).

Page 1 of 16

### Dimethomorph

Page 2 of 16 Dimethomorph is a systemic mor pholine fungicide developed for c ontrol of downy mildews, late blights, and crown and root rots for grapes, potatoes, tomatoes, and other vegetables. Its mode of action is via inhibition of sterol (ergosterol) synthesis. Exposures can be expected to occur via the dietary, drinking water, and o ccupational routes for dimethomorph.

The toxicology database for dimethomorph is complete; no additional data are required to support the registration review. An acute neurotox icity study has recently been received and the endpoints/doses will be evaluated for risk assessment during the Registration Review. Dimethomorph has low acute toxicity by the oral, de rmal, or inhalation route of exposure. It is not an eye or skin irritant, and is not a skin se nsitizer. There is no evidence that dimethomorph is a neurotoxic, teratogenic, re productive, carcinogenic, mutage nic or immunot oxic chemical. Dimethomorph is classified as "not likely to be carcinogenic to huma ns" based upon lack of evidence of carcinogenicity in rats and mice.

There is no evidence for increased quantitati ve or qualitative susc eptibility of the young following in utero and pre-and post-natal exposure to di methomorph based on the results from developmental studies conducted with rats and rabbits, as well as a two-generation reproduction study conducted with rats. The risk assessment team concluded that the 10-fold FQPA Safety Factor can be reduced to 1.

The dietary exposure database is adequate to support the regist ration review of dimethomorph. An acute endpoint was not selected for dimethom orph; therefore, the Agency conducted only a chronic dietary (food and drinking water) exposur e and risk assessment. Based on the current uses of dimethomorph and HED’s policies a nd procedures for performing dietary risk assessment, no population subgroups have chronic diet ary risk estimates that are of concern to HED.

There are currently no registered residential uses associated w ith dimethomorph; therefore, no short- and intermediate-term aggreg ate risk assessments are required.

The occupational exposure databa se is adequate to support the registration review process for dimethomorph. In accordance with the updated Pa rt 158 data requirements (2007), one or more Dislodgeable Foliar Residue (DFR ) studies are required when a pesticide has residential or occupational uses that could re sult in post-applicati on dermal exposure. Based on HED policy, a DFR study is not required for dimethomorph at th is time. The requirement of a DFR study may need to be reconsidered if application rates, us e patterns, or points of de parture change. In the 2008 and 2000 exposure assessments, all of the non-cancer occupationa l handler and postapplication risk estimates were below the Agen cy’s level of concern. No new occupational handler or post-application worker studies are needed at this time . Revised occupational handler assessments would be based upon revisions to the Agency’s scenario-speci fic surrogate handler exposure data ( http://www.epa.gov/pesticides/sci ence/handler-exposure-table.pdf ).

Introduction

HED evaluated the most recent human health risk assessments for dimethomorph in association with the available toxicity, exposure, and usage information to determine if sufficient data are available and if further updates are needed to support registration review . Recent human health

### Dimethomorph

Page 3 of 16 risk assessments include a 2011 assessment fo r the use of dimethomorph on grapes, bulb vegetables, leafy Brassica vegetables and leafy vegeta bles (Memo, D387381, S. Piper 09/15/2011). In performing this risk assessment, HED considered the latest Agency science policies and risk assessment methodologies.

Dimethomorph is a systemic morpholine fungici de and was developed for control of downy mildews, late blights, crown and root rots . The structure and chemical properties of dimethomorph can be found in Attachment 1. Its mode of action is the inhibition of sterol (ergosterol) synthesis. It is currently registered for use on bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy Brassica greens, head and stem Brassica vegetables, hops, lettuce, potatoes, taro, grapes, and gi nseng. The registered appli cation methods for dimethomorph include the use of aerial and ground equipment.

Tolerances are established for residues of dimethomorph in or on food commodities under 40 CFR § 180.493. Tolerances are established for the indirect or inadvertent residues of dimethomorph under 40 CFR §180.493(d) in/on cereal grain commodities. These tolerances are summarized in Attachment 5, along with the International Residue Limits. The residue of concern for the tolerance expression and risk assessment is the parent compound, dimethomorph (comprised of E and Z isomers).

Hazard Identification/Toxicology

The toxicology database for dimethomorph is co mplete; no additional data are required. An acute neurotoxicity study has recently been subm itted to the Agency and will be evaluated during Registration Review.

Dimethomorph has low acute toxicity by the oral, de rmal, or inhalation route of exposure. It is not an eye or skin irritant, and is not a skin se nsitizer. There is no evidence that dimethomorph is a neurotoxic, developmental, re productive, carcinogenic, muta genic or immunotoxic chemical. For endpoint selection, there is no appropriate toxicity endpoint available to quantitate risk from a single exposure to dimethomorph. Consequently, there is no acute reference dose (aRfD). The chronic reference dose (cRfD) is based on decreas ed body weights and liver effects in females of a chronic/carcinogenicity study in rats. The short- and intermediate-term dermal endpoint is not selected since there is no dermal or syst emic toxicity observed at the limit dose (1000 mg/kg/day) in a repeated dose de rmal toxicity study in rats an d there are no developmental, reproductive of neurotoxic concerns. The Point of Departure (PODs) for short-term inhalation exposure risk assessment is based on decr eased body weight, body weight gain and food consumption in a developmental toxicity study in rats. The POD for the intermediate-term inhalation exposure risk assessment is based on decr eased prostate weight and liver effect in a subchronic oral toxicity study in dogs. At this time, ther e are no residential uses for dimethomorph. Therefore, discussion of risk via the exposure from the dermal and inhalation routes are unnecessary for th is risk assessment with resp ect to residential exposures. Dimethomorph is classified as "not likely to be carcinogenic to humans" based upon lack of evidence of carcinogenicity in rats and mice. Therefore, a cancer ri sk assessment is not required.

There is no evidence for increased quantitati ve or qualitative sus ceptibility of the young following in utero and pre-and post-natal exposure to di methomorph based on the results from developmental studies conducted with rats and rabbits, as well as a two-generation reproduction

### Dimethomorph

Page 4 of 16 study conducted with rats. The risk assessment team concluded that the 10-fold FQPA Safety Factor to be reduced to 1.

Metabolism studies in the rat indicate that di methomorph is extensively absorbed, metabolized and excreted through the urine and feces ( 80-90%). Retention of dimethomorph or [ 14 

### C]- dimethomorph-derived radioactivity was generally  1% for most tissues although the liver exhibited slightly higher levels (1.4%) and higher levels in the ga strointestinal tract organs was due to radioactivity in the lumenal contents. Ur inary metabolites resulted from demethylation of the dimethoxyphenyl ring and oxidation of the morpholine ring.

Conclusions for Hazard Identification/Toxicology

The toxicology database for dimethomorph is complete; no additional data are required. However, an acute neurotoxicity study has been received and the endpoints/doses will be evaluated for risk assessment during the Regi stration Review. The selected PODs and toxicological endpoints from the most recent human health risk assessment are summarized in Attachment 5.

Dietary Exposure

The existing residue chemistry database for di methomorph is adequate for risk assessment purposes. As stated above, dimethomorph is regi stered for use on a wide variety of crops, and permanent tolerances have been established (40 CFR § 180.493) ranging from 0.05 ppm to 60 ppm in plant commodities. Tolerances are establis hed for the indirect or inadvertent residues of dimethomorph under 40 CFR §180.493(d) in/on cerea l grain commodities. Based on the results of metabolism studies in ruminants and poultry, and a cattle feeding study , tolerances are not required for residues in meat, m ilk, poultry nor eggs as a result of ingestion of dimethomorph residues in the livestock feed. A cceptable analytical methods are av ailable to enforce tolerances for residues of dimethomorph in plant commodities.

An unrefined dietary risk assessment was completed in 2011 (S. Piper, D393434, 09/07/2011). HED used the Dietary Exposure Evaluation Mo del (DEEM-FCIDTM Version 2.03) to conduct the most recent chronic aggregate dietary (food and drinking water) risk assessments for dimethomorph. This model incorporates consum ption data from the USDA’s Continuing Survey of Food Intakes by Individuals taken betw een 1994 and 1996 along with a supplemental children’s survey taken in 1998.

For the most recent dietary risk assessment, EFED provided conservative estimated drinking water concentrations in surface water, from Tier 1 FIRST modeling that were based on applications of the chemical to broccoli. In the Preliminary Problem Formulation memo (D406660) EFED described an unidentified degrad ate recovered at up to 16% of the applied radioactivity in aerobic aquatic metabolism. During registration review , HED will consult with EFED and determine whether the unidentified degradate should be considered in the drinking water component of the diet ary exposure assessment.

HED has not previously identified a toxicological endpoint attribut able to a single exposure of dimethomorph; therefore, an acute dietary e xposure assessment was not conducted. However, the registrant recently submitted an acute neur otoxicity study, which will be evaluated during

### Dimethomorph

Page 5 of 16 registration review for a potential acute POD.

The unrefined chronic dietary analysis for dime thomorph is a conservative estimate of dietary exposure with tolerance level residues and 100% crop treated. The risk estimate from chronic dietary exposure to dimethomorph as represen ted by the % population adjusted dose (PAD) is below HED’s level of concern for the U. S. population (14% cPAD) and all population subgroups.

Conclusions for Dietary Exposure

The dietary exposure database is adequate to support the existing registrati ons and tolerances. No new residue chemistry data are required. An updated dietary assessment will likely be conducted during registration review if an acute POD is identified from the recently submitted neurotoxicity study. Furthermore, the residues of concern in drinking water may be updated as well, and incorporated into th e dietary exposure assessment.

Residential Exposure and Risks There are no residential uses for dimethomorph; therefore, a residential exposure assessment will not be required.

Residential exposures resulting from off-site tr ansport (e.g., spray drift or volatilization) may occur as a result of applications of dimethomorph. The Agency is in the process of evaluating these types of exposures and will examine the need for spray drift and vol atilization assessments for dimethomorph during registration review.

Conclusions for Residential Exposure and Risks

Currently, there are no uses for dimethomorph that would result in direct residential exposure. However, residential bystander i nhalation exposures resulting from off-site transport (e.g., spray drift or volatilization) may occu r as a result of applications of dimethomorph. The need for a bystander inhalation risk assessment for dimethomorph will be examined during registration review.

Aggregate Risk Assessment

There are currently no register ed residential uses, nor are any proposed for dimethomorph. Therefore, at this time, dietar y (food + water) exposure is the only component of an aggregate exposure analysis and risk assessment.

Occupational Exposure and Risks

Dimethomorph is currently registered for use on a variety of agricultural vegetable, fruit, grain and forest trees, herbaceous plants, ornamentals (flowering and foliage types, herbaceous and woody types, ground cover), woody shrubs and vines, trees and ferns. It is applied by groundboom, aerially, and by chemigation.

### Dimethomorph

Page 6 of 16 Occupational Handlers and Post-Application

Prior occupational and residentia l exposure assessments for dime thomorph did not identify any risk estimates of concern (MOEs ≥ 100) at baseline PPE (or minimum REI for post-application) for workers. Recently, HED received a dermal toxi city study and no toxicity was observed up to the limit dose. Since no toxicity was observe d at the limit dose, a quantitative occupational dermal risk assessment for short- and interm ediate-term exposure is no longer necessary (D387381, S. Piper 09/15/2011). Future quantita tive risk assessments will only consider occupational inhalation exposure.

Conclusions for Occupational Exposure and Risks

The occupational exposure databa se is adequate to support the registration review process for dimethomorph. In accordance with the updated Pa rt 158 data requirements (2007), one or more DFR studies are required when a pesticide has resi dential or occupational uses that could result in post-application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment

, HED analyzed a number of DFR studies and select ed a new default value for the fraction of the application rate available to be di slodged after a fo liar application (F AR 

### ). This default value is 25% and is based on an analysis of 19 DFR studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupa tional post-application assessments. Of the analyzed DFR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged re sidue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific DFR study ( Guidance for Requiring/Waiving Turf Transfe rrable Residue (TTR) and Disl odgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council ). For dimethomorph, a DFR study is not required at this time since the dermal MOE is gr eater than 400 based on default values for the fraction of application rate available for transfer after a foliar application. The requirement of a DFR study may need to be reconsidered if applica tion rates, use patterns, or points of departure change. Updated occupational handler exposure assessments may be required under registration review based upon revisions to the Agency’s scen ario-specific surrogate handler exposure data (http://www.epa.gov/pesticides/sci ence/handler-exposure-table.pdf). An occupational postapplication assessment may also be required under registration review if toxicological endpoints change or other new data are received by the Agency that impact exposure estimates.

Public Health and Pesticide Epidemiology Data

An updated review of dimethomorph incident re port was recently prepared by HED (S. Recore, D406665, 10/15/2012). For this evaluation, the OPP Incident Data System (IDS) indicated no incidents involving dimethomorph. Only one case (classified as low severity) was reported for dimethomorph to the NIOSH SENSOR-Pesticide database; and dimethomorph is not being included in the Agricultural Health Study (AHS).

The Agency will continue to monitor the incide nt information and if a concern is triggered, additional analysis will be incl uded in the risk assessment.

### Dimethomorph

Page 7 of 16 Tolerance Assessment and International Harmonization

Tolerances are established in 40 CFR §180.493 fo r residues of the fungicide dimethomorph in/on various raw agricultural comm odities (RACs). Tolerances ar e established for the indirect or inadvertent residues of dimethomorph under 40 CFR §180.493(d) in/on cereal grain commodities (see Attachment 6). There are currently no Canadian or Mexican maximum residue limits (MRLs) for residues of dimethom orph, but Codex MRLs have been established for grapes and raisins. The Codex MRLs fo r grapes (2 ppm) and raisins (5 ppm) are not harmonized with the established US tolerances in grapes (4 ppm) and raisins (6 ppm). The Agency cannot decrease the tolerance in grape to 2 ppm because the field trials conducted at the maximum application rate result ed in residues as high as 2.55 ppm. The current tolerance definition for dimethomorph (40 CFR §180.493) is appropriate regarding scope and compliance.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.epa.gov/compliance/resour ces/policies/ej/exec_order_12898.pdf

. 

### The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health ri sk assessments, including, but not limited to, people who obtain drinking water fro m sources near agricultural ar eas, the variability of diets within the U.S., and people who may be expos ed when harvesting crops. Should these high exposures indicate potential risks of concern, OPP will further refi ne the risk assessments to ensure that the risk estimates are ba sed on the best available information.

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental, and repr oductive effects in different taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and selected the most sensitive endpoi nts for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), dimethomorph is subject to the endocrine screening part of the Endocri ne Disruptor Screeni ng Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal

### Dimethomorph

Page 8 of 16 systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredients and 9 inert ingredients. Dimethomorph is not among the group of 58 pesticide active ingred ients on the initial list to be screened under the EDSP. Accordingly, as part of registrati on review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP scr eening assays for dimethomorph. For further information on the status of the EDSP, the polic ies and procedures, the list of 67 chemicals, future lists, the test guidelines , and the Tier 1 screening batt ery, please visit EPA’s website: http://www.epa.gov/endo/

.

Cumulative Risk Assessment

The Food Quality Protection Act (FQPA) requires th e Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxic ity. The Agency determined that there was insufficient evidence to suggest dimethomorph sh ares a common mechanism of toxicity with other chemical substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity a nd to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Program concerning common mechanism determinations and procedur es for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Data Requirements

At this time, the Agency does not anticipate that additional residue chemistry, toxicology, or occupational/ residential exposure data will be re quired for the registration review process of dimethomorph.

References

DP#: 387381 Subject: Dimethomorph. Human Health Ri sk Assessment to Support Amended Use on Grape, Bulb Vegetables, Leafy Brassica Vegetables, and Leafy Vegetables. From: S.Piper, Y. Yang, and M. Hawkins To: T. Gibson, M. Waller Date: 09/15/11 MRIDs: NA

### Dimethomorph

Page 9 of 16 DP#: 349253 Subject: Dimethomorph. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Proposed Amended Uses for Grapes, Leafy Vegetables, Leafy Brassica Vegetables and Bu lb Vegetables. From: S.Piper To: T. Gibson, M. Waller Date: 09/07/11 MRIDs: NA

Attachments Attachment 1: Chemical Identity Table Attachment 2: Physical/Chemical Characteristics Attachment 3: Toxicology Data Requirement Attachment 4: Toxicity Profile for Dimethomorph Attachment 5: Dimethomor ph Endpoint Selection Table Attachment 6: Internatio nal Residue Limit Status

### Dimethomorph

Page 10 of 16 Attachment 1: Chemical Identity Table

Chemical Identity

Chemical structure

Common name Dimethomorph Company experimental name BAS 550F IUPAC name ( E,Z )-4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine CAS name 4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morpholine CAS registry number 110488-70-5 End-use product (EP) BAS 550 11F (FORUM® Fungicide (4.17 ai/gal SC formulation); EPA Reg. No. 241-427)



### Attachment 2: Physical/C hemical Characteristics

Physical and Chemical Properties

Parameter Value Reference Melting point/range 125-149oC DP# 316328, 7/18/05, W. Cutchin pH Not applicable; not soluble in water Density 1.318 g/cm 3 at 20oC Water solubility (20oC) water, pH 5 19 mg/L water, pH 7 18 mg/L water, pH 9 16 mg/L Solvent solubility (20oC) n-hexane 0.11 mg/mL methanol 39.0 mg/mL toluene 49.5 mg/mL acetone 100 mg/mL dichloromethane 461 mg/mL Vapor pressure E-isomer: 9.7 x 10 -7 Pa at 25oC Z-isomer: 1.0 x 10 -6 Pa at 25oC Dissociation constant, pK a Not determinable (the solubility of dimethomorph is very low, and the ionized and nonionized forms have identical absorption coefficients) Octanol/water partition coefficient, Log(K O W ) E-isomer: K ow = 430 (log K ow = 2.63) at 20oC Z-isomer: K ow = 543 (log K ow = 2.73) at 20oC UV/visible absorption spectrum Not available OCH 3

OCH 3 Cl O N O

### Dimethomorph

Page 11 of 16 Attachment 3: Toxicology Data Requirement

Test Technical

Required Conducted

870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (non-rodent) 870.3200 21/28-Day Dermal 870.3250 90-Day Dermal 870.3465 90-Day Inhalation yes yes yes

no

no yes yes yes

no

no 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (non-rodent) 870.3800 Reproduction yes yes yes yes yes yes

870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (non-rodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes yes yes yes yes 870.5100 Mutagenicity—Gene Mutation (bacterial) 870.5300 Mutagenicity—Gene Mutation (mammalian) 870.5375 Mutagenicity—Structural Chromosomal Aberrations 870.5395 Mutagenicity—Other Genotoxic Effects 870.5500 Mutagenicity—Other Genotoxic Effects yes yes yes yes yes yes yes yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90-Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90-Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity no

no yes yes

no no

no yes yes

no

870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

no yes yes

yes yes

1 The acute neurotoxicity study is not required at this time.



### Attachment 4: Toxicity Profile for Dimethomorph

Acute Toxicit y Profile for Dimethomorph.

Guideline Number Stud y T y pe MRID(s) Results Toxicit y Category 870.1100 Acute oral [Rat] 42233902 LD 50 = 3900 (3300-4500) m g /k g (M,F) III 870.1200 Acute dermal [Rat] 42233903 LD 50 ≥ 5000 m g /k g IV 870.1300 Acute inhalation [Rat] 42233904 LC 50 ≥ 4.24 m g /L III 870.2400 Acute e y e irritation [Rabbit] 42233905 Con j unctival irritation clearin g in 4 da y s III 870.2500 Acute dermal irritation [Rabbit] 42233907 N o irritation reporte d IV 870.2600 Skin sensitization [Guinea pi g ] 42233906 N ot a sensitize r

### Dimethomorph

Page 12 of 16 Subchronic, Chronic and Other Toxicit y Profile for Dimethomor p h. Guideline Number/ Stud y T yp e MRID(s) [ y ear]/ Classification/Doses Results

870.3100 90-Day oral toxicity [dog] 42233908 [1991] Acceptable/guideline 0, 150, 450, 1350 ppm M: 0, 5, 15, 43 mg/kg/day F: 0, 6, 15, 44 mg/kg/day N OAEL = 15 mg/kg/day LOAEL = 43 mg/kg/day based on decrease in the absolute and relative weights of the prostate and possible threshold liver effects.

870.3150 90-Day oral toxicity [rat] 42233910 [1991] Core minimum 0, 40, 200, 1000 ppm M: 0, 2.9, 14.2, 73 mg/kg/day F: 0, 3.2, 15.8, 82 m g /k g /da y N OAEL >73/82 [M/F] mg/kg/day LOAEL was not established in this study, because the highest dose tested produced no biologically significant effects.

870.3200 28-day dermal toxicity [rat] 48326908[2010] Acceptable/guideline 0,100,300,1000 mg/kg/day 6 hr/day 5day/wk [M/F] N OAEL=1000 mg/kg/day [M/F] No effects seen at the limit dose

870.3700a Prenatal developmental [rabbit] 42233918 [1989] Unacceptable/core supplemental [Initial rating] 0, 135, 300, 650 mg/kg/day Maternal N OAEL = 300 mg/kg/da y LOAEL = 650 mg/kg/day based on an increased incidence of abortion confirmed in a range-finding study. Developmental NOAEL could not be determined. LOAEL could not be determined. 870.3700b Prenatal developmental [rabbit] 44175303 Acceptable Information supplemental to MRID# 42233918 Maternal N OAEL = 300 mg/kg/da y LOAEL = 650 mg/kg/day based on an increased incidence of abortion confirmed in a range-finding study. Developmental NOAEL =650 mg/kg/day [highest dose tested]. LOAEL could not be determined - no effects observed at highest dose tested. 870.3700c Prenatal developmental [rat] 42233919 [1989] Unacceptable/core supplemental [Initial rating] 0, 20, 60, 160 mg/kg/day Materna l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body weights and body weight gain. Developmenta l NOAEL could not be determined LOAEL = could not be determined. 870.3700 d Prenatal developmental [rat] 44175302 Acceptable Information supplemental to MRID# 42233919 Materna l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on reductions in food consumption, mean body weights and body weight gain. Developmenta l NOAEL = 60 mg/kg/day LOAEL = 160 mg/kg/day based on the incidence of post implantation loss 870.3800 Reproduction and fertility effects [rat] 42233920 [1990] Acceptable/guideline 0, 100, 300, 1000 ppm Parental/S y stemic N OAEL = 300 pp m LOAEL = 1000 ppm based on decreased body weights and body weight gains. Reproductive NOAEL = 300 ppm LOAEL = 1000 ppm based on decreased incisor eruption on day 10 postpartum. Offspring NOAEL was not reported LOAEL was not reported. 870.4100a Chronic toxicity [rat] 42233912 [1991] Acceptable/guideline 0, 150, 450, 1350 ppm M: 0, 9.4, 36.2, 99.9 mg/kg/day F: 0, 11.9, 57.7, 157.8 mg/kg/day N OAEL = 36.2/11.9 [M/F] mg/kg/day LOAEL = 57.7/99.9 [M/F] mg/kg/day based on decreased body weight and increased inci dence of arteritis in male rats and decreased body weight and significant increased incidence of "ground-glass" foci in the liver in female rats.

870.4100b Chronic toxicity [dog] 42233911 [1991] Acceptable/guideline 0, 150, 450, 1350 ppm M: 0, 4.9, 14.7, 44.6 mg/kg/day N OAEL = 14.7 mg/kg/da y LOAEL = 44.6mg/kg/day based on decreased prostate weight.

### Dimethomorph

Page 13 of 16 Subchronic, Chronic and Other Toxicit y Profile for Dimethomor p h. Guideline Number/ Stud y T yp e MRID(s) [ y ear]/ Classification/Doses Results

F: 0, 5.0, 15.7, 47.0 mg/kg/day 870.4200 Carcinogenicity [rat] 42233916 [1991] Acceptable/guideline 0, 200, 750, 20000 ppm M: 0, 8.8, 33.9, 94.6 mg/kg/day F: 0, 11.3, 46.3, 132.5 mg/kg/day N OAEL [systemic] = 33.9/11.3 [M/F] mg/kg/da y LOAEL [systemic] = 94.6/46.3 [M/F] mg/kg/day based on decreased body weight, gross and microscopic lesions in blood vessels, and liver lesions in males and decreased body weight, gross and microscopic lesions blood vessels, bone marrow hypercellularity, and liver lesions in females. There was no evidence of carcino g enicit y 870.4300 Carcinogenicity [mouse] 42233914 [1991] Acceptable/guideline 0, 10, 100, 1000 mg/kg/day N OAEL = 100 mg/kg/day LOAEL [systemic] = 1000 mg/kg/day based on decreased body weight gain in males. There was no evidence of carcino g enicit y Gene Mutation 870.5100a 42233921 [1985] Acceptable N egative for inducing reverse gene mutation in either Salmonella his-mutants or E. coli trp-cells exposed beyond precipitating concentrations [500 ug/plate], up to the limit dose, 5000 ug/plate, w/without metabolic activation. Gene Mutation 870.5100b 42233926 [1989] Acceptable N egative for inducing reverse gene mutation in Salmonella TA strains and E. coli WP2 uvr A exposed, with/without activation, up to 5000 u g /plate. In vitro mammalian cell gene mutation

test 870.5300a 42233923 [1987] Acceptable N egative for inducing forward mutation at the hypoxanthine-guanine phosphoribosyl transferase locus in Chinese hamster lung [V79] cells treated up to cytotoxic levels [230 ug/mL/-S9; 300 ug/mL/+S9]



### . In vitro mammalian cell gene mutation

test 870.5300b 42233927 [1991] Acceptable N egative for inducing forward mutation at the hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus in Chinese hamster lung [V79] exposed, with/without activation, up to cytotoxic concentrations [180 ug/mL/-S9; 333 ug/mL/+S9]. In vitro mammalian chromosome aberration test 870.5375a 42233924 [1986] Unacceptable Reportedly positive for chromosome aberrations at the highest doses tested [160 ug/mL/-S9; 170 ug/mL/+S9].

In vitro mammalian chromosome aberration test 870.5375b 42233925 [1987] Acceptable [Confirmatory repeat of Study LMP-180 C, MRID 422339-24]. Positive for increased chromosome aberrations at high doses [160 ug/mL/-S9; 170 ug/mL/+S9]. In vitro mammalian chromosome aberration test 870.5375c 42233928 [1991] Acceptable Presumptively [weakly] positive, but only in activated cultures treated at the HDT, in human lymphocyte cultures treated up to the highly toxic dose, 422 ug/mL; negative in the absence of activation at all doses. Mammalian erythrocyte micronucleus test 870.5395a 42233930 [1991] Acceptable N egative for inducing micronuclei in bone marrow cells of mice administered test article i.p. up to severely toxic levels [200 mg/kg].

Mammalian erythrocyte micronucleus test 870.5395b 42233931 [1989] Acceptable N egative for inducing micronuclei in bone marrow cells of mice treated orally at th e limit dose, 5000 mg/kg.

Mutagenicity - DNA damage/repair in vitro 870.5500 42233922 [1986] Unacceptable Reportedly negative for inducing unscheduled DNA synthesis [as measured by liquid scintillation counting] in rat hepatocytes cultured [for only 3 hours] at doses up to 250 ug/mL, a weakly cytotoxic level. Other Effects - Morphologic transformation of 42233929 [1986] Acceptable N egative for transformation in Syrian hamster embryo cells treated, in the presence and absence of activation, up to cytotoxic concentrations [265 ug/mL/+S9; 50 ug/mL/-

### Dimethomorph

Page 14 of 16 Subchronic, Chronic and Other Toxicit y Profile for Dimethomor p h. Guideline Number/ Stud y T yp e MRID(s) [ y ear]/ Classification/Doses Results

cells in culture 870.8800 S9]

870.6200 Subchronic neurotoxicity 1 [rat] 48326902 [2004] Acceptable/guideline 0,60,600,6000 ppm M:0,4.2,43.8,432.9 mg/kg/day F:0,5.0,50.9,510.1 m g /k g /da y N OAEL= 432.9/510.1 mg/kg/day (M/F), HDT No evidence of neurotoxicity.

870.7485 Metabolism and pharmacokinetics [rat] 42233932 [1994] Acceptable 10 mg/kg single dose; 10 mg/kg 14-day repeated dose; 10 mg/kg 7-day repeated dose; 500 mg/kg single dose Oral administration of dimethomorph results in rapid excretion into the urine and feces of rats. For all treatment protocols, most [80-90%] of the radiolabel administered was excreted in the feces. A considerably smaller amount [6-16%] was excreted in the urine and only minimal levels [0.1-0.4%] were detected in the organs and tissues. Rapid absorption may be inferred by the rapid excretion of metabolites in the urine and bile. Saturation of absorption following single high doses [500 mg/kg] was indicated by large amounts [  50%] of radioactivity in the feces being associated with parent compound. For low- or high-dose treatment, urinary excretion in female rats tended to be greater [up to 2-fold in low-dose rats] than that of male rats. Retention of dimethomorph or [ 14 C]-dimethomorphderived radioactivity was generally  1% for most tissues although the liver exhibited slightly higher levels [1.4%] and higher levels in the gastrointestinal tract organs was due to radioactivity in the lumenal contents. Urinary metabolites resulted from demethylation of the dimethoxyphenyl ring and oxidation of the morpholine ring. Biliary excretion exhibited first-order kinetics with a low-dose [10 mg/kg] half-life of approximately 3 hours and a high-dose [500 mg/kg] half-life of 11 hours for males and about 6 hours for females. Biliary metabolites accounted for most of the fe cal excretion following lowdose treatment. The major biliary metabolites were glucuronides of one and possibly two of the compounds produced by demethylation of the dimethoxyphenyl ring. The report provided a proposed metabolic pathway for dimethomorph. 870.7600 Dermal penetration [rat] 43917221 [1995] Acceptable/guideline 7.73 [2.5% w/v aqueous suspension] or 79.62 [25% w/v aqueous suspension] mg/kg. The dermal absorption factor is 5%.

870.7800 Immunotoxicity [rat] 48326901 (2010) Acceptable/guideline 0,300,800,2400 ppm [M] 0, 23,61,184 mg/kg/da y N OAEL = 2400 ppm (184 mg/kg/day, HDT) No evidence of immunotoxicity.

1 An acute neurotoxicity study has recen tly been received and is under review.

### Dimethomorph

Page 15 of 16 Attachment 5: Dimethomorph Endpoint Selection Table

Summar y of Toxicolo g ical Doses and Endpoints for Use in Dimethomorph Human Health Risk Assessments. Exposure Scenario Point of Departure, Uncertainty/FQPA Safety Factors RfD, PAD, Level of Concern for Risk Assessment Stud y and Toxicolo g ical Effects

Acute Dietar y (Females 13-49) N o endpoint attributable to a single dose was identified.

Acute Dietar y (General Population) N o endpoint attributable to a single dose was identified.

Chronic Dietary (All Populations) N OAEL = 11 mg/kg/day UF A = 10x UF H = 10x FQPA SF = 1

UF = 100 cPAD = 0.1 mg/kg/day Carcinogenicity study in r a t s. LOAEL = 46.3 mg/kg/day, based on decreased body weight and increases in liver lesions in female rats.

Dermal Shor t - and Intermediate-Term N o toxicity was observed at the limit dose in a 28-day dermal toxicity study in rats. No quantitative risk assessment is necessary.

Dermal Long-Ter m (>6 Months) N o long-term exposure anticipated from currently use pattern.

Inhalation Shor t -Ter m (1-30 Days) Oral study NOAEL= 60 mg/kg/day (inhalation toxicity assumed to be equivalent to oral toxicity %) LOC for MOE <100 Developmental t oxicity study in rats. LOAEL = 160 mg/kg/day based on decreased body weight, body weight gain, and food consumption. Inhalation Intermediate-Term (1-6 Months) Oral study NOAEL= 15 mg/kg/day (inhalation toxicity assumed to be equivalent to oral toxicity) LOC for MOE <100 Subchronic feeding study in dogs. LOAEL = 43 mg/kg/day based on decreased absolute and relative prostate weight, and possible threshold liver effects. Inhalation Long-Ter m (>6 Months) N o long-term exposure anticipated from currently use pattern.

Cancer (Oral, Dermal, Inhalation) Classification : This chemical is classified as “ not likely” to be a human carcinogen.

Point of Departure (POD) = data point or estimated point, derived from observed dose-response data, and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra species). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). MOE = margin of exposure. LOC = level of concern.

### Dimethomorph

Page 16 of 16 Attachment 6: International Residue Li mit Status (Dimethomorph PC1268800; 08/23/2011)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 40 CFR 180.493: Plants/Livestock: dimethomorph, (E,Z) 4-[3-(4-chlorophenyl)-3-(3,4- dimethoxyphenyl)-1-oxo-2- propenyl]morpholine ( E,Z )-4-[3-(4-chlorophenyl)-3- (3,4-dimethoxyphenyl)- 1-oxo-2-propenyl]morpholine dimethomorph (sum of isomers)



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 

### Codex Grapes 4.0 2 ppm grapes Brassica, head and stem, subgroup 5A 5.0 1 ppm broccoli, 2 ppm cabbage head 0.03 ppm kohlrabi Brassica, leafy greens, subgroup 5B 30.0

Leafy Vegetable, crop group 4 20.0 10 ppm corn salad, lettuce, head Onion bulb 0.6 Green Onion 15.0

Grape, raisin 3 6.0 5 ppm dried

grapes (currants, raisins and sultanas) Completed by: M. Negussie; 08/25/2011

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 There are no US registrations as of March 4, 2009, for the use of dimethomorph on grapes grown for raisin production.