Dimethomorph Human Health Risk Assessment DP No. D416888 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: October 22, 2014 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Dimethomorph: Human Health Risk Assessment to Support Establishment of a 

Tolerance Without U.S. Registration for Papaya. 

PC Code: 268800 

Decision No.: 485316 

Petition No.: 3E8218 

Risk Assessment Type: Single Chemical/ 

Aggregate 

TXRNo.:NA 

MRIDNo.: NA 

DP Barcode: 416888 

Registration No.: NA 

Regulatory Action: Tolerance Assessment 

(No S3) 

Case No.: NA 

CAS No.: 110488-70-5 

40 CFR: 180.493 

FROM: Sumitra Bose Biswas, C~em~t R~ Assessor ~ /J• ~)WU- ' 

Sheila Piper, Chemist (J~ ~ p 

Yung Yang, Ph.D., Toxicologist !{) · ~~ __ V ' 

Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist 11 L~>tt?U..OfUMlJ 

Risk Assessment Branch VI 

Health Effects Division (7509P) , 

THROUGH: 

Risk 

Donna 

Assessment 

Davis, Acting 

Branch 

ChieVI Q.,u~ 

Health Effects Division (7509P) 

TO: Tamue Gibson, M.S., Chemical Review Manager 

Shaja Joyner, Product Manager 

Rachel Holloman, Branch Chief 

Fungicide Herbicide Branch/ Registration Division (7505P) 

Page 1 of25 
Dimethomorph Human Health Risk Assessment DP No. D416888

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TABLE OF CONTENTS

1.0 Executive Summary................................................................................................................... 3

2.0 HED Recommendations............................................................................................................. 4

2.1 Data Deficiencies....................................................................................................................... 4

2.2 Tolerance Considerations........................................................................................................... 4

2.2.2 Recommended Tolerances......................................................................................................... 5

2.2.3 Revisions to Petitioned-For Tolerances.................................................................................... 5

2.3 Label Recommendations........................................................................................................... 5

3.0 Introduction................................................................................................................................ 6

3.1 Chemical Identity....................................................................................................................... 6

3.3 Pesticide Use Pattern.................................................................................................................. 7

3.5 Consideration of Environmental Justice ................................................................................... 8

4.0 Hazard Characterization and Dose-Response Assessment....................................................... 9

4.1 Summary of Toxicological Effects........................................................................................... 9

4.2 Safety factor for Infants and Children (FQPA Safety Factor).................................................. 9

4.2.1 Completeness of the Toxicology Database............................................................................. 10

4.2.2 Evidence of Neurotoxicity ...................................................................................................... 10

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......................... 10

4.2.4 Residual Uncertainty in the Exposure Database..................................................................... 10

4.3 Toxicity Endpoint and Point of Departure Selections ............................................................ 10

4.3.1 Dose-Response Assessment.................................................................................................... 10

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment........................ 12

4.3.3 Cancer Classification and Risk Assessment Recommendation.............................................. 12

4.3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment 12

5.1 Residue of Concern Summary and Rationale .......................................................................... 14

5.2 Food Residue Profile................................................................................................................ 15

5.3 Water Residue Profile .............................................................................................................. 15

5.4 Dietary Risk Assessment ......................................................................................................... 16

5.4.1 Description of Residue Data Used in Dietary Assessment...................................................... 16

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................................. 16

5.4.3 Acute Dietary Risk Assessment............................................................................................... 17

5.4.4 Chronic Dietary Risk Assessment ........................................................................................... 17

5.4.5 Cancer Dietary Risk Assessment............................................................................................. 17

5.4.6 Dietary Summary Table........................................................................................................... 17

6.0 Residential Exposure/Risk Characterization............................................................................ 18

7.0 Aggregate Exposure/Risk Characterization............................................................................. 18

8.0 Cumulative Exposure/Risk Characterization........................................................................... 18

9.0 Occupational Exposure/Risk Characterization ........................................................................ 18

10.0 References................................................................................................................................ 19

Appendix A: Toxicology Assessment ................................................................................................ 20

Appendix B. International Residue Limits Table .............................................................................. 25
Dimethomorph Human Health Risk Assessment DP No. D416888

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1.0 Executive Summary

The Registration Division requested that HED prepare a human health risk assessment for 

dimethomorph to support establishment of a tolerance without U.S. registration on papaya. 

Dimethomorph, (E,Z)-4-[3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine, is a 

systemic morpholine active ingredient having fungicidal activity. Dimethomorph was developed for 

control of downy mildew, late blight, and crown and root rot. 

BASF Corporation has petitioned to establish a permanent tolerance without U.S. registration for the 

combined residues of fungicide dimethomorph (BAS 550 F) (E,Z)-4-[3-(4-chlorophenyl)-3-(3,4-

dimethoxyphenyl)acryloyl]morpholine in/on imported papaya at 1.5 ppm. The registrant has 

indicated that Brazil is the only country using dimethomorph on papaya. The available Brazilian

field trial data reflect the Brazilian use of dimethomorph in/on papaya with no more than three 

applications at a maximum label rate of 500 g a.i./ha (0.446 lb ai/A) during the growing season and 7 

days of pre-harvest interval (PHI).

The toxicology database for dimethomorph is complete, no additional data is required. 

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 

developmental, reproductive, carcinogenic, mutagenic or immunotoxic chemical. The target organ is 

the liver. 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 of increased qualitative or 

quantitative susceptibility in the young and there is no evidence of neurotoxicity with dimethomorph 

and exposure estimates are unlikely to underestimate risk; therefore, the 10-fold FQPA Safety Factor 

can be reduced to 1x all assessments with the exception of the acute dietary assessment. The FQPA 

SF is retained for the acute dietary risk assessment to account for extrapolation of LOAEL to 

NOAEL for the acute dietary point of departure (PoD). Acute and chronic dietary (food and water), 

and short- and intermediate-term inhalation points of departure have been selected for risk 

assessment. Dimethomorph does not pose a dermal hazard.

There are no outstanding residue chemistry data. Based on the previous plant metabolism studies 

with three representative crops (potato, grape and lettuce) the qualitative nature of the dimethomorph 

residues is considered to be adequately understood. The residue of concern for the tolerance 

expression and risk assessment is the parent compound, dimethomorph (comprised of E and Z 

isomers). There are no animal feed items associated with the subject petitions. Thus, a discussion of 

animal metabolism is not required to support the requested new uses. Acceptable data were 

submitted depicting residues in target crops. These data are supported by storage stability data and 

were generated using adequately validated analytical methods. Processing data are not required to 

support a use on papaya. There is an analytical method to enforce the proposed tolerance. There are 

no issues with respect to international harmonization associated with this petition. The data are 

adequate to support tolerance evaluation/enforcement and human health risk assessment.

Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted

which included all existing uses as well as the proposed papaya new import use. These unrefined 
Dimethomorph Human Health Risk Assessment DP No. D416888

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assessments are based on tolerance-level residues, 100% crop treated, and DEEM default processing 

factors. For food and drinking water, the acute dietary risk estimate is below HED’s level of concern 

(<100% of the acute population adjusted dose (aPAD)) for the general U.S. population (25% aPAD) 

and all population sub-groups; the most highly exposed population subgroup was children 3-5 years 

old (39% aPAD) at the 95th percentile of exposure. The resulting food and water chronic exposure 

estimates were less than HED’s level of concern (<100% cPAD) for general U.S. population (16% 

cPAD) and all population sub-groups; the most highly exposed population subgroup was children 1-2 

years old with 25% cPAD. 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 dietary risk 

assessment is not required.

There are no registered or proposed residential uses, or commercial/professional uses at residential 

sites associated with dimethomorph at this time. Therefore, a quantitative residential exposure 

assessment is not required. Further, since there are no residential uses, acute and chronic aggregate 

includes only food and water and as noted above, there are no risks of concern. 

There are no occupational exposures associated with the proposed import tolerances; therefore, a 

new occupational exposure assessment was not conducted for this risk assessment.

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

2.0 HED Recommendations

There are no residue chemistry considerations that would preclude establishment of the requested 

tolerance without U.S. registration for dimethomorph on papaya at 1.5 ppm.

2.1 Data Deficiencies

There are no data deficiencies associated with the proposed tolerance without U.S. registration for 

dimethomorph on papaya. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The high performance liquid chromatography with ultraviolet detection (HPLC/UV) method FAMS 

002-04 has been determined to be adequate for tolerance enforcement purposes for determining 

residues of dimethomorph in plant commodities. This method is adequate to enforce the proposed 

papaya tolerance. Briefly the method is described as follows. Homogenized samples are extracted 

with acetone and the extract is mixed with sodium chloride solution and partitioned with 

dichloromethane (DCM). The DCM phase is evaporated to dryness and redissolved in methanol for 
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cleanup by gel permeation chromatography. The extract is then cleaned up on a silica gel column, 

using acetone:n-hexane (20:80, v:v) to elute residues. The eluate is evaporated to dryness and 

redissolved in methanol for HPLC/UV analysis. The reported limit of quantitation (LOQ) is 0.01 

ppm and limit of detection (LOD) is 0.002 ppm for papaya. The method has been successfully 

validated. A confirmatory method is also available, Method M 2577, a gas chromatographic (GC)

method with nitrogen phosphorus detection (NPD). 

Dimethomorph has previously been subjected to testing via the FDA multiresidue methods protocols 

of PAM I. Dimethomorph was not evaluated using Protocols A and B, based on its structure. 

Protocol C evaluation yielded marginal results for dimethomorph. Dimethomorph is recovered 

using Protocol D. Protocol E evaluation of dimethomorph yielded no recovery of the analytical 

standard from the Florisil column using either PAM I 211.14 or 252.12 eluting systems (D192776, 

D. Davis, 3/13/95).

2.2.2 Recommended Tolerances

The proposed and recommended tolerance without U.S. registration for dimethomorph is 1.5 ppm. 

The current tolerance expressions are not in compliance with HED’s Interim Guidance on Tolerance 

Expressions (5/27/09, S. Knizner) and should be revised as the following:

Tolerances are established for the residues of the fungicide dimethomorph, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only dimethomorph, (E,Z) 4-[3-(4-

chlorophenyl)-3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]morpholine, in or on the commodity.

Table 2.2.2. Tolerance Summary for Dimethomorph, §180.493

 Commodity Established/Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

 Papaya1 1.5 1.5 

1 No U.S. registration. 

2.2.3 Revisions to Petitioned-For Tolerances

No revision to the petitioned-for tolerance is required. 

2.2.4 International Harmonization

There are no established Canadian, Mexican or Codex maximum residue limits (MRLs) for residues 

of dimethomorph in/on papaya associated with this review; therefore there are no issues with respect 

to international harmonization associated with this petition.

2.3 Label Recommendations
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This petition is for a tolerance without U.S. registration; therefore a discussion of label 

recommendations is not applicable.

3.0 Introduction

Dimethomorph is a systemic morpholine fungicide and was developed for control of downy mildew, 

late blight, and crown and root rot. 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 currently established for residues of dimethomorph in or on food commodities under 

40 CFR 40 §180.493, at levels ranging from 0.5 to 60.0 ppm. Tolerances are established for the 

indirect or inadvertent residues of dimethomorph under 40 CFR §180.493(d) in/on cereal grain 

commodities.

3.1 Chemical Identity

Table 3.1. Dimethomorph Nomenclature.

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

3.2 Physical/Chemical Characteristics

OCH3

Cl OCH3

O

N

O
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Dimethomorph is a colorless or grey crystalline powder that is stable under normal temperature 

conditions. It is stable to hydrolysis and will remain stable up to five years in the dark. It is a nonvolatile fungicide that has a relatively low octanol/water partition coefficient and solubility. Also, 

dimethomorph has a low soil mobility and a low leaching potential. See Table 3.2 for the

physicochemical properties of dimethomorph. 

Table 3.2. Physicochemical Properties of Dimethomorph.

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/cm3at 20oC 

Water solubility (20oC) pH 5 19 mg/L

pH 7 18 mg/L

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

3.3 Pesticide Use Pattern

BASF Corporation has petitioned to establish a permanent tolerance without U.S. registration for the 

residues of dimethomorph (BAS 550 F) in/on imported papaya grown in Brazil. The registrant has 

indicated that Brazil is the only country using dimethomorph on papaya. For use on the requested 

crop dimethomorph is formulated as a 500 g ai/kg wettable powder. The proposed foreign use 

pattern of dimethomorph under the field condition in Brazil is summarized in Table 3.3.
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Table 3.3. Summary of Proposed Directions for Dimethomorph

Applic. 

Timing, 

Type, and 

Equip.

Formulation

Applic. 

Rate 

(lb 

ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Papaya

Post 

emergence; 

Foliar; 

ground

50% ai WP

500g/kg 

0.446 

lb/ ai/A 4

1.78 lb ai/A 7

Do not exceed the 

number of 3 

application per 

calendar year at a total 

rate between 0.357 lb 

ai/A and 0.446 lb 

ai/A, and a PHI of 7 

days.

3.4 Anticipated Exposure Pathways

Humans may be exposed to dimethomorph in food and drinking water, since dimethomorph may be 

applied directly to growing crops and application may result in dimethomorph reaching surface and 

ground water drinking water sources. There are no residential uses for this chemical. While there is 

the potential for occupation exposure to workers applying dimethomorph from the domestically 

registered uses, there is no increased worker exposure expected from this new use since no domestic 

registration is sought for the use on papaya. 

3.5 Consideration of 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide 

exposures that are based on patterns of that subgroup’s food and water consumption, and activities in 

and around the home that involve pesticide use in a residential setting. Extensive data on food 

consumption patterns are compiled by the U.S. Department of Agriculture under the National Health 

and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). These food 

consumption patterns are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, 

ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to 

smaller, specialized subgroups, and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for children, youths, and adults 

entering or playing on treated areas post-application are evaluated. Exposure risk estimates were not 

of concern. Further considerations are currently in development, as OPP has committed resources 
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and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

The most recent risk assessment for dimethomorph (D399514, 3/6/2012) was conducted prior to the 

receipt and review of an acute neurotoxicity (ACN) study. This study has been reviewed and the 

findings incorporated into this risk assessment. 

The toxicology database for dimethomorph is complete, no additional data is required. The current 

40 CFR Part 158 Toxicology Data Requirement requires a subchronic inhalation study for 

dimethomorph; however, the Hazard and Science Policy Council (HASPOC) determined that based 

on a weight-of-evidence (WOE) approach, a subchronic inhalation study is not required to support 

the registered uses of dimethomorph (TXR#0056964, 2014) at this time. The scientific quality of 

the database for dimethomorph is relatively high and the toxicity profile can be characterized for a 

wide range of effects, including potential developmental, reproductive, neurotoxic, carcinogenic, and 

immunotoxic effects. 

4.1 Summary of Toxicological Effects

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

developmental, reproductive, carcinogenic, mutagenic or immunotoxic chemical. 

No biologically significant effect was observed in the rat subchronic oral toxicity study while 

decreased body weight and increased incidence of arteritis in male rats and decreased body weights 

and increased incidence of “ground-glass” foci in livers of female rats were observed in the rat 

chronic toxicity study. In the dog subchronic oral toxicity study, decreased absolute and relative 

prostate weights, and slight liver effects were observed. No toxicity was observed at the limit dose in 

the rat 28-day dermal toxicity study. The developmental toxicity studies showed no increased 

sensitivity to offspring of either rats or rabbits as demonstrated by NOEL’s equal to or higher than 

those producing toxicity in the maternal animals. Likewise, in the two generation reproduction study, 

there was no toxicity to the offspring at doses lower than that causing parental toxicity.

In an acute neurotoxicity study, functional observational battery (FOB) findings and reduced motor 

activity were observed. However, these findings were considered an impairment of the overall 

condition of the animals following treatment, rather than direct neurotoxic effects of the 

dimethomorph exposure. No neurotoxic effects were observed in the subchronic neurotoxicity study 

in rats and there is no evidence of neurotoxicity throughout the dimethomorph toxicity database. 

There was no evidence of immunotoxicity in the guideline immunotoxicity study.

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.

4.2 Safety factor for Infants and Children (FQPA Safety Factor)
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The toxicity database is complete, there is no evidence of increased qualitative or quantitative 

susceptibility in the young, there is no evidence of neurotoxicity with dimethomorph and exposure 

estimates are unlikely to underestimate risk; therefore, the 10-fold FQPA Safety Factor can be

reduced to 1x for all assessments except the acute dietary assessment. The FQPA SF is retained for 

the acute dietary risk assessment to account for extrapolation of LOAEL to NOAEL for the acute 

dietary PoD.

4.2.1 Completeness of the Toxicology Database

The toxicology database for dimethomorph is complete and adequate to support risk assessments. 

All part 158 data requirements have either been satisfied or waived for this chemical.

4.2.2 Evidence of Neurotoxicity

In an acute neurotoxicity study, FOB findings and reduced motor activity were observed at 250 

mg/kg and doses above on Day 0 only. These findings were considered an impairment of the overall 

condition of the animals following treatment, rather than direct neurotoxic effects of the 

dimethomorph exposure based on the absence of any neurohistopathological changes in the treated 

animals and the transient nature of the observed FOB and neurobehavioral assessments. In a 

subchronic neurotoxicity study, no neurotoxic effects were observed in rats fed dimethomorph up to 

the highest dose tested at 2400 ppm (178/204 mg/kg/day for males/females, respectively) for 90 

days. In addition, the toxicology database does not reveal any evidence of neurotoxic clinical signs, 

changes in brain weight, or histopathology of the nervous system in any study with dimethomorph. 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The toxicology data on dimethomorph provides no indication of enhanced sensitivity of infants and 

children based on the results from developmental studies conducted with rats and rabbits as well as a 

two-generation reproduction study conducted with rats. There were no toxic effects observed in 

either the rat developmental toxicity or the rat two-generation reproductive toxicity studies that were 

lower than doses which produced toxic effects in the parents. No developmental toxicity was 

demonstrated in the rabbit developmental toxicity study. 

4.2.4 Residual Uncertainty in the Exposure Database

The acute and chronic dietary exposure assessment assumed 100% of the proposed and registered 

crops were treated, and incorporated tolerance level residues for all uses. The dietary (food and 

drinking water) exposure assessment does not underestimate the potential exposure for infants, 

children, or women of child bearing age.

4.3 Toxicity Endpoint and Point of Departure Selections

4.3.1 Dose-Response Assessment
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Acute Dietary Endpoint for the General Population: In an acute neurotoxicity study in rats (MRID 

48980106), reduced motor activity was observed at the lowest dose tested (LOAEL=250 mg/kg). 

The route and a single exposure of this study are appropriate for acute dietary risk assessment. The 

UF is 1000x (10x for interspecies extrapolation, 10x for intraspecies variation and, FQPA SFLof 10x 

for extrapolation of LOAEL to NOAEL). The acute population adjusted dose (aPAD) for general 

population is 0.25 mg/kg.

Acute Dietary Endpoint for Female 13-49 Years of Age: No endpoint was selected for this 

population (female 13-49 years of ages). The developmental toxicity NOAEL of 60 mg/kg/day from 

a developmental toxicity study in rats, based on post-implantation loss at 160 mg/kg/day, was 

considered for establishing the acute point of departure (PoD) for females 13-49. However, it was 

determined that this endpoint was not appropriate for use in this risk assessment, since the effect at 

the high dose was minimal and was not supported by a decrement in litter size (12.4 fetuses per dam

in the control, compared to 11.3 fetuses per dam at the high dose). The maternal effects (decreased 

body weight gain and food consumption) were not considered to be attributable to a single exposure, 

and thus not appropriate for this risk assessment. No appropriate toxicological endpoints attributable 

to a single exposure were identified in other oral studies. Consequently, it was determined that there 

was no basis for selecting a dose and endpoint for an acute PoD for females 13-49 years of age.

Chronic Dietary Endpoint for the General Population: The rat chronic and carcinogenicity studies 

(MRIDs #42233912 and #42233916) have comparable NOAELs (11.9 versus 11.3 mg/kg/day) and 

endpoints with increased incidences of pigmented or hypertrophied hepatocytes, and “ground glass” 

foci in livers of female rats at LOAELS of 99.9 and 46.3 mg/kg/day, respectively. Females appeared 

to be more sensitive in these studies. Therefore the studies were considered co-critical in establishing 

a PoD for chronic dietary risk assessment. An UF of 100x (10x for interspecies extrapolation and 

10x for intraspecies variation) is applied to the NOAEL of 11 mg/kg/day to obtain a chronic 

reference dose (cRfD) of 0.1 mg/kg/day. The FQPA factor is reduced to1x. The chronic population 

adjusted dose (cPAD) is 0.1 mg/kg/day.

Incidental Oral Exposure (Short- and Intermediate-Term): There is no residential use for 

dimethomorph, so a toxicity endpoint for incidental oral exposure has not been established.

Dermal Exposure (Short-, Intermediate-, and Long-Term): There is a 28-day dermal toxicity study in 

rats (MRID# 48326908). The NOAEL was 1000 mg/kg/day (the highest dose test, HDT) with no 

toxic effect seen. Since no toxicity was observed at the limit dose for dermal exposure and no 

developmental toxicity concern has been identified, a quantitative dermal risk assessment for shortand intermediated-term occupational, dermal exposure is not necessary. There are currently no 

registered uses for dimethomorph that result in long-term dermal exposure, therefore, a long-term 

dermal risk assessment is not needed.

Inhalation Exposure (Short, Intermediate-, and Long-Term): There was no inhalation study available 

except the acute inhalation study (Toxicity Category III). A subchronic toxicity study in dogs 

(MRID# 42233908) was selected for short and intermediated-term inhalation exposure. The NOAEL 

is 15 mg/kg/day, the LOAEL is 43 mg/kg/day based on decreased absolute and relative prostate 

weights. Since an oral study was selected, the inhalation exposure component (μg ai/day) using 

100% absorption rate should be converted to an equivalent oral dose (mg/kg/day) for risk 
Dimethomorph Human Health Risk Assessment DP No. D416888

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assessments There are currently no registered uses for dimethomorph that result in long-term 

inhalation exposure, therefore, a long-term inhalation risk assessment is not required. 

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dimethomorph does not pose a dermal risk; therefore quantification of dermal risk is not required. 

Oral and inhalation exposure can be combined since route specific inhalation data is not available, 

and inhalation toxicity is evaluated based on oral studies. 

4.3.3 Cancer Classification and Risk Assessment Recommendation

The Hazard Identification Assessment Review Committee (HIARC) has classified dimethomorph as 

"not likely to be carcinogenic to humans" based upon lack of evidence of carcinogenicity in rats and

mice (HIARC Memo, May 13, 1998). Therefore, a cancer risk assessment is not required.

4.3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

 Table TABLE 4.5.4.1 Summary of Toxicological Doses and Endpoints for Use in Dimethomorph Human 

Health Risk Assessments.

Exposure

Scenario

Point of Departure, 

Uncertainty/FQPA Safety 

Factors

LOC for Risk 

Assessment

Study and Toxicological 

Effects

Acute Dietary

(General Population)

LOAEL = 250 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SFL = 10x

aRfD= 0.25 mg/kg

aPAD=0.25 mg/kg

MRID 48980106

Acute Neurotoxicity Study

LOAEL=250 mg/kg/day 

based on reduced motor 

activity in both sexes.

Acute Dietary

(Females 13-49)

No appropriate endpoint was 

identified including 

developmental toxicity studies in 

rats and rabbits.

Not applicable. No study selected.

Chronic Dietary

(All Populations)

NOAEL = 11 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

cRfD= 0.1 mg/kg/d

cPAD= 0.1 mg/kg/d

MRID 42233912, 42233916

Carcinogenicity study in rats. 

LOAEL = 46.3 mg/kg/day,

based on decreased body 

weight and increases in liver 

lesions in female rats.

Incidental Oral- All 

time periods

Not applicable.

No registered residential uses.

Not applicable No study selected.

Dermal Short- and 

Intermediate-Term 

No toxicity was observed at the 

limit dose in a 28-day dermal 

toxicity study. No quantitative 

risk assessment is necessary.

Not applicable. No study selected.

Dermal Long-Term

(>6 Months)

No long-term exposure. Not applicable. No study selected.

Inhalation Short- and 

Intermediate-Term

(1-6 Months)

Oral, NOAEL= 15 mg/kg/day

(inhalation absorption factor = 

100%)

LOC = 100 MRID 42233908

Subchronic feeding study in 

dogs. LOAEL = 43 

mg/kg/day based on decreased 
Dimethomorph Human Health Risk Assessment DP No. D416888

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 Table TABLE 4.5.4.1 Summary of Toxicological Doses and Endpoints for Use in Dimethomorph Human 

Health Risk Assessments.

Exposure

Scenario

Point of Departure, 

Uncertainty/FQPA Safety 

Factors

LOC for Risk 

Assessment

Study and Toxicological 

Effects

absolute and relative prostate 

weights.

Inhalation Long-Term

(>6 Months)

No long-term exposure. Not applicable. No study selected.

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. FQPA SFL = extrapolation from LOAEL to 

NOAEL. RfD= reference dose. PAD = population adjusted dose (a = acute, c = chronic). LOC = level of concern.

4.3.5 Endocrine Disruption 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 

the reregistration decision for dimethomorph, 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), trifluralin 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 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. When additional appropriate 

screening and/or testing protocols being considered under the Agency’s EDSP have been developed, 
Dimethomorph Human Health Risk Assessment DP No. D416888

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dimethomorph may be subjected to further screening and/or testing to better characterize effects 

related to endocrine disruption. For further information on the status of the EDSP, the policies and 

procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit 

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

5.0 Dietary Exposure and Risk Assessment

5.1 Residue of Concern Summary and Rationale

5.1.1 Summary of Plant and Animal Metabolism Studies

No new plant metabolism studies were submitted for imported papaya. Based on the previous 

metabolism studies with three representative crops (potato, grape and lettuce) the qualitative nature 

of the dimethomorph residues in papaya is considered to be adequately understood (D192776 & 

D219530, D. Davis, 3/31/95 and 10/31/95). In all three studies, parent dimethomorph was the 

predominant residue. The residue of concern for the tolerance expression and risk assessment is the 

parent compound, dimethomorph (comprised of E and Z isomers).

There are no livestock feedstuffs items associated with the subject petition. Therefore, a discussion 

of animal metabolism is not required to support the proposed tolerance.

5.1.2 Summary of Environmental Degradation

Dimethomorph is not expected to be affected by abiotic degradation processes, such as hydrolysis 

and photolysis, in soil or under aquatic conditions. Biotic transformation appears to be the major 

route of dissipation in the environment. Dimethomorph was moderately persistent in an aerobic soil 

(half-life = 117 days). There are strong indications that significantly more rapid dissipation may 

occur under anaerobic conditions in soil and aquatic systems. 

The residue of concern in drinking water for risk assessment purposes is the parent compound, 

dimethomorph, comprised of E and Z isomers (D349254; Jose Luis Melendez; 3 September 2008).

5.1.3 Comparison of Metabolic Pathways

The registrant has previously submitted acceptable studies depicting the metabolic fate of 

dimethomorph in plants, rats and livestock. Dimethomorph is the predominant residue in both plants 

and animals according to the metabolism studies.

Metabolism appears to be similar in a variety of plant commodities. Based on the plant metabolism 

study, unchanged parent is the only significant component of the total residue in grapes, potatoes and 

lettuce and other representative rotational crops. The predominant residue (dimethomorph) was 

mostly found as a surface residue in most plants, with negligible systemic translocation, while in 

potato only low residues were found in tubers (almost all in the peel), suggesting that translocation 

from treated aerial parts to the tuber is negligible. The major metabolic pathways are demethylation 
Dimethomorph Human Health Risk Assessment DP No. D416888

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of the 4-methoxy group of the dimethoxyphenyl ring followed by conjugate formation, the other 

being the stepwise degradation of the morpholine ring. 

Dimethomorph is extensively metabolized in rats by demethylation of one of the methoxy groups 

and formation of O-conjugate and degradation products of morpholine ring opening. Unchanged 

parent dimethomorph was the only detect in rats. Lactating goat study shows that 90% of the 

administered dose was excreted in feces and urine and radioactivity in the edible organs and tissues 

was readily and almost completely extracted, indicating that dimethomorph or its metabolites were 

not bound in the organs and tissues. The major component of the extractable residue in liver, muscle 

and fat was the unchanged parent. The metabolic pathway for dimethomorph in the lactating goat is 

similar to that for rats, and involves the demethylation of one of the phenolic methoxy-groups, with 

an alternative pathway being the cleavage of the morpholine-ring. Extractability of Total 

Radioactive Residues (TRR) in laying hens was high and predominant residue was the parent 

compound. The metabolic pathways observed in laying hens also similar to the goat and rats study. 

5.1.4 Residues of Concern Summary and Rationale

TABLE 5.1.4 Summary of Metabolites and Degradates to Be Included in Risk Assessment and 

Tolerance Expression

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants Primary crops Dimethomorph Dimethomorph 

Rotational crops

Livestock Ruminants Dimethomorph NA*

Poultry

Drinking water Dimethomorph NA*

*NA- Not Applicable

5.2 Food Residue Profile

No new plant metabolism studies were submitted. The results from the previously plant metabolism 

studies indicate that the major component of the extractable residue was unchanged parent 

dimethomorph in both fruit and leaves, and that residues are generally low. The highest residues are 

generally found in the foliage (leaves) of plants, and not in the fruit itself. The residue is expected to 

be a surface residue consisting of primarily parent compound. The available metabolism data in 

plants shows that dimethomorph undergoes limited translocation or degradation. 

5.3 Water Residue Profile

There are no uses associated with this petition that would impact U.S. water resources. For the 

aggregate risk assessment, HED has considered the currently registered domestic use that will result 

in the highest estimated drinking water concentration (EDWC). EFED has determined that broccoli 

(representative of brassica head and stem) is the use with the major exposure and highest percent 

crop area (I. Abdel-Saheb, D387377, 7/27/11). The EDWCs for dimethomorph were calculated 
Dimethomorph Human Health Risk Assessment DP No. D416888

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based on a maximum application rate of 1.4 lb ai/A/season for broccoli. Water residues were 

incorporated into the dietary risk assessment for food categories “water, direct, all sources” and 

“water, indirect, all sources.” The groundwater value was generated using the Screening 

Concentration in Groundwater (SCI-GROW) Model and the surface water values were generated 

using a Tier 1 broccoli model. The surface water estimate was used for both acute and chronic 

assessment (81.1 ppb for acute and 24.7 ppb for chronic) because these values were higher than the 

groundwater value. According to a personal conversation between Donna Davis (HED) and Mark 

Corbin (EFED) on 8/21/2014, PRZM-GW was not run for this chemical and the EDWCs would 

probably be a little higher than the current surface water number. However, Mark agreed that since 

there is no risk issue for this chemical, the old drinking water numbers are good for this action. In 

future new PRZM-GW numbers will be used for domestic use. The models and the descriptions are 

available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

TABLE 5.3 Maximum Tier 1 Estimated Drinking Water Concentration (EDWCs) for 

Drinking Water Risk Assessment Based on Aerial Application of Dimethomorph.

Drinking Water Source [Model 

Used]

Crop Use [Rate Modeled] EDWC (ppb)

Groundwater [SCI-GROW] Broccoli [1.4 lb ai/A] Acute and Chronic 0.264

Surface Water [FIRST] Broccoli [1.4 lb ai/A] Acute 81.1

Broccoli [1.4 lb ai/A] Chronic 24.7

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

An updated acute and chronic dietary (food and drinking water) exposure and risk assessments were 

conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake 

Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food consumption data from 

the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, 

What We Eat in America, (NHANES/WWEIA). The unrefined acute and chronic analyses are based 

on tolerance-level residues, 100% crop treated assumptions for all commodities, and DEEMTM 

default processing factors or empirical processing factors where available. The drinking water 

estimates provided by EFED are modeled estimates, and were generated using the most conservative 

model available for the existing uses. The unrefined acute and chronic approach to dietary risk 

exposure analysis will not underestimate risk to the general U.S. population or any population 

subgroup.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated refinements were not used in this assessment. 
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5.4.3 Acute Dietary Risk Assessment

The acute analysis for all population subgroups, including infants and children, was unrefined and 

used tolerance-level residues and 100% crop-treated (PCT). The resulting acute food and drinking 

water risk estimates are below HED’s level of concern (<100% aPAD) at the 95th percentile of the 

exposure distribution for the general U.S. population (25% aPAD), and all population subgroups.

The most highly-exposed population subgroup was children 3 to 5 years old which utilized 39% of 

the aPAD at the 95th percentile of exposure. Thus, acute dietary exposure to dimethomorph for all 

population subgroups is not of concern. The detailed results for the general population and all 

population subgroups is shown in Table 5.4.6, below.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) risk estimate utilizes 16% of the chronic populationadjusted dose (cPAD) for the U.S. population. The estimated risk for the most highly exposed 

population subgroup (children 1-2 years) is 25% of the cPAD. Thus, chronic dietary exposure to 

dimethomorph for all population subgroups is not of concern. The detailed results for the general 

population and all population subgroups are shown in Table 5.4.6, below.

5.4.5 Cancer Dietary Risk Assessment

Dimethomorph is classified as a “not likely” human carcinogen. A cancer dietary exposure analysis 

is not required.

5.4.6 Dietary Summary Table

The acute and chronic dietary risks for dimethomorph are summarized below.

Table 5.4.6 Summary of the Dietary Exposure and Risk Estimates for Dimethomorph1

Population 

Subgroup

Acute Assessment (95th Percentile) Chronic Assessment

aPAD 

mg/kg/day

Exposure 

Estimate 

mg/kg/day

% 

aPAD

cPAD

mg/kg/day

Exposure 

Estimate 

mg/kg/day

% cPAD

U.S. Population

0.25

 0.063603 25 

0.1

0.016379 16

All infants 0.052513 21 0.009773 9.8

Children 1-2 yrs 0.086871 35 0.025425 25

Children 3-5 yrs 0.096278 39 0.022638 23

Children 6-12 yrs 0.054574 22 0.013773 14

Youth 13-19 yrs 0.048841 20 0.011315 11

Adults 20-49 yrs 0.064193 26 0.016698 17

Adults 50-99 yrs 0.063408 25 0.017084 17

Females 13-49 yrs 0.067352 27 0.016670 17
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1 The populations with the greatest risk estimates are bolded.

6.0 Residential Exposure/Risk Characterization

There are no registered or proposed residential uses, or commercial/professional uses at residential 

sites associated with dimethomorph; therefore, a quantitative residential exposure assessment is not 

required for this risk assessment.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and duration of 

exposure.

For dimethomorph, there are currently no registered residential uses, nor are any proposed. 

Therefore, at this time, dietary (food + water) exposure is the only component of an aggregate 

exposure analysis and risk assessment. As shown in Sections 5.4.3 and 5.4.4, there are no aggregate 

dietary (food plus water) risks of concern for dimethomorph. 

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common 

mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 

dimethomorph and any other substances and dimethomorph does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA 

has not assumed that dimethomorph has a common mechanism of toxicity with other 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 Programs 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/.

9.0 Occupational Exposure/Risk Characterization

There are no occupational exposures associated with the proposed import tolerances; therefore, a 

new occupational exposure assessment was not conducted for this import tolerance petition on 

papayas. 
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10.0 References

Residue Chemistry References

Dimethomorph: Petition for the Establishment of Tolerances Without U.S. Registration on 

Papaya. Summary of Analytical Chemistry and Residue Data. DP Barcode D 423323; S. Biswas; 

10/22/2014

Dimethomorph: Human Health Risk Assessment to Support Amended proposed Use on 

Grapes, Bulb Vegetables, Leafy Brassica Vegetables, and Leafy Vegetables. PC Code 268800; 

DP Barcode D387381; S. Piper; 09/15/2011. 

Addendum to Dimethomorph: Human Health Risk Assessment to Support Amended proposed 

Use on Grapes, Bulb Vegetables, Leafy Brassica Vegetables, and Leafy Vegetables. PC Code 

268800; DP Barcode D399514; S. Piper; 03/06/2012.

Drinking Water Assessment

Dimethomorph: Drinking Water Assessment for the Amended Directions for Use of 

Dimethomorph in Brassica Subgroups 5A & 5B, and Green Onions, Use on Grapes; 

Dimethomorph New Use on Leafy Vegetables; New ai Ametoctradin Coformulated with 

Dimethomorph for (non-food use and food uses) in Human Health Risk Assessment; D387377, I. 

Abdel-Saheb, 7/25/11.

Dietary Exposure Assessment

Dimethomorph: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure 

and Risk Assessment for the Establishment of Tolerances for Residues of Dimethomorph in/on 

Imported Papaya. DP Barcode D423324; S. Biswas; 10/22/2014.

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. Barcode D393434; S. Piper; 09/07/2011
Dimethomorph Human Health Risk Assessment DP No. D416888

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Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40CFR §158.340) for food use of dimethomorph are in Table A.1, below. Use of 

the new guideline numbers does not imply that the new (1998) guideline protocols were used. 

TABLE A.1 Toxicology Data Requirements for Dimethomorph.

Test Technical

Required Satisified

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

yes

yes

yes

yes

no

waived1

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

1The requirement for a subchronic inhalation study is waived. 
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A.2 Toxicity Profiles

TABLE A.2.1 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

TABLE A.2.2 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 prostate weights.

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 gains.

Developmental NOAEL = 60 mg/kg/day

LOAEL = 160 mg/kg/day based on the incidence of post 

implantation loss
Dimethomorph Human Health Risk Assessment DP No. D416888

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TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ 

Study Type

MRID(s) [year]/ 

Classification/Doses Results

870.3800

Reproduction and 

fertility effects

[rat]

42233920 [1990]

Acceptable/guideline

0, 100, 300, 1000 ppm

M: 0,6.9,20.8,69 mg/kg/day

F: 0, 8.0,24,79.3 mg/kg/day

Parental/Systemic NOAEL = 20.8/24 (M/F) mg/kg/day

LOAEL = 69/79.3 (M/F) mg/kg/day based on decreased 

body weights and body weight gains.

Reproductive NOAEL = 20.8/24 (M/F) mg/kg/day

LOAEL = 69/79.3 (M/F) mg/kg/day 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

F: 0, 5.0, 15.7, 47.0 

mg/kg/day

NOAEL = 14.7 mg/kg/day

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

weight.

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 gaisn 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].
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TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ 

Study Type

MRID(s) [year]/ 

Classification/Doses Results

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 

cells in culture

870.8800

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/-

S9]
Dimethomorph Human Health Risk Assessment DP No. D416888

Page 24 of 25

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Dimethomorph.

Guideline Number/ 

Study Type

MRID(s) [year]/ 

Classification/Doses Results

870.6200

Acute neurotoxicity

[rat]

48980106 (2011)

Acceptable/non-guideline

0, 250, 500, 2000 mg/kg

NOAEL<250 mg/kg, LOAEL=250 mg/kg based on 

decreased motor activity, impairment of gait and rearing in 

both sexes.

870.6200

Subchronic 

neurotoxicity

[rat]

48326902 [2004]

Acceptable/guideline

0,300, 800, 2400 ppm

M:0,21.7,58.7,177.9 

mg/kg/day

F:0,25.7,69.6,204 mg/kg/day

Systemic NOAEL= 58.7/69.9 mg/kg/day (M/F), 

LOAEL=177.9/204 mg/kg/day based on decreases in body 

weight and weight gains.

Neurotoxicity NOAEL= 177.9/204 mg/kg/day (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 coefficient 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.
Dimethomorph Human Health Risk Assessment DP No. D416888

Page 25 of 25

Appendix B. International Residue Limits Table

Dimethomorph (268800; 08/12/2014)

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

Imported Papaya 1.5

Completed: M. Negussie; 08/12/14

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.