Mandipropamid Human Health Risk Assessment 0425240 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: February 24, 20 16 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Mandipropamid: Human Health Risk Assessment For Amended Use of the 

Fungicide on Potato, to Replace the Established Tolerance in Tuberous and Corm Vegetable 

Subgroup IC, and to Revise the Established Tolerance in Potato Wet Peel. 

PC Code: 036602 

Decision No.: 497834, <1'!1141, '11 .ss', "1•73110 

Petition No.: 4F8329 

Risk Assessment Type: Single Chemical Aggregate 

TXRNo.: NA 

MRlD No.: None 

DP Number: 0 425240, 0425239, 0425241, 

0 425242 

Registration No.: I 00-1254 

Regulatory Action: Section 3 

Case No.: 7058 

CAS No.: 374726-62-2 

40 CFR: § 180.637 

FROM: Elizabeth Holman, Physical ~c ~ Risk Assessor ~ ~ 

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Health Effects Division (7509P) 

THROUGH: Christina Swartz, Chief ~Ar-­ Risk Assessment Branch II 

Health Effects Division (7509P) 

TO: Tony Kish and Shaunta Hill, RM Team 22 

Fungicide Branch (FB) 

Registration Division (RD), 7505P 

Page I of 38 
Mandipropamid Human Health Risk Assessment 0 425240 

Table of Contents 

1.0 Executive Summary .............................................................................................................. 4 

2.0 HED Recommendations ................. .......... .................... ............. ............................................ 5 

2.1 Data Deficiencies .............................................................................................................. 5 

2.2 Tolerance Considerations .................................................................................................. 5 

2.2.1 Enforcement Analytical Method .................. ............................ .................................. 5 

2.2.2 Recommended Tolerances ......................................................................................... 6 

2.2.3 Revisions to Petitioned-For Tolerances ..................................................................... 6 

2.2.4 International Harmonization .................................................... ............. ..................... 7 

2.3 Label Recommendations ................................................................................................... 7 

3.0 Introduction ............................................................................. .............................................. ? 

3 .1 Chemical Identity .......... .................................................................................................... 7 

3.2 Pesticide Use Pattern .......................................................... ............................................... 8 

3.3 Anticipated Exposure Pathways ............................................ ........... ................................. 9 

3 .4 Consideration of Environmental Justice ......................................................................... 10 

4.0 Hazard Characterization and Dose-Response Assessment ................................................. 10 

4.1 Summary of Toxicological Effects ................................................................................. 10 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ....................................... .12 

4.2.1 Completeness of the Toxicology Database .............................................................. 12 

4.2.2 Evidence of Neurotoxicity ......... .............................................................................. 12 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .......... 12 

4.2.4 Residual Uncertainty in the Exposure Database ..................................................... .1 3 

4.3 Toxicity Endpoint and Point of Departure Selections ..................................................... 13 

5.0 Dietary Exposure and Risk Assessment ............................................................................. 15 

5 .1 Residues of Concern Summary and Rationale ................................................................ 15 

5.2 Food Residue Profile ..................... ........... .......... ............................................................. 16 

5.2.1 Crop Field Trials (860.1500) ................................................................................... 16 

5.2.2 Field Rotational Crops (860.1900) .......................................................................... 18 

5.2.3 Processed Food and Feed (860.1520) ...................................................................... 18 

5.3 Water Residue Profile ....................................................................... .............................. 19 

5.4 Dietary Risk Assessment. ................................................................................................ 20 

5.4.1 Description of Residue Data Used in Dietary Assessment.. .. ....... ........................... 20 

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................. 21 

5.4.3 Acute Dietary Risk Assessment ............................................................................... 2 1 

5.4.4 Chronic Dietary Risk Assessment ........................................................................... 21 

5.4.5 Cancer Dietary Risk Assessment ............................................. ................................ 21 

5.4.6 Summary Table ........................................................................................................ 21 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ..................................... 22 

6.1 Residential Bystander Post-application Inhalation Exposure ......................................... 22 

6.2 Spray Drift ....................................................................................................................... 22 

7 .0 Aggregate Exposure/Risk Characterization ........................................................................ 23 

7 .1 Acute & Chronic Aggregate Risk ................................................................................... 23 

7.2 Short- and Intermediate-Term Aggregate Risk ............................................................... 23 

8.0 Cumulative Exposure/Risk Characterization ...... ............................................................... .23 

9.0 Occupational Exposure/Risk Characterization .................................... ............................... 24 

10.0 References ............. ....................................................... ..... .................................................. 27 

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Mandipropamid Human Health Risk Assessment D425240

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Appendix A. International Residue Limits...................................................................................28

Appendix B. Toxicology Profile...................................................................................................29

B.1 Toxicology Data Requirements.......................................................................................29

B.2 Toxicity Profiles..............................................................................................................30

B.2.3 Immunotoxicity........................................................................................................35

Appendix C. Physical/Chemical Properties..................................................................................37

Appendix D. Review of Human Research....................................................................................38
Mandipropamid Human Health Risk Assessment D425240

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1.0 Executive Summary

Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, 

Inc. for the control of foliar oomycete pathogens in a range of crops including Plasmopara 

viticola in grapes, Phytophthora infestans in potatoes and tomatoes, and Pseudoperonospora 

cubensis in cucurbits. Permanent tolerances are established for residues of mandipropamid in or 

on a variety of plant commodities, at levels ranging from 0.01 ppm in tuberous and corm 

vegetable subgroup 1C, to 200 ppm in dried basil leaves (40CFR §180.637[a]). 

Syngenta Crop Protection has submitted a petition requesting amended use on potatoes to add 

seed piece treatment. In conjunction with the requested amended use, Syngenta has proposed the 

establishment of a permanent tolerance for residues of mandipropamid in/on potato at 0.08 ppm. 

In addition, Syngenta has requested amendment of the existing tolerance in potato wet peel to 

0.12 ppm, and revision of the existing commodity definition for tuberous and corm vegetable 

subgroup 1C to read “vegetable, tuberous and corm, subgroup 1C (except potato).” 

The toxicology database is adequate. Mandipropamid has low acute toxicity via oral, dermal, 

and inhalation routes; and no dermal or eye irritation (Toxicity Category IV). It is not a skin 

sensitizer. Liver toxicity was the primary effect and was observed in rats, mice and dogs. There 

was no evidence of increased neonatal or postnatal sensitivity in the developmental and 

reproduction toxicity studies, and no evidence of developmental effects, neurotoxicity, 

mutagenicity or carcinogenicity after exposure to mandipropamid. The FQPA Safety Factor 

(SF) has been reduced to 1X.

Based on the available data, there are no effects attributable to a single exposure to 

mandipropamid which are appropriate for assessing acute risks, including acute dietary exposure. 

Similarly, there are no effects associated with dermal exposure. Only inhalation and chronic 

dietary endpoints and points of departure have been selected for risk assessment.

The data submitted in support of the current action (Petition #4F8329) along with previously 

reviewed data, are adequate for purposes of risk assessment and tolerance assessment for the 

proposed revised use pattern on potato under review. Maximum residues of mandipropamid are 

expected to occur at relatively low levels (<0.09 ppm in subgroup 1C, and <0.15 ppm in potato 

wet peel) from the revised use pattern combining seed piece treatment and foliar use on potato, 

as proposed in the current petition. Further, metabolism data, storage stability and analytical 

methods are considered adequate to support the recommended tolerances. 

A screening-level dietary assessment (food + drinking water), based on tolerance-level residues 

and 100% of crop treated for all included commodities, and conservative assumptions with 

respect to mandipropamid residues in drinking water sources, indicates that chronic dietary risks

are below HED’s level of concern for all population subgroups. There are no uses of 

mandipropamid that would result in residential exposure; therefore, chronic dietary is the only 

aggregate scenario, and there are no aggregate risks of concern.

Occupational risk estimates associated with the new uses are also below HED’s level of concern. 

No chemical-specific handler exposure data were submitted in support of this registration; 
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therefore, HED relied on surrogate data in accordance with standard policies. Default 

assumptions established by the HED Science Advisory Council for Exposure (ExpoSAC) were 

used for parameters such as body weight and amount handled. Occupational assessments for 

mandipropamid are based on inhalation exposures only. All occupational handler scenarios for 

the proposed uses resulted in MOEs greater than 100 at baseline (i.e., baseline attire with no 

respirator) and, therefore, are not of concern, and no additional personal protective equipment 

(PPE) will be needed on the proposed label. Although a point of departure from an oral study 

was used to assess handler inhalation risk, the calculated MOEs are all ≥6,400, thus providing an 

ample margin to account for any uncertainties in the route-to-route extrapolation. 

Occupational post-application risk estimates for agricultural workers following treatments to 

agricultural crops were not assessed, since no dermal endpoint of concern was identified. In 

addition, mandipropamid is categorized as a reduced risk chemical. Therefore, the restricted 

entry interval (REI) of 4 hours is considered appropriate.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed at this time. If new policies or procedures are 

put into place, the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for mandipropamid.

The risk assessment is based, in part, on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies are compliant with 

applicable ethical requirements (refer to Appendix D).

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment (see Section 3.5).

2.0 HED Recommendations

HED recommends in favor of establishing tolerances for residues of mandipropamid as specified 

in Section 2.2.2.

2.1 Data Deficiencies

None. 

2.2 Tolerance Considerations

HED has examined the toxicology and residue chemistry database for mandipropamid. There 

are no issues that would preclude establishing tolerances for mandipropamid for the commodities 

listed in Table 2.2.2.

2.2.1 Enforcement Analytical Method
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There is an adequate enforcement method available for the quantitation of mandipropamid in 

plant commodities. Method RAM 415/01, using high performance liquid chromatography with 

tandem mass spectrometric detection (LC/MS/MS), has been adequately validated by an 

independent laboratory. It has a validated limit of quantitation (LOQ) of 0.01 ppm. An 

acceptable confirmatory method is also available. 

The FDA Multiresidue methods are not adequate for determining residues of mandipropamid.

2.2.2 Recommended Tolerances

HED has examined the residue chemistry database for mandipropamid. Pending submission of a 

revised Section F (to propose tolerance levels in accordance with those recommended by HED, 

and to correct some of the commodity definitions), there are no residue chemistry issues that 

would preclude establishing tolerances in the requested commodities. The recommended 

tolerances are listed in Table 2.2.2, below.

TABLE 2.2.2 Tolerance Summary for Mandipropamid.

Commodity Established

Tolerance 

(ppm)

Proposed 

Tolerance 

(ppm)

Tolerance

Recommended 

by HED (ppm)

Comments; Correct Commodity 

Definition

Potato None 0.08 None Revise the subgroup 1C tolerance.

Potato, wet peel 0.03* 0.12 0.15 Based on the submitted potato 

processing study and the highest 

average field trial (HAFT).

Vegetable, tuberous and corm, 

subgroup 1C

0.01* None 0.09 Based on the submitted potato field 

trial data. 

Vegetable, tuberous and corm, 

subgroup 1C, except potato

None 0.01 None Cannot establish this tolerance; 

potato is the only representative 

commodity for subgroup 1C.

* A tolerance is currently established at the listed tolerance level in the corresponding commodity. 

2.2.3 Revisions to Petitioned-For Tolerances

Instead of the proposed tolerance in potato (0.08 ppm), HED recommends revision of the 

tolerance for residues in tuberous and corm vegetable subgroup 1C from 0.01 to 0.09 ppm. The 

proposed tolerance was based on a dataset that only included results from trials conducted in the 

US. One of the Canadian field trials (in Branchton, ON) had a total application rate exceeding 

the proposed US and Canadian maximum total use rates (0.52-0.54 lb ai/A) by >25%. The 

calculated tolerance in subgroup 1C, based on US and Canadian potato field trial data (excluding 

the ON trial results) entered into OECD’s tolerance calculation procedure, was 0.07 ppm. 

However, HED is recommending a tolerance in subgroup 1C of 0.09 ppm, in order to harmonize 

with PMRA’s recommended MRL. This MRL was based on using the 17-day pre-harvest 

interval (PHI) residue value from one of the US trials (in Richland, IA) instead of the residue 

value in the sample taken at a PHI of 14 days (the proposed PHI). PMRA uses the highest 

residue from any sample taken at a PHI within ±25% of the target PHI, while HED uses the 

residue value from the sample taken at (or closest to) the proposed PHI. 
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The proposed tolerance in potato wet peel (0.12 ppm) was based on the average processing factor 

(2.0X) multiplied by the HAFT (0.056 ppm). However, the recommended tolerance (0.15 ppm) 

is based on the rounding protocol in the User Guide for the OECD tolerance calculation 

procedure. 

It is not appropriate to establish the proposed tolerance in tuberous and corm vegetable subgroup 

1C (except potato), because potato is the only representative commodity for subgroup 1C. For 

the same reason, the proposed separate tolerance in potato is unnecessary. 

2.2.4 International Harmonization

The established Codex MRL in potato, and PMRA’s MRLs in potato and various tuberous and 

corm vegetables are in harmonization with the current US tolerance in tuberous and corm 

vegetables subgroup 1C at 0.01 ppm (Appendix A). These existing tolerances are based on a 

foliar use pattern only. PMRA and EPA jointly reviewed the potato field trial and processing 

data in the current action; therefore, EPA and PMRA are harmonized on the recommended 

tolerance/MRL in subgroup 1C. PMRA will not establish a tolerance in potato wet peel, as it is 

considered a livestock feed item by PMRA, whereas it is considered a human food item by HED

(although it is often used as livestock feed). With the recommended increased tolerance in 

subgroup 1C, the US tolerance will no longer be in harmonization with Codex’s MRL in potato. 

Harmonization with the Codex value is not feasible, given that the Codex MRL is based on the 

foliar use pattern only, and the recommended amended tolerance is based on the proposed 

combination of seed piece treatment and foliar uses. 

2.3 Label Recommendations

None. 

3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of mandipropamid are presented in Table 3.1. 

Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, 

Inc. for the control of foliar oomycete pathogens in a range of crops.
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Table 3.1. Test Compound Nomenclature.

Compound

Common name Mandipropamid

Company experimental name NOA 446510

IUPAC name (RS)-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-

prop-2-ynyloxy-acetamide

CAS name 4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]-α-(2-propynyloxy)-

benzeneacetamide

CAS registry number 374726-62-2

End-use product (EP) Revus® (2.08 lb ai/gal; EPA Reg. No. 100-1254), (Alternate Brand Name: Mandy 

Flowable Fungicide)

3.2 Physical/Chemical Characteristics

The information regarding physical chemical characteristics of mandipropamid does not indicate 

that there are any special concerns in terms of bioaccumulation, exposure or other risk 

assessment considerations. A table of physical and chemical properties for mandipropamid is 

included in Appendix C.

3.3 Pesticide Use Pattern

Syngenta is requesting a label amendment for Revus Fungicide (EPA Registration #100-1254). 

The proposed amended use is for the addition of seed piece treatment use on potato. Revus 

Fungicide is an SC formulation containing 23.3% ai by weight, which is equivalent to 2.08 lb 

ai/gal (250 g ai/L). The proposed use directions for seed piece treatment were provided in the 

petition materials, and are summarized in Table 3.3 (below). They appear to reflect the proposed 

US use pattern. 

TABLE 3.3 Summary of Proposed Directions for Use of Mandipropamid on Potato Seed Pieces

Followed by Foliar Applications to Growing Potato Plants.

Application

Timing; Type; 

Equipment

Use Rate

(lb ai/100 lb

seed) [g ai/100 

kg seed]

Max. 

Number of

Uses per 

Season

Max. Seasonal 

Use Rate

(lb ai/A)

[g ai/A]

PHI

(Days)

Use Directions and Limitations

Seed Treatment Directions

Seed piece 

treatment;

standard seed 

treatment 

equipment.

0.00325-0.01 

[3.25-10]

1 0.52

[235.9]

For any type of 

application

NS1 Apply by mist treatment to potato 

seed pieces. Apply liquid seed 

treatments in a volume of 2-4 fl 

oz/100 lb potato. Treat within 5 

hours of cutting. Plant within 48 

Cl

O

HC

O

N

H

O

CH3

O

CH
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TABLE 3.3 Summary of Proposed Directions for Use of Mandipropamid on Potato Seed Pieces

Followed by Foliar Applications to Growing Potato Plants.

hours of treatment. Seed treatment 

may be followed by up to 3 foliar 

applications of mandipropamid.

Application

Timing; Type; 

Equipment

Use Rate

(lb ai/A)

[g ai/A]

Max. 

Number of

Uses per 

Season

Max. Seasonal 

Use Rate

(lb ai/A)

[g ai/A]

PHI

(Days)

Use Directions and Limitations

Foliar Application Directions

Prior to disease

development;

ground, aerial 

or chemigation 

equipment.

0.09-0.13

[41-59]

3 0.52

[235.9]

For any type of 

application

14 RTI2 = 7 to 10 days. Make no

more than 2 consecutive applications 

before switching to another effective 

non-Group 40 fungicide. Use the 

shorter interval and/or higher rates 

under high pressure, or when

conditions are conducive to disease. 

The addition of a spreading and/or 

penetrating type adjuvant such as a 

COC3 or NIS4 or blend is

recommended when applying by 

ground or air. 

1. NS = Not Specified. 

2. RTI = Re-Treatment Interval. 

3. COC = Crop Oil Concentrate. 

4. NIS = Non-Ionic Surfactant. 

Conclusions: The submitted use directions for the 2.08 lb ai/gal SC formulation of 

mandipropamid are adequate to allow evaluation of the residue data relative to the proposed 

potato seed piece treatment use. No label additions, revisions or clarifications are needed at this 

time. 

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

amended use of mandipropamid on potato. Humans may be exposed to mandipropamid in 

food and drinking water, since it may be applied directly to growing crops and application may 

result in mandipropamid reaching surface and ground water sources of drinking water. There 

are no residential uses of mandipropamid, so there is not likely to be exposure in residential or 

non-occupational settings. In an occupational setting, handlers may be exposed while 

handling the pesticide prior to application, as well as during application. There is a potential 

for post-application exposure for workers re-entering treated fields.

Risk assessments have been previously conducted for mandipropamid; toxicity data submitted 

prior to the last risk assessment but not incorporated into HED’s review have been evaluated in 

the current assessment, but did not affect HED’s conclusions with respect to hazard 

characterization and endpoint selection. A detailed description of the toxicity data and 

metabolism information may be found in the risk assessment dated 6/12/2008 (D. Dotson, 

D344351). The current risk assessment considers all of the aforementioned exposure 
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pathways based on the existing uses of mandipropamid, and also considers the potential for 

increased dietary (food + water) exposure associated with the new uses.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

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

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

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

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled from the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) 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.

4.0 Hazard Characterization and Dose-Response Assessment

A comprehensive human health risk assessment for mandipropamid was conducted in 2009 (D. 

Rate, 8 June 2009, D365918). Since this risk assessment, an immunotoxicity study (MRID 

48771701) was received which fulfills a previously identified data gap. In this study, no 

evidence of immunotoxicity was observed up to the highest dose tested (649 mg/kg/day). In 

addition, HED’s Hazard and Science Policy Council (HASPOC) determined that a subchronic 

inhalation study in the rat is not required for mandipropamid (Alstine, J. 14 March 2013, TXR 

#0056610). Therefore, the toxicology database for mandipropamid is considered to be complete. 

No other changes have been made to the hazard characterization of mandipropamid since the 

2009 risk assessment. 

4.1 Summary of Toxicological Effects

Subchronic and chronic studies indicate that the liver is the primary target organ for 

mandipropamid. Liver effects were identified in subchronic studies with rats, mice, and dogs. 

Liver effects included: periportal hypertrophy (rats), increased eosinophilia (rats and mice), 

increased plasma albumin, total protein, cholesterol, and gamma-glutamyl transferase (rats), 
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increased liver weights (rats, mice and dogs), increased liver enzymes (dogs), increased pigment 

in hepatocytes and Kupffer cells (dogs), and centrilobular hepatocyte vacuolation (dogs). In the 

chronic dog study, increases in microscopic pigment in the liver and increased liver enzymes 

were observed. No liver effects were observed in chronic rat and mouse studies up to the highest 

doses tested. Instead, nephrotoxicity was observed in the chronic rat study and only decreased 

body weight and food utilization was observed in the chronic mouse study. The findings of liver 

toxicity and nephrotoxicity are consistent with the results from metabolism studies where the 

tissues with the highest levels of radioactivity were the liver followed by the kidney. 

No evidence of neurotoxicity was observed in the acute or subchronic neurotoxicity screening 

battery. No systemic or dermal toxicity was observed following dermal exposure for 28 days up 

to the limit dose.

No evidence of increased quantitative or qualitative susceptibility was seen in developmental 

toxicity studies in rats and rabbits or in a reproduction study in rats. The only effects observed in 

fetuses or pups were in the two-generation reproduction study, where decreased pup body weight 

was observed in the presence of maternal toxicity (decreased body weight, body weight gain, and 

food utilization). In addition, there was a delay in preputial separation in F1 males which was 

considered to be the result of lower body weights.

There was no evidence of tumors in the carcinogenicity study in mice or in the 

chronic/carcinogenicity study in rats and there was no evidence that mandipropamid was

mutagenic or clastogenic. Therefore, mandipropamid is classified as “not likely to be 

carcinogenic to humans.”

In metabolism studies, absorption of [14C]-mandipropamid was 67-74% at 3 mg/kg and 30-45% 

at 300 mg/kg after 48 hours, indicating saturation of absorption. The rate of absorption was 

higher in females resulting in a blood Tmax (time to maximum concentration) at 3 mg/kg of 8.5 

hours for males and 4.5 hours for females; at 300 mg/kg Tmax was 24 hours for males and 10 

hours for females. Most of the radioactivity was eliminated in the feces except for the 3 mg/kg 

females where elimination in urine and feces were similar. In bile cannulated rats, elimination in 

the bile was high at 3 mg/kg (55-73% of the dose) but was lower at 300 mg/kg (22-28% of the 

dose, with a corresponding increase of residues in feces in males and urine in females). The 

highest level of radioactivity in tissues was in the liver followed by the kidney.

Bioaccumulation was not observed in any tissue and the dose remaining in the body after 168 

hours was less than 1.1%. The major metabolic transformations involved loss of one or both 

propargyl groups followed by glucuronidation and O-demethylation. The parent and the 

following metabolites were detected at ≥5% of the applied dose at 3 and/or 300 mg/kg: NOA 

458422 (loss of one propargyl group), NOA 458422 glucuronide, SYN 534133 (loss of both 

propargyl groups, with one glucuronidated) and CGA 380778 (loss of one propargyl group). The 

amount of NOA 458422 glucuronide in females was almost 3-fold more than in males, which 

coincided with a lesser amount of parent and NOA 458422 in females. Parent was the major 

residue detected in feces of animals of both sexes regardless of bile duct cannulation status, 

while SYN 534133 was the major metabolite in the urine of male rats that didn’t undergo bile 

duct cannulation and NOA 458422 glucuronide was the major metabolite in the urine and bile of 
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male rats that did undergo bile cannulation. NOA 458422 glucuronide was also the major 

metabolite in urine and bile of female rats regardless of bile duct cannulation status. A dermal 

penetration study in rats was conducted for mandipropamid. In the study, <0.17-3.44% of the 

applied dose was absorbed.

Mandipropamid has low acute toxicity via oral, dermal, and inhalation routes (Toxicity Category 

IV); and no dermal or eye irritation (Toxicity Category IV). It is not a skin sensitizer.

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

HED has determined that the required 10X Food Quality Protection Act (FQPA) Safety Factor 

should be reduced to 1X in assessing the risk posed by mandipropamid. This recommendation 

was based on the following considerations:

• The toxicity database is complete with no data gaps for the assessment of the effects of 

mandipropamid following in utero and/or postnatal exposure. 

• There is no evidence of neurotoxicity following exposure to mandipropamid.

• There is no indication of quantitative or qualitative susceptibility of rats or rabbits to in 

utero and/or postnatal exposure to mandipropamid.

• The risk assessment does not underestimate exposure, since the dietary assessment is 

based on conservative assumptions such as tolerance-level residues in foods, 100% crop 

treated, and upper-bound modeled estimates of residues in drinking water. In addition, 

there are no registered residential uses for mandipropamid.

4.2.1 Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing preand postnatal susceptibility. Acceptable/guideline developmental toxicity studies in rats and 

rabbits and a reproduction study in rats, as well as acute and subchronic neurotoxicity studies in 

rats were available for FQPA assessment. There is no concern for increased susceptibility in the 

developing young, and no evidence of neurotoxicity in the database. Therefore, a developmental 

neurotoxicity study is not required.

4.2.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity observed in any of the studies in the toxicology database. 

In the acute neurotoxicity study, the rats were dosed up to the limit dose (2000 mg/kg). In the 

90-day neurotoxicity study in rats, the only effects appeared to be decreased body weight, body 

weight gain and food utilization in males up to the highest dose tested (192.5 mg/kg/day for 

males and 206.7 mg/kg/day for females).

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal
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There were no treatment-related effects observed in dams or fetuses in the developmental 

toxicity studies in rats or rabbits up to the limit dose of 1000 mg/kg/day. In the rat reproductive 

study, decreased pup weight occurred only in the presence of comparable maternal toxicity 

(decreased body weight). Therefore, HED concludes that there is no increased quantitative or 

qualitative susceptibility to rat or rabbit offspring exposed in utero and/or postnatally to 

mandipropamid, and there are no residual uncertainties with respect to pre- or postnatal 

exposure.

4.2.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. There are no exposure data gaps and 

the current dietary exposure assessment is based on high-end assumptions such as tolerance-level

residue values, 100% crop treated, and modeled estimates of drinking water residues. There are 

currently no registered or proposed residential uses for mandipropamid, so exposure is limited to 

dietary exposure. Therefore, the assessment is conservative and does not underestimate 

exposure.

4.3 Toxicity Endpoint and Point of Departure Selections

The toxicological endpoints and points of departure selected for dietary and occupational 

exposure and risk assessment are summarized in Tables 4.3.1 and 4.3.2. There have been no 

changes to any of the previously selected endpoints, points of departure, or the cancer 

classification for mandipropamid from the previous risk assessment (D365918, D. Rate, 

6/8/2009).

For short- and intermediate-term inhalation risk assessment, a no observed adverse effects level 

(NOAEL) equal to 41 mg/kg/day was selected from a 90-day rat oral study in which decreased 

body weights, decreased body weight gains; and decreased food utilization were observed in 

males; and hepatotoxicity was observed in both sexes at the lowest observed adverse effects level 

(LOAEL) of 260 mg/kg/day. 

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure

Scenario

Point of Departure Uncertainty/

FQPA 

Safety 

Factors 

RfD, PAD, Level of 

Concern for Risk

Assessment

Study and Toxicological 

Effects

Acute Dietary 

(General 

population, 

including 

Infants and 

Children and 

females 13-49)

N/A N/A N/A No appropriate endpoint was 

identified in the TOX 

databases.
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Table 4.3.1. Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure

Scenario

Point of Departure Uncertainty/

FQPA 

Safety 

Factors 

RfD, PAD, Level of 

Concern for Risk

Assessment

Study and Toxicological 

Effects

Chronic Dietary

(all populations)

NOAEL = 5

mg/kg/day

UFA=10X

UFH=10X

FQPA SF = 

1X

Chronic RfD = 0.05

mg/kg/day 

cPAD = 0.05 

mg/kg/day 

Chronic Toxicity Study in 

Dogs

LOAEL = 40 mg/kg/day, 

based on increased incidence 

and severity of microscopic 

pigment in the liver and 

increased alkaline 

phosphatase activity in both 

sexes as well as increased 

alanine aminotransferase 

activity in males.

Cancer (oral, 

dermal, 

inhalation) 

No Evidence of Carcinogenicity. Classified as “Not Likely to be Carcinogenic to Humans.”

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population 

adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable.

Table 4.3.2. Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Occupational 

Human Health Risk Assessments.

Exposure

Scenario

Point of Departure Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment

Study and Toxicological 

Effects

Dermal 

Short-Term (1 -

30 days) and 

IntermediateTerm (1-6 

months)

N/A N/A N/A No appropriate endpoint 

was identified, and a risk 

assessment was not 

conducted.

28-day dermal toxicity study 

– rat,

no systemic or dermal effect 

up to the limit dose of 1000 

mg/kg/day; there were no 

neurotoxicity or 

developmental concerns.

Inhalation 

Short-Term

(1 - 30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL = 41 mg/kg 

/day

UFA=10X

UFH=10X

LOC =100 90-day oral toxicity – rats

LOAEL = 260 mg/kg/day, 

based on decreased body 

weights, body weight gains 

and food utilization in males 

and slight hepatotoxicity in 

both sexes.
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Table 4.3.2. Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Occupational 

Human Health Risk Assessments.

Exposure

Scenario

Point of Departure Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment

Study and Toxicological 

Effects

Cancer (oral, 

dermal, 

inhalation) 

No Evidence of Carcinogenicity. Classified as “Not Likely to be Carcinogenic to Humans.”

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The nature of the residue in plants, rotational crops, and ruminants is adequately understood. For 

the purposes of tolerance enforcement and risk assessment, the residue of concern in primary

crops, rotational crops, and ruminants is the parent mandipropamid, with the exception of root 

and tuber vegetables, where the metabolite SYN 500003 is included for risk assessment. The 

metabolism data indicate that there is no reasonable expectation of finite residues in milk, meat, 

and/or meat byproducts (40 CFR §180.6, Category 3) as a result of the proposed use. There are 

no poultry feed items associated with the proposed use.

Drinking Water

D409108; R. Shamblen; 7/9/2013.

The assessment included mandipropamid and its major aquatic degradates, SYN 500003 and 

SYN 504851, in drinking water. Two significant degradates were observed in the aerobic 

aquatic metabolism study SYN 504851 (maximum 29% of applied material; very mobile) and 

SYN 500003 (maximum 9.4%; mobile). Based on the European Union monograph, SYN 

500003 has a short residence time in soil (DT50 = 2 days), but is considerably more stable under 

aerobic aquatic conditions (DT50 = 30 days). Five degradates were found in the aerobic soil 

metabolism study, but the maximum level of any of these was 4.25% of applied material.

An acute oral and Ames-test were performed for the metabolite SYN 500003. This metabolite 

was not detected in rat metabolism studies. SYN 500003 was administered once by oral gavage 

to female rats at doses of 550 or 2000 mg/kg. The oral LD50 was calculated to be 1049 mg/kg, 

indicating it’s more acutely toxic via the oral route than the parent compound (however, it is only 

0.005-0.006 ppm or 10.5-12.7% of the total radioactive residues (TRR) in root and tuber crops). 

The study is acceptable/guideline, with the SYN 500003 degradate classified as Toxicity 

Category III for oral toxicity. In addition, a bacterial reverse gene mutation assay (Ames Test) 

with SYN 500003 was conducted. No evidence of induced mutant colonies over background 

was detected in that study.
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HED notes that SYN 500003 still possesses a propargyl side chain like those found in the parent. 

Loss of this side chain could produce the reactive compound propiolaldehyde. The latter is 

believed to be the source of the liver toxicity of propargyl alcohol, for which the petitioner has 

submitted a 14-day repeat exposure study with rats showing similar hepatotoxicity as seen with 

mandipropamid. Therefore, HED concludes that metabolites and degradates still having a 

propargyl side should be considered comparably as toxic as the parent fungicide.

No toxicity data were submitted for the metabolite SYN 504851. While SYN 504851 does not 

have the propargyl side chain, it could generate a reactive aldehyde (e.g., acrolein) similar to 

propiolaldehyde with a vinyl group instead of the alkyne function. Therefore, in the absence of 

repeated dose studies, HED concludes this degradate should also be considered toxicologically 

equivalent to the parent.

Table 5.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment and 

Tolerance Expression.

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants Primary Crop Mandipropamid

(Parent + SYN 500003 for 

root and tuber vegetables )

Mandipropamid

Rotational Crop Not applicable Mandipropamid*

Livestock Ruminant Not applicable Not applicable 

Poultry Not applicable Not applicable

Drinking Water Parent, SYN 504851 and 

SYN 500003

Not Applicable

*Although the parent compound is a residue of concern in rotational crops, tolerances are not needed for the existing 

or proposed uses based on the absence of residues in the field rotational crops study following the label’s 30-day 

plant-back interval (PBI). 

5.2 Food Residue Profile

The nature of the residue in plants, rotational crops, and ruminants is adequately understood. For 

the purposes of tolerance enforcement and risk assessment, the terminal residue of concern in 

primary crops, rotational crops, and ruminants is the parent mandipropamid, with the exception 

of root and tuber vegetables, where the metabolite SYN 500003 is included for risk assessment. 

The only livestock feed items associated with the proposed seed piece treatment use on potato 

are potato culls and processed waste. Both feed items are fed to cattle at 30% of the diet for beef 

cattle, and 10% of the diet for dairy cattle; neither is fed to poultry nor swine. Based on the 

highest average field trial (HAFT) residue of 0.056 ppm in potato culls, and the median residue 

of 0.14 ppm in potato processed waste, the recalculated dietary burdens to beef and dairy cattle 

are 0.112 and 0.037 ppm, respectively. 
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No livestock feeding studies were submitted with this petition. An acceptable ruminant 

metabolism study is available. Goats were dosed with radiolabeled mandipropamid at 30-36 

ppm (268-320X the calculated dietary burden to cattle) in the feed for 7 consecutive days. The 

parent compound was identified only in fat (0.013-0.019 ppm), milk (0.013 ppm), and liver 

(0.004-0.007 ppm). SYN500003 was not identified in any ruminant tissue or milk. Based on the 

highest detected residue of 0.019 ppm in goat fat, and anticipated residues from feeding potato 

culls and processed waste containing mandipropamid at the recommended tolerance levels of 

0.09 ppm in potato and 0.15 ppm in potato wet peel, there is no reasonable expectation of finite 

residues of mandipropamid in ruminants (40CFR §180.6[a][3]) as a result of the proposed use. 

Based on the ruminant metabolism study, ruminants are only likely to receive SYN500003 from 

consumption of feed items containing SYN500003 as a result of treatment with mandipropamid. 

In the submitted potato field trial studies, HAFT residues of SYN500003 (in parent equivalents) 

were roughly half those of the parent. Therefore, HED concludes that there is no reasonable

expectation of finite residues of SYN500003 in ruminants (40CFR §180.6[a][3]) as a result of 

the proposed use on potato. 

The data submitted in support of the current action (Petition #4F8329) along with previously 

reviewed data, are adequate for purposes of risk assessment and tolerance assessment for the 

proposed revised use pattern on potato under review. Maximum residues of mandipropamid are 

expected to occur at relatively low levels (<0.09 ppm in subgroup 1C, and <0.15 ppm in potato 

wet peel) from the revised use pattern combining seed piece treatment and foliar use on potato, 

as proposed in the current petition. 

Mandipropamid residues generally tend to decline or remain stable with increasing PHI, and do 

not usually increase to any significant degree. Following foliar applications, mandipropamid is 

present primarily as surface residues; translocation does not appear to be extensive. There is 

little to no uptake of mandipropamid by the roots. In general, mandipropamid residues do not 

tend to concentrate in processed fractions, other than via dehydration or from surface residues. 

Residues of mandipropamid are not expected to accumulate above the LOQ in rotational crops. 

HED previously concluded that rotational crop tolerances are not required for mandipropamid. 

5.2.1 Crop Field Trials (860.1500)

D428278; W. Drew; 02/23/2016.

Adequate field trial data were provided to support the proposed tolerances for the amended use 

on potato. The field trials were considered to have been conducted in geographically 

representative locations, with application rates, RTIs and PHIs reflecting the proposed label 

directions for use. In all cases, the tolerances are based on detectable residues in the 

crops/commodities. A table reflecting the results of the submitted field trial data is provided 

below.

 
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Table 5.2.1. Summary of Residues from Potato Field Trials with Mandipropamid.

Matrix Analyte Total Use 

Rate 

(lb ai/A

[g ai/ha])

PHI 

(Days)

n

1 Residues (ppm)

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

Combined US Trials (MRID #49470401) and Canadian Trials (MRID #49470404)

Potato

tubers

Mandipropamid0.536-

0.631

[600-707]

12-15 24 <0.010 0.066 <0.010 0.056 0.014 0.018 0.012

SYN500003

as reported

<0.005 0.014 <0.005 0.013 0.005 0.006 0.002

SYN500003

parent 

equiv.

<0.009 0.025 <0.009 0.023 0.009 0.011 0.004

Combined4 <0.019 0.075 <0.019 0.065 0.035 0.030 0.013

1. n = number of field trials. 

2. Values based on total number of samples. 

3. Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = 

standard deviation. For computation of the LAFT, HAFT, median, mean and standard deviation, values 

<LOQ were assumed to be at the LOQ. LOQs were 0.010 ppm for mandipropamid, 0.005 ppm for 

SYN500003 (as reported), and 0.009 ppm for SYN500003 (parent equivalent). 

4. Combined residues of mandipropamid and SYN500003 are in parent equivalents. It should be noted that the 

maximum and HAFT residues for the parent compound and metabolite SYN500003 were observed in 

different samples. Therefore, the sums of these residues are not equal to the maximum and HAFT 

combined residues. 

5.2.2 Field Rotational Crops (860.1900)

D328534, D337543; D. McNeilly; 28 August 2007

An adequate limited field rotational crop study was reviewed in petitions #6F7057 and #7F7184. 

Mandipropamid residues were below the LOQ (<0.010 ppm) in all samples of rotated radish 

roots, radish tops, spinach leaves, fall wheat forage, spring wheat forage, wheat hay, wheat grain, 

and wheat straw planted at the 28/31-day and 61-day PBIs. HED has determined that the 

rotational crop restriction on the label which states “Do not plant any crop which is not registered 

for use with mandipropamid for a period of 30 days after the last application” is appropriate. 

Given the label restriction, tolerances in rotational crops are not needed. 

5.2.3 Processed Food and Feed (860.1520)

D428278; W. Drew; 02/23/2016.

The submitted processing data for potato are adequate, and together with the HAFT from the 

corresponding field trial studies support an increase in the established tolerance for 

mandipropamid in potato wet peel, from the existing tolerance of 0.03 to the HED-recommended 

increased tolerance of 0.15 ppm. The data indicate that residues of mandipropamid concentrate 

in wet peel (mean processing factor of 2.0X) and residues of SYN500003 concentrate in potato 

flakes and chips (>1.7X and >1.4X) processed from potato bearing quantifiable residues of both 

analytes following combined seed piece treatment and foliar application of the 2.08 lb ai/gal SC 

formulation at an exaggerated rate (approximately 5X). Acceptable methods were used for 

quantitation of the residues of concern for root and tuber vegetables, which are mandipropamid 

for tolerance enforcement, and SYN500003 for risk assessment. The data are supported by 

adequate storage stability data. 
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In general, the results observed in this study for mandipropamid are consistent with those 

observed in an earlier potato processing study reflecting foliar applications only. In that study, 

residues concentrated in wet peel (>3X) processed from potato in which residues were below the 

LOQ (<0.010 ppm); residues were below the LOQ in all other potato processed commodities. In 

the preceding processing study, residues of SYN500003 were below the LOQ in the RAC and all 

processed fractions. In the current study, concentration of residues of SYN500003 in flakes and 

chips appears to have been associated with drying (chips were baked rather than fried at the 

processing facility). 

5.3 Water Residue Profile

D409108; R. Shamblen; Jul 9, 2013.

EFED has concluded that the proposed amended use on potato has no impact on the drinking 

water estimates (based on email communication with B. Anderson, 08/24/2015). Therefore, the 

drinking water estimates from the existing use pattern have been used in this assessment. The

estimated drinking water concentrations (EDWCs) used in the dietary risk assessments were 

provided by the Environmental Fate and Effects Division (EFED), (D409108, R. Shamblen, 

7/9/2013). The EDWCs were incorporated directly into these dietary assessments in the food 

categories “water, direct, all sources” and “water, indirect, all sources.” The EDWCs for 

mandipropamid were generated using the FQPA Index Reservoir Screening Tool (FIRST)

Version 1.1.1 model for surface water, and both the Pesticide Root Zone Model for Ground 

Water (PRZM-GW v. 1.01) and Screening Concentration in Ground Water (SCI-GROW version 

2.3) models for groundwater. Modeled surface water and groundwater EDWCs are based on the 

maximum label application rate to tomato and basil (chronic value).

A Total Residue (TR) modeling approach was used to estimate aerobic aquatic half-lives, and 

estimate drinking water concentrations in surface waters. EFED conducted a Tier 1 drinking 

water exposure assessment for the fungicide mandipropamid. Tier 1 exposure modeling results 

are summarized in Table 5.3. PRZM-GW resulting in the highest estimate of the potential for 

mandipropamid residues in ground water sources of drinking water. Maximum EDWCs in 

ground water are 87 and 79 μg/L for acute and chronic exposures, respectively. These values are 

as much as 480 times higher than SCI-GROW model results. Maximum acute and chronic 

EDWCs in surface waters are 79 and 9.0 μg/L, respectively.
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Table 5.3. Tier 1 Estimated Drinking Water Concentrations (EDWC) for Maximum Mandipropamid Use 

Patterns.

Drinking Water Source

(Model, Version)

PCA

(%)

Crop Use Pattern

(Maximum Annual Rate)

Acute

(μg/L)

Chronic 

(μg/L)

Surface Water (FIRST, 1.1.1) 91 Tomato & Basil 

(2.08 lbs a.i./A) 79 9.0

Ground Water (PRZM-GW, 1.01) N/A Tomato & Basil 

(2.08 lbs a.i./A) 87 79

Ground Water (SCI-GROW, 2.3) N/A Tomato & Basil 

(2.08 lbs a.i./A) 0.18

Abbreviations: A= acre; a.i. = active ingredient; ha = hectare; kg = kilograms; μg = micrograms; lbs = pounds (US); 

N/A = not applicable

Note that although EFED provided HED with estimates of acute surface and ground water 

estimates, these have not been incorporated into the dietary model due to the lack of an acute 

endpoint for mandipropamid.

The drinking water models and descriptions are available at the EPA internet site: 

http://www.epa.gov/oppefed/models/water/.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

D428940; E. Holman; 02/23/2016.

A chronic dietary exposure assessment was performed for mandipropamid. The assumptions 

underlying this unrefined assessment were 100% crop treated (CT), HED-recommended 

tolerance levels or tolerance-level residues (with the exception of vegetable, tuberous and corm, 

crop subgroup 1C), and default DEEM-FCID (ver. 7.81) processing factors (with the exception 

of chemical-specific processing factors for grape wine and sherry). The mean (i.e., relevant to 

chronic exposure) drinking water estimate of 79 ppb was provided by EFED, and directly 

incorporated into the chronic assessment.

As noted previously (see Section 5.1), for the purposes of tolerance enforcement and risk 

assessment, the residue of concern in primary crops, rotational crops, and ruminants is the parent 

mandipropamid, with the exception of root and tuber vegetables, where the metabolite SYN 

500003 is included for risk assessment. The HED-recommended tolerance-level residues for the 

proposed amended use on potato (D428278, W. Drew, 02/23/2016) is 0.09 ppm, with the 

amended tolerance being issued for the entire vegetable, tuberous and corm, subgroup 1C. For 

the purposes of this chronic dietary risk assessment, this subgroup was assessed at 0.115 ppm, 

which assumes tolerance-level residues of parent mandipropamid (0.09 ppm) and also includes 

the SYN 500003 metabolite in parent-equivalents (at 0.025 ppm).
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5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary assessment is based on 100% CT assumptions for all commodities.

5.4.3 Acute Dietary Risk Assessment

No acute dietary toxicity endpoint could be identified based on the toxicology data currently 

available for mandipropamid.

5.4.4 Chronic Dietary Risk Assessment

All populations were evaluated for chronic dietary risk. No risks of concern were identified in 

the chronic dietary exposure analysis. The most highly exposed population subgroup is children 

1-2 years old which utilizes 42% of the cPAD (Table 5.4.6). The general U.S. population 

utilizes 26% of the cPAD. Since highly conservative assumptions were used in the assessment, 

actual dietary exposures for all population subgroups is expected to be much lower than those 

shown in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

The Cancer Assessment Review Committee (CARC) classified mandipropamid as “Not likely to 

be a human carcinogen;” therefore a cancer assessment was not performed.

5.4.6 Summary Table

D428940; E. Holman; 02/23/2016.

The results of the dietary exposure and risk analysis for chronic dietary exposures are 

summarized below in Table 5.4.6.

Table 5.4.6. Summary of Dietary Exposure and Risk for Mandipropamid (Food and Drinking 

Water)

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 N/A

0.013145 26

N/A N/A

All Infants (< 1 year old) 0.011004 22

Children 1-2 years old 0.021060 42

Children 3-5 years old 0.019313 39

Children 6-12 years old 0.012005 24

Youth 13-19 years old 0.009525 19

Adults 20-49 years old 0.013220 26

Adults 50-99 years old 0.013149 26

Females 13-49 years old 0.013039 26

N/A = Not applicable.
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered or proposed residential uses for mandipropamid. Therefore, a residential 

exposure assessment is not required.

6.1 Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

mandipropamid.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for mandipropamid. The agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), 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). 1 The agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

These proposed use patterns are unlikely to result in spray drift due to how it is applied (e.g., 

seed treatment). However, there is potential from drift resulting from treatment of other 

agricultural crops that will be addressed in Registration Review. 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 previously performed for flaggers as part of the existing use pattern for mandipropamid. 

 

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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This exposure scenario is representative of a worst-case inhalation (drift) exposure and may be 

considered protective of most outdoor agricultural and commercial post-application inhalation 

exposure scenarios. 

7.0 Aggregate Exposure/Risk Characterization

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

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

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

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

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

duration of exposure. 

7.1 Acute & Chronic Aggregate Risk

Acute and chronic (both cancer and non-cancer) aggregate exposures include food plus drinking 

water exposures. No acute dietary toxicity endpoint could be identified based on the toxicology 

data currently available for mandipropamid. As demonstrated under Section 5.4, chronic 

aggregate risk is not of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

Short-and intermediate-term aggregate exposures take into account residential exposure plus 

average exposure levels to food and water (considered to be a background exposure level). For 

mandipropamid, there are no residential uses, and therefore short- and/or intermediate-term 

aggregate risks are not of concern. 

8.0 Cumulative Exposure/Risk Characterization

FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base 

its assessment of the risk posed by the chemical on, among other things, available information 

concerning the cumulative effects to human health that may result from dietary, residential, or 

other non-occupational exposure to other substances that have a common mechanism of toxicity. 

The reason for consideration of other substances is due to the possibility that low-level exposures 

to multiple chemical substances that cause a common toxic effect by a common mechanism 

could lead to the same adverse health effect as would a higher level of exposure to any of the 

other substances individually. A person exposed to a pesticide at a level that is considered safe 

may in fact experience harm if that person is also exposed to other substances that cause a 

common toxic effect by a mechanism common with that of the subject pesticide, even if the 

individual exposure levels to the other substances are also considered safe.

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

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

to mandipropamid and any other substances, and mandipropamid does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this tolerance action, 
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therefore, EPA has not assumed that mandipropamid has a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

D428298; B. Bobowiec; June 17, 2015

For potato seed pieces, possible exposure from use of mandipropamid as a commercial seed 

treatment may occur during the following scenarios:

 Mixing/loading liquid formulation into the potato seed piece application equipment; and

 Planting treated seed pieces.

The maximum single application rates for potato seed treatment is 0.01 lb ai/100 lb of potato 

seed. Information from industry regarding amount handled as summarized in EXPOSAC Policy 

15.1 SOP for Amount of Seed Treated per Day was used to assess the potato seed piece 

treatment. 

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months 

as intermediate-term. Based on the proposed use pattern, directions (e.g., 2-4 applications per 

season) and resistance management practices (e.g., no more than 2 consecutive applications), 

short- and intermediate-term exposures are expected for occupational handlers. Since the same 

endpoint and point of departure were selected for short- and intermediate-term durations, shortterm exposure and risk estimates are considered to be protective of intermediate-term exposure 

and risk for the potato seed treatment use. Long-term exposures are not expected; therefore, a 

long-term assessment was not conducted.

Additionally, there was no dermal POD selected for mandipropamid; therefore, no dermal 

exposure was quantitatively assessed. 

Results of inhalation exposure are presented for “baseline” level of PPE, defined as a single layer 

of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, 

and no respirator. The mandipropamid product labels direct mixers, loaders, applicators and 

other handlers to wear long-sleeved shirt and long pants, shoes plus socks. PPE recommended 

on the proposed label for early entry to treated areas include: coveralls, chemical-resistant gloves 

made of any waterproof material, shoes plus socks. 

The maximum application rate for each exposure scenario is presented as the worst-case, and 

standard assumptions were used with respect to the area treated for each crop/application 

method, along with the assumption of 80 kg body weight. Since no short- or intermediate-term 

dermal endpoints of concern were identified, there is no dermal risk associated with exposure to 

mandipropamid. Only inhalation risk estimates have been assessed. Summaries of the risks for 

occupational handlers are included in Table 9.1.
Mandipropamid Human Health Risk Assessment D425240

Page 25 of 38

All occupational handler scenarios resulted in inhalation MOEs greater than the level of concern 

(MOEs≥100 for inhalation) at baseline attire with no respirator). No additional PPE 

recommendations have been identified for the proposed label. 

Table 9.1. Mandipropamid Occupational Handler Short-and Intermediate-Term Exposure and Risk 

Estimates for Potato Seed Treatment 

Exposure 

Scenario

Crop 

or 

Target

Inhalation Unit Exposure 

(μg/lb ai)1

Maximum

Application 

Rate 2

Amount or Area 

Treated3

lbs seed treated or 

planted/day

Inhalation

Mitigation Level

Amount 

Handled 

per day

(lb ai/day)

Dose 5

(mg/kg/day)

MOE 6

(Target = 

100)

Short and Intermediate Term Commercial Potato Seed Treatment

Mixing, 

Loading, and 

apply liquid 

formulation to 

seed pieces

(Short-term)7

Potato 

Seed 

Pieces

6.4

Baseline Inhalation (μg/lb ai) 0.01 lb 

ai/100 lb 

seed

800,000 lb seed pieces 0.0064 6,400

Mixing, 

Loading, and 

apply liquid 

formulation to 

seed pieces

(Intermediateterm)8

400,000 lb seed pieces 0.0032 13,000

Secondary 

Handler (potato 

seed planter)

3.4

Baseline Inhalation (μg/lb ai)

800,000 lb seed pieces

0.0034 12,000

1. Exposure Science Advisory Council Policy 14 and MRID 47054702.

2. Application Rates based on proposed uses on label for mandipropamid product Revus (Reg. No.100-1254). 

Application rates in fluid oz. product/100 seed provided on the label were converted to lb ai/100 lb seed.

3. Exposure Science Advisory Council 15.1

4. Baseline Inhalation: No respirator; 

5. Inhalation Dose (mg/kg/day) = daily unit exposure (μg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb 

seed/day) x conversion factor (1 mg/1,000 μg) / body weight (80 kg).

6. Inhalation MOE = NOAEL (41 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100.

7. 800,000 lb potato seed pieces for mixing/loading and applying liquid formulation for “typical” hourly output of 

the largest liquid treater (Model 42-1000 cwt per hour)

times 8 hour work day,

8. 400,000 lb potato seed pieces for mixing/loading, and applying liquid formulation for “typical” intermediate or 

mid-size liquid treater (Model 36-500 cwt) times 8 hour

work day.

Occupational Post-Application Assessments

Dermal

The potential for dermal post-application exposures following the planting of potato-treated 

seeds is negligible because sustained levels of contact with treated seed after it has been placed 
Mandipropamid Human Health Risk Assessment D425240

Page 26 of 38

in the soil or other planting media would not be expected because no routine cultural practice 

required for the production of agricultural commodities involves such an activity as defined in 

the no/low contact criteria in the Worker Protection Standard (WPS). There is the possibility for 

agricultural workers to have post-application exposure to mandipropamid following the planting 

of treated potato seed pieces. Although there is potential for dermal post-application exposure, 

no dermal endpoint was selected because the rat 28-day dermal toxicity study demonstrated no 

toxicity up to the limit dose (1,000 mg/kg/day). Therefore, a quantitative dermal postapplication exposure assessment was not conducted.

The restricted entry interval (REI) listed on the master label is based on the acute toxicity of the 

technical material. Mandipropamid has low acute dermal toxicity (Toxicity Category IV), and is 

not an ocular or dermal irritant, nor a dermal sensitizer. Mandipropamid is not classified as a 

carcinogen or a neurotoxicant. In addition, it is not associated with known reproductive or 

developmental effects. Based on this information, mandipropamid is categorized as a reduced 

risk chemical. Therefore, the REI of 4 hours is adequate to protect agricultural workers from 

post-application exposures to mandipropamid. 

Inhalation

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. 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 

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

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for mandipropamid.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

HED assumes that inhalation exposures are negligible following planting of treated potato seed 

pieces. A quantitative inhalation exposure assessment was performed for 

occupational/commercial seed treaters and planters as well as mixer/loader/applicators to nonbearing citrus. Handler exposures resulting from application of pesticides outdoors is likely to 

result in higher exposure than post-application exposure. Therefore, it is expected that these 

handler inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.
Mandipropamid Human Health Risk Assessment D425240

Page 27 of 38

10.0 References

Mandipropamid: Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk 

Assessment for the Section 3 Amended Use of the Fungicide on Potato to Add Seed Treatment 

Use. D428940, E. Holman; 02/23/2016.

Mandipropamid. Occupational and Residential Exposure Assessment for the Proposed Uses on 

Non-bearing Citrus and Seed Piece Treatment on Potatoes. D428298, B. Boboweic; June 17 

2015.

Mandipropamid. Petition Proposing the Establishment of a Permanent Tolerance for Residues 

Resulting from Amended Use of the Fungicide on Potato, to Replace the Established Tolerance 

in Tuberous and Corm Vegetable Subgroup 1C, and to Revise the Established Tolerance in 

Potato Wet Peel. Summary of Analytical Chemistry and Residue Data. D428278, W. Drew;

02/23/2016.

Mandipropamid. Drinking Water Exposure Assessment for Proposed Section 3 New Uses on: 

Basil, Ginseng and Succulent Beans; and Expanded Uses on Bulb Vegetables, Cucurbits, 

Grapes, and Fruiting Vegetables including Tomatoes., D409108, R. Shamblen, 7/9/2013.

Mandipropamid. Request to Register New Food/Feed Uses on Head and Stem Brassica, Leafy 

Brassica Greens, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables (except Brassica), 

Tuberous and Corm Vegetables, Grapes, and Onions (Dry Bulb and Green). Summary of 

Analytical Chemistry and Residue Data. Petition Numbers 6F7057 and 7F7184.; D328534, 

D337543; D. McNeilly; 28 August 2007. 

Mandipropamid; Human Health Risk Assessment for Proposed Use on Hops. D365918, D. 

Rate; June 8 2009. 
Mandipropamid Human Health Risk Assessment D425240

Page 28 of 38

Appendix A. International Residue Limits

Mandipropamid (PC Code 036602)

Summary of US Tolerances and International Maximum Residue Limits.

Residue Definitions

US (40CFR §180.637) Canada Codex

Plants: Mandipropamid (4-chloro-N-

[2-[3-methoxy-4-(2-

propynyloxy)phenyl] ethyl]-α-(2-

propynyloxy)- benzeneacetamide). 

Mandipropamid (4-chloro-N-[2-[3-

methoxy-4-(2-propynyloxy) phenyl]ethyl]-

α-(2-propynyloxy)- benzeneacetamide). 

Mandipropamid. 

Commodity2 Tolerance 

(ppm)3

Commodity MRL 

(mg/kg)

Commodity MRL 

(mg/kg)4

Vegetable, tuberous and 

corm, subgroup 1C 

0.09 Potato, arracacha, arrowroot, 

cassava root, chayote root, 

Chinese artichoke, chufa, edible 

canna, ginger root, Jerusalem 

artichoke, leren, sweet potato 

root, tanier corm, taro corm, true 

yam tuber, turmeric root, yam 

bean root

0.09 Potato 0.01

Potato, wet peel 0.15

Completed: M. Negussie, 23 April 2015. 

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

2. Includes only commodities of interest for this action. 

3. Tolerance values are those recommended by HED, not those proposed by the petitioner. 

4. Absent at the LOQ. 
Mandipropamid Human Health Risk Assessment D425240

Page 29 of 38

Appendix B. Toxicology Profile

B.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses of mandipropamid are in Table B1. Use of the 

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

acute and chronic toxicity profiles are shown in Tables B.2.1 and B.2.2, respectively.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation.......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity ..........................................

870.3250 90-Day Dermal Toxicity ...............................................

870.3465 28/90-Day Inhalation Toxicity ......................................

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Prenatal Developmental Toxicity (rodent) ....................

870.3700b Prenatal Developmental Toxicity (nonrodent) ..............

870.3800 Reproduction and Fertility Effects ................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse) ...............................................

870.4300 Combined Chronic Toxicity/Carcinogenicity ...............

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test ..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test..

870.5385 Mutagenicity—Structural Chromosomal Aberrations...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

no

no

no

-

-

-

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes
Mandipropamid Human Health Risk Assessment D425240

Page 30 of 38

B.2 Toxicity Profiles

Table B.2.1 Acute Toxicity Profile - Mandipropamid

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral rat 46800201 LD50 > 5000 

mg/kg

IV

870.1200 Acute dermal rat 46800202 LD50 > 5050 

mg/kg

IV

870.1300 Acute inhalation rat 46800204 LC50 > 5.19 ± 

0.55 mg/L

IV

870.2400 Acute eye irritation rabbit 46800206 Iritis and positive 

signs of 

conjunctivitis 

clearing within 

24 hours.

IV

870.2500 Acute dermal irritation rabbit 46800208 PDI = 0.33 IV

870.2600 Skin sensitization guinea pig 46800210 Replaced by 

47259001.

N/A

870.2600 Skin sensitization mouse 47259001 Test substance is 

not a dermal 

sensitizer.

Negative
Mandipropamid Human Health Risk Assessment D425240

Page 31 of 38

Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid

Guideline 

No. 

Study Type MRID No. 

(year)/ 

Classification 

Dose levels Results

870.3100 90-Day oral 

toxicity (rat)

46800216

(2005)

Acceptable/

Guideline

ppm= 0, 100, 500, 

3000, 5000

mg/kg/day=

M: 0, 8, 41, 260, 

435

F: 0, 9, 45, 260, 

444

NOAEL = 41/45 mg/kg/day M/F

LOAEL = 260 mg/kg/day both sexes, 

based on decreased body weights, 

weight gains and food utilization in 

males and slight hepatotoxicity in both 

sexes

830.3100 28-Day oral 

toxicity (rat)

46800214

(2005)

Acceptable/

Guideline

ppm = 0, 1000, 

3000, 10,000, 

16,000 [10,000 & 

16,000 died < day 

4]

mg/kg/day =

M: 0, 135, 418, 

624, 604

F: 0, 121, 381, 784, 

1410

NOAEL = not established

LOAEL = M=135, F=121 mg/kg/day, 

based on decreased food consumption 

in both sexes and decreased body 

weights and weight gains in males 

(liver changes at 418/381 mg/kg/day 

M/F).

870.3100 90-Day oral 

toxicity (mouse)

46800213 

46800217

(2005)

Acceptable/

Guideline

ppm= 0, 300, 800, 

2000, 5000

mg/kg/day=

M: 0, 37, 98, 248, 

624

F: 0, 47, 129, 316, 

800

NOAEL = M/F = 248/316 mg/kg/day

LOAEL = M/F = 624/800 mg/kg/day, 

based on decreased body weight gain 

in males and females (as well as the 

suggestion of effects on the liver: 

increased weights in both sexes and 

microscopic pathology).

870.3150 90-Day oral 

toxicity (dog)

46800218

46800219

46800220

(2005)

Acceptable/

Guideline

mg/kg/day= 

0, 5, 25, 100, 400 

(capsule)

NOAEL = 100 mg/kg/day

LOAEL = 400 mg/kg/day, based on 

liver toxicity (increased cholesterol, 

alkaline phosphatase activity, ALT 

activity, liver weights and microscopic 

pigment in hepatocytes and Kupffer 

cells in both sexes and centrilobular 

hepatocyte vacuolation in females).

870.3200 21/28-Day dermal 

toxicity (rat)

46800222

46800221

( 2005)

Acceptable/

Guideline

mg/kg/day= 

0, 250, 500, 1000 

(limit dose) 

Systemic/Dermal NOAEL = 1000 

mg/kg/day

LOAEL = not determined

870.3700a Prenatal 

developmental 

(rat)

46800224

46800223

(2005)

46800228

(2001)

Acceptable/ 

Guideline

mg/kg/day= 

0, 50, 200, 1000

Maternal NOAEL = 1000 mg/kg/day

LOAEL = not determined

Developmental NOAEL = 1000 

mg/kg/day

LOAEL = not determined

870.3700b Prenatal 

developmental 

(rabbit)

46800227 

46800225 

46800226 

46800229 

(2005)

Acceptable/ 

Guideline

mg/kg/day= 

0, 50, 250, 1000

Maternal NOAEL = 1000 mg/kg/day

LOAEL = not determined

Developmental NOAEL = 1000 

mg/kg/day

LOAEL = not determined
Mandipropamid Human Health Risk Assessment D425240

Page 32 of 38

Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid

Guideline 

No. 

Study Type MRID No. 

(year)/ 

Classification 

Dose levels Results

870.3800 Reproduction and 

fertility effects

(rat)

46800230

46800231 

(2005)

Acceptable/ 

Guideline

ppm=(males/

females)

0, 50, 250, 1500

mg/kg/day= 

(mean of premating 

both sets of 

parents) = 0/0, 

4.6/5.0, 22.9/24.5, 

146.3/148.2

Parental/Systemic NOAEL = M/F = 

22.9/24.5 mg/kg/day

LOAEL = M/F = 146.3/148.2 

mg/kg/day, based on decreased body 

weights, weight gains, food 

consumption and food utilization in 

males

Reproductive NOAEL = M = 

146.3/148.2 mg/kg/day

LOAEL = not determined

Offspring NOAEL = M/F = 22.9/24.5 

mg/kg/day

LOAEL = M/F = 146.3/148.2 

mg/kg/day, based on decreased pup 

body weights in both sexes.

870.4100 Chronic toxicity 

(dog)

46800232 

(2005)

Acceptable/ 

Guideline

mg/kg/day=

0, 5, 40, 400 

(capsule)

NOAEL = 5 mg/kg/day

LOAEL = 40 mg/kg/day, based on 

evidence of liver toxicity (increased 

incidence and severity of microscopic 

pigment in the liver and increased 

alkaline phosphatase activity in both 

sexes as well as increased alanine 

aminotransferase activity in males).

870.4300 Combined chronic 

toxicity/ 

carcinogenicity

(rat)

46800234 

(2005)

Acceptable/ 

Guideline

ppm = 0, 50, 250, 

1000

mg/kg/day= M/F =

0/0, 3.0/3.5, 

15.2/17.6, 

61.3/69.7

NOAEL = M/F = 15.2/17.6

LOAEL = 61.3/69.7mg/kg/day, based 

on decreased body weight gain and 

food utilization and increased 

nephrotoxicity in males.

There was no evidence of 

carcinogenicity in rats.

870.4200 Carcinogenicity

(mouse)

46800233 

(2005)

Acceptable/

Guideline

ppm = 0, 100, 500, 

2000

mg/kg/day= M/F =

0/0, 10.6/13.2, 

55.2/67.8, 

222.7/284.6

NOAEL = M/F = 55/68 mg/kg/day

LOAEL = 223/285 mg/kg/day, based 

on decreased body weight gain in both 

sexes and decreased food utilization in 

males. 

There was no evidence of 

carcinogenicity in mice.

870.5100 Bacterial Reverse 

Mutation Assay 

46800235 

(2005)

Acceptable/ 

Guideline

Tested up to limit 

dose of 5000 

μg/plate

Negative

870. 5300 In Vitro

Mammalian Cell 

Gene Mutation 

Test – Mouse 

Lymphoma 

46800236 

(2005)

Acceptable/ 

Guideline

Tested up to limit 

dose (4119 μg/mL)

Negative
Mandipropamid Human Health Risk Assessment D425240

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Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid

Guideline 

No. 

Study Type MRID No. 

(year)/ 

Classification 

Dose levels Results

870. 5375 In Vitro 

Chromosome 

Aberration test –

Human Peripheral 

Blood 

Lymphocytes

46800237 

(2002)

Acceptable/ 

Guideline

Up to cytotoxic 

concentrations

Negative

870.5395 Micronucleus 

Assay in Rats

46800238 

(2005)

Acceptable/ 

Guideline

Limit dose of 2000 

mg/kg

Negative

870.5550 In Vivo/In Vitro

Unscheduled 

DNA Synthesis 

Assay in Primary 

Rat Hepatocytes

46800239

Acceptable/ 

Guideline

mg/kg = 0 or 2000 Negative

870.6200a Acute 

neurotoxicity 

(rats)

46800242

(2005)

46800241

(2003)

Acceptable/ 

Guideline

mg/kg = 0, 200, 

600, 2000 (limit 

dose)

NOAEL = M/F = 2000 mg/kg

LOAEL = M/F = not observed

870.6200b Subchronic 

neurotoxicity 

(rats)

46800240 

(2005)

Acceptable/ 

Guideline

ppm = 0, 100, 500, 

2500

mg/kg/day = M/F = 

0/0, 7.4/8.4, 

37.3/41.0, 

192.5/206.7

NOAEL = M/F = 37/41 mg/kg/day

LOAEL = M/F = 192/207 mg/kg/day, 

based on slightly decreased body 

weight, weight gain and food 

utilization in males. 
Mandipropamid Human Health Risk Assessment D425240

Page 34 of 38

Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid

Guideline 

No. 

Study Type MRID No. 

(year)/ 

Classification 

Dose levels Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

46800243-

46800246 

(2005)

Acceptable/ 

Guideline

mg/kg/day =

single oral 3 or 300 

methoxy label

repeated 3 methoxy 

label

single oral 3 or 300 

methoxy/chloro 

labels

After 48 hours, absorption was 67-74% 

at 3 mg/kg and 30-45% at 300 mg/kg. 

Blood Tmax at 3 mg/kg was 8.5 hours 

for M and 4.5 hours for F; at 300 

mg/kg was 24 hours for M and 10 

hours for F (rate of resorption greater 

in F; extent and rate greater in low 

dose). Recoveries at 168 hours 88-

99% (most eliminated by 48 hours). 

Excluding 3 mg/kg F, most excreted in 

feces; at 3 mg/kg F, feces and urine 

similar. Elimination after 48 hours in 

bile was high at 3 mg/kg (55-73%), but 

was 22-28% at 300 mg/kg. Liver had 

highest concentration at all 

measurements. More radioactivity in 

plasma than whole blood. Identified 

compounds 66-94% of administered 

dose in each group (168 hours). Parent 

and following metabolites at ≥5% at 3 

and/or 300 mg/kg: NOA 458422, NOA 

458422 glucuronide, SYN 534133 and 

CGA 380778. Differences in 

metabolic profile due to sex, dose and 

radiolabel position. Each unknown 

compound < 5%. Major metabolic 

transformations involved loss of one or 

both propargyl groups followed by 

glucuronidation and O-demethylation. 

870.7600 Dermal 

Penetration (rat)

46800248 

(2005)

Acceptable/ 

Guideline

Nominal doses: 

mg/cm2skin = 

0.00152, 0.0076, 

2.54.

Spray strength 

dilutions of 1/333 

and 1/1667 v/v.

Recovery was 96-112%. Minimal 

absorption (<0.17 to 3.44% of applied 

dose). 91-105% recovered from 6 hour 

skin wash. Greatest absorption in 

1/1667 aqueous dilution 114 hours 

after 6 hours of exposure (3.44% 

absorbed).

870.7800 Immunotoxicity 

(mouse)

48771701 

(2011)

Acceptable/Gu

ideline

0, 56,187 and 649 

mg/kg/day

NOAEL = 649 mg/kg/day

LOAEL = not established

NonGuidelineMethods 

Development and 

Validation for 

Dietary 

Formulation 

Analyses

46800215 

(2002)

Acceptable/ 

Non-Guideline

N/A Validation of analytical method for 

determining concentrations, stability 

and homogeneity of test article in 

dietary formulations.

NonGuidelineIn Vitro Dermal 

Penetration Study, 

Rat epidermis

46800247 

(2003)

Acceptable/ 

Non-Guideline

μg/cm2skin = 2570 

or 2510

Absorption rate greatest during first 30 

minutes of exposure, 0.715-0.746 

μg/cm2/hour. Absorption rates over 24 

hours were 0.077-0.091 μg/cm2/hour. 
Mandipropamid Human Health Risk Assessment D425240

Page 35 of 38

Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid

Guideline 

No. 

Study Type MRID No. 

(year)/ 

Classification 

Dose levels Results

NonGuidelineIn Vitro Dermal 

Penetration Study, 

Rat epidermis

46800251 

(2005)

Acceptable/ 

Non-Guideline

μg/cm2skin = 1.35, 

6.69, 2538

Absorption was poor (recovery of 

applied radioactivity 99-105%). 

Absorption rates over 24 hours were 

<0.04 μg/cm2/hour in concentrate 

formulation and 0.01 μg/cm2/hour in 

aqueous spray dilutions. 

NonGuidelineIn Vitro Dermal 

Penetration Study, 

Pig epidermis

46800249

(2003)

Acceptable/

Non-Guideline

μg/cm2skin = 

neat: 38,600

in acetone: 39.9

Absorption was poor (<0.01%). 

Absorption rate for neat was greatest 

during first 4 hours (0.03 μg/cm2/hour) 

and was 0.02 μg/cm2/hour over 24 

hours. Absorption rate for acetone was 

3.58% (first hour = 0.56, 24 hours = 

0.05 μg/cm2/hour). Absorption 

enhanced by acetone.

NonGuidelineIn Vitro Dermal 

Penetration Study, 

Human epidermis

46800250

(2005)

Acceptable/

Non-Guideline

μg/cm2skin = 1.35, 

6.69, 2538

Recovery of radioactivity was 95-

102%. Absorption was minimal. Over 

24 hours, absorption was <0.04 

μg/cm2/hour in the concentrate 

formulation and ≤0.001 μg/cm2/hour in 

the aqueous spray dilutions.

B.2.3 Immunotoxicity

Immunotoxicity study in mice.

In an immunotoxicity study (MRID 48771701), Mandipropamid (96.5% a.i., Lot No. 

SEZ2BP007) was administered to female CD-1 mice (10/dose) in the diet at concentrations of 0, 

300, 1000, or 3000 ppm (equivalent to 0, 56, 187, and 649 mg/kg bw/day, respectively) for 28 

consecutive days. A concurrent (positive control) group of 10 female mice received cyclophosphamide monohydrate (CPH) 10 mg/kg bw/day by gavage for the duration of the study. On Day 

25, all mice were immunized with sheep red blood cells (SRBC), a single intravenous (IV) 

injection 0.25 mL (dose volume of 2 × 108/mL). During the study, clinical condition, 

bodyweight, food and water consumption were evaluated. At sacrifice, blood was collected for 

the determination of anti-SRBC specific IgM, and the liver, thymus, and spleen were removed 

and weighed. The anti-SRBC IgM concentration was measured with Enzyme Linked 

Immunosorbent Assay (ELISA).

The positive control group treated with cyclophosphamide (CPH) had one death on Day 3 but the 

cause was unable to determine. There were no treatment related clinical signs of toxicity or 

effects on body weight, food intake, or organ weights. The positive control group had 

statistically significant decreased (p< 0.05) body weight throughout the study, and the terminal 

body weight gain was ~50% of the concurrent control. The average absolute spleen weight of

CPH-treated mice was decreased by 16% at study termination, but there was no difference in 

relative spleen weight when compared to the controls. 
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The systemic NOAEL was 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose tested. 

A systemic LOAEL was not established.

There were no statistically significant decreased in anti-SRBC specific IgM levels in the in 

treated groups when compare to the vehicle control group. High inter-individual variability was 

noted in all the treatment groups as well as in the control group. Evaluation of the individual 

animal data of this study did not show any trend or distribution that would demonstrate 

significant suppression of anti-SRBC antibody response. Positive control group had 91% 

decreased in the IgM response. This confirmed the ability of the test system to detect immunosuppressive effects and confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database 

for mandipropamid does not reveal any evidence of immunotoxicity. The overall weight of 

evidence suggests that the chemical does not directly target the immune system. Under HED 

guidance a NK cell activity assay is not required at this time.

The immunotoxicity NOAEL was 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose 

tested. Immunotoxicity LOAEL was not established.

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline
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Appendix C. Physical/Chemical Properties

Table A.C. Physical and chemical Properties of the Technical Grade of Mandipropamid.

Parameter Value Reference

Melting point/range 96.4-97.3oC MRID 46800006 

(100-REIR.doc, S. 

Mathur, 

22/MAY/2007)

Molecular formula/weight C23H22ClNO4 / 411.9

pH 6-8 at 25oC (1% aqueous dispersion)

Density 1.24 x 103 kg/m3at 22oC

Water solubility (25°C) 4.2 mg/L 

Solvent solubility (25°C) n-hexane 42 mg/L

n-octanol 4.8 g/L

toluene 29 g/L

methanol 66 g/L

ethyl acetate 120 g/L

acetone 300 g/L

dichloromethane 400 g/L

Vapor pressure <9.4 x 10-7 Pa at 25°C or <7.0 x 10-9 mmHg

Dissociation constant, pKa No dissociation constant in the pH range of 1 to 

12

Octanol/water partition coefficient, 

Log(POW)

3.3 at 25oC
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Appendix D. Review of Human Research

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, listed below, have been 

reviewed for ethical conduct. The studies were considered appropriate for use in risk 

assessments.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 

1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and 

the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational 

Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection 

Agency. Released June 21, 2011.