EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Laura Nollen, (703) 305-7390; nollen.laura@epa.gov

IR-4, Rutgers, The State University of New Jersey, 500 College Road East Suite 201 W, 

Princeton, NJ 08540 supported by Syngenta Crop Protection, LLC

Pesticide Petition #2E8126

EPA has received a pesticide petition from IR-4, which Syngenta Crop Protection, 

LLC supports, requesting, pursuant to section 408(d) of the Federal Food, Drug, and 

Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a 

tolerance for residues of mandipropamid in or on the raw agricultural commodities basil, 

fresh at 30 parts per million (ppm); basil, dried at 200 ppm; ginseng at 0.3 ppm; bean, 

succulent at 0.90 ppm; cowpea, forage at 15 ppm; vegetable, fruiting, group 8-10 at 1.0 

ppm; fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit at 2.0 ppm; 

onion, bulb, subgroup 3-07A at 0.1 ppm; and onion, green, subgroup 3-07B at 7.0 ppm. 

Upon establishment of the tolerances above, the petition additionally requests to 

remove the established tolerances from 40 CFR 180.637 of mandipropamid in or on 

grape at 1.4 ppm; onion, dry bulb at 0.05 ppm; onion, green at 4 ppm; okra at 1.0 ppm; 

and vegetable, fruiting, group 8 at 1.0 ppm. 

EPA has determined that the petition contains data or information regarding the 

elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully

evaluated the sufficiency of the submitted data at this time or whether the data supports 

granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. Metabolism studies of mandipropamid in three different crop 

groups (fruits - grape, leafy crop - lettuce and root and tuber vegetables - potato) have 

demonstrated that the compound undergoes extensive metabolism to form a range of 

metabolites which are more polar than parent. The extent of metabolism is related to the 

length of time between application of mandipropamid and harvest of the crop. When this 

time period is short, as in lettuce, mandipropamid is the principal residue (up to 93.5% 

TRR), levels of metabolites are very low and are structurally similar to parent. In the case 

of the other two crops, grape and potato, the multiple application regimes over a 

relatively long time period, allowed more extensive metabolism to take place. Unchanged 

mandipropamid remained as the major component in all aerial crop parts (ranging from 

approximately 40% to 80% TRR) and metabolites structurally very similar to parent were 

still evident, however, it was possible to identify more of the minor metabolites and to 
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establish further steps in the biotransformation pathway. Overall, extensive degradation 

of the molecule was demonstrated, although individual metabolites were detected only at 

low levels and there was no evidence for accumulation of any specific compound.

2. Analytical method. Analytical method RAM 415-01 was developed for 

determination of mandipropamid residues in crops. This method involves extraction of 

mandipropamid residues from crop samples by homogenization with acetonitrile:water 

(80:20 v/v). Extracts are centrifuged and aliquots diluted with water prior to being 

cleaned-up using polymeric solid-phase extraction cartridges. Residues of 

mandipropamid are quantified using high performance liquid chromatography with triple 

quadruple mass spectrometric detection (LC-MS/MS). This method has been successfully

validated at an independent facility and therefore is suitable for use as the enforcement 

method for the determination of residues of mandipropamid in crops.

The multi-residue method was not successful at determining residues of mandipropamid.

3. Magnitude of residues.

Basil, fresh; Basil, dried Six residue trials were conducted, four field trials in Wisconsin, 

North Carolina, California, and British Columbia and two greenhouse trials in Maryland 

and Florida. A total of approximately 0.52 lb ai/A was applied to the treated plots in four 

foliar directed applications of Revus 2.08SC at a rate of approximately 0.13 lb ai/A each. 

A nonionic surfactant was included in each tank mix. Fresh basil stems and leaves and 

additional basil for drying were collected 1 day after the final application from each trial 

and at 3, 7, and 11 days from one field trial. The basil for drying was dried for up to 3 

days.

Maximum residues of mandipropamid in 1-day samples were 19 ppm (fresh) and 91 ppm 

(dried). Residues in samples grown in the greenhouse were comparable to those in 

samples grown in the field. Residues declined over time. Data from this study may be 

used to support a tolerance proposal for mandipropamid on basil. The establishment of a 

tolerance would provide growers with a safe and effective fungicide, yet would not 

expose humans or the environment to unreasonable adverse effects.

Ginseng Four residue field trials were conducted in Wisconsin and British Columbia. A 

total of approximately 0.52 lb ai/A was applied to the treated plots in four foliar broadcast 

applications of Revus 2.08SC at a rate of approximately 0.13 lb ai/A each. A nonionic 

surfactant was included in each tank mix. Fresh ginseng roots were collected 2 days after 

the final application and at 0, 7, 15, and 21 days from one trial. The roots were dried for 

up to 19 days in commercial facilities simulating commercial practices.

Maximum mandipropamid residues at 2 days were 0.167 ppm. Residues did not change 

significantly between 0 and 21 days after the last application. No residues of SYN50003 

above the LLMV were observed in any sample. Data from this study may be used to 

support a tolerance proposal for mandipropamid on ginseng. The establishment of a 

tolerance would provide growers with a safe and effective fungicide, yet would not 

expose humans or the environment to unreasonable adverse effects.
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Bean, succulent; Cowpea, forage Ten residue trials in New York (EPA Region 1), 

Maryland, (EPA Region 2), Georgia (EPA Region 2), Florida (EPA Region 3), 

Wisconsin (EPA Region 5), Michigan (EPA Region 5), one in Ohio (EPA Region 5), two 

in California (EPA Region 10) and Washington (EPA Region 11). At all trials, four foliar 

(broadcast or directed) applications of Revus 2.08 SC at a rate of approximately 0.13 lb 

ai/A each were applied, for a total application of approximately 0.52 lb ai/A. A non-ionic 

surfactant or a crop oil concentrate type additive was added to the spray tank mix. The 

applications were made at 7 (+/- 1) day intervals starting at 19-22 days before harvest.

The results from the trials show that the maximum residues in snap bean RACS, pods 

with seeds and plants with pods following a total application of between 0.49 to 0.54 lb ai 

A and a pre-harvest interval (PHI) of 1 day were 0.761 and 9.84 ppm, respectively.

Data from this study along with additional data generated by the registrant may be used 

to support a Section 3 tolerance proposal for mandipropamid on succulent beans. The 

establishment of a tolerance would provide growers with a safe and effective fungicide, 

yet would not expose humans or the environment to unreasonable adverse effects.

Vegetable, fruiting, group 8-10 Tolerance is requested based on expanding the current 

tolerance for Vegetable, fruiting, group 8 to the newly established crop group 8-10.

Fruit, small, fine climbing, subgroup 13-07F, except fuzzy kiwifruit Tolerance is 

requested based on expanding the current tolerance for grape to the newly established 

crop group 13-07F. If the crop subgroup 13-07F is established then it is requested that 

the grape tolerance be deleted.

Onion, bulb, subgroup 3-07A Tolerance is requested based on expanding the current 

tolerance for onion, dry bulb to the newly established crop group 3-07A. if the crop 

subgroup 3-07A is established the it is requested the tolerance for onion, dry bulb, be 

deleted.

Onion, green subgroup 3-07B Tolerance is requested based on expanding the current 

tolerance for onion, green to the newly established crop group 3-07B. If the crop 

subgroup 3-07B is established then it is requested the tolerance for Onion, green be 

deleted.

B. Toxicological Profile

1. Acute toxicity. Mandipropamid is not acutely toxic, with Category IV toxicity

for the eye, oral, dermal, and inhalation routes. Mandipropamid is not a skin irritant 

(Category IV) and it is not a skin sensitizer. 

2. Genotoxicty. Mandipropamid was negative (non-mutagenic) in: In vitro

Bacterial reverse mutation, In vitro cytogenetics, human lymphocytes, In vitro

Mammalian cell gene mutation (mouse lymphoma), In vivo Rat bone marrow 
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micronucleus, and In vivo Unscheduled DNA synthesis – rat liver. A weight of the 

evidence evaluation demonstrates that mandipropamid is not genotoxic in mammalian 

systems

3. Reproductive and developmental toxicity.

[Developmental toxicity in the rat and rabbit were tested up to a limit dose of 1000 

mg/kg/day. No adverse developmental effects were observed. There were no 

developmental effects of concern. The NOEL/LOEL is 1000 mg/kg/day.

Reproductive toxicity in the 2-generation reproduction study in rats, mandipropamid was 

tested at 1500 ppm (equivalent to 138-154mg/kg/d males: 140.4-156.0mg/kg/d females). 

No reproduction effects of concern were observed. The NOEL is > 1500ppm.]

4. Subchronic toxicity. [[i. Rat 90-day feeding study. A subchronic feeding study

in rats conducted for 13 weeks had a NOAEL of (41.1 mg/kg/day males) (44.7 mg/kg/day

females) and a LOAEL of (260.3 mg/kg/day males) and 260.4 mg/kg/day females based 

on: reduction in bodyweight and bodyweight gain, reduced food utilization in males. 

Reductions in red blood cell parameters increased liver weight, increased periportal 

hypertrophy/ eosinophilia and changes in some clinical chemistry parameters.

ii. Dog 90-day feeding study. A subchronic feeding study in dogs conducted for three 

months had a NOAEL of 25 mg/kg/day in males/females and a LOAEL of 100 

mg/kg/day in males/females based on increased liver weight, marked elevations in liver 

enzymes and, pigment deposition in the liver.

iii. Rat 28-day dermal study. No toxicity was seen at the limit dose of 1000 mg/kg/day. 

The NOAEL is greater than 1000 mg/kg/day.

iv. Rat 90 day neuropathology study. A subchronic feeding study in rats conducted for 

three months had a NOAEL of >192.5 mg/kg/>206.7 mg/kg in males/females. No 

adverse effects of treatment and no evidence of neurotoxicity.]

5. Chronic toxicity.

[i. Rat. A 24-month chronic/carcinogenicity study in male and female rats was conducted 

at 0, 50, 250, 1,000 ppm. The NOAEL was 250 ppm (15.2/17.6 mg/kg/day in 

males/females) with a LOAEL of 1000 ppm (61.3/69.72 mg/kg/day in males/females) 

based on: reduction in bodyweight and bodyweight gain, reduced food utilization in 

males, reductions in red blood cell parameters, increased liver weight, increased 

periportal hypertrophy / eosinophilia, changes in some clinical chemistry parameters and 

increased incidence of chronic progressive nephropathy.

ii. Mouse. An 80-week chronic/oncogenicity study was conducted in male and female 

mice dosed at 0, 100, 500, 2,000 ppm. The NOAEL was 500 ppm (55.2/67.8 mg/kg/day

in males/females) and the LOAEL was 2000 ppm (222.7/284.6 mg/kg/day in 

males/females) based on: reduction in body weight and body weight gain, reduced food 

utilization in males, and increased liver weight.
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iii. Dog. A 1-year feeding study in dogs resulted in a NOAEL of 5 mg/kg/day. The 

LOAEL was 40 mg/kg/day based on increased platelet counts in males & liver toxicity

characterized by increased liver weight, marked elevations in liver enzymes (ALP & 

ALT) and pigment deposition within liver, consistent with porphyrin. The reference dose 

was based on this study with an UF = 100 the RfD = 0.05 mg/ kg/day.

iv. Carcinogenicity. Mandipropamid was not oncogenic in the rat or mouse.

6. Animal metabolism. The absorption, distribution, excretion, and metabolism of 

mandipropamid in rats and goats were investigated. Mandipropamid is well absorbed and 

completely metabolized in the rat and goat. Excretion is rapid and there is no 

accumulation of mandipropamid or metabolites in tissues.

7. Metabolite toxicology. The primary residue of concern was mandipropamid 

parent.

8. Endocrine disruption. The endocrine system includes the reproductive 

hormones estrogen and androgens as well as the thyroid hormone system. 

Mandipropamid is not known to interfere with reproductive hormones and does not have 

reproductive toxicity.

C. Aggregate Exposure

1. Dietary Exposure. A Tier I chronic aggregate risk assessment was completed 

for mandipropamid using the Dietary Exposure Evaluation Model (DEEM-FCIDTM, 

version 2.16) from Exponent. The exposure assessment included all approved uses of 

mandipropamid as follows: brassica, head and stem (Crop Group 5A), brassica, leafy

greens (Crop Group 5B), grape and raisin, hop (dried cones), okra, onion (green and dry

bulb), potato (wet peel), cucurbit vegetables (Crop Group 9), fruiting vegetables (Crop 

Group 8), leafy vegetables except Brassica (Crop Group 4), and tuberous and corm 

vegetables (Crop Group 1C), plus proposed IR4 use on basil, ginseng, succulent beans 

and greenhouse tomatoes. Processing factors were taken from the DEEMTM (version 

7.87) default values, which were manually input into the DEEM-FCIDTM software. 

Percent of crop treated values were conservatively estimated to be 100% for all crop uses 

of mandipropamid. Drinking water estimates were incorporated directly into the dietary

exposure assessments using the highest estimated drinking water concentrations 

(EDWCs) for surface and ground water. All consumption data for these assessments 

were taken from the USDA’s Continuing Survey of Food Intake by individuals (CSFII) 

with the 1994-96 consumption database and the Supplemental CSFII children’s survey

(1998) consumption database.

i. Food Acute Exposure. No appropriate endpoints were identified for 

acute dietary exposure; therefore no acute risk assessment was performed.

Chronic Exposure. The mandipropamid chronic food risk assessment was 

performed for all population subgroups using a chronic reference dose of 0.05 mg/kg/day
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based upon a chronic toxicity study in rats with a no observed adverse effect level 

(NOAEL) of 5.0 mg/kg/day and an uncertainty factor of 100x. The 100x safety factor 

includes intra- and inter-species variations. No additional FQPA safety factor was 

applied. For the purpose of aggregate risk assessment, the exposure values were 

expressed in terms of margin of exposure (MOE), which was calculated by dividing the 

NOAEL by the exposure for each population subgroup. In addition, exposure was 

expressed as a percent of the chronic reference dose (% cRfD). Chronic (food only) 

exposure to the U.S. population resulted in a MOE of 458 (21.8% of the cRfD of 0.05 

mg/kg/day). The most exposed sub-population was children (1-2 years old) with a MOE 

of 301 (33.2% of the cRfD of 0.05 mg/kg/day). Since the Benchmark MOE for this 

assessment was 100 and since the EPA generally has no concern for exposures above the 

benchmark or below 100% of the RfD, Syngenta believes that there is a reasonable 

certainty that no harm will result from dietary (food only) exposure to residues arising 

from all current, pending, and proposed uses for mandipropamid.

Cancer. A quantitative risk assessment using a cancer endpoint was not 

performed.

ii. Drinking Water: The Estimated Drinking Water Concentrations (EDWCs) of 

mandipropamid (determined as combined residues of mandipropamid, SYN500003, and 

SYN504851) were determined using Tier l screening models, SCI-GROW which 

estimates pesticide concentration in ground water and FIRST which estimates pesticide 

concentration in surface water. EDWCs of mandipropamid from currently registered, 

pending, plus the proposed uses on basil, ginseng, succulent beans, and greenhouse 

tomatoes were determined. For ground water, the highest currently registered use rate 

provided a combined EDWC of 0.11 ppb (chronic). For surface water, the pending 

ornamentals use provided a combined chronic EDWC of 1.085 ppb. Since the surface 

water EDWCs exceed the ground water EDWC, the surface water values were used for 

risk assessment purposes and will be considered protective for any ground water 

exposure concerns. 

Chronic Exposure from Drinking Water. The chronic surface water EDWC of 1.085 

ppb was input directly into the DEEM-FCIDTM software as “water, direct and indirect, all 

sources” to model the chronic drinking water exposures. Chronic drinking water 

exposure to the U.S. population resulted in a MOE of 218,635 (0.05% of the chronic RfD 

of 0.05 mg/kg-bw/day). Chronic drinking water exposure to the most exposed subpopulation (infants, <1 year old) resulted in a MOE of 66,687 (0.15% of the chronic RfD 

of 0.05 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and 

since EPA generally has no concern for exposures above the benchmark or below 100% 

of the chronic RfD, Syngenta believes that there is a reasonable certainty that no harm 

will result from chronic drinking water exposure to residues arising from the current, 

pending, and proposed uses for mandipropamid.

2. Non-Dietary Exposure: Currently, there are no registered residential uses for 

mandipropamid. A pending use on ornamentals is restricted to professional applications 
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on outdoor ornamentals, commercial nurseries and indoor greenhouses. Therefore, there 

are no residential exposure contributions to the aggregate risk.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity: Section 

408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, 

or revoke a tolerance, the Agency consider “available information” concerning the 

cumulative effects of a particular pesticide’s residues and “other substances that have a

common mechanism of toxicity”. The EPA does not have, at this time, available data to 

determine whether mandipropamid has a common mechanism of toxicity with other 

substances or how to include this pesticide in a cumulative risk assessment. For the 

purposes of this tolerance action, the EPA has not assumed that mandipropamid has a 

common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. Population. The chronic dietary exposure analysis (food plus drinking 

water) showed that exposure from all mandipropamid uses resulted in a MOE of 457 

(21.8% of the cRfD of 0.05 mg/kg/day) for the general U.S. population, which also 

exceeds the benchmark MOE of 100. Based on the completeness and reliability of the 

toxicity data supporting these petitions, Syngenta believes that there is a reasonable 

certainty that no harm will result from aggregate exposure to residues arising from all 

current, pending, and proposed mandipropamid uses, including anticipated dietary

exposure from food, water and all other types of non-occupational exposures.

2. Infants and children. No appropriate endpoints were identified for acute 

dietary exposure; therefore no acute risk assessment was performed. The chronic 

aggregate dietary (food plus drinking water) exposure analysis showed that exposure 

from all pending and proposed mandipropamid uses would result in a MOE of 300 

(33.3% of the cRfD of 0.05 mg/kg/day) for the most sensitive population subgroup, 

children 1-2 years old, which exceeds the benchmark MOE of 100. Based on the 

completeness and reliability of the toxicity data supporting these petitions, Syngenta 

believes that there is a reasonable certainty that no harm will result to infants and children 

from aggregate exposure to residues arising from all current, pending, and proposed 

mandipropamid uses, including anticipated dietary exposure from food, water and all 

other types of non-occupational exposures.

F. International Tolerances

The current Maximum Residue Limits (MRLs) set for mandipropamid by the Codex 

Alimentarius Commission are Grape, table 2ppm, Grape, wine 2ppm, Onion, bulb 

0.1ppm and Onion, green 7ppm. International MRLs for the fungicide mandipropamid 

have been established for various agricultural commodities in a number of countries in

the European Union including Austria, Belgium, Croatia, Czech Republic, Denmark, 

Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Netherlands, 
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Norway, Poland, Portugal, Romania, Spain, Sweden, and the United Kingdom.