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f a ~ UNITED STATES ENVIRONMENTAL PROTECTION AGENCY \ SS ~ ~~ WASHINGTON, D.C. 20460 ~ -<:-0 -4t PAO'Tf-C 

MEMORANDUM 

DATE: January 31,2013 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Dim.ethomorph: Human Health Assessment Seeping Document in Support of 

Registration Review. 

PC Code: 268800 

Decision Nos.: 471598 

Petition Nos.: NA 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcodes: D406661 

Registration No.: 241-427 

Regulatory Action: Registration Review 

Case No.: NA 

CAS No.: 110488-70-5 

40 CFR: 180.493 

FROM: SheilaPiper,Chemist 

Yung Yang, Ph.D., Toxicolo

~~Jv~ gist · . 

6--~ hti . " 

Risk 

Monica 

Assessment 

Hawkins, 

Branch 

Ph.D., M.P.H.

VI 

, E vironme al Health Scientist ~"' ~~ 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Acting Branch Chief ~ / L_</ / 

Risk Assessment Branch VI ~ C7 7'(--

Health Effects Division (7509P) 

TO: Monica Wait, Chemical Review Manager 

Avivah Jakob, Team Leader 

Pesticide Re-Evaluation Division (7505P) 

Risk Management & Implementation Branch 3 (RMIB3) 

Executive Summary 

The Health Effects Division Dimethomorph Risk Assessment Team has evaluated the database 

and the most recent human health risk assessment for the fungicide dimethomorph. HED 

performed this evaluation in order to determine the scope of work necessary to support the 

established tolerances and existing registrations. The primary source of information for this 

evaluation was the most recent human health risk assessment written for dimethomorph (Memo, 

D387381, S. Piper, 09/15/2011). 

Page 1 of 16 
Dimethomorph 

Page 2 of 16 

Dimethomorph is a systemic morpholine fungicide developed for control 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 occupational routes for dimethomorph. 

The toxicology database for dimethomorph is complete; no additional data are required to 

support the registration review. An acute neurotoxicity 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, dermal, or inhalation route of exposure. It is 

not an eye or skin irritant, and is not a skin sensitizer. There is no evidence that dimethomorph is 

a neurotoxic, teratogenic, reproductive, carcinogenic, mutagenic or immunotoxic chemical. 

Dimethomorph is classified as "not likely to be carcinogenic to humans" based upon lack of 

evidence of carcinogenicity in rats and mice. 

There is no evidence for increased quantitative or qualitative susceptibility of the young 

following in utero and pre-and post-natal exposure to dimethomorph 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 registration review of dimethomorph. 

An acute endpoint was not selected for dimethomorph; therefore, the Agency conducted only a 

chronic dietary (food and drinking water) exposure and risk assessment. Based on the current 

uses of dimethomorph and HED’s policies and procedures for performing dietary risk 

assessment, no population subgroups have chronic dietary risk estimates that are of concern to 

HED. 

There are currently no registered residential uses associated with dimethomorph; therefore, no 

short- and intermediate-term aggregate risk assessments are required. 

The occupational exposure database is adequate to support the registration review process for 

dimethomorph. In accordance with the updated Part 158 data requirements (2007), one or more 

Dislodgeable Foliar Residue (DFR) studies are required when a pesticide has residential or 

occupational uses that could result in post-application dermal exposure. Based on HED policy, a 

DFR study is not required for dimethomorph at this time. The requirement of a DFR study may 

need to be reconsidered if application rates, use patterns, or points of departure change. In the 

2008 and 2000 exposure assessments, all of the non-cancer occupational handler and postapplication risk estimates were below the Agency’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-specific surrogate handler 

exposure data (http://www.epa.gov/pesticides/science/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 for the use of dimethomorph on grapes, bulb 

vegetables, leafy Brassica vegetables and leafy vegetables (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 fungicide 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 ginseng. The registered application 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 complete; no additional data are required. An 

acute neurotoxicity study has recently been submitted to the Agency and will be evaluated during 

Registration Review. 

Dimethomorph has low acute toxicity by the oral, dermal, or inhalation route of exposure. It is 

not an eye or skin irritant, and is not a skin sensitizer. There is no evidence that dimethomorph is 

a neurotoxic, developmental, reproductive, carcinogenic, mutagenic 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 decreased 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 systemic toxicity observed at the limit dose (1000 

mg/kg/day) in a repeated dose dermal toxicity study in rats and there are no developmental, 

reproductive of neurotoxic concerns. The Point of Departure (PODs) for short-term inhalation 

exposure risk assessment is based on decreased 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 decreased prostate weight and liver effect in a 

subchronic oral toxicity study in dogs. At this time, there are no residential uses for 

dimethomorph. Therefore, discussion of risk via the exposure from the dermal and inhalation 

routes are unnecessary for this risk assessment with respect 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 risk assessment is not required. 

There is no evidence for increased quantitative or qualitative susceptibility of the young 

following in utero and pre-and post-natal exposure to dimethomorph 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 dimethomorph is extensively absorbed, metabolized 

and excreted through the urine and feces (80-90%). Retention of dimethomorph or [14C]-

dimethomorph-derived 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. 

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 Registration 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 dimethomorph is adequate for risk assessment 

purposes. As stated above, dimethomorph is registered 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 established for the indirect or inadvertent residues of 

dimethomorph under 40 CFR §180.493(d) in/on cereal 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, milk, poultry nor eggs as a result of ingestion of dimethomorph 

residues in the livestock feed. Acceptable analytical methods are available 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 Model (DEEM-FCIDTM Version 2.03) to conduct the 

most recent chronic aggregate dietary (food and drinking water) risk assessments for 

dimethomorph. This model incorporates consumption data from the USDA’s Continuing Survey 

of Food Intakes by Individuals taken between 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 degradate 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 dietary exposure assessment. 

HED has not previously identified a toxicological endpoint attributable to a single exposure of 

dimethomorph; therefore, an acute dietary exposure assessment was not conducted. However, 

the registrant recently submitted an acute neurotoxicity study, which will be evaluated during 
Dimethomorph 

Page 5 of 16 

registration review for a potential acute POD. 

The unrefined chronic dietary analysis for dimethomorph 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 represented 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 registrations 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 the 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 transport (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 volatilization 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 inhalation exposures resulting from off-site transport (e.g., spray 

drift or volatilization) may occur 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 registered residential uses, nor are any proposed for dimethomorph. 

Therefore, at this time, dietary (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 residential exposure assessments for dimethomorph 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 toxicity study and no toxicity was observed up to 

the limit dose. Since no toxicity was observed at the limit dose, a quantitative occupational 

dermal risk assessment for short- and intermediate-term exposure is no longer necessary 

(D387381, S. Piper 09/15/2011). Future quantitative risk assessments will only consider 

occupational inhalation exposure. 

Conclusions for Occupational Exposure and Risks 

The occupational exposure database is adequate to support the registration review process for 

dimethomorph. In accordance with the updated Part 158 data requirements (2007), one or more 

DFR studies are required when a pesticide has residential 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 selected a new default value for the fraction of the 

application rate available to be dislodged after a foliar application (FAR). This default value is 

25% and is based on an analysis of 19 DFR studies where the FAR value ranged from 2% to 89%. 

This value is recommended for use in both residential and occupational post-application 

assessments. Of the analyzed DFR studies, the maximum FAR 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 residue 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 Transferrable Residue (TTR) and Dislodgeable 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 greater 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 application 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 scenario-specific surrogate handler exposure data 

(http://www.epa.gov/pesticides/science/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 report 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 incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment. 
Dimethomorph 

Page 7 of 16 

Tolerance Assessment and International Harmonization

Tolerances are established in 40 CFR §180.493 for residues of the fungicide dimethomorph 

in/on various raw agricultural commodities (RACs). Tolerances are 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 dimethomorph, but Codex MRLs have been established 

for grapes and raisins. The Codex MRLs for 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 resulted 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 justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.epa.gov/compliance/resources/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 risk assessments, including, but not limited to, 

people who obtain drinking water from sources near agricultural areas, the variability of diets 

within the U.S., and people who may be exposed when harvesting crops. Should these high 

exposures indicate potential risks of concern, OPP will further refine the risk assessments to 

ensure that the risk estimates are based on the best available information. 

Endocrine Disruptor Screening Program 

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental, and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and 

selected the most sensitive endpoints 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 Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether 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 other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 
Dimethomorph 

Page 8 of 16 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects 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 pesticide active ingredients and 9 inert ingredients. Dimethomorph 

is not among the group of 58 pesticide active ingredients on the initial list to be screened under 

the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data 

call-ins, requiring the submission of EDSP screening assays for dimethomorph. For further 

information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, 

future lists, the test guidelines, and the Tier 1 screening battery, please visit EPA’s website: 

http://www.epa.gov/endo/. 

Cumulative Risk Assessment 

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of 

chemicals sharing a common mechanism of toxicity. The Agency determined that there was 

insufficient evidence to suggest dimethomorph shares 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 and 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 procedures 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 required for the registration review process of 

dimethomorph. 

References 

DP#: 387381 

Subject: Dimethomorph. Human Health Risk 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 Bulb 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: Dimethomorph Endpoint Selection Table 

Attachment 6: International 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/Chemical 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/cm3 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, pKa Not determinable (the solubility of 

dimethomorph is very low, and the ionized 

and nonionized forms have identical 

absorption coefficients) 

Octanol/water partition coefficient, 

Log(KOW) 

E-isomer: Kow = 430 (log Kow = 2.63) at 20oC 

Z-isomer: Kow = 543 (log Kow = 2.73) at 20oC 

UV/visible absorption spectrum Not available 

OCH3

Cl OCH3

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 Toxicity Profile for Dimethomorph.

Guideline 

Number 

Study Type MRID(s) Results Toxicity

Category 

870.1100 Acute oral [Rat] 42233902 LD50 = 3900 (3300-4500) mg/kg (M,F) III

870.1200 Acute dermal [Rat] 42233903 LD50 ≥ 5000 mg/kg IV

870.1300 Acute inhalation [Rat] 42233904 LC50 ≥ 4.24 mg/L III

870.2400 Acute eye irritation [Rabbit] 42233905 Conjunctival irritation clearing in 4 days III

870.2500 Acute dermal irritation [Rabbit] 42233907 No irritation reported IV

870.2600 Skin sensitization [Guinea pig] 42233906 Not a sensitizer
Dimethomorph 

Page 12 of 16 

Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ 

Study Type 

MRID(s) [year]/ 

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

NOAEL = 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 mg/kg/day

NOAEL >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]

NOAEL=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 NOAEL = 300 mg/kg/day

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 NOAEL = 300 mg/kg/day

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 

Maternal NOAEL = 60 mg/kg/day 

LOAEL = 160 mg/kg/day based on reductions in food 

consumption, mean body weights and body weight gain. 

Developmental NOAEL could not be determined 

LOAEL = could not be determined. 

870.3700d

Prenatal 

developmental 

[rat] 

44175302 

Acceptable 

Information supplemental to 

MRID# 42233919 

Maternal NOAEL = 60 mg/kg/day 

LOAEL = 160 mg/kg/day based on reductions in food 

consumption, mean body weights and body weight gain. 

Developmental 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/Systemic NOAEL = 300 ppm

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 

NOAEL = 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 incidence 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 

NOAEL = 14.7 mg/kg/day

LOAEL = 44.6mg/kg/day based on decreased prostate 

weight. 
Dimethomorph 

Page 13 of 16 

Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ 

Study Type 

MRID(s) [year]/ 

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 

NOAEL [systemic] = 33.9/11.3 [M/F] mg/kg/day

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 carcinogenicity

870.4300 

Carcinogenicity 

[mouse] 

42233914 [1991] 

Acceptable/guideline 

0, 10, 100, 1000 mg/kg/day 

NOAEL = 100 mg/kg/day

LOAEL [systemic] = 1000 mg/kg/day based on decreased 

body weight gain in males. 

There was no evidence of carcinogenicity

Gene Mutation 

870.5100a 

42233921 [1985] 

Acceptable 

Negative 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 

Negative for inducing reverse gene mutation in 

Salmonella TA strains and E. coli WP2 uvr A exposed, 

with/without activation, up to 5000 ug/plate. 

In vitro mammalian 

cell gene mutation 

test 

870.5300a 

42233923 [1987] 

Acceptable 

Negative 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 

Negative 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 

Negative 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 

Negative for inducing micronuclei in bone marrow cells of 

mice treated orally at the 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 

Negative 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 Toxicity Profile for Dimethomorph.

Guideline Number/ 

Study Type 

MRID(s) [year]/ 

Classification/Doses Results 

cells in culture 

870.8800 

S9]

870.6200 

Subchronic 

neurotoxicity1 

[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 mg/kg/day

NOAEL= 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 [14C]-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 fecal 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/day

NOAEL = 2400 ppm (184 mg/kg/day, HDT) 

No evidence of immunotoxicity. 

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

 
Dimethomorph 

Page 15 of 16 

Attachment 5: Dimethomorph Endpoint Selection Table 

Summary of Toxicological 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

Study and Toxicological 

Effects 

Acute Dietary

(Females 13-49) 

No endpoint attributable to a single dose was identified.

Acute Dietary

(General Population) 

No endpoint attributable to a single dose was identified.

Chronic Dietary 

(All Populations) 

NOAEL = 11 mg/kg/day

UFA = 10x 

UFH = 10x 

FQPA SF = 1 

UF = 100 

cPAD = 0.1 

mg/kg/day 

Carcinogenicity study in rats. 

LOAEL = 46.3 mg/kg/day, 

based on decreased body 

weight and increases in liver 

lesions in female rats. 

Dermal Short- and 

Intermediate-Term 

No toxicity was observed at the limit dose in a 28-day dermal toxicity study in rats. No 

quantitative risk assessment is necessary. 

Dermal Long-Term

(>6 Months) 

No long-term exposure anticipated from currently use pattern.

Inhalation Short-Term

(1-30 Days) 

Oral study NOAEL= 

60 mg/kg/day 

(inhalation toxicity assumed to be 

equivalent to oral toxicity %) 

LOC for MOE <100 Developmental toxicity 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-Term

(>6 Months) 

No 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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). 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 Limit Status (Dimethomorph PC1268800; 08/23/2011) 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico2 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) 

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

US Canada Mexico2 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, raisin3 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.