Mandip r opamid H uman H ealt h R i sk Assessment 0425240



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D .C. 20460



### MEMORANDUM

D ate : Fe bru ary 24, 20 1 6 OFFICE OF C HEMI CA L SAFETY AND POLLUTIO N PREVENTION

SUBJECT: Mand ipr opa mid : H uman H ea l t h Ri s k Assess m e nt F o r A m e nd e d Use of th e Fun g i c ide on Po t a t o , to R ep la c e the E st abli s h e d To l e ran ce in Tub e rou s and Co rm V eg etab l e Su b g roup IC

, and t o R ev i se t h e Es t a bli s h e d T o l era n ce in P o tato W et P ee l.

PC C o de: 036602

D ec i s i o n No.: 497834

, <1'!11 41,**'11 .ss',**  "1•7311 0
Petition No.: 4F8329
R i s k A s se s sment T y p e: Single Chemical Aggregate
TXRNo.: NA
MRlD No.: No n e DP N u mber: 0 425240, 0425239

, 0425241,
0 425242
R eg i s tr a tion N o.: I 00-1254
R eg ul at o r y Actio n : Section 3
C a se No.: 7058
C A S No

. : 374726-62-2
40 C FR: § 18 0.637



### FROM: E li zabe th Ho lm an, Ph ys i ca l**~c ~**  Ri s k Assessor**~ ~**  Wi lli am T. Dr ew, Chem i s t 

# W !**~** Ja im e D ' Agost i no, Ph

. D

., Tox i colog i s t 

# 12 /::-.:--..__,

Ri sk Assessment B r anch 11**~c:::.c:s:::-** ---**~** Healt h Effects Div i s i on (7509 P )

Brid ge t B o b ow i ec, Biol og i s t

# ~**~** Ri sk Assess m e nt Branch VI

H ea lth Effec t s Di v i s ion ( 7 5 0 9P)



### THROUGH: C hri st i na Swartz, C hi ef

# ~Ar-­ Ri sk Assess m ent B ranc h II

H ea lth Effec t s Div i s ion (7509 P )

TO: Tony K i sh a n d S h aun t a Hill

, RM T ea m 22

F un g i c id e Br anc h ( FB )

R eg i stra t io n Di v i s ion (RD ), 7 5 0 5 P

Page I of 3 8Mandipropamid Human Health Ri s k Assessment 0 425240

Tab l e of Co n tents


### 1 .0 Executive S ummar y

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

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

.............................................................................................................. 5
2

. 2 Tolerance Considerat ion s

... . .... . . ... ... ....................................................... . ........... .... .. ..... .... 5
2 .2.1 Enforcement Analytical Method

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

......................................................................................... 6
2.2.3 Revisions to Petition ed -For Tolerances

..................................................................... 6
2.2.4 In te rnational Harmoniza tion

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

........................................... . ... . ... .. .. .. .. . ... . .. . .. .. .. . .. . .. . .. . .......... . .. . .. 7
3 .0 Introduction

................ .................................... ................... . ... .. .. . ... . ... . .. . ... . .. . .. . .. . .. . .. . .... . .. . .. . . . 

### ?
3 .1 Chemical Id ent ity

... .. ... .. ... . .. .......... . ............................................................ ....................... 7
3.2 Pesticide Use Pattern

................................. . ......... . .... . ... . ... .. .. . ... . ... . .. . ... . .. . .. . .. . .. . .. . .. . .. . .. . . . .. . 8
3.3 Anticipated Exposure Pathways

............... .. ... . .... .. ... . ... . .... . .. .. ... . .. . .. .. .. . ... . .. . .. . .......... . .. . ..... . 9
3 .4 Consideration of Environmental Justice

....................................................... . ................. 10
4.0 Hazard Characterization and D ose -R esponse Assessment

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

... . .... .. ... . .......... . .......................... . ............................. 10
4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

...... . ...... . .. . ...... . .. . .... . ....... .12
4.2.1 Comp l eteness of the Toxicology Database

.............................................................. 1 2
4.2.2 Evidence of Neurotoxicity

. .. .... .. ... .. ... .. ... .. ... .. ... .. .. .. ... . ... . .. .. .. .. .. . .. . .. . ..... . ..... . .. . .. . .. . .. . 12
4.2.3 Evide nc e of Sensitivity/Suscept ibili ty 

### in the Developing or Young Animal

.......... 12
4.2.4 Re s idu a l Uncertainty 

### in the Exposure Database

..................................................... .1 3
4

. 3 Toxicity Endpoint and Point of Departure Selections

..................................................... 13
5.0 Dietar y Exposure and Risk Assessment

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

.. . ... .. ... . ....... . ....... . .................................... 1 5
5.2 Food Residue Profile

.. ... . ... .. .... . ... .. .... . .... .. ... .. ... .. ... . .... . ... . ... . ... . ... . ...... . ............................. 16
5

. 2.1 Crop Field Trials (860.1500)

.......................................................................... . ....... . 16
5.2.2 Field Rotational Crops (860.1900)

.......................................................................... 18
5.2.3 Processed Food and Feed (860 .1520 )

.. .... . .... . ... . .... . ... . ... . ......................................... 18
5.3 Water R es idu e Profil e

.. ... .. ... .. .... . ... . ..... . ............................ . .. .. .. . ... . .. .. .. . .. . .. . ... . . . .. . .. . .. . . . .. . . 19
5.4 Di etary Risk Assessment.

................................................................................................ 20
5.4.1 Description of Re sidue Data Used in Dietary Assessment..

.. .. . .. .. ..... . .. . .. . .. . .... . ....... 20
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................................. 21
5.4 .3 Ac ut e Dietary Risk Assessment

................................... . ...... . ... . ... . .. . .. . ..... . ........ . .. . .. . . 2 1
5.4.4 Chronic Dietary Risk Assessment

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

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

.................................................................................................. . .. . .. 21
6.0 Residential (Non-Occ upational ) Exposure/Risk Characterization

..................................... 22
6.1 Residential B ystander P ost -applic ation Inhalation Exposure

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

........................................................................................ . .. . ... . .. . .. . .. . .. . .. . .. . . . .. . 22
7 .0 Aggregate Exposure / Ri sk C harac ter iza tion

. .. ....... ..................... ... . ...... ............................. .. 23
7 .1 Acute & 

### Chronic Aggregate Risk

.. . ..... . ... .. .... . ... .. ... .. ... . ... . ... . ... . .. . ... . ............................... 23
7

. 2 Short- and Intermediate-Term Aggregate Risk

.......................................................... . .... 23
8

. 0 Cumulat ive Exposure/Risk C haract e rization

.... .. ... .. ... .. ..................................................... .23
9.0 Occupational Exposure / Risk Characterization

........................... . ... . .. .. .. . .. . .. . .. . .. . .. . .. . .. . ....... 24
10.0 R efe r e nce s

. .. .. .. .. .. .. ... . ... .. ... .. ... .. ... .. ... .. ... ... ... .. ... .. .... . ... .. ... .. .................................................. 27

Pa ge 2 o f38Mandipropamid Human Health Risk Assessment D4252 40

Page 3 of 38 

### Appendix A. International Residue Limits

................................ ................................ ................... 28 Appendix B. Toxicology Profile

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

................................ ................................ ....................... 29
B.2 Toxicity Profiles

................................ ................................ ................................ .............. 30
B.2.3 Immunotoxicity

................................ ................................ ................................ ........ 35 Appendix C. Physical/Chemical Properties

................................ ................................ .................. 37 Appendix D. Review of Human Research

................................ ................................ .................... 38Mandipropamid Human Health Risk Assessment D4252 40

Page 4 of 38 

### 1.0 Executive Summary

Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, Inc. for the control of foliar oomycete pathogens in a range of crops including Plasmopara
viticola in grapes, Phytophthora infestans in potatoes and tomatoes, and Pseudoperonospora
cubensis in cucurbits. Permanent tolerances are established for residues of mandipropamid in or on a variety of plant commodities, at levels ranging from 0.0 1 ppm in tuberous and corm

v egetable subgroup 1C

, to 20 0 ppm in dried b asil lea ves ( 40CFR §180.637[a]).

Syngenta Crop Protection has submitted a petition requesting amended use on potatoes to add seed piece treatment. In conjunction with the requested amended use , Syngenta has proposed the
establishment of a permanent tolerance f or residues of mandipropamid in/on potato at 0.08 ppm. In addition, Syngenta has requested amendment of the existing tolerance in potato wet peel to 0.12 ppm, and revision of the existing commodity definition for tuberous and corm vegetable subgroup 1C to read “vegetable, tuberous and corm, subgroup 1C (except potato).”

The toxicology database is adequate

. Mandipropamid has low acute toxicity via oral, dermal, and inhalation routes; and no dermal or eye irritation (Toxicity Category IV). It is not a s kin
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 ap propriate for assessing acute risks , including acute dietary exposure

. Similarly, there are no effects associated with dermal exposure. O nly inhalation and chronic dietary endpoints and points of departure have been selected for risk assessment

.

The dat a submitted in support of the current action (P etition #4F8329) along with previously reviewed data, are adequate for purposes of risk assessment and tolerance assessment for the proposed revised use pattern on potato under review. Maximum residues of man dipropamid are expected to occur at relatively low levels (<0.0 9 ppm in subgroup 1C , and <0 .15 ppm in potato wet peel ) from the revised use pattern combining seed piece treatment and foliar use on potato

,
as proposed in the current petition. Further, meta bolism data, storage stability and analytical methods are considered adequate to support the recommended tolerances.

A screening

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

- level residues and 100% of crop treated for all include d commodities

, and conservative assumptions with respect to mandipropamid residues in drinking water sources, indicates that chronic dietary risk s

are below HED ’s level of concern for all population subgroups. There are no uses of mandipropamid that would result in residential exposure; therefore, chronic dietary is the only aggregate scenario, and there are no aggregate risks of concern.

Occupational risk estimates associated with th e new uses are also below HED ’s level of concern.
No chemical

- specific handler exposure data were submitted in support of this registration;Mandipropamid Human Health Risk Assessment D4252 40

Page 5 of 38 

### therefore, HED relied on surrogate data in accordance with standard policies. Default assumptions established by the HED Science Advisory Council for Exposure (Expo SAC) 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 baselin e (i.e., bas eline attire with no respirator ) and, therefore , are not of concern , and no additional personal protective equipment (PPE) will be needed on the proposed label

. Although a point of departure from an oral study
was used to assess handler inhala tion risk, the calculated MOEs are all ≥ 6,4 00, thus providing an ample margin to account for any uncertainties in the route

- to

- route extrapolation.

Occupational post

- application risk estimates for agricultural workers following treatments to agricultu ral crops were not assessed, since no dermal endpoint of concern was identified. In addition, m andipropamid is categorized as a reduced risk chemical. Therefore, the restricted entry interval ( REI ) of 4 hours is considered appropriate

.

Based on the Agen cy'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 occupationa l post

- application inhalation exposure assessment for mandipropamid.

The risk assessment is based, in part, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies are compliant with applicable ethical requirements (refer to Appendix D ).

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment (see Section 3.5 ).

2.0 HED Recommendations

HED recommend s in favor o f establishing tolerance s for residues of mandipropamid as specified
in Section 2.2

. 2.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

HED has examined the toxicology and residue chemistry database for mandipropamid. There are no issues that would preclude establishing tolerance s for mandipropamid for t he commo dities
listed in Table 2.2.2.

2.2.1 Enforcement Analytical MethodMandipropamid Human Health Risk Assessment D4252 40

Page 6 of 38 

### There is an adequate enforcement method available for the quantitation of mandipropamid in plant commodities. M ethod RAM 415/01 , using h igh performance l iquid 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 accord ance with those recommended by HED

, and to correct some of the commodity definitions) , there are no residue chemistry issues that would preclude establishing tolerance s in the requested commodities . The recommended
tolerances are listed in Table 2.2.2, below.

TABLE 2.2.2 Tolerance Summary for Mandipropamid. Commodity Established

T olerance (ppm) Proposed

Tolerance (ppm) Tolerance

Recommended by HED (ppm) Comments ; C orrect Commodity Definition

Potato None 0.08 None Revise the subgroup 1C tolerance. Potato, wet peel 0.03 * 0.12 0.15 Based on the submitted potato processing study and the highest average field trial ( HAFT )

. Vegetable, tuberous and corm, subgroup 1C 0.01 * None 0.09 Based on the submitted p otato field
trial data

. Vegetable, tuberous and corm, subgroup 1C, except potato None 0.01 None Cannot establish this tolerance; potato is the only representative commodity for subgroup 1C

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



### 2.2. 3 Revisions to Petitioned

- For Tolerances

Instead of the proposed tolerance in potato (0. 08 ppm), HED recommends revision of the
tolerance for residues in tuberous and corm vegetable subgroup 1C from 0.01 to 0. 09 ppm . The proposed tolerance was based on a dataset th at only included results from trials conducted in the US. One of the Canadian field trials (in Branchton, ON) had a total application rate exceeding the proposed US and Canadian maximum total use rates (0.52

- 0.54 lb ai/A) by >25%. The
calculat ed toleranc e in subgroup 1C

, based on US and Canadian potato field trial data (excluding the ON trial results) entered into OECD’s tolerance calculation procedure , was 0.07 ppm

. However, HED is recommending a tolerance in subgroup 1C of 0.09 ppm, in order to harmoni ze with PMRA’s recommend ed MRL. This MRL was based on using the 17

- day pre

- harvest interval ( PHI ) residue value from one of the US trials (in Richland, IA ) instead of the residue value in the sample taken at a PHI of 14 days (the proposed PHI). PMRA uses the highest residue from any sample taken at a PHI within ±25% of the target PHI, while HED uses the residue value from the sample taken at (or closest to) the proposed PHI.Mandipropamid Human Health Risk Assessment D4252 40

Page 7 of 38 

### The proposed tolerance in potato wet peel (0.12 ppm) was based on the average processing factor (2.0X) multiplied by the HAFT (0.056 ppm). However, the recommended tolerance (0.15 ppm) is based on the rounding protocol in the User Guide for the OECD tolerance calculation procedure

.

It is not appropriate to establish the proposed tolerance in tuberous and corm vegetable subgroup
1C ( except potato ), because potato is the only representative commodity for subgroup 1C . For the same reason, the proposed separate tolerance in potato is unnecessary.

2.2. 4 International Harmonization

The established Codex MRL in potato, and PMRA’s MRLs in potato and various tuberous and corm vegetables are in harmonization with the current US tolerance in tuberous and corm vegetables subgroup 1C at 0.01 ppm ( Appendix A ). These existing tolerances ar e based on a foliar use pattern only. PMRA and EPA jointly reviewed the potato field trial and processing data in the current action; therefore, EPA and PMRA are harmonized on the recommended
tolerance/MRL in subgroup 1C

. PMRA will not establish a tolera nce in potato wet peel, as it is considered a livestock feed item by PMRA, whereas it is considered a human food item by HED (although it is often used as livestock feed)

. With the recommended increased tolerance in subgroup 1C , the US tolerance will no l onger be in harmonization with Codex’s MRL in potato. Harmonization with the Codex value is not feasible, given that the Codex MRL is based on the foliar use pattern only, and the recommended amended tolerance is based on the proposed
combination of seed piece treatment and foliar uses.

2.3 Label Recommendations

None.

3.0 In troduction

3.1 Chemical Identity

The chemical structure and nomenclature of mandipropamid are presented in Table 3 .1. Mandipropamid is a fungicide in the mandelamide class deve loped by Syngenta Crop Protection, Inc. for the control of foliar oomycete pathogens in a range of crops.Mandipropamid Human Health Risk Assessment D4252 40

Page 8 of 38 T able 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) Re vus ® (2.08 lb ai/gal; EPA Reg. No. 100

- 1254), (Alternate Brand Name: Mandy Flowable Fungicide)



### 3.2 Physical/Chemical Characteristics

The information regarding physical chemical characteristics of mandipropamid does not indicate that there are any special concerns in terms of bioaccumulation, exposure or other risk assessment considerations. A table of physical and chemical properties f or mandipropamid is included in Appendix C.

3. 3 Pesticide Use Pattern

Syngenta is requesting a label amendment for Revus Fungicide (EPA Registration # 100

- 1254). The proposed amended use is for the addition of seed piece treatment use on potato. Revus Fungicide is an SC formulation containing 23.3% ai by weight, which is equivalent to 2.08 lb ai/gal (250 g ai/L ) . T he proposed use directions for seed piece treatment were provided in the petition materials, and are summarized in Table 3. 3 (below). The y appear to reflect the proposed US use pattern.

TABLE 3. 3 Summary of Proposed Directions for Use of Mandipropamid on Potato Seed Pieces Followed by Foliar Applications to Growing Potato Plants

. Applic ation Timing ; Type; Equipment Use Rate

( lb ai/100 lb
seed ) [ g ai/100 kg seed ] Max.

Number of
Uses per Season Max. Seasonal

Use Rate ( lb ai/A ) [g ai/A] PHI

(D ays) Use Directions and Limitations

Seed Treatment Directions Seed piece

treatment ;

s tandard seed

treatment equipment

. 0.00325

- 0.01

[3.25

- 10 ] 1 0.52 [ 235.9 ]
For a ny type of application NS 1 Apply by mist treatment to potato
seed pieces . Apply liquid seed
treatments in a volume of 2

- 4 fl oz/100 lb potato. Treat within 5 hours of cutting. Plant within 48Mandipropamid Human Health Risk Assessment D4252 40

Page 9 of 38 TABLE 3. 3 Summary of Proposed Directions for Use of Mandipropamid on Potato Seed Pieces Followed by Foliar Applications to Growing Potato Plants

. hours of treatment. Seed treatment may be foll owed by up to 3 foliar applications of mandipropamid. Applic ation Timing ; Type; Equipment Use Rate

(lb ai/A) [g ai/A] Max.

Number of
Uses per Season Max. Seasonal

Use Rate ( lb ai/A ) [g ai/A] PHI

(D ays) Use Directions and Limitations

Foliar Application Directions

P rior to disease development ; ground, aerial

or chemigation equipment. 0.09

- 0.13

[41

- 59] 3 0.52 [235.9] For any type of application 14 RTI 2 = 7 to 10 days. Make no more than 2 consecutive applications
before switching to another effective

non

- Group 40 fungicide. Use the
shorter interval and/or higher rates under high pressure

, or when
conditions are conducive to disease.
The addit ion of a spreading and/or penetrating type adjuvant such as a
COC 3 or NIS 4 or blend is recommended when applyin g by ground or air. 1. NS = Not Specified.
2. RTI = Re

- Treatment Interval.
3. COC = C rop Oil C oncentrate

. 4. NIS = N on

- Ionic S urfactant

.



### Conclusions: The submitted use directions for the 2.08 lb ai/gal SC formulation of mandipropamid are adequate to allow evaluation of the residue data relative to the proposed potato seed piece treatment use. No label additions, revisions or clarifications are needed at this
time.

3. 4 Anticipated Exposure Pathways

The Registration Division has re quested an assessment of human health risk to support the amended use of mandipropamid on potato . Humans may be exposed to mandipropamid in food and drinking water, since it may be applied directly to growing crops and application may
result in mandipropamid reaching surface and ground water sources of drinking water. There
are no residential uses of mandipropamid , so there is not likely to be exposure in residential or

non

- occupational settings. In an occupational setting, handlers may be expo sed while handling the pesticide prior to application, as well as during application. There is a potential for post

- application exposure for worke rs re

- entering treated fields.

Risk assessments have been previously conducted for mandipropamid ; t oxicity data submitted prior to the last risk assessment but not incorporated into HED’s review have been evaluated in
the current a ssessment , but did not affect HED’s conclusions with respect to hazard characterization and endpoint selection . A detailed description of the toxicity data and metabolism information may be found in the risk assessment dated 6 / 1 2/ 2008 ( D. Dotson

, D34 43 5 1 ) . Th e current risk assessment considers all of the aforementioned exposureMandipropamid Human Health Risk Assessment D4252 40

Page 10 of 38 

### pathways based on the existing uses of mandiprop amid , and also considers the potential for increased dietary (food + water) exposure associated with the new uses

.

3. 5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to populat ion 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 com piled 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 ca tegorized 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 circumstance s warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further

co nsiderations 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 s pecific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

A comprehensive human health risk assessment for mandipropamid was conducted in 200 9 ( D. Rate, 8 Ju ne 2009, D 36591 8 )

. Since this risk assessment, an immunotoxicity study ( MRID
4 8 771701 ) 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
# 0056 610). Therefore, the toxicology database for mandipropamid is considered to be complete. No other changes have been made to the hazard characterization of mandipropamid since the
2009 risk assessment.

4.1 Summary of Toxicological Effects

Subchronic and chronic studies indicate that the liver is the primary target organ for mandipropamid. Liver effects were identified in subchronic st udies with rats, mice, and d ogs. Liver effects included: periportal hypertrophy (rats), increased eosinophilia (rats and mice), increased plasma albumin, total protein, cholesterol, and gamma

- glutamyl transferase (rats),Mandipropamid Human Health Risk Assessment D4252 40

Page 11 of 38 

### increased liver weights (rats, mic e 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

we re 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 mou se 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 qualit ative 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 observe d 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 clastogeni c. Therefore, mandipropamid is classified as “not likely to be carcinogenic to humans.”

In metabolism studies, absorption of [ 14 

### C]

- mandipropamid was 67

- 74% at 3 mg/kg and 30

- 45% at 300 mg/kg after 48 hours, indicating saturation of absorption. The rate of absorption was higher in females resulting in a blood T max 

### (time to maximum concentration) at 3 mg/kg of 8.5 hours for males and 4.5 hours for females; at 300 mg/kg T max 

### 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 eli mination 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 fe males). The highest level of radioactivity in tissues was in th e liver followed by the kidney.

Bioaccumulation was not observed in any tissue and the dose remaining in the body after 168 hours was less than 1.1%. The major metabolic transformations invo lved loss of one or both propargyl groups followed by glucuronidation and O

- demethylation. The parent and the following metabolites were detected at ≥ 5% of the applied dose at 3 and/or 300 mg/kg: NOA 458422 (loss of one propargyl group), NOA 458422 glucuro nide, SYN 534133 (loss of both propargyl groups, with one glucuronidated) and CGA 380778 (loss of one propargyl group). The amount of NOA 458422 glucuronide in females was almost 3

- fold more than in males, which coincided with a lesser amount of parent an d NOA 458422 in females. Parent was the major residue detected in feces of animals of both sexes regardless of bile duct cannulation status,
while SYN 534133 was the major metabolite in the urine of male rats that didn’t undergo bile
duct cannulation and NOA 458422 glucuronide was the major metabolite in the urine and bile ofMandipropamid Human Health Risk Assessment D4252 40

Page 12 of 38 

### male rats that did undergo bile cannulation. NOA 458422 glucuronide was also the major metabolite in urine and bile of female rats regardless of bile duct cannulation status. A derm al 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 F actor for Infants and Children (FQPA Safety Factor)

HED has determined that the required 10X F ood Q uality P rotection A ct (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 fol lowing 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 mandipro pamid

.

• The risk assessment does not underestimate exposure, since t he 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 o f the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing pre

and postnatal susceptibility

. Acceptabl e/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
deve loping young , and no evidence of neurotoxicity in the database. Therefore, a developmental neurotoxicity study is not required

.

4.2.2 Evidence of N eurotoxicity

There was no evidence of neurotoxicity observed in any of the studies in the toxicology database. In the acute neurotoxicity study, the rats were dosed up to the limit dose (2000 mg/kg). In the
90

- day neurotoxicity study in rats, the only effects appeared to be decreased body weight, body weight gain and food utilization in males up to the highest dose tested (192.5 mg/kg/day for males and 206.7 mg/kg/day for females).

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young AnimalMandipropamid Human Health Risk Assessment D4252 40

Page 13 of 38 

### 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 comp arable maternal toxicity (decreased body weight)

. Therefore, HED conclude s 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 unc ertainties with respect to pre

- or postnatal

exposure

.

4.2.4 Residual Uncertainty in the Exposure Datab ase

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 D eparture 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, o r the cancer classification for mandipropamid from the previous risk assessment (D36591 8 , D. Rate,
6 /8/2009).

For short

- and intermediate

- term inhalation risk assessment, a no observed adverse effects level (NOAEL) equal to 41 mg/kg/day was selected from a 90

- day rat oral study in which decreased body weights, decreased body weight gains; and decreased food utilization were observed in males; and hepatotoxicity was observed in both sexes at the lowest observed adverse effects level (LOAEL) of 260 mg/kg/day

.

Table 4.3.1

. Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Dietary and Non

Occupational 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

.Mandipropamid Human Health Risk Assessment D4252 40

Page 14 of 38 Table 4.3.1

. Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Dietary and Non

Occupational Human Health Risk Assessments

. Exposure Scenario Point of Departure Uncertainty/ FQPA Safety
Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and Toxicological
Effects

Chronic Dietary (all populations) NOAEL = 5

mg/kg/day UF A =10X

UF H =10X FQPA SF =
1X Chronic RfD = 0.0 5

mg/kg/day

cPAD = 0.0 5 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 adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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
Intermediate

Term (1

- 6 months) N/A N/A N/A No appropriate endpoint was identified, and a risk

assessment was not conducted.
28

- day dermal toxicity study

– rat, no systemic or dermal effect up to the limit dose of 1000 mg/kg/day; there were no neurotoxicity or developmental concerns.

Inhalation
Short

- Term (1

- 30 days)
and
Intermediate

Term (1

- 6 months) NOAEL = 41 mg/kg

/day UF A =10X

UF H =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.Mandipropamid Human Health Risk Assessment D4252 40

Page 15 of 38 Table 4.3.2

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

Human Health Risk Assessments

. Exposure Scenario Point of Departure Uncertainty
Factors Level of Concern

for Risk
Assessment Study and Toxicological
Effects

Cancer (oral, dermal, inhalation) No Evidence of Carcinogenicity. Classified as “Not Likely to be Carcinogenic to Humans.”

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from a nimal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = le vel of concern.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary a nd Rationale

The nature of the residue in plants, rotational crops, and ruminants is adequately understood. For the purposes of tolerance enforcement and risk assessment, the residue of concern in primary

crops, rotational crops, and ruminants is the parent mandipropamid

, with the exception of root and tuber vegetables

, where the metabolite SYN 500003 is included for risk assessment. The metabolism data indicate that there is no reasonable expectation of finite residues in milk, meat, and/or meat byproducts (40 CFR §180.6, Category 3) as a result of the proposed use. There are no poultry feed items associated with the proposed use.

Drinking Water

D409108 ; R. Shamblen ; 7/9/2013

.



### The assessment included mandipro pamid 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 (DT 50 

### = 2 days), but is considerably more stable under aerobic aquatic conditions (DT 50 

### = 30 days). Five degradates were found in the aerobic soil
metabolism st udy, 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 LD 50 

### was calculated to be 1049 mg/kg

, in dicating it’s more acutely toxic via the oral route than the parent compound (however, it is only
0.005

- 0.006 ppm or 10.5

- 12.7% of the total radioactive residues ( TRR ) in root and tuber crops)

. The study is acceptable/guideline , with the SYN 500003 degradate classified as Toxicity Category III for oral toxicity . In addition, a bacterial reverse gene mutation assay (Ames Test)
with SYN 500003 was conducte d. No evidence of induced mutant colonies over background was detected in that study.Mandipropamid Human Health Risk Assessment D4252 40

Page 16 of 38 

### 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 propiolal dehyde. 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 conclude s 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 c ould 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

equ ivalent to the parent.

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

Tolerance Expression.

Matrix Residues I ncluded in Risk
Assessment Residues I ncluded in Tolerance Expression

Plants Primary Crop M andipropamid

(Parent + SYN 500003 for root and tuber vegetables ) M andipropamid

Rotational Crop Not applicable M andipropamid*

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 exist i ng or proposed uses based on the absence of residues in the field rotational crops study following the label’s 30

- day plant

- back interval (PBI)

.



### 5 .2 Food Residue Profile

The nature of the residue in plants, rotational crops, and ruminants is adequately understood. For
th e 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 incl uded for risk assessment.

The only livestock feed items associated with the proposed seed piece treatment use on potato are potato culls and processed waste. Both feed items are fed to cattle at 30% of the diet for beef
cattle

, and 10% of the diet for dairy cattle; neither is fed to poultry n or swine. Based on the highest average field trial ( HAFT ) residue of 0.056 ppm in potato culls, and the median residue
of 0.1 4 ppm in p otato processed waste , the re calculated dietary burden s to beef and dairy cattle are 0.112 and 0.037 ppm, respectively.Mandipropamid Human Health Risk Assessment D4252 40

Page 17 of 38 

### No livestock feeding studies were submitted with this petition. An acceptable ruminant metabolism study is available. Goats were dosed with radiolabeled mandipropamid at 30

- 36 ppm (268

- 320X the calculated dietary burden to cattle) in the feed for 7 consecutive days. The parent compound was identified only in fat (0.013

- 0.019 ppm), milk (0.013 ppm), and liver (0.004

- 0.007 ppm). SYN500003 was not identified in any ruminant tissue or milk . Based on the highest detected residue of 0.019 ppm in goat fat, and anticipated residues from feeding potato culls and processed waste containing mandipropamid at the recommended tolerance level s of
0.0 9 ppm in potato and 0.15 ppm in potato wet peel, th ere is no reasonable expectation of finite
residues of mandipropamid in ruminants ( 40CFR §180.6[ a ][3] ) as a result of the proposed use.

Based on the ruminant metabolism study, ruminants are only likely to receive SYN500003 from consumption of feed items containing SYN500003 as a result of treatment with mandipropamid. In the submitted potato field trial studies, HAFT residues of SYN500003 (in parent equivalents) were roughly half those of the parent

. T herefore, HED concludes that there is no reasonable expectation of finite residues of SYN500003 in ruminants (40CFR §180.6 [ a ][3] ) as a result of the proposed use on potato.

The data submitted in support of the current action (P etition #4F8329) along with previously reviewed data, are adequate for purpos es of risk assessment and tolerance assessment for the proposed revised use pattern on potato under review. Maximum residues of mandipropamid are expected to occur at relatively low levels (<0.0 9 ppm in subgroup 1C , and <0 .15 ppm in potato wet peel ) from the revised use pattern combining seed piece treatment and foliar use on potato

,
as proposed in the current petition.

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

not usually increase to any significant degree. Following foliar applications, mandipropamid is present primarily as surface residues; translocation does not appear to be extensive. There is little to no uptake of mandipropamid by the roots . In general, mandipropam id residues do not tend to concentrate in processed fractions, other than via dehydration or from surface residues.

Residues of mandipropamid are not expected to accumulate above the LOQ in rotational crops. HED previously concluded that rotational cro p tolerances are not required for mandipropamid

.

5.2.1 Crop Field Trials (860.1500)

D4 28278 ; W

. Drew ; 02/23/2016

.



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

. The field trials were considered to have been conducted in geographically representative locations, with application rates, RTI s and PHIs reflecting the proposed label
directions for use . In all cases, the tolerances are based on detectable residues in the crops/commodit ies. A table reflecting the results of the submitted field trial data is provided
below

.Mandipropamid Human Health Risk Assessment D4252 40

Page 18 of 38 Table 5.2.1

. Summary of Residues from Potato Field Trials with Mandipropamid.
Matrix Analyte Total Use
Rate (lb ai/A [g ai/ha]) PHI

( D ays) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

Combined US Trials (MRID # 49470401) and Canad i a n Trials (MRID # 49470404)

Potato
tubers Mandi

propamid 0.536

-

0.631 [600

- 707] 12

- 15 24 <0.01 0 0.066 <0.01 0 0.056 0.014 0.018 0.012

SYN500003 as reported < 0.005 0.014 <0.005 0.013 0.005 0.006 0.002

SYN500003 parent

eq uiv

. <0.009 0.025 <0.009 0.023 0.009 0.011 0.004

Combined 4 <0.019 0.075 <0.019 0.065 0.035 0.030 0.013

1. n = n umber of field trials.
2. Values based on total number of samples.
3. Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean and standard deviation, values <LOQ were assumed to be at the LOQ

. LOQ s were 0.010 ppm for mandipropamid, 0.005 ppm for SYN500003 (as reported), and 0.009 ppm for SYN500003 (parent equivalent).
4. Combined residues of mandipropamid and SYN500003 are in parent equivalents . It should be noted that the
maximum and HAFT resid ues for the parent compound and metabolite SYN500003 were observed in different samples. Therefore, the sums of these residues are not equal to the maximum and HAFT
combined residues.



### 5.2.2 Field Rotational Crops (860.1900)
D328534, D337543; D. McNeilly; 28 August 2007



### An adequate limited field rotational crop study was reviewed in p etitions #6F7057 and #7F7184. Mandipropamid residues were below the LOQ (< 0.010 ppm) in all samples of rotated radish roots, radish tops, spinach leaves, fall wheat forage, spring wheat forage, wheat hay, wheat grain, and wheat straw planted at the 28/31

- day and 61

- day PBIs. HED has determined that the rotational crop restriction on the label which states “ D o not plant any crop which is not registered
for use with m andipropamid for a period of 30 days after the last application” is appropriate. Given the label restriction, tolerances in rotational crops are not needed.

5.2 .3 Processed Food and Feed (860.1520)

D4 28278; W

. Drew ; 02/23/2016

.



### The submitted processing data for potato are adequate, and together with the HAFT from the corresponding field trial studies support an increase in the established tolerance for mandipropamid in potato wet peel , from the existing tolerance of 0.03 to the HED

- recommended
increased tolerance of 0.15 ppm

. The data indicate that residues of mandipropamid concentrate in wet peel (mean processing factor of 2.0X) and residues of SYN500003 concentrate in potato flakes and chips (>1.7X and >1.4X) processed from potato bearing quantifiabl e residues of both analytes following combined seed piece treatment and foliar application of the 2.08 lb ai/gal SC
formulation at an exaggerated rate (approximately 5X). Acceptable methods were used for quantitation of the residues of concern for root an d tuber vegetables , which are mandipropamid
for tolerance enforcement

, and SYN500003 for risk assessment. The data are supported by adequate storage stability data.Mandipropamid Human Health Risk Assessment D4252 40

Page 19 of 38 

### In general, the results observed in this study for mandipropamid are consistent with those observed in an earlier potato processing study reflecting foliar applications only. In that study, residues concentrated in wet peel (>3X) processed from potato in which residues were below the LOQ (<0.010 ppm); residues were below the LOQ in all other potato processed commodities. In the preceding processing study, residues of SYN500003 were below the LOQ in the RAC and all processed fractions. In the current stud y, concentration of residues of SYN500003 in flakes and chips appears to have been associated with drying (chips were baked rather than fried at the processing facility).

5.3 Water Residue Profile

D 409108 ; R. Shamblen ; Jul 9

, 20 13

.



### EFED has concluded t hat the proposed amended use on potato has no impact on the drinking water estimates (based on email communication with B. Anderson, 08/24/2015). Therefore, the drinking water estimates from the existing use pattern have been used in this assessment. The estimated drinking water concentrations (EDWCs) used in the dietary risk assessments were provided by the Environmental Fate and Effects Division (EFED )

, ( D409108, R. Shamblen, 7/9/2013). The EDWCs were incorporated directly into these dietary assessment s 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 Z one Model for Ground Water (PRZM

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

- GROW version 2.3) models for groundwater. Modeled surface water and groundwater EDWCs are based on the maximum label application rate to tomato and basil (chroni c value).

A Total Residue (TR) modeling approach was used to estimate aerobic aquatic half

- lives, and estimate drinking water concentrations in surface waters. EFED conducted a Tier 1 drinking water exposure assessment for the fungicide mandipropamid. Tier 1 exposure model ing 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 EDWC s 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.Mandipropamid Human Health Risk Assessment D4252 40

Page 20 of 38 Table 5.3. Tier 1 Estimated Drinking Water Concentrations ( EDWC) for Maximum Mandipropamid Use
Patterns. Drinking Water Source

(Model, Version) PCA (%) Crop Use Pattern

(Maximum Annual Rate) Acute (μg/L) Chronic

(μg/L)

Surface Water (FIRST, 1.1.1) 91 Tomato & Basil (2.08 lbs a.i./A) 79 9.0

Ground Water (PRZM

- GW, 1.01) N/A Tomato & Basil (2.08 lbs a.i./A) 87 79

Ground Water (SCI

- GROW, 2.3) N/A Tomato & Basil (2.08 lbs a.i./A) 0.18

Abbreviations: A= acre; a.i. = active ingredient; ha = hectare; kg = kilograms ; μg = micrograms; lbs = pounds (US); N/A = not applicable



### Note that although EFED provided HED with estimates of acute surface and ground water estimates, these have not been incorporated into the dietary model due to the lack of an acute endpoint for mandipro pamid.

The drinking water models and description s 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 U sed in Dietary Assessment

D4 28940 ; E. Holman ; 02/23/2016

.



### A c hronic dietary exposure assessment w as performed for mandipropamid. The assumptions underlying this unrefined assessment were 100% crop treated (CT), HED

- recommended
tolerance levels or tolerance

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

crop subgroup 1C), and default DEEM

- FCID  (ver. 7.81) processing factors (with the exception
of chemical

- specific processing factors for grape wine and sherry ). The mean (i.e., relevant to chronic exposure) drinking water e stimate of 79 ppb was provided by EFED

, and directly incorporated into the chroni c assessment.

As noted previously (see Section 5.1), f or the purposes of tolerance enforcement and risk assessment, the residue of concern in primary crops, rotational crops, and ruminants is the parent mandipropamid

, with the exception of root and tuber vegetables

, where the metabolite SYN
500003 is included for risk assessment. The HED

- recommended tolerance

- level residues for th e proposed amended use on potato (D428278, W. Drew, 02/23/2016 ) is 0.09 ppm, with the amended tolerance being issued for the entire vegetable, tuberous and corm, subgroup 1C. For the purposes of this chronic dietary risk assessment, this subgroup was asse ssed at 0.115 ppm , which assumes tolerance

- level residues of parent mandipropamid (0.09 ppm) and also includes
the SYN 500003 metabolite in parent

- equivalents (at 0.025 ppm).Mandipropamid Human Health Risk Assessment D4252 40

Page 21 of 38 

### 5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

No acute dietary toxicity endpoint could be identified based on the toxicology data currently available for mandipropamid.

5.4.4 Chronic Dietary Risk Assessment

All populations were evaluated for chronic dietary risk. No risks of concern were identified in the chronic dietary exposure analysis. The most highly exposed population subgroup is children
1

- 2 years old which utilizes 4 2 % of the cPAD (Table 5. 4 .6 ). The general U.S. population
utilizes 2 6 % 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 mandipro pamid as “Not likely to
be a human c arcinogen ;” therefore a cancer assessment was not performed.

5.4.6 Summary Table
D428940; E. Holman; 02/23/2016

.



### The resu lts of the dietary exposure and risk analys i s for chronic dietary exposures are summarized below in Table 5.4.6.

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

Population Subgroup Acute Dietary Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk General U.S. Population

N/A N/A 0.013145 26

N/A N/A All Infants (< 1 year old) 0.011004 22
Children 1

- 2 years old 0.021060 42
Children 3

- 5 years old 0.019313 39
Children 6

- 12 years old 0.012005 24
Youth 13

- 19 years old 0.009525 19
Adults 20

- 49 years old 0.013220 26
Adults 50

- 99 years old 0.013149 26
Females 13

- 49 years old 0.013039 26 N/A = Not applicable.Mandipropamid Human Health Risk Assessment D4252 40

Page 22 of 38 

### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no registered or proposed residential uses for mandipropamid

. Therefore, a residential exposure assessment is not required.

6. 1 Residential Bystander Post

- application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inha lation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for mandipropamid.

6. 2 Spray Drift

Spray drift is a potentia l source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and

a irblast) employed for mandipropamid

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data
Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies f or pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 

### The agency has also developed a policy on how to appropriately consider spray drift as a potentia l source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during
the Registration Review process which ensures that all uses for that pesticide will be considered
concurrentl y. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the qua ntification
of indirect non

- occupational exposure to drift.

These proposed use patterns are unlikely to result in spray drift due to how it is applied (e.g., seed treatment). However, there is potential from drift resulting from treatment of other agricultural crops that will be addressed in Registration Review. Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment

was previously performed for flaggers as pa rt of the existing use pattern for mandipropamid

.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmMandipropamid Human Health Risk Assessment D4252 40

Page 23 of 38 

### This exposure scenario is representative of a wors t

- case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation

exposure scenar ios

.

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, e xposures 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 a nd 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 exposure s 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 risk s 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, amon g other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or
other non

- occupational exposure to other substances that have a common mechanism of toxicity.
The reason for consideratio n 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

o ther 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,Mandipropamid Human Health Risk Assessment D4252 40

Page 24 of 38 

### therefore, EPA has not assumed that mandipropamid h as 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

D 428298 ; B

. Bobowiec ; June 17, 2015



### For potato seed pieces, possible exposure from use of mandipropamid as a commercial seed treatment may occur during the followin g scenarios:

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

 Planting treated seed pieces

.

The maximum single application rates for potato seed treatment is 0.01 lb ai/100 lb of potato
seed. Information from industry regarding amount handled as summarized in EXPOSAC Policy 15.1 SOP for Amount of Seed Treated per Day was used to assess the potato seed piece

treatment.

HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months
as inte rmediate

- term. Based on the proposed use pattern

, directions (e.g., 2

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

, short

- and intermediate

- term exposures are expected for occupational handlers. Since the same endpoint and point of departure were selected for short

- and intermediate

- term durations, short

term exposure and risk estimates are considered to be protective of intermediate

- term exposur e and risk for the potato seed treatment use

. Long

- term exposures are not expected; therefore, a long

- term assessment was not conducted.

Additionally, th ere was no dermal POD selected for mandipropamid; therefore, no dermal exposure was quantitatively as sessed.

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 re commended on the proposed label for early entry to treated areas include: coveralls, chemical

- resistant gloves made of any wa terproof 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 o f 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

occup ational handlers are included in Table 9 .1

.Mandipropamid Human Health Risk Assessment D4252 40

Page 25 of 38 

### All occupational handler scenarios resulted in inhalation MOEs greater than the level of concern (MOEs ≥ 100 for inhalation) at baseline attire with no respirator)

. No additional PPE
recommendations have been identified for the proposed label

.

Table 9.1 . Mandipropamid Occupational Handler Short

- and Intermediate

- Term Exposure and Risk
Estimates for Potato Seed Treatment

Exposure
Scenario Crop

or Target Inhalation Unit Exposure

(μg/lb ai) 1 Maximum

Application
Rate 2 Amount or Area

Treated 3

lbs seed treated or planted/day Inhalation

Mitigation Level Amount
Handled per day (lb ai/day) Dose 5 (mg/kg/day) MOE 6

(Target = 100)

Short and Intermediate Term Commercial Potato Seed Treatment Mixing, Loading, and apply liquid
formulation to seed pieces (Short

- term) 7

Potato

Seed
Pieces 6.4 Baseline Inhalation (μg/lb ai) 0.01 lb
ai/100 lb
seed 800,000 lb seed pieces 0.0064 6,400

Mixing, Loading, and apply liquid
formulation to seed pieces (Intermediate

term) 8 400,000 lb seed pieces 0.0032 13,000

Secondary Handler (potato seed planter) 3.4

Baseline Inhalation (μg/lb ai) 800,000 lb seed pieces
0.0034 12,000

1. Exposure Science Advisory Council Policy 14 and MRID 47054702.
2. Application Rates based on proposed uses on label for mandipropamid product Revus (Reg. No.100

- 1254). Application rates in fluid oz. product/100 seed provided on the label were converted to lb ai/100 lb seed.
3

. Exposure Science Advisory Council 15.1
4. Baseline Inhalation: No respirator;
5. Inhalation Dose (mg/kg/day) = daily unit exposure (μg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x conversion factor (1 mg/1,000 μg) / body weight (80 kg).
6. Inhalation MOE = NOAE L (41 mg/kg/day) / inhalation daily dose (mg/ kg/ day). Level of concern = 100.
7

. 800,000 lb potato seed pieces for mixing/loading and applying liquid formulation for “typical” hourly output of the largest liquid treater (Model 42

- 1000 cwt per hour) times 8 hour work day,
8

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

- size liquid treater (Model 36

- 500 cwt) times 8 hour work day.



### Occupational Post

- Application Assessments

Dermal

The potential for dermal post

- application exposures following the planting of potato

- treated seeds is negligible because s ustained levels of contact with treated seed after it has been placedMandipropamid Human Health Risk Assessment D4252 40

Page 26 of 38 

### in the soil or other planting media would not be expected beca use no routine cultural practice required for the production of agricultural commodities involves such an activity as defined in
the no/low contact criteria in the Worker Protection Standard (WPS)

. There is the possibility for agricultural workers to have post

- application exposure to mandipropamid following the planting of treated potato seed pieces. Although there is potential for dermal post

- application exposure, no dermal endpoint was selected because the rat 28

- day dermal toxicity study demonstrated n o 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 mat erial. 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.

I nh alation

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and re ceived the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux st udies, route

- specific inhalation toxicological studies) or further analysis is required for mandipropamid.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

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

HED assumes that inhalation exposures are n egligible following planting of treated potato seed pieces. A quantitative inhalation exposure assessment was performed for occupational/commercial seed treaters and planters as well as mixer/loader/applicators to non

bearing citrus

. Handler exposure s resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.Mandipropamid Human Health Risk Assessment D4252 40

Page 27 of 38 

### 10.0 References

Mandipropamid: Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Amended Use of the Fungicide on Potato to Add Seed Treatment
Use. D4 28940

, E. Holman ; 02/23/2016

.



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

- bearing Citrus and Seed Piece Treatment on Potatoes. D 4 28298

, B. Boboweic ; June 17
2015

.



### Mandipropamid. Petition Proposing the Establishment of a Permanent Tolerance for Residues Resulting from Amended Use of the Fungicide on Potato, to Replace the Established Tolerance in Tuberous and Corm Vegetable Subgroup 1C, and to Revise the Established Tolerance in Potato Wet Peel. Summary of Analytical Chem istry and Residue Data. D4 28278 , W. Drew ; 02/23/2016

.



### Mandipropamid. Drinking Water Exposure Assessment for Proposed Section 3 New Uses on: Basil, Ginseng and Succulent Beans; and Expanded Uses on Bulb Vegetables, Cucurbits, Grapes, and Fruiting Vegetables including Tomatoes., D409108, R. Shamblen, 7/9/2013

.



### Mandipropamid. Request to Register New Food/Feed Uses on Head and Stem Brassica, Leafy Brassica Greens, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables (except Brassica),
Tuberous and Corm Vegetables, Grapes, and Onions (Dry Bulb and Green). Summary of Analytical Chemistry and Residue Data. Petition Numbers 6F7057 and 7F7184. ; D328534, D337543; D. McNeilly; 28 August 2007.

Mandipropamid; Human Health Risk Assessment for Propos ed Use on Hops. D365918, D. Rate; June 8 2009.Mandipropamid Human Health Risk Assessment D4252 40

Page 28 of 38 

### Appendix A. International Residue Limits

Mandipropamid (PC Code 036602 ) Summary of US Tolerances and International Maximum Residue Limits.

Residue Definitions US (40CFR §180.637) Canada Codex
Plants: Mandipropamid (4

- chloro

- N

- [2

- [3

- methoxy

- 4

- (2

- propynyloxy)phenyl] ethyl]

- α

- (2

- propynyloxy)

- benzeneacetamide). Mandipropamid (4

- chloro

- N

- [2

- [3

- methoxy

- 4

- (2

- propynyloxy) phenyl]ethyl]

-

α

- (2

- propynyloxy)

- benzeneacetamide). Mandipropamid.

Comm odity 2 Tolerance

(ppm) 3 Commodity MRL (mg/kg) Commodity MRL (mg/kg) 4
Vegetable, tuberous and corm, subgroup 1C 0.09 Potato

, arracacha, arrowroot,

cassava root , chayote root

, Chinese artichoke, chufa, edible canna, ginger root, Jerusalem artichoke, leren

, sweet potato root, tanier corm, taro corm , true yam tuber , turmeric root , yam bean root 0.09 P otato 0.01

Potato, wet peel 0.15

Completed: M. Negussie, 2 3 April 2015

. 1. Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes. 2. Includes only commodities of interest for this action. 3. Tolerance values are those recommended by HED, not those proposed by the petitioner.
4. A bsent at the LOQ.Mandipropamid Human Health Risk Assessment D4252 40

Page 29 of 38 

### A ppendix B. Toxicology Profile

B .1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses of mandipropamid are in Table B 1. 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 Carcino genicity (rat)

................................ ...................... 870.4200b Car c in ogenicity (mouse)

................................ ............... 870.4300 Combined Chronic Toxicity / Carci nogenicity

............... 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 Neurotox icity Screening Battery (rat)

................. 870.6200b 90

- Day Neuro toxicity Screening Battery (rat)

.............. 870.6300 Develop mental Neuro toxicity

................................ ....... no

no

no -

-

- 870.7485 Metabolism and Pharmacokinetics

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

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

................................ ............................. yes

yes

yes yes

yes

yesMandipropamid Human Health Risk Assessment D4252 40

Page 30 of 38 

### B .2 Toxicity Profile s

Table B.2.1 Acute Toxicity Profile

- Mandipropamid

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

870.1100 Acute oral rat 46800201 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal rat 46800202 LD 50 > 5050 mg/kg IV

870.1300 Acute inhalation rat 46800204 LC 50 > 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. NegativeMandipropamid Human Health Risk Assessment D4252 40

Page 31 of 38 Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid
Guideline
No. Study Type MRID No. (year)/
Classification Dose levels Results

870.3100 90

- Day oral

toxicity (rat) 46800216

(2005) Acceptable/
Guideline ppm= 0, 100, 500,

3000, 5000 mg/kg/day= M: 0, 8, 41, 260,
435 F: 0, 9, 45, 260,
444 NOAEL = 41/45 mg/kg/day M/F

LOAEL = 260 mg/kg/day both sexes, based on decreased body weights, weight gains and food utilization in males and slight hepatotoxicity in both

sexes

830.3100 28

- Day oral

toxicity (rat) 46800214

(2005) Acceptable/
Guideline ppm = 0, 1000,

3000, 10,000, 16,000 [10,000 & 16,000 died < day 4] mg/kg/day = M: 0, 135, 418, 624, 604 F: 0, 121, 381, 784,
1410 NOAEL = not established

LOAEL = M=135, F=121 mg/kg/day, based on decreased food consumption in both sexes and decreased body weights and weight gains in males (liver changes at 418/381 mg/kg/day M/F).

870.3100 90

- Day oral

toxicity (mouse) 46800213

46800217 (2005) Acceptable/
Guideline ppm= 0, 300, 800,

2000, 5000 mg/kg/day= M: 0, 37, 98, 248,
624 F: 0, 47, 129, 316,
800 NOAEL = M/F = 248/316 mg/kg/day

LOAEL = M/F = 624/800 mg/kg/day, based on decreased body weight gain in males and females (as well as the suggestion of effects on the liver: increased weights in both sexes and microscopic pathology).
870.3150 90

- Day oral

toxicity (dog) 46800218

46800219
46800220 (2005) Acceptable/
Guideline mg/kg/day=

0, 5, 25, 100, 400 (capsule) NOAEL = 100 mg/kg/day

LOAEL = 400 mg/kg/day, based on liver toxicity (increased cholesterol, alkaline phosphatase activity, ALT activity, liver weights and microscopic pigment in hepatocytes and Kupffer
cells in both sexes and centrilobular hepatocyte vacuolation in females).
870.3200 21/28

- Day dermal

toxicity (rat) 46800222

46800221 ( 2005) Acceptable/
Guideline mg/kg/day=

0, 250, 500, 1000 (limit dose) Systemic/Dermal NOAEL = 1000

mg/kg/day
LOAEL = not determined

870.3700a Prenatal

developmental (rat) 46800224

46800223 (2005)
46800228 (2001) Acceptable/
Guideline mg/kg/day=

0, 50, 200, 1000 Maternal NOAEL = 1000 mg/kg/day

LOAEL = not determined Developmental NOAEL = 1000 mg/kg/day
LOAEL = not determined

870.3700b Prenatal

developmental (rabbit) 46800227

46800225
46800226
46800229 (2005) Acceptable/
Guideline mg/kg/day=

0, 50, 250, 1000 Materna l NOAEL = 1000 mg/kg/day

LOAEL = not determined Developmenta l NOAEL = 1000 mg/kg/day
LOAEL = not determinedMandipropamid Human Health Risk Assessment D4252 40

Page 32 of 38 Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid
Guideline
No. Study Type MRID No. (year)/
Classification Dose levels Results

870.3800 Reproduction and

fertility effects (rat) 46800230

46800231 (2005) Acceptable/
Guideline ppm=(males/

females) 0, 50, 250, 1500 mg/kg/day= (mean of premating
both sets of parents) = 0/0, 4.6/5.0, 22.9/24.5,
146.3/148.2 Parental/Systemic NOAEL = M/F =

22.9/24.5 mg/kg/day
LOAEL = M/F = 146.3/148.2 mg/kg/day, based on decreased body weights, weight gains, food consumption and food utilization in
males Reproductive NOAEL = M =
146.3/148.2 mg/kg/day
LOAEL = not determined Offspring NOAEL = M/F = 22.9/24.5 mg/kg/day
LOAEL = M/F = 146.3/148.2 mg/kg/day, based on decreased pup body weights in both sexes.
870.4100 Chronic toxicity

(dog) 46800232

(2005) Acceptable/
Guideline mg/kg/day=

0, 5, 40, 400 (capsule) NOAEL = 5 mg/kg/day

LOAEL = 40 mg/kg/day, based on evidence of liver toxicity (increased incidence and severity of microscopic pigment in the liver and increased alkaline phosphatase activity in both
sexes as well as increased alanine aminotransferase activity in males).
870.4300 Combined chronic

toxicity/ carcinogenicity (rat) 46800234

(2005) Acceptable/
Guideline ppm = 0, 50, 250,

1000 mg/kg/day= M/F = 0/0, 3.0/3.5, 15.2/17.6,
61.3/69.7 NOAEL = M/F = 15.2/17.6

LOAEL = 61.3/69.7mg/kg/day, based on decreased body weight gain and
food utilization and increased nephrotoxicity in males.
There was no evidence of carcinogenicity in rats.
870.4200 Carcinogenicity

(mouse) 46800233

(2005) Acceptable/
Guideline ppm = 0, 100, 500,

2000 mg/kg/day= M/F = 0/0, 10.6/13.2, 55.2/67.8,
222.7/284.6 NOAEL = M/F = 55/68 mg/kg/day

LOAEL = 223/285 mg/kg/day, based on decreased body weight gain in both
sexes and decreased food utilization in
males.
There was no evidence of carcinogenicity in mice.
870.5100 Bacterial Reverse

Mutation Assay 46800235

(2005) Acceptable/
Guideline Tested up to limit

dose of 5000 μg/plate Negative

870. 5300 In Vitro

Mammalian Cell
Gene Mutation
Test

– Mouse Lymphoma 46800236

(2005) Acceptable/
Guideline Tested up to limit

dose (4119 μg/mL) NegativeMandipropamid Human Health Risk Assessment D4252 40

Page 33 of 38 Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid
Guideline
No. Study Type MRID No. (year)/
Classification Dose levels Results

870. 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 D4252 40

Page 34 of 38 Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid
Guideline
No. Study Type MRID No. (year)/
Classification Dose levels Results

870.7485 Metabolism and

pharmacokinetics (rat) 46800243

-

46800246 (2005) Acceptable/
Guideline mg/kg/day =

single oral 3 or 300 methoxy label

repeated 3 methoxy
label

single oral 3 or 300 methoxy/chloro
labels After 48 hours, absorption was 67

- 74%

at 3 mg/kg and 30

- 45% at 300 mg/kg.
Blood T max 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 whol e 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 se x, 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/cm 2 skin = 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

Non

Guideline Methods

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.

Non

Guideline In Vitro Dermal

Penetration Study, Rat epidermis 46800247

(2003) Acceptable/
Non

- Guideline μg/cm 2 skin = 2570

or 2510 Absorption rate greatest during first 30

minutes of exposure, 0.715

- 0.746 μg/cm 2 /hour. Absorption rates over 24
hours were 0.077

- 0.091 μg/cm 2 /hour.Mandipropamid Human Health Risk Assessment D4252 40

Page 35 of 38 Table B.2.2 Subchronic, Chronic and Other Toxicity Profile for Mandipropamid
Guideline
No. Study Type MRID No. (year)/
Classification Dose levels Results

Non

Guideline In Vitro Dermal

Penetration Study, Rat epidermis 46800251

(2005) Acceptable/
Non

- Guideline μg/cm 2 skin = 1.35,

6.69, 2538 Absorption was poor (recovery of

applied radioactivity 99

- 105%). Absorption rates over 24 hours were
<0.04 μg/cm 2 /hour in concentrate formulation and 0.01 μg/cm 2 /hour in aqueous spray dilutions.

Non

Guideline In Vitro Dermal

Penetration Study, Pig epidermis 46800249

(2003) Acceptable/
Non

- Guideline μg/cm 2 skin =

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/cm 2 /hour) and was 0.02 μg/cm 2 /hour over 24 hours. Absorption rate for acetone was 3.58% (first hour = 0.56, 24 hours = 0.05 μg/cm 2 /hour). Absorption enhanced by acetone.

Non

Guideline In Vitro Dermal

Penetration Study, Human epidermis 46800250

(2005) Acceptable/
Non

- Guideline μg/cm 2 skin = 1.35,

6.69, 2538 Recovery of radioactivity was 95

-

102%. Absorption was minimal. Over 24 hours, absorption was <0.04 μg/cm 2 /hour in the concentrate formulation and ≤0.001 μg/cm 2 /hour in the aqueous spray dilutions.



### B.2.3 Immunotoxicity

Immunotoxicity study in mice.

In an immunotoxicity study (MRID 48771701), M andipropamid (96.5% a.i., Lot No. SEZ2BP007) was administered to female CD

- 1 mice (10 /dose ) in the diet at con cen trations of 0, 300, 1000, or 3000 ppm (equivalent to 0, 56, 187, and 649 mg/kg bw/day , respectively ) for 28
consecutive days. A con current (positive control) group of 10 female mice received cyclophos

pha mide monohydrate (CPH) 10 mg/kg bw/day by gavage for the duration of the study. On Day 25, a ll mice were im mun ized with sheep red blood cells (SRBC), a single intravenous (IV) injection 0.25 mL ( dose volume of 2 × 10 8 

### /mL ). During the study, clinical c ondition, bodyweight, food and water consumption were evaluated. At sacrifice, blood was collected for
the deter mination of anti

- S RBC 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 wei ght, 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
CP H

- treated mice was decreased by 16% at study termina tion , but there was no difference in relative spleen weight when compared to the controls

.Mandipropamid Human Health Risk Assessment D4252 40

Page 36 of 38 

### The systemic NOAEL was 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose tested. A systemic LOA EL was not established.

There were no stati stically 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 grou p had 91% decreased in the IgM resp onse

. This confirmed the ability of the test system to detect immuno

suppressive 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 guidelineMandipropamid Human Health Risk Assessment D4252 40

Page 37 of 38 

### 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 C 23 H 22 ClNO 4 / 411.9
pH 6

- 8 at 25oC (1% aqueous dispersion)
Density 1.24 x 10 3 kg/m 3 at 22oC
Water solubility (25°C) 4.2 mg/L
Solvent solubility (25°C) n

- hexane 42 mg/L

n

- octanol 4.8 g/L
toluene 29 g/L
methanol 66 g/L ethyl acetate 120 g/L

acetone 300 g/L
dichloromethane 400 g/L
Vapor pressure <9.4 x 10

- 7 Pa at 25°C or <7.0 x 10

- 9 mmHg
Dissociation constant, pK a No dissociation constant in the pH range of 1 to
12
Octanol/water partition coefficient, Log(P OW ) 3.3 at 25oCMandipropamid Human Health Risk Assessment D4252 40

Page 38 of 38 

### 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 s tudies, listed below , have been
reviewed for ethica l conduct. The studies were considered appropria te 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.