Mandipropamid Human Health Risk Assessment D414944

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: Aug 27, 2013

SUBJECT: Mandipropamid: Revised Human Health Risk Assessment For New Uses On Basil, 

Ginseng and Snap Beans, as Well as Crop Group Expansions for Fruiting Vegetable; Small Fruit, 

Vine Climbing, Except Fuzzy Kiwifruit; and Bulb Onion and Green Onion Subgroups. 

PC Code: 036602 DP Number: D414944

Decision No.: 472747 Registration No.: 100-1254

Petition No.: 2E8126 Regulatory Action: Section 3 

Risk Assessment Type: Single Chemical 

Aggregate

Case No.: 7058

TXR No.: NA CAS No.: 374726-62-2

MRID No.: None 40 CFR: §180.637

FROM: Dennis McNeilly, Chemist and Risk Assessor

Jaime D’Agostino, Toxicologist

William T. Drew, Chemist

Zaida Figueroa, Industrial Hygienist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Michael A. Doherty, Ph.D., Chemist

Christina Swartz, Chief

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Laura Nollen/Barbara Madden, RM 05

Risk Integration, Minor Use, Emergency Response Branch

Registration Division (7505P)

This document is the same as D409103, except it was revised to include the Toxicity Profile Tables

in Appendix B2.
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Table of Contents

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

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

2.1 Data Deficiencies ................................................................................................................ 6

2.2 Tolerance Considerations.................................................................................................... 6

2.2.1 Enforcement Analytical Method.................................................................................. 7

2.2.2 Recommended Tolerances........................................................................................... 7

2.2.3 Revisions to Petitioned-For Tolerances....................................................................... 7

2.2.4 International Harmonization ........................................................................................ 8

2.3 Label Recommendations..................................................................................................... 8

3.0 Introduction............................................................................................................................. 9

3.1 Chemical Identity ................................................................................................................ 9

3.2 Pesticide Use Pattern........................................................................................................... 9

3.3 Anticipated Exposure Pathways........................................................................................ 10

3.4 Consideration of Environmental Justice ........................................................................... 11

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

4.1 Summary of Toxicological Effects ................................................................................... 12

4.2 Safety Factor for Infants and Children (FQPA Safety Factor).......................................... 13

4.2.1 Completeness of the Toxicology Database................................................................ 13

4.2.2 Evidence of Neurotoxicity ......................................................................................... 13

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ............ 14

4.2.4 Residual Uncertainty in the Exposure Database........................................................ 14

4.3 Toxicity Endpoint and Point of Departure Selections....................................................... 14

5.0 Dietary Exposure and Risk Assessment ............................................................................... 16

5.1 Residues of Concern Summary and Rationale.................................................................. 16

5.2 Food Residue Profile......................................................................................................... 17

5.2.1 Crop Field Trials (860.1500) ..................................................................................... 18

5.2.2 Field Rotational Crops (860.1900) ............................................................................ 19

5.2.3 Processed Food and Feed (860.1520)........................................................................ 20

5.3 Water Residue Profile ....................................................................................................... 20

5.4 Dietary Risk Assessment................................................................................................... 21

5.4.1 Description of Residue Data Used in Dietary Assessment........................................ 21

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................... 22

5.4.3 Acute Dietary Risk Assessment................................................................................. 22

5.4.4 Chronic Dietary Risk Assessment ............................................................................. 22

5.4.5 Cancer Dietary Risk Assessment............................................................................... 22

5.4.6 Summary Table.......................................................................................................... 22

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ....................................... 23

6.1 Residential Bystander Post-application Inhalation Exposure ........................................... 23

6.2 Spray Drift......................................................................................................................... 23

7.0 Aggregate Exposure/Risk Characterization.......................................................................... 24

7.1 Acute & Chronic Aggregate Risk ..................................................................................... 24

7.2 Short- and Intermediate-Term Aggregate Risk................................................................. 24

8.0 Cumulative Exposure/Risk Characterization........................................................................ 24

9.0 Occupational Exposure/Risk Characterization ..................................................................... 25

10.0 References............................................................................................................................. 30
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Appendix A. International Residue Limits..................................................................................... 31

Appendix B. Toxicology Profile..................................................................................................... 32

B.1 Toxicology Data Requirements......................................................................................... 32

B.2 Toxicity Profiles................................................................................................................ 33

B.2.3 Immunotoxicity.......................................................................................................... 38

Appendix C. Physical/Chemical Properties.................................................................................... 40

Appendix D. Review of Human Research...................................................................................... 41
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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.

IR-4 has requested new Section 3 uses for mandipropamid and tolerances for residues of 

mandipropamid in/on fresh basil, dried basil, ginseng, cowpea forage, succulent beans, and for 

greenhouse tomatoes. In addition, there is a proposal to expand the current use on grapes to the 

new crop subgroup 13-07F for small fruit vine, except fuzzy kiwifruit; to expand the use on onion, 

dry bulb to bulb onion (subgroup 3-07A); to expand the use on green onions to green onion 

(subgroup 3-07B); and finally to expand the use on fruiting vegetables (crop group 8) to the 

updated fruiting vegetables crop group (8-10). Revus (EPA Reg. No. 100-1254) is a suspension 

concentrate (SC) formulation containing 23.3% ai by weight, equivalent to 2.08 lb ai/gal (250 

grams/liter).

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.

Adequate field trials were conducted on basil, ginseng, and snap beans; in addition, adequate 

greenhouse trials were submitted for tomatoes. Further, metabolism data, storage stability and 

analytical methods are considered adequate to support the recommended tolerances for both new 

uses and crop group expansions. HED notes however that the submitted data for snap beans do not 

support the proposed tolerances for succulent bean and cowpea forage. In addition a tolerance 

cannot be established for cowpea forage, a livestock feed item, due to the lack of a validated 

livestock analytical enforcement method.

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.
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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; 

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; 

engineering control for aerial applications (enclosed cockpits)) 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 ≥65,000, thus providing an ample margin to account for any uncertainties 

in the route-to-route extrapolation. 

Furthermore, since there is no difference between the occupational scenarios and the 

agronomics/practices previously assessed, the exposure resulting from mandipropamid use on the 

additional crops in the expanded crop groups are already covered by an existing risk assessment 

(D357873, M. Dow, 10/28/2008). Therefore, a new occupational assessment for the registered 

uses was not needed to support the tolerances for crop group expansion. 

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.

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 in Appendix D, have 

been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review. 

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

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

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

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

2.0 HED Recommendations

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

in Section 2.2.2.
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2.1 Data Deficiencies

No additional data are required to support HED’s currently recommended tolerances, however 

additional data would be need to support all of the proposed tolerances associated with the petition. 

The submitted snap bean data do not support the proposed tolerances in succulent beans and 

cowpea forage (ChemSAC meeting; 17 July 2013). Additional field trial data on a succulent 

shelled bean cultivar (such as lima beans) would be necessary in order to establish a tolerance in 

succulent beans. Because of the possibility of detectable residues occurring in dairy cattle 

commodities (fat, milk and liver) arising from the feeding of treated cowpea forage, the concurrent 

establishment of mandipropamid tolerances at the limit of quantitation (LOQ) in those 

commodities would be necessary. However, with no validated analytical method for enforcing 

tolerances in livestock commodities, it is not possible to establish such tolerances. Therefore, the 

proposed tolerance in cowpea forage cannot be established until a validated method for 

determining mandipropamid residues in livestock (cattle) commodities is available. Any such 

method submitted would need an independent laboratory validation (ILV). (If tolerances for 

additional livestock feed items other than cowpea forage are proposed, a livestock feeding study

should be submitted.)

Since the last risk assessment, an immunotoxicity study 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 (TXR 

#0056610, J. Alstine, 3/14/2013).

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. The submitted snap bean data do not support the proposed tolerance in 

succulent bean, and a cowpea forage tolerance cannot be established due to the lack of a livestock 

analytical enforcement method.

Notes to RD: a) When the crop subgroup 13-07F tolerance is established, then the grape tolerance 

should be deleted. b) When the crop subgroup 3-07A tolerance is established, then the tolerance 

for onion, dry bulb, should be deleted. c) When the crop subgroup 3-07B tolerance is established,

then the tolerance for onion, green should be deleted. d) According to HED’s Interim Guidance 

on Tolerance Expressions (S. Knizner; 27 May 2009), the tolerance expression for mandipropamid 

cited in 40CFR §180.637[a] should be revised to state: Tolerances are established for residues of 

mandipropamid, including its metabolites and degradates, in or on the commodities listed in the 

table below. Compliance with the tolerance levels specified below is to be determined by 

measuring only mandipropamid (4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]-α-(2-

propynyloxy)benzeneacetamide) in or on the commodity.
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2.2.1 Enforcement Analytical Method

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, except for those in cowpea 

forage and succulent beans. The recommended tolerances are listed in Table 2.2.2, below.

Table 2.2.2. Tolerance Summary for Mandipropamid.

Commodity as Proposed by 

Registrant

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Basil, fresh 30 30 Basil, fresh leaves

Basil, dried 200 200 Basil, dried leaves

Bean, succulent 0.90 None Field trial data on a succulent 

shelled bean cultivar is needed. 

Bean, snap None 0.90 The snap bean field trials support 

the establishment of this tolerance. 

Ginseng 0.3 0.30

Cowpea, forage 15 None A validated method (i.e. with an 

ILV) for residues in cattle 

commodities is needed. 

Vegetable, fruiting, group 8-10 1.0 1.0

Fruit, small, vine climbing, subgroup 

13-07F, except fuzzy kiwifruit

2.0 2.0 Fruit, small, vine climbing, except 

fuzzy kiwifruit, subgroup 13-07F.

See footnote a below.

Onion, bulb, subgroup 3-07A 0.1 0.10 See footnote b below.

Onion, green, subgroup 3-07B 7.0 7.0 See footnote c below.

* Notes: a) When the crop subgroup 13-07F tolerance is established, then the grape tolerance should be deleted. b) When the crop 

subgroup 3-07A tolerance is established, then the tolerance for onion, dry bulb should be deleted. c) When the crop subgroup 3-

07B tolerance is established, then the tolerance for Onion, green should be deleted.

2.2.3 Revisions to Petitioned-For Tolerances

Instead of the proposed tolerance in ginseng (0.3 ppm), HED recommends establishing the 

tolerance at 0.30 ppm, in order to avoid the situation where a field sample containing residues 

significantly above the tolerance (0.34 ppm, for example) would be considered non-violative. For 
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the same reason, HED recommends that the proposed tolerance of 0.1 ppm in bulb onions 

(subgroup 3-07A) be revised to 0.10 ppm.

The submitted snap bean data do not support the proposed tolerance in succulent beans. A cowpea 

forage tolerance cannot be established due to the lack of a livestock analytical enforcement 

method, and a supporting livestock analytical method ILV (See Section 2.1). Therefore, HED is 

not recommending in favor of the proposed tolerances in succulent beans and cowpea forage.

2.2.4 International Harmonization

Neither Codex nor PMRA have established MRLs for mandipropamid in any of the commodities 

associated with the proposed new uses. As such, there is no harmonization issue associated with 

Codex for the proposed new uses in the current action. PMRA and EPA are jointly reviewing the 

basil, ginseng and snap bean data in the current action, and EPA and PMRA are harmonized for 

fresh basil, dried basil, and ginseng. PMRA is establishing an MRL in edible-podded beans at 0.9 

ppm, while HED is recommending for a tolerance in snap beans at 0.90 ppm. Although the 

tolerance/MRL level is harmonized, HED cannot harmonize with PMRA on the commodity

definition, as the submitted snap bean data do not support use on all succulent beans, since no data 

were submitted for a succulent shelled bean, and/or do not meet the requirements of subgroup 6A, 

since no data were submitted for an edible-podded pea.

Both the current tolerance in crop group 8 (1.0 ppm) and the proposed tolerance in crop group 8-10 

(1.0 ppm) are harmonized with the Codex (bell and non-bell peppers) and PMRA’s (tomatoes, 

okras and peppers) MRLs. For the other crop group expansions, EPA is harmonizing with Codex, 

even though this will result in discrepancies between US tolerances and Canadian MRLs. The 

proposed tolerance of 2.0 ppm in subgroup 13-07F, translated from grape data, will be harmonized 

with the Codex MRL in grapes, but will no longer be harmonized with PMRA’s MRL of 1.4 

mg/kg in grapes. The proposed tolerance of 0.1 ppm in subgroup 3-07A, translated from dry bulb 

onion data, will be harmonized with the Codex MRL in bulb onions, but will no longer be 

harmonized with PMRA’s MRL of 0.05 ppm in various bulb onions. The proposed tolerance of 

7.0 ppm in subgroup 3-07B, translated from green onion data, will be harmonized with the Codex 

MRL in spring onions, but will no longer be harmonized with PMRA’s MRL of 4.0 ppm in various 

green onions.

2.3 Label Recommendations

Because the submitted snap bean data do not support the proposed use on all succulent beans, the 

section containing directions for use on succulent beans (“Bean, succulent”) should instead refer to 

snap beans (“Bean, snap”), and the listing of succulent bean commodities should be deleted. The 

requested use on greenhouse tomatoes listed in the proposed label is supported by the submitted 

greenhouse trial data.

A cowpea forage tolerance cannot be established due to the lack of a livestock analytical 

enforcement method, and supporting livestock analytical method ILV. Use on cowpea forage must 

not be added to the label at this time.
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3.0 Introduction

3.1 Chemical Identity

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

physicochemical properties of the technical grade mandipropamid are presented in Appendix C. 

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.

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 Pesticide Use Pattern

IR-4 has requested that new Section 3 uses of the fungicide mandipropamid be added to the label 

for Revus 2.08SC (EPA Reg. No. 100-1254). The proposed new uses would be on basil, cowpea 

forage, ginseng, succulent beans, and greenhouse tomatoes. The proposed use directions are 

summarized in Table 3.2.

Table 3.2. Summary of Directions for Use of Mandipropamid. 

Application Type; 

Equipment1

Use 

Rate

(lb ai/A)

Max. Uses 

Per Season

Max. Seasonal 

Use Rate

(lb ai/A)

PHI2

(Days)

Use Directions, Application Timing, 

and Limitations3

Basil

Foliar; any ground 

or aerial equipment.

0.09 -

0.13

4 0.52 1 RTI4of 7-10 days. 

Ginseng

Foliar; any ground 

or aerial equipment.

0.09 -

0.13

4 0.52 2 RTI of 7-10 days. 

Succulent Beans (Cowpea Forage)

Cl

O

HC

O

N

H

O

CH3

O

CH
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Table 3.2. Summary of Directions for Use of Mandipropamid. 

Application Type; 

Equipment1

Use 

Rate

(lb ai/A)

Max. Uses 

Per Season

Max. Seasonal 

Use Rate

(lb ai/A)

PHI2

(Days)

Use Directions, Application Timing, 

and Limitations3

Foliar; any ground 

or aerial equipment.

0.09 -

0.13

4 0.52 1 RTI of 7-10 days. 

Greenhouse Tomatoes

Foliar; any ground 

or aerial equipment.

0.09 -

0.13

4 0.52 1 RTI of 7-10 days. May be applied via 

chemigation. 

1. For ground application, apply in a minimum of 10 gallons of water per acre (GPA), unless specified otherwise on 

the label. Do not apply through any ultra-low volume (ULV) spray system. For aerial application, use only on 

crops where aerial applications are indicated. Apply in a minimum of 5 GPA, unless specified otherwise on this

label. Do not apply through any ULV spray system. For chemigation, use only on crops where chemigation is 

specified on the label. Apply no more than 2 sequential applications unless otherwise stated in the crop-specific 

section. Do not use in transplant production. 

2. PHI = Pre-Harvest Interval. 

3. Begin applications prior to disease development. Use the shorter interval and/or higher rates under high pressure, or 

when conditions are conducive to disease. The addition of a spreading/penetrating type adjuvant such as a non-ionic 

based surfactant (NIS) or crop oil concentrate (COC) or blend is recommended. 

4. RTI = Re-Treatment Interval. 

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, 

flaggers 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, chemicalresistant gloves made of any waterproof material, shoes plus socks.

Conclusions: The use directions are adequate to allow for evaluation of the residue data. 

However, as the submitted snap bean data do not support the proposed use on succulent beans, the 

label section containing directions for use on succulent beans (“Bean, succulent”) should instead 

refer to snap beans (“Bean, snap”), and the listing of all other succulent bean commodities should 

be deleted. A cowpea forage tolerance cannot be established due to the lack of a livestock 

analytical enforcement method, and supporting livestock analytical method ILV. 

3.3 Anticipated Exposure Pathways

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

proposed tolerances for mandipropamid on basil, ginseng, succulent beans (including snap

beans), and greenhouse tomatoes, as well as addition of the use on basil, ginseng, succulent 

beans, and greenhouse tomatoes to the Revus®label. 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 
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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 pathways 

based on the existing uses of mandipropamid, and also considers the potential for increased 

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

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 (D365919, D. Rate, 

7/8/2009).

3.4 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 postapplication 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 July 2009, D365919). Since the last 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.
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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), 

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. The rate of absorption was higher in females resulting in a blood Tmax 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 parent and the following metabolites were detected at ≥5% of the 

applied dose at 3 and/or 300 mg/kg: NOA 458422, NOA 458422 glucuronide, SYN 534133 and 

CGA 380778. 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 
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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 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. The major 

metabolic transformations involved loss of one or both propargyl groups followed by

glucuronidation and O-demethylation. 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).
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4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

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 (D365919, D. Rate, 7/8/2009).
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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

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.

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.
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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

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.

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 uses, except for 

the use on cowpea forage which is a feed item for dairy cows. There are no poultry feed items 

associated with the proposed uses.

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, 
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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 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.

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

plantback interval. 

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 significant livestock feed item associated with the proposed new uses is cowpea forage, 
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which is not fed to beef cattle, swine or poultry. It is fed to dairy cattle at up to 20% of the diet in 

select locations, or as seasonally available. At the proposed tolerance level of 15 ppm, the 

calculated dietary burden to dairy cattle is 10 ppm (the contribution to dietary burden from the 

only current feed items, potato culls and processed waste, is negligible at 0.025 ppm). 

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 

(3-3.6X the dietary burden to dairy 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). Based on the highest detected residue of 0.019 ppm in goat fat, anticipated residues from 

feeding cowpea forage containing mandipropamid at the recommended tolerance level of 15 ppm 

would be roughly 0.006 ppm. HED’s ChemSAC recommended against establishing a tolerance in 

cowpea forage, due to the potential for finite residues in cattle commodities (fat, milk and liver). 

Establishing a tolerance in cowpea forage would necessitate the concurrent establishment of 

tolerances at the LOQ in cattle fat, milk and liver, which would require a suitable method for the 

enforcement of tolerances in these commodities. However, with no validated method for enforcing 

tolerances in cattle commodities, it is not possible to establish tolerances in them (minutes from 

ChemSAC meeting of 17 July 2013). The proposed tolerance in cowpea forage cannot be 

established until a validated method for determining mandipropamid residues in livestock (cattle) 

commodities is available.

5.2.1 Crop Field Trials (860.1500)

D409363; W. Drew; Aug 27, 2013.

Adequate field trial data were provided to support the proposed tolerances for residues in basil and 

dried basil. The residue data in snap beans are adequate to support tolerances in snap beans, but 

not in all succulent beans (ChemSAC meeting; 17 July 2013); if tolerances in succulent beans are 

desired, then additional field trial data on a succulent shelled bean cultivar (such as lima beans) 

will be necessary. Adequate field trial data were submitted to support the use on ginseng, as well 

as on greenhouse tomatoes. The additional data for tomatoes grown in a greenhouse do not 

indicate the need for any change to the existing tolerances. In all cases, the studies were 

considered to have been conducted in geographically representative locations (except greenhouse 

tomatoes for which no location is specified), with application rates, re-treatment intervals and preharvest intervals (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 Residue Data from Crop Field and Greenhouse Trials with Mandipropamid. 

Commodity Total 

Use Rate

(lb ai/A)

PHI 

(Days)

Residue Levels (ppm)

n Min. Max. LAFT* HAFT* Median Mean Std. Dev.

Basil (field and greenhouse)

Fresh stems 

and leaves

0.520-

0.528

1 1213.5 19 - - 9.0 9.3 4.8

6

2

- - 3.6 19 8.8 9.4 5.0

Dried stems 

and leaves

0.520-

0.528

1 6

1, 2 36 91 - - 63 63 20

Ginseng (field only)

Mandipropamid

Roots 0.521-

0.547

2 8

1

0.0222 0.167 - - 0.0586 0.0717 0.0551

4

2

- - 0.0271 0.119 0.0705 0.0718 0.0475

Metabolite SYN500003

Roots 0.521-

0.547

2 8

1

<0.005 <0.005 - - <0.005 <0.005 -

4

2

- - <0.005 <0.005 <0.005 <0.005 -

Snap bean (field only)

Pods with 

seed

0.490-

0.540

1 2010.0858 0.761 - - 0.210 0.256 0.175

102- - 0.10 0.58 0.220 0.256 0.164

Plants with 

pods

0.490-

0.540

1 2011.24 9.84 - - 4.15 4.14 2.34

102- - 1.27 9.27 4.35 4.14 2.36

Tomato (greenhouse only)

Fruit 0.480-

0.651

1 8

1

0.045 0.339 - - 0.147 0.168 0.101

4

2

- - 0.059 0.289 0.115 0.168 0.105

* LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial. 

1. n = total number of samples. 

2. n = total number of field trials.

For the crop group expansions, the requested tolerances are supported by existing data. These 

include Vegetable, fruiting, crop group 8-10; Fruit, small, vine climbing, except fuzzy kiwifruit, 

subgroup 13-07F; Onion, bulb, subgroup 3-07A; and Onion, green subgroup 3-07B. Concomitant 

with the establishment of the new crop subgroup tolerances, the grape, dry bulb onion and green 

onion tolerances should be deleted.

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 (<0.01 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.
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5.2.3 Processed Food and Feed (860.1520)

Because there are no processed commodities for ginseng or succulent beans, processing studies are 

not required for these RACs. The processed commodity for basil is dried basil, for which adequate 

data were provided in support of the petition. A processing study is not needed for tomatoes, as 

this requirement was addressed in a previous document (D328534; D. McNeilly; August 28, 

2007). 

5.3 Water Residue Profile

D409108; R. Shamblen; Jul 9, 2013.

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 (PRZMGW 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. Previous drinking water assessments 

calculated separate half-lives for the parent compound and two degradates of concern, for which 

exposure was estimated with separate model runs. Simple addition of the exposure estimates for 

mandipropamid and it’s degradates of concern was used to generate estimated drinking water 

concentrations. Previous authors acknowledge this approach is conservative because the exposure 

estimates may not be temporally coincident. The TR method, however, tallies the parent 

compound and its degradates of concern prior to calculating a Total Residue half-life.

The Environmental Fate and Effects Division (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 estimated drinking water 

concentrations (EDWC) 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

Two previous Tier 1 drinking water assessments of mandipropamid produced nearly identical 

exposure estimates (USEPA, 2007; and, 2011). Results of multiple FIRST (v.1.1.0) model 

scenarios indicated EDWCs in surface waters ranging from 7 to 36 μg/L for chronic and acute 

exposures. Ground water exposure estimates in both assessments were about 2.4 μg/L when 

calculated by SCI-GROW (v. 2.3). PRZM-GW (v. 1.01) was not used in the 2007 and 2011 

assessments.

Differences between the previous two and current drinking water exposure assessments reveal that 

ground water exposure concentrations decreased by more than a factor of 13 (as determined using 

the SCI-GROW model), whereas acute surface water exposure concentrations nearly doubled. 

These differences are likely attributed to a variety of recent changes incorporated into the drinking 

water assessment (see D409108, R. Shamblen, 7/9/2013).

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

D412238; D. McNeilly; Aug 27, 2013.

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 
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chronic exposure) drinking water estimate of 79 ppb was provided by the Environmental Fate and 

Effects Division (EFED) and directly incorporated into the chronic assessment.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary assessment is based on 100% crop treated 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 46% of the cPAD (Table 5.4.6). The general U.S. population utilizes 27% 

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

D412238; D.McNeilly; Aug 27, 2013.

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

below in Table 5.4.6.
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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

0.013475 27

N/A N/A

All Infants (< 1 year old) 0.011653 23

Children 1-2 years old 0.022893 46

Children 3-5 years old 0.020342 41

Children 6-12 years old 0.012364 25

Youth 13-19 years old 0.009617 19

Adults 20-49 years old 0.013459 27

Adults 50-99 years old 0.013425 27

Females 13-49 years old 0.013293 27

N/A = Not applicable.

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

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

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

inhalation toxicity (Toxicity Category IV), low vapor pressure (<7.0 x 10-9 mm Hg at 25oC), and 

the low proposed use rate (0.13 lb ai/A). However, 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 Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 20101. The Agency is in the process of evaluating 

the SAP report and may, as appropriate, develop policies and procedures to identify the need for 

and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's 

risk assessments. If new policies or procedures are developed, the Agency may revisit the need for 

a quantitative post-application inhalation exposure assessment for mandipropamid.

6.2 Spray Drift

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

This is particularly the case with aerial applications allowed on mandipropamid labels, but, to a 

lesser extent, could also be a potential source of exposure from ground application methods

employed for mandipropamid. The Agency has been working with the Spray Drift Task Force, 

EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to 

develop the best spray drift management practices (see the Agency’s Spray Drift website for 

 

1 Available at: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemicalby-chemical basis, the Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift with specific products 

with significant risks associated with drift.

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

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

exposure assessment was performed for flaggers. 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 
Mandipropamid Human Health Risk Assessment D414944

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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, 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

D412239; Z. Figueroa; Aug 27, 2013

Based on the anticipated use patterns and current labeling, types of equipment and techniques that 

can potentially be used, occupational handler exposure is expected from the proposed uses. The 

quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

Mixer/Loaders

1. Mixing/loading liquid concentrates to support aerial applications,

2. Mixing/loading liquid concentrates to support chemigation applications,

3. Mixing/loading liquid concentrates to support groundboom applications,

Applicators

4. Applying sprays with aircraft (enclosed cockpit),

5. Applying sprays with groundboom equipment, 

Flaggers

6. Flagging to support aerial spray applications, and

Mixer/Loader/Applicators

7. Mixing/loading/applying liquid concentrates to support mechanically-pressurized handgun

applications.
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The maximum single application rates for the proposed uses ranged from 0.09-0.13 lb ai/acre. The 

inputs for area treated were based on information in ExpoSAC Policy 9.1.

Based on the proposed use pattern, directions (e.g., 2-4 applications per season with a minimum 7-

10 day spray interval) 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, short-term exposure and risk estimates are considered to be protective of intermediateterm exposure and risk. Long-term exposures are not expected; therefore, a long-term assessment 

was not conducted.

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.

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

(MOEs > 100 for inhalation) at some level of risk mitigation (i.e., baseline attire with no respirator; 

engineering control for aerial applications (enclosed cockpits)). No additional PPE 

recommendations are needed on the proposed label.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for human 

flaggers where appropriate, agricultural aviation has changed dramatically over the past two 

decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their 

membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from 

the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide 

applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent 

(2012) NAAA survey. The Agency will continue to monitor all available information sources to 

best assess and characterize the exposure potential for human flaggers in agricultural aerial 

applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available reflect

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 
Mandipropamid Human Health Risk Assessment D414944

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pilots are not required to wear protective gloves duration the application. With this level of 

protection, there are no risk estimates of concern for applicators.
Mandipropamid Human Health Risk Assessment D414944

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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Mandipropamid.

Exposure Scenario Crop or Target

Inhalation Unit Exposure (μg/lb ai)1 Maximum

Application Rate 2

Amount or Area 

Treated3

Inhalation

Mitigation Level Dose (mg/kg/day)4 MOE5

Mixer/Loader

M/L Liquids for Aerial 

Applications

[AHETF/PHED]

Basil, Snap bean, 

Ginseng

0.219

(Baseline; No Respirator) 0.13 350 A 0.000125 330,000

M/L Liquids for 

Chemigation

[AHETF/PHED]

Basil, Snap bean, 

Ginseng

0.219

(Baseline; No Respirator) 0.13 350 A 0.000125 330,000

M/L Liquids for 

Groundboom Applications

[AHETF/PHED]

Basil, Snap bean, 

Ginseng

0.219

(Baseline; No Respirator) 0.13 80 A 0.0000285 1,400,000

Applicator

Sprays for Aerial 

Applications

[PHED]

Basil, Snap bean, 

Ginseng

0.0049

Engineering control (enclosed 

cockpits)

0.13 350 A 0.0000028 15,000,000

Sprays for Groundboom 

Applications

[AHETF/PHED]

Basil, Snap bean, 

Ginseng

0.34

(Baseline; No Respirator) 0.13 80 A 0.000044 930,000

Flagger

Sprays for Aerial 

Applications

[PHED]

Basil, Snap bean, 

Ginseng

0.35

(Baseline; No Respirator) 0.13 350 A 0.000199 210,000

Mixer/Loader/Applicator

M/L/A Liquids for 

Mechanically-pressurized 

Handgun Applications

[PHED]

Basil, Snap bean, 

Ginseng

3.9

(Baseline; No Respirator) 0.013 1,000 gals 0.000634 65,000

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2013); Level of mitigation: Baseline; Eng. control for aerial applications (enclosed cockpits).

2. Based on registered or proposed label (EPA Reg. No. 100-1254).

3. Exposure Science Advisory Council Policy #9.1.

4. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/A) × Area Treated (A/day) ÷ BW (80 kg).

5. Inhalation MOE = Inhalation NOAEL (41 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). LOC=100.
Mandipropamid Human Health Risk Assessment D414944

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Occupational Post-Application Assessments

Dermal

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 post-application 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

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

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

inhalation toxicity (Toxicity Category IV), low vapor pressure (<7.0 x 10-9 mm Hg at 25oC), and 

the low proposed use rate (0.13 lb ai/A). However, there are multiple potential sources of postapplication 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, 20102. The Agency is in the process of evaluating 

the SAP report as well as available post-application inhalation exposure data generated by the 

ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, 

subsequently, the way to incorporate occupational post-application inhalation exposure into the 

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

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

for mandipropamid.

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

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure 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.

 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Mandipropamid Human Health Risk Assessment D414944

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10.0 References

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

Assessment for the Section 3 Registration Action on Fresh Basil, Dried Basil, Ginseng, Fruiting 

Vegetable (Crop Group 8-10); Small Fruit, Vine Climbing (Crop Subgroup 13-07F), except 

Fuzzy Kiwifruit; Snap Bean, Bulb Onion (Crop Subgroup 3-07A), and Green Onion (Crop 

Subgroup 3-07B). D412238, D.McNeilly; Aug 27, 2013.

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

Basil, Snap Bean, and Ginseng, and the Request to Update Several Existing Crop Groups with 

Revised Crop Group Definitions. D412239, Zaida Figueroa; Aug 27, 2013.

Mandipropamid. Petition to Establish Permanent Tolerances (and Section 3 Registration) for 

Residues Resulting from Use of the Fungicide on Basil, Succulent Beans, Cowpea Forage, 

Ginseng and Greenhouse Tomatoes; to Update Fruiting Vegetables Group 8 to Group 8-10; to 

Extend the Tolerance in Grapes to Subgroup 13-07F, the Tolerance in Dry Bulb Onions to 

Subgroup 3-07A, and the Tolerance in Green Onions to Subgroup 3-07B. Summary of Analytical 

Chemistry and Residue Data. D409363, W. Drew; Aug 27, 2013.

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. Section 3 Registration Request to Register New Uses on Hops and Tobacco 

and Confirmatory Residue Analytical Method for Determination of Residues in Crop Matrices. 

Summary of Analytical Chemistry and Residue Data.; D348229, D352322, D. Rate; 11 

December 2008. 

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. 

Ecological Risk Assessment for the Mandipropamid Section 3 New Use on Outdoor/Non-food 

Ornamentals and Listed Vegetables Grown for Transplant and Retail Sale to Consumers; 

D382369; C. Wendel; 26 July 2011. 
Mandipropamid Human Health Risk Assessment D414944

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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 MRL4

(mg/kg)

Basil, fresh leaves 30

Basil, dried leaves 200

Bean, succulent

Bean, snap

NA

0.9

Ginseng 0.30

Cowpea, forage NA

Vegetable, fruiting, 

group 8-10

1.0 Bell peppers, eggplants, groundcherries, non-bell peppers, 

okras, pepinos, pepper hybrids, 

tomatillos, tomatoes

1 Bell peppers, 

non-bell peppers

1

Dried chili 

peppers

10

Tomatoes 0.3

Fruit, small, vine 

climbing, except fuzzy 

kiwifruit, subgroup 

13-07F

2.0 Grapes 1.4 Grapes 2

Onion, bulb, subgroup 

3-07A

0.10 Chinese onions, daylilies, dry 

bulb onions, fritillaria, bulbs, 

garlic, great-headed garlic, lilies, 

pearl onions, potato onions, 

serpent garlic, shallot bulbs

0.05 Bulb onions 0.1

Onion, green, subgroup 

3-07B

7.0 Beltsville bunching onions, 

elegans hosta, fresh Chinese 

chive leaves, fresh chive leaves), 

fresh onions, fritillaria leaves, 

green onions, kurrats, lady's 

leek, leeks, macrostem onions, 

shallot leaves, tree onion tops, 

Welsh onion tops, wild leeks

4 Spring onions 7

Completed: M. Negussie, 27 June 2013. 

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. Po = post-harvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as a processed commodity of post-harvest treated stored wheat. (Fat) = to 

be measured in the fat portion of the sample. MRLs indicated as “proposed” have not been finalized by the 

CCPR and the CAC. 
Mandipropamid Human Health Risk Assessment D414944

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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 D414944

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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 D414944

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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

870.3100 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 D414944

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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

870.3800 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
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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 D414944

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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

870.7485 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 D414944

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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

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. 
Mandipropamid Human Health Risk Assessment D414944

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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
Mandipropamid Human Health Risk Assessment D414944

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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 103kg/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 10-7Pa 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
Mandipropamid Human Health Risk Assessment D414944

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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.