Dimethomorph Human Health Risk Assessment DP No. 387381

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

DATE: September 15, 2011

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

Grapes, Bulb Vegetables, Leafy Brassica Vegetables, and Leafy Vegetables.

PC Code: 268800 DP Barcode: D387381

Decision No.: 437308, 443783, 443255 Registration No.: 241-427

Petition No.: 0F7751; 0F7800; 0F7816 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical/

Aggregate

Case No.: NA

TXR No.: NA CAS No.: 110488-70-5

MRID No.: NA 40 CFR: 180.493

FROM: Sheila Piper, Chemist/Risk Assessor

Yung Yang, Ph.D., Toxicologist

Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist

Risk Assessment Branch VI

Health Effects Division (7509P)

THROUGH: Felecia Fort, Chief

Risk Assessment Branch VI

Health Effects Division (7509P)

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

Mary L. Waller, PM 21

Fungicide Branch/ Registration Division (7505P)
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The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with 

estimating the risk to human health from exposure to pesticides. BASF Corporation has 

requested the removal of regional restriction on grapes and amended the uses on bulb vegetables

(crop group 3), leafy Brassica vegetables (crop group 5) and leafy vegetables (crop group 4). 

The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure 

data and conduct dietary, occupational, and aggregate exposure assessments, as needed, to 

estimate the risk to human health that will result from the proposed use of dimethomorph on 

grapes, bulb vegetables, leafy Brassica vegetables and leafy vegetables. HED has evaluated the 

toxicity and exposure databases for the active ingredient, dimethomorph, and has conducted a 

human health risk assessment in support of the proposed use. HED has determined that potential 

exposure could occur via the dietary and occupational pathway. 

A summary of the findings and an assessment of human health risk resulting from the proposed 

use for dimethomorph are provided in this document. The HED team members contributing to 

this risk assessment include Monica Hawkins (occupational/residential assessments), Yung Yang

(hazard evaluation), and Sheila Piper (residue chemistry, dietary assessment and risk 

assessment). Ibrahim Abdel-Saheb, Environmental Scientist, Environmental Risk Branch IV, 

Environmental Fate and Effects Division (EFED), provided the drinking water exposure 

assessment.
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1.0 Executive Summary................................................................................................................... 5

2.0 HED Recommendations............................................................................................................. 7

2.1 Data Deficiencies/Conditions of Registration ........................................................................... 7

3.0 Ingredient Profile ....................................................................................................................... 8

3.1 Structure and Nomenclature ...................................................................................................... 8

3.2 Physical/Chemical Characteristics............................................................................................ 9

3.3 Summary of Existing/Proposed Uses....................................................................................... 10

4.0 Hazard Characterization and Dose-Response Assessment......................................... 11

4.1 Hazard and Dose-Response Characterization............................................................. 11

4.1.1 Database Summary ................................................................................................. 11

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)....................................... 12

4.3 FQPA Considerations................................................................................................. 12

4.3.1 Adequacy of the Toxicity Database........................................................................ 12

4.3.2 Evidence of Neurotoxicity ...................................................................................... 12

4.3.3 Developmental Toxicity Studies............................................................................. 13

4.3.4 Reproductive Toxicity Study .................................................................................. 13

4.3.5 Additional Information from Literature Sources.................................................... 14

4.3.6 Pre- and/or Post-Natal Toxicity .............................................................................. 14

4.3.6.1 Determination of Susceptibility .......................................................................... 14

4.3.6.2 Degree of Concern Analysis, and Residual Uncertainties for Pre- and/or PostNatal Susceptibility............................................................................................................... 14

4.3.7 Recommendation for a Developmental Neurotoxicity Study................................. 14

4.4 FQPA Safety Factor for Infants and Children ............................................................ 14

4.5 Hazard Identification and Toxicity Endpoint Selection ............................................. 15

4.5.1 Acute Reference Dose (aRfD) - Females Age 13-49.............................................. 15

4.5.2 Acute Reference Dose (aRfD) - General Population.............................................. 15

4.5.3 Chronic Reference Dose (cRfD)............................................................................. 15

4.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)..................................... 16

4.5.5 Dermal Absorption.................................................................................................. 16

4.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term)..................................... 17

4.5.7 Inhalation Exposure (Short-, Intermediate- and Long-Term)................................. 17

4.5.7.1 Occupational Inhalation Exposure (Short-Term)................................................ 17

4.5.7.2 Occupational Inhalation Exposure (Intermediate-Term) .................................... 17

4.5.8 Level of Concern (LOC) for Margin of Exposure (MOE) ..................................... 18

4.5.9 Recommendation for Aggregate Exposure Risk Assessments............................... 18

4.5.10 Classification of Carcinogenic Potential................................................................. 18

4.5.11 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments.......................................................................................................................... 19

4.6 Endocrine Disruption.................................................................................................. 20

5.0 Dietary Exposure and Risk Assessment ..................................................................... 20

5.1 Metabolite/Degradate Residue Profile........................................................................ 20

5.1.1 Summary of Plant and Animal Metabolism Studies............................................... 20
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5.1.2 Summary of Environmental Degradation ............................................................... 21

5.1.3 Comparison of Metabolic Pathways....................................................................... 21

5.1.4 Residues of Concern Summary and Rationale........................................................ 21

5.2 Food Residue Profile............................................................................................................... 22

5.3 Water Residue Profile ............................................................................................................. 25

5.4 Dietary Risk Assessment ........................................................................................................ 26

5.4.1 Anticipated Residue and Percent Crop Treated (%CT) Information...................... 26

5.4.2 Acute Dietary Risk Assessment.............................................................................. 26

5.4.3 Chronic Dietary Risk Assessment .......................................................................... 26

5.4.4 Cancer Dietary Risk Assessment............................................................................ 27

5.4.5 Dietary Summary Table.......................................................................................... 27

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 27

6.1 Residential Handler Exposure .................................................................................... 27

6.2 Residential Post-Application Exposure...................................................................... 28

6.3 Spray Drift .................................................................................................................. 28

6.4 Residential Bystander Post-application Inhalation..................................................... 28

7.0 Cumulative Exposure/Risk Characterization........................................................................... 29

8.0 Occupational Exposure/Risk Characterization........................................................... 29

8.1 Short-and Intermediate-Term Handler Risk ............................................................... 29

8.2 Occupational Post-Application................................................................................... 30

9.0 Environmental Justice Considerations..................................................................................... 30

10.0 Data Needs and Label Recommendations .............................................................. 31

10.1 Toxicology .............................................................................................................. 31

10.2 Residue Chemistry................................................................................................................... 31

11.0 References................................................................................................................................ 32
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1.0 Executive Summary

BASF Corporation is proposing an amended registration of the 4.17 lb ai/gal suspension 

concentrates (SC) formulation of dimethomorph (Forum® Fungicide, EPA Reg. No. 241-427) to 

reduce the preharvest intervals (PHIs) for grapes from 28 to 14 days, reduce the maximum number 

of applications from 5 to 4 and to expand the use from its current regionally restricted use to a 

national registration. In addition, the registrant is proposing amended uses on bulb vegetables

(crop group 3), leafy Brassica vegetables (crop group 5) and leafy vegetables (crop group 4). In 

support of the proposed amendment, BASF Corporation, under PP0F7751, 0F7800 and 0F7816 is 

proposing that the 40 CFR 180.493 be amended to reflect the following tolerances:

Grapes...................................................................3.5 ppm

Brassica, head and stem, subgroup 5A ................5.0 ppm

Brassica, leafy greens, subgroup 5B...................30.0 ppm

Leafy Vegetable, crop group 4 ...........................16.0 ppm

Green Onion .......................................................11.0 ppm

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 mildews, late blights, crown and root rots. It is currently registered for use 

on bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy Brassica greens, head and 

stem Brassica vegetables, hops, lettuce (head and leaf), potatoes, taro, and ginseng; tolerances 

have also been established on imported grapes and raisins. Its mode of action is via inhibition of 

sterol (ergosterol) synthesis. 

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

assessment. The Agency believes that the current toxicological database is adequate to evaluate 

the hazards associated with these amended uses.

Dimethomorph has low acute toxicity via the oral and dermal routes of exposure. The available 

data for dimethomorph do not show evidence of neurotoxicity, and a developmental 

neurotoxicity study is not warranted at this time. An acute neurotoxicity study was not 

submitted; however, HED believes that conducting an acute neurotoxicity study is unlikely to 

add value to the risk assessment or identify a lower point of departure for risk assessment. 

Therefore, an acute neutoxicity study is not needed at this time. 

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 
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due to radioactivity in the lumenal contents. Urinary metabolites resulted from demethylation of 

the dimethoxyphenyl ring and oxidation of the morpholine ring.

No appropriate toxicological endpoints attributable to a single exposure were identified in oral 

studies. Because no acute toxicity endpoints were identified, risks from acute exposure are not 

of concern to HED. Chronic risk is regulated based on effects seen in body weight decrements 

and liver effects in the female rat. Dimethomorph has been classified as showing no evidence of 

human carcinogenicity. Therefore, cancer risk from dimethomorph is not of concern to HED. 

The dose for short-term exposure is the maternal NOAEL established in the rat developmental 

toxicity study, whereas the dose for intermediate-term exposure is the NOAEL established in the 

90-day dog feeding study. In a 28-day rat dermal toxicity study, 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, risk assessment for dermal exposure is not necessary. Inhalation absorption is 

assumed to be 100 percent. At this time, there are no residential uses for dimethomorph. 

Therefore, discussion of dermal and inhalation toxicity are unnecessary for this risk assessment 

with respect to residential exposures. 

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 observed at lower doses than those which produced toxic effects in the parents. 

No developmental toxicity was demonstrated in the rabbit developmental toxicity study. 

Because of these reasons the 10-fold FQPA Safety Factor, to account for enhanced sensitivity of 

infants and children, was reduced to 1. 

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

chronic dietary (food and drinking water) exposure and risk assessment. Chronic dietary risks 

are not of concern for the U.S. population and all subpopulations. For food and drinking water, 

the chronic aggregate dietary risk was calculated at 14% of the cPAD (chronic population 

adjusted dose). The exposure estimate for the most highly exposed subpopulation (children 1-2 

years) is 27% of the cPAD.

There are no residential uses for dimethomorph at this time, nor are any proposed. Also, there 

are no registered or proposed uses of dimethomorph that would result in treatment of recreational 

areas. Therefore, assessment for residential handler and post-application exposures is not 

required at this time.

Since there are no acute endpoints of concern, an acute aggregate risk assessment was not 

conducted. There are currently no registered residential uses associated with dimethomorph; 

therefore, no short- and intermediate-term aggregate risk assessments are required. 

HED has assessed occupational exposures to dimethomorph. These assessments include 
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scenarios for mixers, loaders, applicators and flaggers, and for post-application exposure of 

workers arising from scouting, harvesting, and other cultivation-related activities. For all of 

these scenarios, risk estimates are below HED’s level of concern (MOEs ≥ 100). The label 

restricted entry interval (REI) of 12-hour is appropriate and in compliance of the Worker 

Protection Standard requirements. 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, which comprise the 

Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force ARTF) 

database, have been determined to require a review of their ethical conduct, have received that 

review, and have been determined to be ethical.

2.0 HED Recommendations

Provided the registrant submits a revised Section F (see Table10.2), there are no human health 

risks of concern that would preclude the establishment or revision of tolerances for the residue of 

dimethomorph under 40 CFR 180.493 as follows:

Grapes...................................................................4.0 ppm

Grape raisins .........................................................6.0 ppm

Brassica, head and stem, subgroup 5A ................5.0 ppm

Brassica, leafy greens, subgroup 5B...................30.0 ppm

Leafy Vegetable except Brassica, subgroup 4A..20.0 ppm

Leaf Petioles,subgroup 4B .................................15.0 ppm

Onion bulb ...........................................................0.6 ppm

Green Onion .......................................................15.0 ppm

2.1 Data Deficiencies/Conditions of Registration

The following data should be submitted with future uses:

RESIDUE CHEMISTRY

860.1200 Directions for Use

Section B of the labels should be amended to prohibit rotation to cereal grains. Also, the

crop rotation restriction will need to be revised to specify a 7 month plant back interval 

(PBI) for soybean and other legume vegetables; all other crops can be planted 12 months

after the last application.

Note to RD: Please delete the expired footnote in the 40 CFR 180.493 for grape raisin 

that states, ―There are no US registrations as of March 4, 2009, for the use of 
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dimethomorph on grapes grown for raisin production.‖ The registrant is requesting 

national tolerances for grapes and the raisin tolerance of 6.0 ppm can remain for US 

registration.

860.1900 Field Accumulation in Rotational Crops

Limited field trials for wheat (20 trials) should be conducted and the geographic 

representation should be the same as that required to establish a tolerance on wheat as 

listed in the OPPTS Guideline 860.1500. [Note: Limited field trials for wheat are not 

required if the registrant agrees to label amendments prohibiting rotation to cereal 

grains]

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is available for dimethomorph, Method FAMS 002-04, which 

utilizes high pressure liquid chromatography with ultraviolet detection (HPLC/UV). The 

reported limits of quantitation (LOQs) range from 0.010 to 0.050 ppm, depending on the sample 

matrix. The method has been successfully validated by BEAD’s Analytical Chemistry Branch 

(ACB). A confirmatory method is also available, Method M 2577, a gas-chromatography 

method with nitrogen/phosphorus detection (GC/NPD). Also, dimethomorph has previously 

been subjected to testing via the FDA multiresidue methods protocols of PAM 1 and 

dimethomorph is recovered using Protocol D. A LC/MS/MS method (BASF Method No 575/0) 

for dimethomorph has been determined to be adequate for data collection in/on grapes, bulb 

vegetables, leafy Brassica vegetables and leafy vegetables. The LOQ is 0.01 ppm.

2.2.2 International Harmonization

There are no Canadian nor Mexican maximum residue limits (MRLs) established for residues of 

dimethomorph in crops associated with this review. Codex MRLs have been finalized for

grapes and raisins at 2 and 5 ppm, respectively. The Codex MRLs are not harmonized with the 

established US tolerances in grapes and raisins (3.5 and 6.0 ppm, respectively), which are based 

on European residue data. 

3.0 Ingredient Profile

Dimethomorph is a systemic fungicide used for the control of downy mildews, late blights, and 

crown and root rots. 

3.1 Structure and Nomenclature
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Table 3.1: Test Compound 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

End-use product (EP) BAS 550 11F (FORUM® Fungicide (4.17 ai/gal SC formulation); EPA Reg. No. 

241-427)

3.2 Physical/Chemical Characteristics

Table 3.2: 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/cm3at 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 10-7Pa at 25oC

Z-isomer: 1.0 x 10-6Pa 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
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3.3 Summary of Existing/Proposed Uses

BASF Corporation has submitted draft label language to support the amended use of 

dimethomorph on grapes. The amended label would reduce the PHI for grapes from 28 to 14 

days, reduce the maximum number of applications from 5 to 4 and to expand the use from its 

current regionally restricted use to a national registration. In addition, the registrant is proposing 

amended uses on bulb vegetables, leafy Brassica vegetables (crop group 5) and leafy vegetables 

(crop group 4) as a 4.17 lb ai/gal SC formulation (EPA Reg. No. 241-427). This is a new 

formulation (SC) being proposed for dimethomorph. There is an existing FlC formulation (EPA 

Reg. No. 241-427). These end-use products (EPs) may be applied by aerial, airblast or ground 

sprays, or via chemigation. The proposed new uses are summarized in Table 3.3.

TABLE 3.3. Summary of Directions for the Proposed Uses of Dimethomorph.

Use Timing; 

Type; 

Equipment

Formulation

[EPA File #]

Applic. 

Rate

(lb 

ai/A)

Max # of 

Applic. 

per 

Season

Max 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(Days)

Use Directions and 

Limitations

Grapes

Post-emergence; 

Foliar; ground 

or aerial

4.17 lb ai/gal 

SC [241-427]

0.20 4 0.80 14 Do Not use less than 

20 gal of water per 

acre for ground and 5 

gal of water for aerial 

applications. The 

minimum application 

interval for Forum is 7 

days.

Brassica Leafy Vegetables

Post-emergence; 

Foliar; ground 

or aerial

4.17 lb ai/gal 

SC [241-427]

0.20 3 0.60 0 Do not use less than 

20 gal of water per 

acre for ground and 

5 gal of water for 

aerial applications. 

The minimum 

application interval 

for Forum is 7 days.
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TABLE 3.3. Summary of Directions for the Proposed Uses of Dimethomorph.

Use Timing; 

Type; 

Equipment

Formulation

[EPA File #]

Applic. 

Rate

(lb 

ai/A)

Max # of 

Applic. 

per 

Season

Max 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(Days)

Use Directions and 

Limitations

Leafy (Except Brassica) Vegetables

Post-emergence; 

Foliar; ground 

or aerial

4.17 lb ai/gal 

SC [241-427]

0.20 3 0.60 0 Do not use less than 

20 gal of water per 

acre for ground and 

5 gal of water for 

aerial applications. 

The minimum 

application interval 

for Forum is 7 days.

Bulb Onion

Post-emergence; 

Foliar; ground 

or aerial

4.17 lb ai/gal 

SC [241-427]

0.20 3 0.60 0 Do not use less than 

20 gal of water per 

acre for ground and 

5 gal of water for 

aerial applications. 

The minimum 

application interval 

for Forum is 5 days

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Hazard and Dose-Response Characterization

Table A.2.1 (in Appendix A) summarizes the acute toxicity of the technical grade of 

dimethomorph. As demonstrated, technical dimethomorph is relatively non-toxic when 

administered acutely to laboratory animals. Table A.2.2 (in Appendix A) summarizes the 

subchronic, chronic and other toxicity of the technical grade of dimethomorph. 

4.1.1 Database Summary

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

risk assessment. The toxicity profile of dimethomorph can be characterized for most effects, 

including potential carcinogenic, mutagenic, developmental, immunotoxic, and neurotoxic 

effects. The doses and endpoints for use in human health risk assessments are summarized in 

Table 4.5.11. Previously, as part of the new EPA guideline requirements (40CFR §158), acute 
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and subchronic neurotoxicity studies, as well as an immunotoxicity study were required. Studies 

for 21/28 day dermal toxicity, immunotoxicity, subchronic neurotoxicity were submitted. 

However, an acute neurotoxicity study was not submitted. There were no neurotoxic effects seen 

at the highest dose tested in a subchronic neurotoxicity study. The available data for 

dimethomorph also do not show evidence of neurotoxicity. HED believes that conducting an 

acute neurotoxicity study is unlikely to add value to the risk assessment or identify a lower point 

of departure for risk assessment. Therefore, an acute neurotoxicity study is not needed at this 

time. 

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

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 (roughly 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]-dimethomorph-derived radioactivity was generally no more 

than 1% for most tissues, although the liver exhibited slightly higher levels (1.4%). Higher 

levels in the gastrointestinal tract organs were caused by 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 low-dose treatment. The major biliary metabolites were glucuronides of one, and 

possibly two, of the compounds produced by demethylation of the dimethoxyphenyl ring. 

4.3 FQPA Considerations

4.3.1 Adequacy of the Toxicity Database

The database is adequate to characterize potential pre- and/or post-natal risk for infants and 

children. Developmental toxicity studies in rats and rabbits, and reproduction studies in rats are 

available for FQPA assessment. Based on the toxicity profile for dimethomorph, a 

developmental neurotoxicity study in rats is not required. 

4.3.2 Evidence of Neurotoxicity

There is a subchronic neurotoxicity studies available while an acute neurotoxicity study was not 

submitted. There was no evidence of neurotoxicity observed in any of the submitted studies for 

dimethomorph. 
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4.3.3 Developmental Toxicity Studies

In a developmental toxicity study in rats, reductions in body weight, body weight gain, and food 

consumption were seen in maternal animals at the LOAEL of 160 mg/kg/day (NOAEL = 60 

mg/kg/day). Increased post-implantation loss was also seen at 160 mg/kg/day. In a 

developmental toxicity study in rabbits, increased incidence of abortion was observed at the 

LOAEL of 650 mg/kg/day (NOAEL = 300 mg/kg/day). No effects were observed in pups at 

doses of up to 650 mg/kg/day. 

4.3.4 Reproductive Toxicity Study

In a multi-generation reproductive toxicity study, the P generation animals were mated in a oneto-one ratio, and given the test material for 15 weeks before they were mated. Selection of the 

parents for the F1 generation was made shortly after weaning on day 21 post-partum. The P1

animals were mated when they were approximately 21 weeks of age, while the F1 generation was 

mated at about 15 weeks of age. 

No clinical signs or necropsy findings which could be associated with administration of the test 

material were noted at any dose level in parental animals. At 1000 ppm, P generation females 

weighed consistently less than controls throughout the 15 week pre-mating period (p<0.05). 

Statistically significant reductions in food consumption were also noted in 1000 ppm females 

during the pre-mating period. In F1 females, body weights were slightly lower in all the dose 

groups but differences were not statistically significant. At the 1000 ppm level, during several 

intervals of the pre-mating period, female weight gain was reduced (p<0.05). No effects were 

apparent in males of the P or F1 generations. For parental systemic toxicity, the NOAEL was 

300 ppm, and the LOAEL was 1000 ppm, based upon decreased body weights and body weight 

gains. 

Reproductive indices were not affected by treatment at any dose level or mating. The percentage 

of pups with incisor eruption was noted at the 1000 ppm dose level in the F1, F2a and F2b

generations with non-significant delays observed at the lower dose levels. During the second 

mating of the F1 generation to produce the F2b generation, a large number of inseminated females 

failed to deliver. This finding appeared to occur in a dose-related manner at all dose levels but 

was not apparent during other matings. It should be noted that the prostate gland was apparently 

affected by the test material in the dog chronic feeding study, and the organ was not weighed in 

the chronic rat study. No organ weight data were presented for the prostate gland in this 

reproduction study but no dose-related histopathology data were apparent in this study. For 

reproductive toxicity, the NOAEL was 300 ppm, and the LOAEL was 1000 ppm, based upon 

decreased incisor eruption on day 10 postpartum. 
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4.3.5 Additional Information from Literature Sources

There is no additional information available from the literature to influence FQPA safety 

findings. 

4.3.6 Pre- and/or Post-Natal Toxicity

4.3.6.1 Determination of Susceptibility

The available data do not provide evidence of any increased susceptibility in the offspring in 

either of the two developmental toxicity studies, nor in the two-generation reproduction study. 

In none of these studies was any toxicity seen in the offspring which occurred at doses lower 

than in the parents. 

4.3.6.2 Degree of Concern Analysis, and Residual Uncertainties for Pre- and/or Post-Natal 

Susceptibility

The purposes of the Degree of Concern analysis are to determine the level of concern for the 

effects observed (when considered in the context of all available toxicity data), and to identify 

any residual uncertainties (after establishing toxicity endpoints, and traditional uncertainty 

factors to be used in the risk assessment). If residual uncertainties are identified, then HED 

determines whether these residual uncertainties can be addressed by an FQPA safety factor, and 

if so, the size of the safety factor needed. 

There are no residual uncertainties with regard to pre- and/or post-natal toxicity following in 

utero exposure to rats or rabbits, and pre and/or post-natal exposures to rats. Therefore, it is 

recommended that the FQPA safety factor be reduced to 1x; no additional safety factors are 

needed (see Section 4.4, below). 

4.3.7 Recommendation for a Developmental Neurotoxicity Study

None of the submitted studies indicate that dimethomorph is a neurotoxic chemical. Neither the 

subchronic nor chronic toxicity studies in rats or dogs, nor the developmental toxicity studies 

indicated that the nervous system was affected by treatment with dimethomorph. There is no 

indication that dimethomorph is a neurotoxic chemical, and there are no residual uncertainties 

regarding pre- and/or post-natal toxicity following dimethomorph exposure. Therefore, a 

developmental neurotoxicity study is not required, and there is no need for additional uncertainty 

factors. 

4.4 FQPA Safety Factor for Infants and Children

Initially (4 May 1998), HED determined that a safety factor was necessary, based on the lack of 

environmental fate data required for the drinking water exposure assessment of dimethomorph. 
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However, EFED assured HED that, even assuming the worst possible model input parameters for 

dimethomorph, risk levels for drinking water exposure are not of concern. Considering this 

inormation, on 8 June 1998, HED recommended that the 10x Safety Factor be removed. 

Additionally: 

1. The developmental and reproductive toxicity data did not indicate 

increased susceptibility of rats or rabbits to in utero and/or postnatal exposure to dimethomorph, 

2. There is no evidence of neurotoxicity,

3. The dietary (food only) exposure assessment did not indicate a concern 

for potential risk to infants and children, even though unrefined 

field study data are used, resulting in an overestimate of dietary 

exposure, and 

4. There are currently no registered residential uses for dimethomorph. 

4.5 Hazard Identification and Toxicity Endpoint Selection

4.5.1 Acute Reference Dose (aRfD) - Females Age 13-49

No appropriate endpoint was identified. 

Comments about Study/Endpoint/Uncertainty Factors: 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 RfD (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 RfD. 

4.5.2 Acute Reference Dose (aRfD) - General Population

No appropriate endpoint was identified. 

Comments about Study/Endpoint/Uncertainty Factors: No appropriate toxicological endpoints 

attributable to a single exposure were identified in oral studies. Consequently, there was no basis 

for selecting a dose and endpoint for an acute RfD. An acute dietary risk assessment is not 

required for any segment of the US population, including infants and children. 

4.5.3 Chronic Reference Dose (cRfD)

Studies Selected: Chronic Toxicity - Rat/Carcinogenicity - Rat

MRID Numbers: 42233912 and 42233916
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Dose and Endpoint for Risk Assessment: NOAEL= 11 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = 11 mg/kg/day (NOAEL) = 0.1 mg/kg/day

 100 (UF)

Comments about Study/Endpoint/Uncertainty Factors: The data evaluation records (DERs) for 

the rat chronic, and rat carcinogenicity studies (MRIDs #42233912 and #42233916) established 

comparable NOAELs (11.9 versus 11.3 mg/kg/day) and endpoints of increased incidences of 

pigmented or hypertrophied hepatocytes, and ―ground glass‖ foci in livers of female rats. 

Females appeared to be more sensitive in these studies. 

Dose and Endpoint for Establishing the RfD : NOAEL= 11 mg/kg/day based on decreased body 

weight and statistically significant increases in liver lesions in female rats at 46.3 mg/kg/day 

(LOAEL). 

4.5.4 Incidental Oral Exposure (Short- and Intermediate-Term) 

There are no residential uses for dimethomorph, so a toxicity endpoint for incidental oral 

exposure is not necessary. 

4.5.5 Dermal Absorption

The total amount of dimethomorph absorbed (expressed as a percent of the [14C]-dose) by rats at 

various times following dermal administration of [14C]-dimethomorph at 7.73 (0.15 mg/cm2) or 

79.62 mg/kg (1.58 mg/cm2) is less than 5% of the dose, and it appears that the absorption is 

concentration dependent. Dermal absorption was 0.05%, 0.07% and 0.27% of the administered 

dose in rats 4, 8 and 24 hours after dermal treatment at 7.73 mg/kg, respectively. Dermal 

absorption was 0.02%, 0.16% and 0.12% of the dose 4, 8 and 24 hours after dermal treatment at 

79.62 mg/kg, respectively. Dermal absorption was approximately 0.4 and 1 mg/kg in terms of 

weight equivalent at 7.73 and 79.62 mg/kg, respectively. Six days after dermal treatment, the 

percent total absorption of the dose at 7.73 and 79.62 mg/kg was 4.76 and 1.20%, respectively. 

Mean percent recovery of 14C for dose levels of 7.73 and 79.62 mg/kg was 104.1% and 92.1%, 

respectively. The majority of the radioactivity was found in skin swabs and gauze wash (80.9 to 

81.8%). The percent of the dose in the skin decreased with dose, being 17.5 % at 7.73 mg/kg, 

and 9.99% at 79.62 mg/kg. 

The dermal absorption coefficient factor is 5%. 
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4.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term)

There is a 28-day dermal toxicity study in rats available. The NOAEL was 1000 mg/kg/day (the 

highest dose test, HDT) with no toxic effect was seen. Since no toxicity was observed at the limit 

dose, risk assessment for short- and intermediated-term occupational dermal exposure is not 

necessary. The current use pattern does not indicate a concern for long-term exposure/risk, and 

no long-term uses are proposed. Therefore, risk assessment for long-term dermal exposure is not 

needed. 

4.5.7 Inhalation Exposure (Short-, Intermediate- and Long-Term)

There are no inhalation studies, except for the acute toxicity study (MRID #43917246). 

Therefore, the oral NOAELs were selected for short-and intermediate-term inhalation risk 

assessments. The use pattern does not indicate a concern for long-term exposure/risk. 

4.5.7.1 Occupational Inhalation Exposure (Short-Term)

Study Selected: Developmental Toxicity - Rat

MRID Numbers: 42233919 and 44175302

Dose and Endpoint for Risk Assessment: NOAEL= 60 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: No inhalation toxicity studies are 

available. The maternal toxicity NOAEL is 60 mg/kg/day, based on decreased body weight, 

decreased body weight gain, and decreased food consumption at 160 mg/kg/day (LOAEL) in an 

oral developmental toxicity study. The effects seen in the dams during gestation days 10-15 

(after 4-5 dosings) are appropriate to use for short-term exposure periods (1-30 days). Since an 

oral NOAEL was selected, the inhalation exposure component (μg ai/day) using 100% 

absorption rate should be converted to an equivalent oral dose (mg/kg/day) in calculating the risk 

for inhalation exposure. 

4.5.7.2 Occupational Inhalation Exposure (Intermediate-Term)

Study Selected: Subchronic Toxicity - Dog

MRID Number: 422339081

Dose and Endpoint for Risk Assessment: NOAEL= 15 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: The NOAEL is 15 mg/kg/day, based 

on decreased absolute and relative prostate weight, and possible threshold liver effects at the 

LOAEL of 43 mg/kg/day in a subchronic oral feeding study in dogs. Since a subchronic 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 intermediate-term (30 days to 6 

months) risk assessments. 
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The current use pattern does not indicate a concern for long-term exposure/risk, and no longterm uses are proposed. 

4.5.8 Level of Concern (LOC) for Margin of Exposure (MOE)

Target MOEs are 100 for occupational inhalation (short- and intermediate-term) exposures. 

TABLE 4.5.8 Summary of LOCs for Dimethomorph Risk Assessment.

Route of Exposure Short-Term

(1-30 Days)

Intermediate-Term

(1-6 Months)

Long-Term

(>6 Months)

Occupational (Worker) Exposure

Dermal NA* NA* NA*

Inhalation 100 100 NA

Residential Exposure

Dermal NA NA NA

Inhalation NA NA NA

Incidental Oral NA NA NA

* NA = Not Applicable. 

4.5.9 Recommendation for Aggregate Exposure Risk Assessments

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. 

4.5.10 Classification of Carcinogenic Potential

In a carcinogenicity study in rat, there was no evidence of increased incidence of any neoplasms 

at the doses tested. The chemical was tested at adequate dosage, based on the high incidence of 

arteritis in males, and the pronounced decrease in body weight in females at the mid- and highdose levels. 

In a carcinogenicity study in mice, there was no dose-related decrease in survival, or in any 

parameter examined on necropsy. The LOAEL for systemic toxicity was 1000 mg/kg/day, based 

on decreased body weight gain in males. The NOAEL was 100 mg/kg/day. There was no 

evidence of carcinogenicity. The high dose tested (1000 mg/kg/day), while probably not the 

maximum tolerated dose, especially in females, is the maximum dose required by the test 

guidelines for a dietary oncogenicity study. 
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Dimethomorph has been classified as ―not likely‖ to be a human carcinogen. 

4.5.11 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments

The toxicity endpoints pertinent to an assessment of risk for dimethomorph are summarized in 

Table 4.5.11, below. 

 Table TABLE 4.5.11 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

(Females 13-49)

No endpoint attributable to a 

single dose was identified.

Not applicable. No study selected.

Acute Dietary

(General Population)

No endpoint attributable to a 

single dose was identified.

Not applicable. No study selected.

Chronic Dietary

(All Populations)

NOAEL = 11 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1

UF = 100

cPAD = 

NOAEL ÷ UF = 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. No risk assessment 

is necessary.

Not applicable. No study selected.

Dermal Long-Term

(>6 Months)

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

Inhalation Short-Term

(1-30 Days)

Oral study NOAEL= 

60 mg/kg/day

(inhalation absorption factor =

100%)

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 absorption factor = 

100%)

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 or risk. 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 
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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. 

4.6 Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to 

determine whether certain substances (including all pesticide active and other ingredients) ―may 

have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, 

or other such endocrine effects as the Administrator may designate.‖ Following 

recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee 

(EDSTAC), EPA determined that there was a scientific basis for including, as part of the 

program, the androgen and thyroid hormone systems, in addition to the estrogen hormone 

system. EPA also adopted EDSTAC’s recommendation to include evaluations of potential 

effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in 

wildlife may help determine whether a substance may have an effect in humans, FFDCA 

authority to require the wildlife evaluations. As the science develops and resources allow, 

screening of additional hormone systems may be added to the Endocrine Disruptor Screening 

Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under the 

Agency’s EDSP have been developed, 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 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Plant Metabolism Studies

The qualitative nature of dimethomorph residues in plants is adequately understood based on 

metabolism studies conducted in three dissimilar crops (potatoes, grapes and lettuce). The 

residue of concern for the tolerance expression and risk assessment is the parent compound, 

dimethomorph (comprised of E and Z isomers).

Animal Metabolism Studies 

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 
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dimethomorph residues in the livestock feed. Furthermore, there are no significant livestock 

feedstuffs associated with the proposed uses on grapes, bulb vegetables, Brassica leafy 

vegetables and leafy vegetables. As a result, tolerances for residues of dimethomorph in 

livestock commodities need not be established.

5.1.2 Summary of Environmental Degradation

The residue of concern in drinking water is dimethomorph (comprised of E and Z isomers). 

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. 

Laboratory studies on mobility of dimethomorph indicated low to medium mobility in soil 

systems, in accordance with McCall et al (1981). The results of the field dissipation study 

appear to confirm the low to medium mobility inferred from laboratory studies. However, 

episodes of high rainfall were shown to increase downward mobility in the field soil profile. 

5.1.3 Comparison of Metabolic Pathways

Oral administration of dimethomorph (10 mg/kg single dose; 10 mg/kg 14-day repeated dose; 10 

mg/kg 7-day repeated dose; 500 mg/kg single dose) 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- and high-dose treatments, urinary 

excretion in female rats tended to be up to 2-fold greater (in low-dose rats) than that of males. 

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 owing 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 half-life of 

approximately 3 hours, and a high-dose half-life of 11 hours for males, and about 6 hours for 

females. Biliary metabolites accounted for most of the fecal excretion following low-dose 

treatment. The major biliary metabolites were glucuronides of one, and possibly two, of the 

compounds produced by demethylation of the dimethoxyphenyl ring. 

5.1.4 Residues of Concern Summary and Rationale
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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 NA* NA

Poultry

Drinking water Dimethomorph NA

* NA = Not Applicable. 

5.2 Food Residue Profile

Processed Food and Feed

The Agency does not require residue data for any processed commodities associated with bulb 

vegetables, and Brassica leafy vegetables and leafy vegetables. Processing study data for grapes 

were submitted previously in conjunction with the tolerance petitions requesting use on imported 

grapes (PP#2E4054 and PP#7F4816). These data indicated that dimethomorph residues do not 

concentrate in grape juice but do concentrate in raisins. Applying the average concentration 

factor of 1.8 to the highest theoretical field trial value (i.e., the HAFT prorated to a 1x 

application rate) obtained in field trials (i.e., 3.07 ppm which was obtained in the previous 

Spanish field trials) yields a maximum theoretical residue level in raisins of 5.5 ppm. This value 

supports a tolerance of 6.0 ppm in raisins. (The highest field trial value reported in the most 

recent grape study for national registration is 1.86 ppm). 

The existing tolerance for dimethomorph residues in raisins was established to support use of 

dimethomorph on grapes grown outside the US; therefore, the tolerance should remain in 40CFR 

§180.493[a] for US registration. 

Storage Stability

Freezer storage stability data are available which demonstrate that residues of dimethomroph are 

stable under frozen storage conditions for up to 24 months in/on grapes, potatoes, broccoli, 

spinach and canola (D381831; S. Piper; 09/31/2011).

Meat, Milk, Poultry, and Eggs
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The Agency has determined that no livestock feeding studies are needed to determine secondary

transfer of dimethomorph residues of concern in milk, eggs, and edible tissues. Therefore, data 

requirements pertaining to meat, milk, poultry, and eggs are not relevant to this tolerance 

petition.

Rotational Crops

Based on previous data, HED concluded that the residue of concern in rotational crops is 

dimethomorph per se and that the following PBIs would be appropriate for dimethomorph uses 

at total seasonal rates of 1 lb ai/A (the maximum seasonal rate at the time): (1) 0 days for potato 

(the only registered crop use at the time); (2) 30 days for wheat, barley, oats, Brassica leafy 

vegetables, and root/tuber/bulb vegetables; (3) 7 months for corn, rice, sorghum, soybeans, and 

other legume vegetables; and (4) 12 months for all other crops (D323873, D.Rate, 10/29/08). 

The results from the latest limited field trial study have shown that following three broadcast 

applications to the soil targeting 0.198-203 lb ai/A application at a 4-6 day RTI, resulting in a 

total rate of 0.598- 0.607 lb ai/A/season. No quantifiable residues of dimethomorph were 

observed in rotational crops (lettuce and radish) planted up to 4 months after the last application, 

with the exception of wheat forage, hay and straw. Quantifiable dimethomorph residues were 

observed in wheat forage (0.03 ppm), hay (0.04 ppm), and straw (0.20 ppm) planted for up to 4 

months after the last application. If the limited field studies indicate that quantifiable residues 

will occur, rotational crop tolerances will be required. The data show higher residues at longer 

PBI, and tolerances may be needed in the cereal group, grain commodities except grain. 

Therefore, limited field trials for wheat (20 trials) commodities should be conducted and the 

geographic representation should be the same as that required to establish a tolerance on wheat 

as listed in the OPPTS Guideline 860.1500. The labels must be amended to prohibit rotation to 

cereal grains. These rotational crop restrictions on cereal grains are needed until additional field 

trial data are submitted. Also, a PBI of 7 months for soybean and other legume vegetables 

should remain, and 12 months for all other crops.

Crop Field Trials

BASF Corporation has submitted a request to revise the use pattern for dimethomorph on grapes, 

bulb vegetables, leafy vegetables and Brassica leafy vegetables using the Forum® Fungicide as a 

foliar suspension concentrate (SC) formulation containing the active ingredient dimethomorph. 

Dimethomorph is currently registered for up to five foliar broadcast applications to grapes at 0.2 

lb ai/A, for a maximum seasonal rate of 1.0 lb ai/A, with a 7-day minimum re-treatment interval 

(RTI) and a 28-day pre-harvest interval (PHI). However, this registration is regionally restricted 

and the use is limited to Rocky Mountains. The registrant has submitted a Section 3 registration 

to remove the regional restriction, change the PHI from 28 days to 14 days and change the 

maximum number of applications from 5 to 4. Previously, to support the proposed uses for 
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dimethomorph on grapes in the U.S., IR-4 is relying on European field trial data submitted to 

establish the current import tolerance for dimethomorph residues in/on grape (PP#s 2E4054 and 

7F4816). The available data will support a tolerance with national registration for residues of 

dimethomorph in/on grapes at 3.5 ppm and raisins at 6.0 ppm. The registrant has provided grape 

field trial data reflecting a 14-day PHI. 

Field trial data were submitted on bulb vegetables, leafy vegetables and Brassica leafy 

vegetables using the Forum® Fungicide as a foliar suspension concentrate (SC) formulation 

containing the active ingredient dimethomorph. At each test location, three broadcast foliar 

applications of a tank mix of suspension concentrate (SC) formulations containing the active 

ingredient dimethomorph were made to bulb vegetables, leafy vegetables and Brassica leafy 

vegetables targeting 0.200 lb ai/A/application (maximum seasonal rate of 0.80 lb 

ai/ha/application) harvested at 0 days after the last application.

The submitted residue data for grapes, bulb vegetables, leafy vegetables and Brassica leafy 

vegetables are adequate. The residue data were entered into the Agency’s OECD MRL 

calculator. The tolerance spreadsheet recommends a tolerance of 4.0 ppm (instead of the 

proposed 3.5 ppm) for residues in/on grapes; 5.0 ppm in/on Brassica, head and stem, CG 5A; 

30.0 ppm in/on Brassica, leafy greens, CG 5B; 20.0 ppm in/on leafy vegetables except Brassica

CG 4A and 15.0 ppm for leaf petioles CG 4B(instead of the proposed 16.0 ppm); 15.0 ppm 

(instead of the proposed 11ppm) in/on green onion and 0.6 ppm in/on onion bulb. 

Table 5.2: Summary of Dimethomorph Residue Data from Field Trials

Matrix

Total 

Applic. 

Rate

(lb a.i./A)

PHI 

(days) n Min. Max. HAFTa

Median

(STMdR

)

b

Mean

(STMR)

c

Std. 

Dev.

Conc. Spray (Treatment 2)

Grape, fruit 0.79-0.82 14-15 13 0.05 1.83 1.83 0.4 0.65 0.61

Dilute Spray (Treatment 3)

Grape, fruit 0.79-0.83 14-15 13 0.11 1.86 1.86 0.65 0.74 0.53

Both Sprays (Treatment 2& 3)

Grape, fruit 0.79-0.83 14-15 26 0.05 1.86 1.67 0.50 0.69 0.56

Bulb onion, 

bulb

0.662-0.711 0 20 0.04 0.40 0.39 0.13 0.15 0.11

Green onion 0.662-0.696 0 6 1.34 6.60 5.36 1.79 2.90 2.06

Overall bulb 

veg. (bulb and 

green onion) 0.662-0.711

0 26 0.04 6.60 5.36 0.18 0.79 1.50

Leaf Lettuce, 

leaves

0.672-0.693 0 18 2.04 10.53 9.88 4.94 5.53 2.63

Head Lettuce, 0.671-0.687 0 16 1.07 4.10 4.10 1.925 2.12 0.95
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fresh, WWL

Spinach, 

leaves

0.668-0.704 0 16 4.20 11.47 11.26 8.15 7.80 2.31

Celery,leaf 

stalk

0.672-0.692 0 18 1.25 8.82 8.21 2.435 3.30 2.23

Broccoli, 

(Flower head 

and stem)

0.663-0.721 0 20 0.19 2.14 2.05 1.11 1.22 0.59

Cabbage, 

head (Fresh 

with wrapper 

leaves)

0.662-0.684 0 20 0.13 4.61 4.26 0.94 1.17 1.14

Cabbage, 

head Fresh 

without 

wrapper 

leaves)

0.662-0.694 0 20 <0.01 0.56 0.50 0.08 0.13 0.15

Mustard 

greens(leaves)

0.659-0.681 0 14 3.44 19.25 15.79 8.37 9.77 4.56

Brassica leafy 

veg. (all RAC 

types)

0.659-0.779 0 54 <0.01 19.25 15.79 1.37 3.42 4.48

For residue values below the LOQ, the LOQ (0.01 ppm) was used for calculation of the HAFT, median, mean, and standard 

deviation.

a HAFT = Highest Average Field Trial value.

b

STMdR = Supervised Trial Median Residue.

c

STMR = Supervised Trial Mean Residue.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in the following memorandum: ―The Amended 

Directions for use of Dimethomorph in Brassica subgroup 5A&5B, Green Onions, Grapes, 

Leafy Vegetables, New ai Ametoctradin Cofomulated with Dimethomorph (non-food uses and 

food uses) for use in Human Health Risk Assessment‖ (I. Abdel-Saheb, D387377, 7/27/11) and 

incorporated directly into the dietary assessment. 

The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary 

exposure analysis and risk assessment for dimethomorph in drinking water. Because the Agency 

does not have comprehensive monitoring data, drinking water concentration estimates are made 

by reliance on simulation or modeling, taking into account data on the physical characteristics of 

dimethomorph. 

The estimated drinking water concentrations (EDWCs) for dimethomorph were calculated based 

on a maximum application rate of 1.4 lb ai/A/season. For the proposed crop applications, the 

chronic EDWC in ground water was 0.264 ppb, from Tier 1 SCI-GROW modeling. The chronic 
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EDWC in surface water, from Tier 1 FIRST modeling, was 24.7 ppb based on applications of the 

chemical to broccoli. Surface water concentrations were estimated using the Tier II model 

Pesticide Root Zone Model 3 (PRZM3; ver. 3.12.2; 5/2/2005)/Exposure Analysis Modeling 

System (EXAMS; ver. 2.98.04.06; 4/25/2005). The model and its description 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 Anticipated Residue and Percent Crop Treated (%CT) Information

Anticipated residues and percent crop treated information were not used in this dietary exposure 

and risk assessment conducted to support the amended uses on grapes, bulb vegetables, Brassica

leafy vegetables and leafy vegetables using the the Forum® Fungicide as a foliar suspension 

concentrate (SC) formulation containing the active ingredient dimethomorph.

5.4.2 Acute Dietary Risk Assessment

No toxic effects attributable to a single dose of dimethomorph were observed in the toxicology 

database; therefore, an acute dietary exposure and risk assessment for this chemical was not 

conducted. 

5.4.3 Chronic Dietary Risk Assessment
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The unrefined chronic dietary risk assessment used tolerance level residues, included modeled 

drinking water estimates, assumed 100% crop treated, and incorporated DEEM default 

processing factors. This highly conservative risk assessment showed no risks of concern (<100%

of the chronic population adjusted dose (cPAD)) for the U.S. general population or any 

population subgroup. The estimated exposure to the U.S. general population resulted in a risk 

equivalent to 14% of the cPAD. The estimated exposure to children 1 – 2 years of age, the most 

highly exposed population subgroup, resulted in a risk equivalent to 27% of the cPAD. Results 

for all population subgroup are summarized in Table 5.4.5, below.

5.4.4 Cancer Dietary Risk Assessment

Dimethomorph is classified as ―Not Likely to be Carcinogenic to Humans‖, therefore, a cancer 

dietary exposure assessment was not conducted.

5.4.5 Dietary Summary Table

Table 5.4.5 Summary of Dietary Exposure and Risk for Dimethomorph

Population Subgroup

Acute Dietary Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population

N/A

13% 14%

N/A

All Infants (< 1 year old) 13% 11%

Children 1-2 years old 0.0276534 27%

Children 3-5 years old 0.021379 22%

Children 6-12 years old 0.013515 14%

Youth 13-19 years old 0.010199 10%

Adults 20-49 years old 0.012865 13%

Adults 50+ years old 0.013144 13%

Females 13-49 years old 0.012569 13%

The population with the highest exposure is in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure
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There are no residential uses for dimethomorph at this time, nor are any proposed. Also, there 

are no registered or proposed uses of dimethomorph that would result in treatment of recreational 

areas. Therefore, assessment for residential handler and post-application exposures is not 

required at this time.

6.2 Residential Post-Application Exposure

See Section 6.1 above. 

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for dimethomorph. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new data base 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift and risks associated with aerial as well as other 

application types where appropriate.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for occupational flaggers. This exposure scenario is 

representative of a worse case inhalation (drift) exposure and may be considered protective of 

most outdoor agricultural and commercial post-application inhalation exposure scenarios. 

6.4 Residential Bystander Post-application Inhalation

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for dimethomorph at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III). However, volatilization of pesticides may be a 

potential source of post-application inhalation exposure to individuals nearby to pesticide 

applications. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 
Dimethomorph Human Health Risk Assessment DP No. 387381

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(SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for dimethomorph.

7.0 Cumulative Exposure/Risk Characterization

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/.

8.0 Occupational Exposure/Risk Characterization

8.1 Short-and Intermediate-Term Handler Risk

The registrant, BASF Corporation, has submitted a Section 3 registration application for 

proposed amended uses of the active ingredient (ai) dimethomorph on grapes, leafy vegetables, 

Brassica leafy vegetables, and bulb and green onions.

Handler Exposure

In 2000 and 2008, HED conducted occupational and residential exposure assessments for use of 

dimethomorph on a variety of agricultural crops including: tomatoes, ginseng, grape, lima bean, 

and turnip greens (Shih-chi Wang, D265380, 7/25/00 and Suku Oonnithan, D350234, 10/24/08). 

The maximum allowable application rate for all of these crops is 0.2 lb active ingredient 

(ai)/Acre. The typical application equipment for dimethomorph includes ground, aerial, and 

chemigation equipment In general, the estimated non-cancer short- and intermediate-term total 

margin of exposures (MOEs) from the 2000 and 2008 assessments to mixers, loaders, 

applicators, and flaggers did not exceed the Agency’s level of concern (MOEs ≥ 100) if the 

handlers wear baseline personal protective equipment (PPE) consisting of long sleeved shirt, 

long pants, and shoes with socks and chemical resistant gloves.
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In addition, in the 2000 and 2008 assessments, quantification of the short-term dermal risk was 

performed using a developmental toxicity rat study. The intermediate-term dermal risk was 

based on a subchronic toxicity dog study. At the time, no dermal toxicity studies were available 

(W.Drew, DP349253, 11/6/08). Recently, a 28-day dermal toxicity study was submitted to HED 

that was considered acceptable. The NOAEL from the study was 1000 mg/kg/day (the highest 

dose tested) with no effects shown. 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.

The proposed amended uses of dimethomorph on grapes, leafy vegetables, Brassica leafy 

vegetables, and bulb and green onions would not result in a change in the maximum application 

rate or the application equipment that would be used compared to what has already been 

assessed. Therefore, an updated occupational handler exposure assessment for the proposed 

amended uses is not required at this time.

8.2 Occupational Post-Application

In 2000 and 2008, HED conducted a post-application exposure assessment for workers when 

they enter dimethomorph-treated fields for a variety of agricultural crops including: tomatoes, 

ginseng, grapes, lima beans, and turnip greens (S.Wang, D265380, 7/25/00 and S.Oonnithan, 

D350234, 10/24/08). In general, the estimated short-and intermediate-term dermal MOEs for the 

occupational post-application activities did not exceed the Agency’s level of concern (MOEs ≥ 

100). These assessments confirmed that the restricted entry interval (REI) of 12 hours on the 

dimethomorph labels is adequate to protect the workers who may enter the treated fields to do 

any crop related activities.

In addition, in the 2000 and 2008 assessments, quantification of the short-term dermal risk was 

performed using a developmental toxicity rat study. The intermediate-term dermal risk was 

based on a subchronic toxicity dog study. At the time, no dermal toxicity studies were available 

(W. Drew, DP349253, 11/6/08). Recently, a 28-day dermal toxicity study was submitted to 

HED that was considered acceptable. The NOAEL from the study was 1000 mg/kg/day (the 

highest dose tested) with no effects shown. 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.

The proposed amended uses of dimethomorph on grapes, leafy vegetables, Brassica leafy 

vegetables, and bulb and green onions would not result in a change in the maximum application 

rate compared to what has already been assessed. Therefore, an updated occupational postapplication exposure assessment for the proposed amended uses is not required at this time.

9.0 Environmental Justice Considerations
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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 USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and 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 toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources 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.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

No additional toxicological data are required at this time. 

10.2 Residue Chemistry

The following residue chemistry deficiencies have been identified. 

860.1200 Directions for Use

Section B of the labels should be amended to prohibit rotation to cereal grains. Also, the crop 

rotation restriction will need to be revised to specify a 7 month plant back interval (PBI) for 

soybean and other legume vegetables; all other crops can be planted 12 months after the last 

application.
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Note to RD: Please delete the expired footnote in the 40 CFR 180.493 for grape raisin that 

states, ―There are no US registrations as of March 4, 2009, for the use of dimethomorph on 

grapes grown for raisin production.‖ The registrant is requesting national tolerances for grapes 

and the raisin tolerance of 6.0 ppm can remain for US registration.

860.1550 Proposed Tolerances

The proposed tolerances must be revised as specified in Table 10.2.

Table 10.2. Tolerance Summary for Dimethomorph

Commodity Established 

Tolerance (ppm)

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct 

Commodity 

Definition

Tolerances to be established under §180.493

Grapes 3.51

3.5 4.0

Brassica, head and 

stem, subgroup 5A

2.0 5.0 5.0

Brassica, leafy 

greens, subgroup 5B

20.0 30.0 30.0

Leafy Vegetable

except Brassica, 

subgroup 4A

10.0 (lettuce) 16.0 20.0

Leaf Petioles, 

subgroup 4B

NA 16.0 15.0

Onion bulb 2.0 11.0 0.6

Green Onion 2.0 11.0 15.0

Grape, raisin 6.02

-- 6.0

1 Tolerances for regional registration under 40 CFR 180.493(c)

2 There are no U.S. registrations as of March 4, 2009, for the use of dimethomorph on grapes grown for 

raisin production

860.1900 Field Accumulation in Rotational Crops

Limited field trials for wheat (20 trials) should be conducted and the geographic representation 

should be the same as that required to establish a tolerance on wheat as listed in the OPPTS 

Guideline 860.1500. [Note: Limited field trials for wheat are not required if the registrant agrees

to label amendments prohibiting rotation to cereal grains]

11.0 References
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DP#: 381813

Subject: Dimethomorph. Application for Proposed Amended Use on Grapes 

(PP#0F7751); and the Section 3 Registration Action on the Bulb Vegetables 

(PP#0F7800); Leafy Brassica Vegetables (PP#0F7800); and Leafy Vegetables 

(PP#0F7816). Summary of Analytical Chemistry and Residue Data.

From: S.Piper

To: T. Gibson, M. Waller

Date: 09/31/11

MRIDs: 47700109, 47700113, 47700114, 47700115, 47700105

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

DP#: 192776

Subject: PP#2E4054. Dimethomorph (in/on Grapes, Potatoes, Animal Tissues and Milk. 

Review of Plant and Animal Metabolism Data, Analytical Methods, Crop Field 

Trials, Ruminant Feeding Study Data and Storage Stability Data to Support the 

Establishment of an Import Tolerance for a New Chemical.

From: D. Davis

To: K. Scanlon/L. Cole

Date: 03/13/95

MRIDs: 42233942

DP#: 237101

Subject: PP#7F4816. Tolerance Petitions for the Use of Dimethomorph on Domestic and 

Imported Tomatoes, Imported Grapes and Imported Hop Evaluation of Residue 

Chemistry and Analytical Methodology.

From: D. Dotson

To: M. Waller/T. Stowe

Date: 035/104/00

MRIDs: 44271201-202; 44388001, 44348901, 44457602, 44457607-44993001
Dimethomorph Human Health Risk Assessment DP No. 387381

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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 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

no1

yes

no

870.7485 General Metabolism

870.7600 Dermal Penetration 

870.7800 Immunotoxicity

yes

no

yes

yes

yes

yes
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1. The requirement for an acute neurotoxicity screening battery (rat) is waived. 

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
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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

870.3100

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 

42233911 [1991]

Acceptable/guideline

NOAEL = 14.7 mg/kg/day

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

[dog] 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

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 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.
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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

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]

870.6200

Subchronic 

neurotoxicity

[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 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. 387381

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